Tonsillary carcinoma after temozolomide treatment for glioblastoma multiforme: treatment-related or dual-pathology?

Glioblastoma multiforme is a primary malignant brain tumor with a prognosis of typically less than 2 years. Standard treatment paradigms include surgery, radiation therapy and temozolomide. Little data exists for temozolomide recommendations after the first 6 months. We present a case of a patient with glioblastoma multiforme treated with surgery, radiation and chronic temozolomide for 6 years. He continues to survive glioblastoma-recurrence-free, but developed tonsillary carcinoma. This case raises the question of whether this secondary solid-organ malignancy is treatment-related or dual pathology.

Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter.

Because the apoptotic pathway is often disrupted in tumor cells, its genetic restoration is a very attractive approach for the treatment of tumors. To treat malignant gliomas with this approach, it would be preferred to restrict induction of apoptosis to tumor cells by establishing a tumor-specific expression system. Telomerase is an attractive target because the vast majority of malignant gliomas have telomerase activity whereas normal brain cells do not. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit [human telomerase reverse transcriptase, (hTERT)]. Therefore, we hypothesized that using a hTERT promoter-driven vector system, an apoptosis-inducible gene may be preferentially restricted to telomerase- or hTERT-positive tumor cells. In this study, we constructed an expression vector consisting of the constitutively active caspase-6 (rev-caspase-6) under the hTERT promoter (hTERT/rev-caspase-6) and then investigated its antitumor effect on malignant glioma cells. The rationale for using the rev-caspase-6 gene is because it induces apoptosis independent of the initiator caspases. We demonstrated that the hTERT/rev-caspase-6 construct induced apoptosis in hTERT-positive malignant glioma cells, but not in hTERT-negative astrocytes, fibroblasts, and alternative lengthening of telomeres cells. In addition, the growth of s.c. tumors in nude mice was significantly suppressed by the treatment with hTERT/rev-caspase-6 construct. The present results strongly suggest that the telomerase-specific transfer of the rev-caspase-6 gene under the hTERT promoter is a novel targeting approach for the treatment of malignant gliomas.

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells.

Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 microM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein light-chain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

High energy phosphate metabolism in experimental permanent focal cerebral ischemia: an in vivo 31P magnetic resonance spectroscopy study.

Relative levels of phosphate metabolites in the brain were examined in vivo by 31P magnetic resonance spectroscopy (MRS) in 50 Sprague-Dawley rats before, during, and after induction of focal permanent cerebral ischemia. After acquisition of baseline spectra, rats were subjected to injury within the core of the MR spectrometer, and 31P spectra were collected for 60 min after injury: in 7 rats, permanent, acute focal cerebral ischemia was induced (ischemia group); in 6 rats, mild hypoxia (FiO2 14%) was induced at the time of the ischemic insult and was maintained for 20 min (ischemia-hypoxia group); in 6 rats, mild hypoxia (FiO2 14%) only was induced for 20 min (hypoxia group). Control studies were performed in 25 rats. Cerebral intracellular pH, calculated from the chemical shift of inorganic phosphate (Pi), decreased immediately after injury in the ischemia and ischemia-hypoxia groups. The first 31P spectrum obtained after injury was characterized by an increase in Pi and a decrease in phosphocreatine (PCr) in the ischemia and ischemia-hypoxia groups; these changes in spectra were significantly greater in the ischemia-hypoxia group. No significant changes in adenosine triphosphate (ATP) were found in either group. Within 60 min of occlusion, 31P spectra returned toward baseline spectra in both ischemia-hypoxia and ischemia groups. No significant changes were seen in spectra of rats subjected to hypoxia alone. These results confirm that 31P MRS is a sensitive measure of early changes of high energy metabolites in focal cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter.

Telomerase activity has a close relationship with malignancies in many cell types and it is tightly regulated at the transcriptional level of human telomerase reverse transcriptase (hTERT). Utilizing the hTERT promoter, the authors developed a gene delivery system of Fas associated protein with death domain (FADD) (hTERT/FADD). FADD is a protein which plays an important role in the apoptotic pathway of Fas. Over-expression of FADD induces apoptosis in the cells regardless of Fas expression on the cell surface. We hypothesized that we might be able to restrict the expression of FADD in malignant glioma cells if we use the gene transfer system under the control of hTERT promoter. This study was designed to investigate whether the hTERT/FADD construct induces apoptosis effectively in malignant glioma cells while keeping normal cells intact. First, using the reverse transcription-polymerase chain reaction (RT-PCR) technique, we confirmed that hTERT mRNA was expressed in human malignant glioma cells (U373-MG, A172 and GB-1), but not in cultured astrocytes (TEN) or fibroblasts (MRC5). After transient transfection with the hTERT/FADD construct, a significant number of FADD-positive cells and apoptotic cells were detected in hTERT-positive malignant glioma cells. In contrast, hTERT-negative astrocytes and fibroblasts remained intact. Furthermore, subcutaneously implanted U373-MG tumors treated with the hTERT/FADD construct reduced in volume significantly compared to the conrol treatment (p=0.0001). Gene transfer of FADD under the control of the hTERT promoter may be a novel and promising therapy to kill hTERT-positive malignant glioma cells while sparing normal brain cells lacking hTERT.

Increased seizure susceptibility in adult rats with neuronal migration disorders.

Recent data show that neuronal migration disorders (NMD) lower the seizure threshold in the immature brain. To assess if this is an age-related phenomenon, kainic acid (KA) was administered to induce status epilepticus in adult rats with NMD. Results of the present study demonstrate that adult rats with NMD had a shorter latency to seizures and longer duration of status epilepticus compared to age-related controls. Furthermore, in rats with NMD seizures were more severe and status epilepticus-induced mortality was worse than in age-matched controls. These data confirm that NMD lower the seizure threshold in the adult rat. The results of the present study combined with our previous studies in the immature rat, suggest that the facilitating effects of NMD on seizures are not age dependent.

Direct endarterectomy of the middle cerebral artery for treatment of symptomatic stenosis: case report.

The authors report the clinical course and surgical technique used to treat a patient with a high-grade stenosis of the proximal middle cerebral artery that had caused a previous infarction and threatened the remaining dominant hemisphere. Trapping of the involved middle cerebral artery segment allowed direct exposure for excision of the atheromatous plaque and subsequent closure of the arteriotomy. Intraoperative angiography confirmed the reestablishment of flow. The patient made an uneventful postoperative recovery. Direct middle cerebral artery endarterectomy has the advantage of potentially reestablishing flow to lenticulostriate branches. The technique may also avoid the problem of occlusion at the site of maximum stenosis that can be caused by the use of an extra/intracranial bypass graft. Middle cerebral artery endarterectomy is a potentially valuable technique that deserves further investigation.

Clinical use of the optical digitizer for intracranial neuronavigation.

OBJECTIVE: Computer-assisted frameless navigation techniques are used in many centers for intracranial neurosurgical procedures. In this study, we assessed the accuracy and the clinical usefulness of a frameless system based on the optical digitizer in a variety of intracranial procedures. METHODS: The optical digitizer (StealthStation, Sofamor Danek, Memphis, TN) was used to perform 170 neurosurgical operations. Its accuracy was judged before and after each operation by comparing the computer-estimated error with the real estimated error measured on the patient's anatomy. Several objective factors were evaluated to assess the clinical usefulness of the optical digitizer. For craniotomies, the intraoperative extent of resection based on computer-generated images was compared with that on postoperative images, and the length of hospital stay of patients undergoing frameless procedures was compared with that of patients undergoing conventional procedures. For needle biopsies, clinical usefulness was based on the rate of success in establishing a histological diagnosis. RESULTS: The optical digitizer was accurate to within 2 mm for all procedures. The computer-estimated error was not significantly different from the real estimated error. The intraoperative extent of resection was accurate in 58 of 60 tumor resection patients, as confirmed on postoperative images. Patients undergoing frameless procedures had a significantly shorter hospital stay than those undergoing conventional procedures (7.5 +/- 1 versus 10.8 +/- 1.3 d, P < 0.05). All biopsies were diagnostic. CONCLUSION: The optical digitizer is an accurate frameless device that offers clinical benefits. These include precise surgical resection, decreased hospitalization time, and accurate tissue diagnosis.

Effects of basic fibroblast growth factor on in vivo cerebral tumorigenesis in rats.

OBJECTIVE: In vitro evidence suggests that basic fibroblast growth factor (bFGF) promotes tumor cell proliferation and angiogenesis. In this study, we evaluated the early and delayed effects of recombinant human bFGF on the early and late phases of in vivo, in situ tumorigenesis in rats. METHODS: Brain tumors were induced by transplacentally exposing fetal rats to N-nitrosoethylurea on Day 17 of pregnancy. On postnatal (PN) Day 60 or 90, N-nitrosoethylurea-exposed rats underwent stereotactic intraventricular implantation of Gelfoam saturated with bFGF (60 micrograms) or vehicle; the rats were killed 4 days (early group) or 30 days (delayed group) later. The early and delayed effects of bFGF on the early phase of tumorigenesis (PN Day 60) were evaluated in 14 and 10 rats, respectively; early and delayed effects on the late phase of tumorigenesis (PN Day 90) were evaluated in 12 rats each. RESULTS: Histological examination 30 days after implantation showed a significantly higher tumor rate in rats that had been treated with bFGF on PN Day 90, compared with vehicle-treated control rats (P < 0.05); furthermore, in the bFGF-treated animals there was significantly greater intratumoral and periventricular glial fibrillary acidic protein expression, as determined immunohistochemically. Increased vascularity in the tumor ipsilateral to the implant was found in 2 of 14 rats that had been treated with bFGF on PN Day 60. CONCLUSION: These findings support in vitro evidence that bFGF and its receptor complex are implicated in the genesis and progression of N-nitrosoethylurea-induced brain tumors in this animal model.

Intracerebral hemorrhage occurring remote from the craniotomy site.

OBJECTIVE: The purpose of this study was to analyze the available clinical data on postoperative intracerebral hemorrhages that occur in locations remote from the sites of craniotomy. METHODS: The findings of 37 cases of postoperative intracerebral hemorrhages occurring remote from the craniotomy sites were reviewed (5 from our records and 32 from the literature). RESULTS: Remote postoperative intracerebral hemorrhages presented within the first few hours postoperatively in 78% of the patients and were not related to the types of lesions for which the craniotomies were performed. Supratentorial procedures that produced infratentorial hemorrhages involved operations in the deep sylvian fissure and paraclinoid region in 81% of the patients and hemorrhages in the cerebellar vermis in 67% of the patients. Infratentorial procedures that produced supratentorial hemorrhages were performed with the patient in the sitting position for 87% of the patients. The remote supratentorial hemorrhages that occurred were superficial and lobar in 84% of the patients, as opposed to deep and basal ganglionic, which are classic locations for hypertensive hemorrhages. Remote intracerebral hemorrhages occurring after craniotomies were not associated with hypertension, coagulopathy, cerebrospinal fluid drainage, or underlying occult lesions. These hemorrhages commonly led to significant complications; 5 of 37 patients (14%) were left severely disabled, and 12 of 37 patients (32%) died. CONCLUSIONS: Remote intracerebral hemorrhage is a rare complication of craniotomy with significant morbidity and mortality. Such hemorrhages likely develop at or soon after surgery, tend to occur preferentially in certain locations, and can be related to the craniotomy site, operative positioning, and nonspecific mechanical factors. They do not seem to be related to hypertension, coagulopathy, cerebrospinal fluid drainage, or underlying pathological abnormalities.

Reoperation for recurrent temporal lobe epilepsy.

The indications for the risks and outcome of reoperation for medically refractory temporal lobe epilepsy have not been well documented. A retrospective review is presented of 40 patients who underwent reoperation on the temporal lobe for recurrent seizures. The mean patient age at the first operation was 22 +/- 7 years (+/- standard deviation). Electrocorticography during the first operation showed interictal epileptic abnormalities from surface electrodes in 97% of the cases and from depth electrodes in the mesiotemporal structures in 38%. The seizures recurred with the same pattern within 6 months after the first operation in 60% of patients and within 2 years in 90%. Postoperative neuroimaging studies showed residual mesiotemporal structures in all cases. The mean time between the two operations was 5.5 +/- 5 years and the mean patient age at the second operation was 28 +/- 8 years. The second operation involved focal resection of the mesiotemporal structures in 30 cases. The mean postoperative follow-up period was 4.8 +/- 2.7 years (range 2 to 11 years). After the second operation, 63% of the patients were seizure-free or had rare seizures (one or two per year). There were no permanent neurological complications. Patients who did not benefit from reoperation had electroencephalographic abnormalities in multiple brain areas. Reoperation for temporal lobe epilepsy effectively controls seizures in the majority of patients, and the procedure is safe if rigorous technical rules are observed. More complete resection of mesiotemporal structures during the first operation, even in the absence of intraoperative electrographic abnormalities, could prevent the need for reoperation in defined cases.

Frameless stereotaxy for surgery of the epilepsies: preliminary experience. Technical note.

Frameless stereotactic techniques used in conjunction with three-dimensional images allow accurate planning and performance of a variety of neurosurgical procedures. The authors have used the frameless stereotactic Allegro Viewing Wand system to provide real-time correlation of the operating field and computerized images in 42 neurosurgical operations, including 31 epilepsy procedures. The system consists of an image-processing computer that creates three-dimensional and triplanar images; a mobile computer to display reformatted magnetic resonance images; and a hand-guided, articulated, position-sensing arm with a probe. At the start of the operation, the probe identifies the patient's facial and scalp features and correlates these with the computerized images. The position-sensing arm can then guide the operation and locate anatomical structures and lesions of interest. This system can be used to advantage in performing smaller craniotomies and intraoperatively locating anatomical structures and lesions to be removed. Postoperative magnetic resonance images demonstrate that this technique was accurate to within 3 mm in measuring the anteroposterior resection of fixed structures, such as hippocampus and corpus callosum. Disadvantages include longer preoperative preparation for data analysis and lack of both real-time computer analysis of tissue removal and angiographic data display. Preliminary experience suggests that the viewing wand system's advantages outweigh the disadvantages, and it is most helpful as an adjunctive navigational device in the microsurgical treatment of epilepsy.

Intracranial meningiomas of the first two decades of life.

Meningiomas arising in the first two decades of life are uncommon and their characteristics are controversial. Some authors believe meningiomas in younger patients occur in different locations, have more malignant histological features, and have a worse prognosis than those in adults. To address this controversy, the authors retrospectively reviewed 23 cases of meningiomas in patients under 21 years of age at diagnosis who were operated on at the University of Turin (1948 to 1990) or at the University of California, San Francisco (1970 to 1989). These tumors represented 2.9% of all tumors in this age group and 1.8% of all meningiomas during the study period at the two institutions. There were 14 males and nine females. The mean age at surgery was 13.3 +/- 5.6 years; nine cases occurred in the first decade and 14 in the second. The most common neurological symptoms were a focal neurological deficit (33%) and seizures (25%). Seventy percent of the tumors were supratentorial. A gross total resection was performed in 60% of the cases. Histologically, the majority (74%) of the tumors were meningothelial or mixed. An increased number of mitoses was observed in 33% of the tumors, focal necrosis in 29%, and invasion of adjacent brain in 14%; however, none of the tumors was classified as a Grade III (anaplastic) meningioma. All patients are alive without evidence of recurrent disease 3 to 22 years (mean +/- standard deviation: 10 +/- 7.3 years) after surgery. This study confirms the rarity of meningiomas of the first two decades of life and the absence of the female predominance associated with meningiomas in adults. The location and histological features of these tumors are similar to those in adults; they have a low recurrence rate, and the outcome and survival rate are excellent.

Magnetic resonance imaging and 31P magnetic resonance spectroscopy for evaluating focal cerebral ischemia.

Recent advances in magnetic resonance (MR) imaging and MR spectroscopy (MRS) allow the noninvasive in vivo study of a variety of anatomical, physiological, and biochemical alterations that may occur in different cerebral pathologies. The authors have investigated the use of MR imaging and MRS to monitor the evolution of experimental focal cerebral ischemia in rats. Permanent focal cerebral ischemia was induced in 36 rats, and 12 normal rats were used as a control group. Changes in high-energy phosphate metabolites were followed in vivo using MRS during the 1st hour and at 3 and 6 hours after ischemic insult. Changes in vivo MR images were evaluated at 1, 3, 6, 12, and 24 hours after ischemic insult. Significant decreases (p less than 0.05) in phosphocreatine/inorganic phosphate ratios and intracellular pH values occurred immediately after the induction of ischemia. The presence of an infarcted area seen on MR images was a constant finding at 3 hours after ischemic insult, and was well defined and localized at 12 and 24 hours. The location of areas of infarction seen on MR images correlated well with areas identified histopathologically. The T1 and T2 MR relaxation times were significantly increased 3 hours after ischemic insult and remained prolonged for at least 24 hours. The results show that MR imaging is a sensitive method to measure cerebral infarction, and that MRS is a sensitive measure of changes that occur in the early phases of ischemia, perhaps when cellular changes may still be reversible. At 3 and 6 hours after the ischemic insult, however, 31P-MRS spectra may appear to be "normal" despite the presence of well-documented areas of infarction.

The therapeutic value of nimodipine in experimental focal cerebral ischemia. Neurological outcome and histopathological findings.

Recent studies suggest that nimodipine, a potent calcium-channel antagonist that causes significant cerebrovascular dilatation, may improve neurological outcome after acute experimental permanent focal cerebral ischemia when given before or immediately after occlusion of the middle cerebral artery (MCA) in various animals. The authors describe the effect of nimodipine on cerebral ischemia in a rat model. At 1, 4, or 6 hours after occlusion of the MCA, rats were treated in a double-blind technique with either nimodipine, placebo, or saline. Neurological and neuropathological evaluation was performed at 24 hours. Neurological outcome was better in rats treated with nimodipine 1, 4, or 6 hours after occlusion (p less than 0.001, p less than 0.01, p less than 0.05 respectively), and the size of areas of infarction was statistically smaller in nimodipine-treated groups (p less than 0.01, p less than 0.01, p less than 0.05, respectively) when compared with control rats treated with saline or placebo. The best neurological outcome and the smallest area of infarction were found in nimodipine-treated rats 1 hour after occlusion. Compared with controls, the size of the periphery of the infarcted area was smaller in nimodipine-treated rats. The results show that nimodipine improves neurological outcome and decreases the size of infarction when administered up to 6 hours after ischemic insult. These results suggest a possible mechanism of action of nimodipine on the "penumbra" of the ischemic area.

Correlation of histopathological features and proliferative potential of gliomas.

One hundred fifty-two intracranial gliomas of various types were reviewed in order to correlate the histopathological features with the proliferative potential of each tumor as reflected by the bromodeoxyuridine (BUdR) labeling index (LI). Patients undergoing surgical removal of gliomas were given a 30-minute intravenous infusion of BUdR (150 to 200 mg/sq m) to label S-phase tumor cells. The tumor specimens were stained immunohistochemically for BUdR and processed for routine histopathological diagnosis. The BUdR LI was calculated as the percentage of labeled cells among cells analyzed. Twenty-seven histological features in three categories (degenerative, vascular, and cellular changes) were considered. A significantly higher BUdR LI (p less than 0.05) was found in tumors with necrosis than in those without this feature; tumors with both coagulative and liquefactive necrosis had the highest BUdR LI (p less than 0.05). Increased vascularity was also associated with a higher BUdR LI (p less than 0.05). Although tumors with abnormal mitotic figures had a significantly higher BUdR LI than those without, the number of mitoses did not correlate with a higher BUdR LI. These results suggest that the number of mitoses is not a good indicator of tumor growth rate. Necrosis and increased vascularity should be heavily weighted in predicting the proliferative potential of individual gliomas.

Histopathological follow-up study of 66 cerebral arteriovenous malformations after therapeutic embolization with polyvinyl alcohol.

Embolization with polyvinyl alcohol (PVA) is an accepted method of rendering complex arteriovenous malformations (AVM's) more amenable to surgery, but its effects on human vascular tissues have not been adequately documented. The authors reviewed the histopathology of 66 intracranial AVM's resected 1 to 76 days after embolization with PVA. The mean age of the patients was 36 years, and their AVM's were located in the cerebral hemispheres (92%), the cerebellum (6%), or the corpus callosum (2%). In 79% of cases, at least one vessel contained PVA particles; in most cases, the vessel was filled with sharp, angular PVA particles in a serpiginous pattern. Polyvinyl alcohol particles indented the endothelium in 69% of cases but were rarely found subendothelially. Clotted blood and fibroblasts were present among the particles, and abundant intraluminal mononuclear and polymorphonuclear inflammatory cells were found in all vessels containing PVA particles. Foreign-body giant cells appeared 2 to 14 days after embolization in the majority of cases. Patchy mural angionecrosis and necrotizing vasculitis were found in 39% of the cases. Recanalized lumina were seen in 18% of PVA-embolized vessels. Foreign materials resembling cotton fibers and other particulate substances, which were probably contaminants of the contrast solution or the embolic material, were found in 65% of the cases. These findings suggest a specific chain of events in the interaction between PVA and vessel wall components and may explain some important sequelae of embolization therapy.

Age-dependent vulnerability to seizures.

Seizure disorders frequently occur early in life. Seizures are classified as reactive, symptomatic, or idiopathic depending on whether their cause can be identified. Reactive seizures are the result of acute environmental perturbations. Early in life, many stressors can produce seizures and the ultimate outcome may depend on the particular precipitating factor and its intensity. Febrile convulsions are the most common reactive seizures, although they must be differentiated from symptomatic seizures precipitated by fever. Symptomatic seizures are often associated with varying degrees of central nervous system (CNS) insults, including congenital malformations and metabolic storage diseases of the gray matter. These seizures may have age-specific characteristics and may at times be difficult to treat with conventional antiepileptic treatments. To develop a better understanding of the pathophysiology of seizures early in life, we have extensively used animal models of epilepsy. In this chapter, we report our findings with a rat model of developmental cortical dysplasias produced by intrauterine injections of methylazoxymethanol acetate. These rats are more susceptible to kainic acid, flurothyl, and hyperthermic seizures than normal rats. Rats with severe cortical dysplasia are most susceptible to seizures. We have also studied the mechanisms involved in the control of seizures during development because status epilepticus is more prevalent in infants than in adults. Our data suggest that the substantia nigra may play a crucial role in status epilepticus as a function of age. In the adult substantia nigra two regions mediate opposing effects on seizures following infusions of gamma-aminobutyric acid type A (GABAA) agents. One region is located in the anterior substantia nigra, and muscimol infusions in this region mediate anticonvulsant effects. The second region is in the posterior substantia nigra, and here muscimol infusions produce proconvulsant effects. In situ hybridization data demonstrate that, at the cellular level, neurons in the two substantia nigra regions differ in the amount of hybridization grains for GABAA receptor alpha 1 and gamma 2L subunit mRNAs. In developing male rats, only the "proconvulsant" region is present up to the age of 21 days. The transition from the immature to mature substantia nigra mediated seizure control occurs between age 25 and 30 days. The identification of age-dependent functional networks involved in the containment of seizures may lead to possible new pharmacologic strategies to control seizures, thus aiding the development of age-appropriate treatments of seizure disorders.

Transsulcal approach to mesiotemporal lesions. Anatomy, technique, and report of three cases.

Surgical resection of mesiotemporal lesions, particularly those in the dominant hemisphere, is often challenging. Standard approaches require excessive brain retraction, removal of normal cortex, or manipulation of the middle cerebral artery branches. This report describes a transsulcal temporal approach to mesiotemporal lesions and its application in three patients. Gross-total resection of the lesion was accomplished in all cases. An anatomical cadaveric study was also performed to delineate the microsurgical anatomy of this approach. Precise knowledge of temporal intraventricular landmarks allows navigation to the lesion without the need for a navigational system. This approach is helpful for neurologically intact patients with mesiotemporal lesions.

Clinical evaluation of multimodality registration in frameless stereotaxy.

Computer-assisted frameless neurosurgery bases its accuracy and reliability on registration. The aim of this prospective study was to compare the clinical accuracy of different registration techniques used for computer-assisted frameless neurosurgery. Ninety-eight registrations in 44 patients were used to compare the clinical accuracy of self-adhesive marker (MR) and facial landmark (FR) registrations used alone or in conjunction with surface-fit registration (MR/SR and FR/SR, respectively) for cranial neurosurgery. The computer estimated error (CEE) of each registration was compared to the real error (RE). This was obtained by holding the frameless pointer at the center of three different markers and measuring the distance from the real-time representation on the computer three-planar images to the center of the marker on the screen. The most accurate registration was obtained using MR; the RE of MR was 1.6 +/- 0.1 mm compared to 3.4 +/- 0.4 mm for FR. Although the smallest CEE error was obtained using MR/SR, this was not sustained by the RE. Furthermore, the RE of FR/SR was significantly larger than the CEE (Student t test, p <.001). This study corroborates previous results showing that, in the clinical setting, self-adhesive marker registration is more accurate than facial landmark registration. Furthermore, although surface-fit registration can be used in conjunction with self-adhesive marker registration, this does not improve the degree of real accuracy for cranial registration.