Kurtis I. Auguste

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response; a review

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.

Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury

We reported previously that astroglia cultured from aquaporin‐4‐deficient (AQP4‐/‐) mice migrate more slowly in vitro than those from wild‐type (AQP4+/+) mice (J. Cell Sci. 2005;118, 5691–5698). Here, we investigate the migration of fluorescently labeled AQP4+/+ and AQP4‐/‐astroglia after implantation into mouse brains in which directional movement was stimulated by a planar stab wound 3 mm away from the axis of the injection needle. Two days after cell injection we determined the location, elongation ratio, and orientation of labeled cells. Migration of AQP4+/+ but not AQP4‐/‐cells toward the stab was greater than away from the stab. AQP4+/+ astroglia moved on average 1.5 mm toward the stab compared with 0.6 mm for AQP4‐/‐cells. More than 25% of the migrating AQP4+/+ cells but <3% of AQP4‐/‐cells appeared elongated (axial ratio>2.5). In transwell assays, AQP4+/+ astroglia migrated faster than AQP4‐/‐cells in a manner dependent on pore size. At 8 h, ~50% of AQP4+/+ cells migrated through 8‐µm diameter pores, whereas equivalent migration of AQP4‐/‐cells was found for 12‐µm diameter pores. These results provide in vivo evidence for AQP4‐dependent astroglial migration and suggest that modulation of AQP4 expression or function might alter glial scarring Auguste, K. I., Jin S., Uchida K., Yan D., Manley G. T., Papadopoulos M. C., Verkman A. S. Greatly impaired migration of implanted aquaporin‐4‐deficient astroglial cells in mouse brain toward a site of injury. FASEB J. 21, 108–116 (2007)

Accelerated Progression of Kaolin-Induced Hydrocephalus in Aquaporin-4-Deficient Mice

Hydrocephalus is caused by an imbalance in cerebrospinal fluid (CSF) production and absorption, resulting in excess ventricular fluid accumulation and neurologic impairment. Current therapy for hydrocephalus involves surgical diversion of excess ventricular fluid. The water-transporting protein aquaporin-4 (AQP4) is expressed at the brain-CSF and blood-brain barriers. Here, we provide evidence for AQP4-facilitated CSF absorption in hydrocephalus by a transparenchymal pathway into the cerebral vasculature. A mouse model of obstructive hydrocephalus was created by injecting kaolin (2.5 mg/mouse) into the cisterna magna. Intracranial pressure (ICP) was ~5mm Hg and ventricular size < 0.3 mm3 in control mice. Lateral ventricle volume increased to 3.7 ± 0.5 and 5.1 ±0.5 mm3 in AQP4 null mice at 3 and 5 days after injection, respectively, significantly greater than 2.6 ± 0.3 and 3.5 ± 0.5 mm3 in wildtype mice (P < 0.005). The corresponding ICP was 22 ± 2 mm Hg at 3 days in AQP4 null mice, significantly greater than 14 ± 1 mm Hg in wildtype mice (P < 0.005). Brain parenchymal water content increased by 2% to 3% by 3 days, corresponding to ~50 μL of fluid, indicating backflow of CSF from the ventricle into the parenchymal extracellular space. A multi-compartment model of hydrocephalus based on experimental data from wildtype mice accurately reproduced the greater severity of hydrocephalus in AQP4 null mice, and predicted a much reduced severity if AQP4 expression/function were increased. Our results indicate a significant role for AQP4-mediated transparenchymal CSF absorption in hydrocephalus and provide a rational basis for evaluation of AQP4 induction as a nonsurgical therapy for hydrocephalus.

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18–77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

Cervical and Intracranial Arterial Anomalies in 70 Patients with PHACE Syndrome

BACKGROUND AND PURPOSE: Cerebral and cervical arterial abnormalities are the most common non-cutaneous anomaly in PHACE syndrome, but the location and type of arterial lesions that occur have not been systematically assessed in a large cohort. Our aim was to characterize the phenotypic spectrum of arteriopathy, assess the frequency with which different arteries are involved, and evaluate spatial relationships between arteriopathy, brain structural lesions, and hemangiomas in PHACE syndrome. MATERIALS AND METHODS: Intracranial MRA and/or CTA images from 70 children and accompanying brain MR images in 59 patients with arteriopathy and PHACE syndrome were reviewed to identify the type and location of arterial lesions and brain abnormalities. Five categories of arteriopathy were identified and used for classification: dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and anomalous arterial course or origin. Univariate logistic regression analyses were performed to test for associations between arteriopathy location, hemangiomas, and brain abnormalities. RESULTS: By study design, all patients had arterial abnormalities, and 57% had >1 form of arteriopathy. Dysgenesis was the most common abnormality (56%), followed by anomalous course and/or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections. CONCLUSIONS: The arteriopathy of PHACE syndrome commonly involves the ICA and its embryonic branches, ipsilateral to the cutaneous hemangioma, with dysgenesis and abnormal arterial course the most commonly noted abnormalities. Brain abnormalities are also typically ipsilateral.

Magnetic resonance neurography for the evaluation of peripheral nerve, brachial plexus, and nerve root disorders.

OBJECT Treatment of spinal and peripheral nerve lesions relies on localization of the pathology by the use of neurological examination, spinal MR imaging and electromyography (EMG)/nerve conduction studies (NCSs). Magnetic resonance neurography (MRN) is a novel imaging technique recently developed for direct imaging of spinal and peripheral nerves. In this study, the authors analyzed the role of MRN in the evaluation of spinal and peripheral nerve lesions. METHODS Imaging studies, medical records, and EMG/NCS results were analyzed retrospectively in a consecutive series of 191 patients who underwent MRN for spinal and peripheral nerve disorders at the University of California, San Francisco between March 1999 and February 2005. Ninety-one (47.6%) of these patients also underwent EMG/NCS studies. RESULTS In those who underwent both MRN and EMG/NCS, MRN provided the same or additional diagnostic information 32 and 45% of patients, respectively. Magnetic resonance neurograms were obtained at a median of 12 months after the onset of symptoms. The utility of MRN correlated with the interval between the onset of symptoms to MRN. Twelve patients underwent repeated MRN for serial evaluation. The decrease in abnormal signal detected on subsequent MRN correlated with time from onset of symptoms and the time interval between MRN, but not with resolution of symptoms. Twenty-one patients underwent MRN postoperatively to assess persistent, recurrent, or new symptoms; of these 3 (14.3%) required a subsequent surgery. CONCLUSIONS Magnetic resonance neurography is a valuable adjunct to conventional MR imaging and EMG/NCS in the evaluation and localization of nerve root, brachial plexus, and peripheral nerve lesions. The authors found that MRN is indicated in patients: 1) in whom EMG and traditional MR imaging are inconclusive; 2) who present with brachial plexopathy who have previously received radiation therapy to the brachial plexus region; 3) who present with brachial plexopathy and have systemic tumors; and 4) in patients under consideration for surgery for peripheral nerve lesions or after trauma. Magnetic resonance neurography is limited by the size of the nerve trunk imaged and the timing of the study.

Dynamic Changes in Phase-Amplitude Coupling Facilitate Spatial Attention Control in Fronto-Parietal Cortex

Electrocorticography reveals how coupling between two frequencies of neuronal oscillation allows the frontal and parietal areas of the cortex to control visual attention from moment to moment in the human brain.

Predictors of seizure freedom after surgery for malformations of cortical development

Malformations of cortical development (MCDs) are a major cause of medically refractory epilepsy. Our aim was to examine a surgical series of patients with cortical malformations to determine the prognostic factors associated with long‐term seizure control.

Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review.

OBJECT Craniopharyngiomas are benign tumors but their close anatomical relationship with critical neurological, endocrine, and vascular structures makes gross-total resection (GTR) with minimal morbidity difficult to achieve. Currently, there is controversy regarding the extent, timing, and modality of treatment for pediatric craniopharyngioma. METHODS The authors performed a systematic review of the published literature on pediatric craniopharyngioma to determine patterns of clinical practice and the reported outcomes of standard treatment strategies. This yielded 109 studies, which contained data describing extent of resection for a total of 531 patients. Differences in outcome were examined based upon extent of resection and choice of radiation treatment. RESULTS Gross-total resection was associated with increased rates of new endocrine dysfunction (OR 5.4, p < 0.001), panhypopituitarism (OR 7.8, p = 0.006), and new neurological deficits (OR 9.9, p = 0.03) compared with biopsy procedures. Subtotal resection (STR) was not associated with an increased rate of new neurological deficits. Gross-total was associated with increased rates of diabetes insipidus (OR 7.7, p = 0.05) compared with the combination of STR and radiotherapy (RT). The addition of RT to STR was associated with increased rates of panhypopituitarism (OR 9.9, p = 0.01) but otherwise similar rates of morbidities. CONCLUSIONS Although subject to the limitations of a literature review, this report suggests that GTR is associated with increased rates of endocrinopathies compared with STR + RT, and this should be considered when planning goals of surgery.

Efficacy of Vagus Nerve Stimulation for Epilepsy by Patient Age, Epilepsy Duration, and Seizure Type

Medically refractory epilepsy is a morbid condition, and many patients are poor candidates for surgical resection because of multifocal seizure origin or eloquence near epileptic foci. Vagus nerve stimulation (VNS) was approved in 1997 by the US Food and Drug Administration as an adjunctive treatment of intractable epilepsy for individuals aged 12 years and more with partial epilepsy. Controversy persists regarding the efficacy of VNS for epilepsy and about which patient populations respond best to therapy. In this article, the authors retrospectively studied a patient outcome registry and report the largest, to their knowledge, analysis of VNS outcomes in epilepsy.