Citations

Object A review of the literature has revealed scant data related to neurosurgical treatment of gravid patients. The authors reviewed their experience with the neurosurgical treatment of pregnant women to better characterize the optimal management strategies for intracranial pathological entities in this population. Methods Between July 1969 and July 2005, 34 patients with documented pregnancy and concomitant intracranial pathological entities were treated at the authors' institution. The average age of the gravid patients at presentation was 27 ± 6 years. Twelve patients harbored vascular and 14 patients harbored neoplastic lesions. Four gravid patients suffered from traumatic intracranial hemorrhage, 2 had primary intracerebral hemorrhage, and 2 had hydrocephalus. The medical records of these patients were reviewed to assess the outcome for the mothers and fetuses. Results Nineteen pregnant patients (56%) underwent a neurosurgical procedure after induction of general anesthesia. Of these, 14 (74%) underwent craniotomies for clipping/resection of their lesion, 2 (10%) underwent stereotactic biopsies, and 3 (16%) underwent CSF shunting procedures. Three patients (9%) delivered by cesarean section followed by their neurosurgical procedure, and 5 (15%) underwent therapeutic abortion preoperatively to allow for radiation therapy early in their pregnancy (4 of these patients underwent surgery prior to their therapeutic abortion). Eleven patients (32%) were treated nonoperatively while pregnant, and 3 of these received their treatment after delivery. There was no operative maternal mortality or permanent morbidity. The fetuses did not suffer from any complications related to the mother's neurosurgical procedure. Conclusions Based on the authors' experience and a review of the literature, surgery for intracranial lesions in pregnant patients is generally well tolerated by both mother and fetus. Preoperative delivery by cesarean section of term or near-term babies is reasonable. Some patients treated conservatively may deteriorate and require an operation.

Abstract Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase 1 (VEGFR-1/FLT1) is expressed as a membrane-bound receptor tyrosine kinase and as an alternatively spliced soluble protein (sVEGFR-1) containing the 1-6 IgG-like domain of its ectodomain. sVEGFR-1 is known as a naturally occurring inhibitor of angiogenesis and as a surrogate marker for cancer progression; it is also linked to pregnancy-induced hypertension called preeclampsia and to avascularity of normal cornea. It remains an open question whether alternative mRNA splicing is the only mechanism by which sVEGFR-1 is generated. In this study, we show that in leukemic cancer cells, PlGF and VEGF-A both induce tyrosine phosphorylation of VEGFR-1 and render it susceptible to ectodomain shedding, resulting in the generation of sVEGFR-1 and an intracellular cytoplasmic fragment. Activation of protein kinase C and tumor necrosis factor-α–converting enzyme family metalloproteases are critically required for the occurrence of sVEGFR-1. Following the removal of the ectodomain, the remnant of VEGFR-1 remains attached to the membrane, and the activity of γ-secretase/presenilin is required for its release from the cell membrane. We propose that sVEGFR-1 produced via ectodomain shedding plays a prominent role in the VEGF receptor system by antagonizing VEGF receptor signaling by acting as a dominant-negative form and/or forming a nonsignaling dimerizing complex with VEGF receptors. [Cancer Res 2009;69(6):2607–14]

Object Cavernous hemangiomas associated with epilepsy present an interesting surgical dilemma in terms of whether one should perform a pure lesionectomy or tailored resection, especially in the temporal lobe given the potential for cognitive damage. This decision is often guided by electrocorticography (ECoG), despite the lack of data regarding its value in cavernoma surgery. The purpose of the present study was several-fold: first, to determine the epilepsy outcome following resection of cavernomas in all brain regions; second, to evaluate the usefulness of ECoG in guiding surgical decision making; and third, to determine the optimum surgical approach for temporal lobe cavernomas. Methods The authors identified from their surgical database 173 patients who had undergone resection of cavernomas. One hundred two of these patients presented with epilepsy, and 61 harbored temporal lobe cavernomas. Preoperatively, all patients were initially evaluated by an epileptologist. The mean follow-up was 37 months. Results Regardless of the cavernoma location, surgery resulted in an excellent seizure control rate: Engel Class I outcome in 88% of patients at 2 years postoperatively. Of 61 patients with temporal lobe cavernomas, the mesial structures were involved in 35. Among the patients with temporal lobe cavernomas, those who underwent ECoG typically had a more extensive parenchymal resection rather than a lesionectomy (p < 0.0001). The use of ECoG in cases of temporal lobe cavernomas resulted in a superior seizure-free outcome: 79% (29 patients) versus 91% (23 patients) of patients at 6 months postresection, 77% (22 patients) versus 90% (20 patients) at 1 year, and 79% (14 patients) versus 83% (18 patients) at 2 years without ECoG versus with ECoG, respectively. Conclusions The surgical removal of cavernomas most often leads to an excellent epilepsy outcome. In cases of temporal lobe cavernomas, the more extensive the ECoG-guided resection, the better the seizure outcome. In addition to upholding the concept of kindling, the data in this study support the use of ECoG in temporal lobe cavernoma surgery in patients presenting with epilepsy.

Abstract Transforming growth factor-β (TGF-β) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-β signaling pathways that promote inhibition of epithelial cell growth are well characterized, less is known about the mechanisms mediating the positive response to this growth factor. Given that TGF-β has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-β signaling pathways is critical. Here, we investigate the role of mammalian target of rapamycin (mTOR), a known effector of phosphatidylinositol 3-kinase (PI3K) and promoter of cell growth, in the fibroblast response to TGF-β. We show that TGF-β activates mTOR complex 1 (mTORC1) in fibroblasts but not epithelial cells via a PI3K-Akt-TSC2–dependent pathway. Rapamycin, the pharmacologic inhibitor of mTOR, prevents TGF-β–mediated anchorage-independent growth without affecting TGF-β transcriptional responses or extracellular matrix protein induction. In addition to mTORC1, we also examined the role of mTORC2 in TGF-β action. mTORC2 promotes TGF-β–induced morphologic transformation and is required for TGF-β–induced Akt S473 phosphorylation but not mTORC1 activation. Interestingly, both mTOR complexes are necessary for TGF-β–mediated growth in soft agar. These results define distinct and overlapping roles for mTORC1 and mTORC2 in the fibroblast response to TGF-β and suggest that inhibitors of mTOR signaling may be useful in treating fibrotic processes, such as desmoplasia. [Cancer Res 2009;69(1):84–93]

Biologically malignant pilocytic astrocytomas are rare. Precise morphologic criteria permitting their identification and clinically meaningful distinction from more ordinary pilocytic astrocytomas have not been developed. The histologic grading schemes applied to fibrillary astrocytomas—ones based on nuclear atypia, increased cellularity, mitotic activity, endothelial proliferation, and necrosis—are thought not to correlate with prognosis in pilocytic astrocytomas. Nonetheless, these features were systematically sought in 107 cerebellar pilocytic astrocytomas, four of which were histologically malignant. The clinical, morphologic, and flow cytometric features of these cases were studied. The incidence of histologic malignancy occurring spontaneously in otherwise typical pilocytic astrocytomas was 0.9%; that occurring after radiation was 1.8%. The four histologically malignant tumors occurred in two males and two females, ages 6 to 18 years. All showed increased mitotic activity (three to five mitoses per high-power microscopic field [250×]). Endothelial proliferation and necrosis were present in three and two cases each. DNA ploidy analysis showed the spontaneously occurring malignant-appearing tumors to be aneuploid, whereas both previously radiated tumors were tetraploid; 5% to 11% of cells were in S phase. The appearance of histologic malignancy in pilocytic astrocytoma is rare and less reliably correlated with prognosis than in patients with fibrillary astrocytomas. Essential features of such tumors include a high mitotic index and perhaps a high percentage of cells in S phase. (J Child Neurol 1994;9:301-310).

Medulloblastoma, the most common embryonal tumor of the central nervous system, affects both children and adults. It poses a significant therapeutic challenge in that age-dependent differences exist, not only in their pathobiology, but in the efficacy of chemotherapy and radiotherapy. This is particularly the case in very young children, whose still developing nervous system exhibits a low tolerance to radiotherapy. We review the epidemiology, clinical presentation, radiologic features, and current therapeutic concepts relative to this unique neoplasm. Efforts are made to highlight clinical controversies. ( J Child Neurol 1992;7:142-155).

Object Patients with normal MR imaging (nonlesional) findings and medically refractory extratemporal epilepsy make up a disproportionate number of nonexcellent outcomes after epilepsy surgery. In this paper, the authors investigated the usefulness of intracranial electroencephalography (iEEG) in the identification of surgical candidates. Methods Between 1992 and 2002, 51 consecutive patients with normal MR imaging findings and extratemporal epilepsy underwent intracranial electrode monitoring. The implantation of intracranial electrodes was determined by seizure semiology, interictal and ictal scalp EEG, SPECT, and in some patients PET studies. The demographics of patients at the time of surgery, lobar localization of electrode implantation, duration of follow-up, and Engel outcome score were abstracted from the Mayo Rochester Epilepsy Surgery Database. A blinded independent review of the iEEG records was conducted for this study. Results Thirty-one (61%) of the 51 patients who underwent iEEG ultimately underwent resection for their epilepsy. For 28 (90.3%) of the 31 patients who had epilepsy surgery, adequate information regarding follow-up (> 1 year), seizure frequency, and iEEG recordings was available. Twenty-six (92.9%) of 28 patients had frontal lobe resections, and 2 had parietal lobe resections. The most common iEEG pattern at seizure onset in the surgically treated group was a focal high-frequency discharge (in 15 [53.6%] of 28 patients). Ten (35.7%) of the 28 surgically treated patients were seizure free. Fourteen (50%) had Engel Class I outcomes, and overall, 17 (60.7%) had significant improvement (Engel Class I and IIAB with ≥80% seizure reduction). Focal high-frequency oscillation at seizure onset was associated with Engel Class I surgical outcome (12 [85.7%] of 14 patients, p = 0.02), and it was uncommon in the nonexcellent outcome group (3 [21.4%] of 14 patients). Conclusions A focal high-frequency oscillation (> 20 Hz) at seizure onset on iEEG may identify patients with nonlesional extratemporal epilepsy who are likely to have an Engel Class I outcome after epilepsy surgery. The prospect of excellent outcome in nonlesional extratemporal lobe epilepsy prior to intracranial monitoring is poor (14 [27.5%] of 51 patients). However, iEEG can further stratify patients and help identify those with a greater likelihood of Engel Class I outcome after surgery.

Object Cerebral cortex electrophysiology is poorly sampled using standard, low spatial resolution clinical intracranial electrodes. Adding microelectrode arrays to the standard clinical macroelectrode arrays increases the spatial resolution and may ultimately improve the clinical utility of intracranial electroencephalography (iEEG). However, the safety of hybrid electrode systems containing standard clinical macroelectrode and microelectrode arrays is not yet known. The authors report on their preliminary experience in 24 patients who underwent implantation of hybrid electrodes. Methods In this study, 24 consecutive patients underwent long-term iEEG monitoring with implanted hybrid depth and subdural grid and strip electrodes; both clinical macroelectrodes and research microelectrodes were used. The patients included 18 women and 6 men with an average age of 35 ± 12 years (range 21–65). The mean hospital stay was 11 ± 4 days (range 5–20), with mean duration of implantation 7.0 ± 3.2 days (range 3–15). Data from the 198 consecutive craniotomies for standard clinical subdural grid insertion (prior to surgery in the 24 patients described here) were used for comparison to investigate the relative risk of complications. Results Focal seizure identification and subsequent resection was performed in 20 patients. One patient underwent a subsequent operation after neurological deterioration secondary to cerebral swelling and a 5-mm subdural hematoma. There were no infections. The overall complication rate was 4.2% (only 1 patient had a complication), which did not significantly differ from the complication rate previously reported by the authors of 6.6% when standard subdural and depth intracranial electrodes were used. There were no deaths or permanent neurological deficits related to electrode implantation. Conclusions The authors demonstrate the use of hybrid subdural strip and grid electrodes containing high-density microwire arrays and standard clinical macroelectrodes. Hybrid electrodes provide high spatial resolution electrophysiology of the neocortex that is impossible with standard clinical iEEG. In this initial study in 24 patients, the complication rate is acceptable, and there does not appear to be increased risk associated with the use of hybrid electrodes compared with standard subdural and depth iEEG electrodes. More research is required to show whether hybrid electrode recordings will improve localization of epileptic foci and tracking the generation of neocortical seizures.