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Death-associated protein kinase expression in human temporal lobe epilepsy.

Experimental and human data suggest programmed (active) cell death may contribute to the progressive hippocampal atrophy seen in patients with refractory temporal lobe epilepsy. Death-associated protein (DAP) kinase is a novel calcium/calmodulin-activated kinase that functions in apoptosis mediated by death receptors. Because seizure-induced neuronal death involves both death receptor activation and calcium, we examined DAP kinase expression, localization, and interactions in hippocampal resections from patients with intractable temporal lobe epilepsy (n = 10) and autopsy controls (n = 6). Expression and phosphorylation of DAP kinase was significantly increased in epilepsy brain compared with control. DAP kinase and DAP kinase-interacting protein 1 (DIP-1) localized to mitochondria in control brain, whereas levels of both were increased in the cytoplasm and microsomal (endoplasmic reticulum) fraction in epilepsy samples. Coimmunoprecipitation analysis showed increased DAP kinase binding to calmodulin, DIP-1, and the Fas-associated protein with death domain (FADD) in epilepsy samples. Finally, immunohistochemistry determined DAP kinase was coexpressed with DIP-1 in neurons. This study provides the first description of DAP kinase and DIP-1 in human brain and suggests DAP kinase is a novel molecular regulator of neuronal death in epilepsy.

Adolescent↗

Unilateral hippocampal sclerosis with contralateral temporal scalp ictal onset.

PURPOSE: To investigate the clinical characteristics and surgical outcomes in patients with unilateral hippocampal sclerosis whose scalp ictal EEG recordings localize to the opposite temporal lobe. METHODS: We retrospectively reviewed the data of all adult patients who had undergone depth electrode implantation for suspected temporal lobe epilepsy (TLE) at UCLA (1993-2000) or the Montreal Neurological Institute (1991-1998) to identify patients who had (a) unilateral hippocampal atrophy, and (b) surface ictal recordings in which the majority of seizures appeared to initiate in the opposite temporal lobe, with few or none that were concordant with the hippocampal atrophy. RESULTS: Of 109 patients with suspected TLE who underwent depth electrode study at the two centers, five patients met the aforementioned criteria. Four of these five had very severe hippocampal atrophy, whereas the fifth had mild atrophy but extensive signal change on magnetic resonance imaging (MRI). Depth electrode recordings in four of the five patients yielded clear ictal onset in the mesial temporal lobe ipsilateral to the imaging abnormality (contralateral to apparent scalp ictal onset). One patient had an unusual bitemporal onset pattern, which was nonetheless suggestive of onset in the sclerotic hippocampus. No patient had intracranial ictal onset contralateral to the imaging abnormality. All patients underwent resection of the structurally abnormal temporal lobe. After follow-up of > or = 2 years, four (80%) of five patients were seizure free, while the fifth showed lesser improvement (class III). CONCLUSIONS: Some patients with severe hippocampal sclerosis (sometimes called a "burned-out hippocampus") have atypical spread of ictal discharges, resulting in apparent gross discordance between imaging and scalp ictal recordings. These patients nonetheless have excellent surgical outcomes on the whole. Whether such patients may forego intracranial recordings requires further study.

Adult↗

Gustatory agnosia.

OBJECTIVE: To report the assessment of a patient exhibiting gustatory agnosia. METHODS: Preoperative and postoperative neuropsychological, neuroimaging, and chemosensory evaluations were performed in a 39-year-old woman undergoing surgical treatment for intractable epilepsy. RESULTS: Preoperative MRIs showed bilateral (right > left) atrophy in the medial temporal lobes and complete atrophy of the left insula. Evaluation of gustatory function revealed normal suprathreshold intensity estimation, affective evaluation, and detection thresholds but elevated recognition thresholds. A functional neuroimaging study showed activation to stimulation of aversive taste in the left amygdala. Surgical treatment entailed resection from the left medial temporal lobe that included the region of amygdala that had responded to taste. Postoperatively, detection, naming, and intensity estimation for taste remained normal, but the patient was unable to recognize different tastes (sweet, sour, salty, and bitter). A second evaluation 2.5 years after her surgery revealed no change in taste ability. CONCLUSION: The anteromedial temporal lobe has an important role in recognizing taste quality.

Adult↗

Use of the intracarotid amobarbital procedure in the evaluation of memory.

The intracarotid amobarbital procedure (IAP) involves the temporary inactivation of one cerebral hemisphere by the injection of sodium amobarbital, which allows independent testing of the contralateral hemisphere. Initially used for lateralization of language, IAP later found a role in the evaluation of memory function in patients with intractable temporal lobe epilepsy being considered for resective surgery. IAP technique varies widely across centers, but, in general, memory is assessed by presenting the patient with a number of items during the period of hemispheric inactivation and testing recall or recognition of these items after the effect of the drug has worn off. Because the medial temporal lobe is not directly perfused by the internal carotid artery, concerns have been raised about the ability of the IAP to test hippocampal memory function. Consequently, a variety of selective procedures have been devised. Findings on both intracranial EEG recordings and pathologic and neuroimaging studies support the association of IAP memory results with hippocampal function. The IAP memory test was originally designed to predict the risk for development of global amnesia following unilateral temporal lobectomy. More recently, it also has been used as an adjunct in lateralizing the seizure focus and for predicting postoperative selective memory deficits and seizure outcome.

Adult↗

Fentanyl-induced electrocorticographic seizures in patients with complex partial epilepsy.

Although electrical seizure activity in response to opioids such as fentanyl has been well described in animals, scalp electroencephalographic (EEG) recordings have failed to demonstrate epileptiform activity following narcotic administration in humans. The purpose of this study was to determine whether fentanyl is capable of evoking electrical seizure activity in patients with complex partial (temporal lobe) seizures. Nine patients were studied in whom recording electrode arrays had been placed in the bitemporal epidural space several days earlier to determine which temporal lobe gave rise to their seizures. The symptomatic temporal lobe was localized by correlating clinical and electrical seizure activity obtained during continuous simultaneous videotape and epidural EEG monitoring. In each patient, clinical seizures and electrical seizure activity were consistently demonstrated to arise unilaterally from one temporal lobe (four on the right, five on the left). During fentanyl induction of anesthesia in preparation for secondary craniotomy for anterior temporal lobectomy, eight of the nine patients exhibited electrical seizure activity at fentanyl doses ranging from 17.7 to 35.71 micrograms.kg-1 (mean 25.75 micrograms.kg-1). More importantly, four of these eight seizures occurred initially in the "healthy" temporal lobe contralateral to the surgically resected lobe from which the clinical seizures had been shown to arise. These findings indicate that, in patients with complex partial seizures, moderate doses of fentanyl can evoke electrical seizure activity. The results of this study could have important implications for neurosurgical centers where electrocorticography is used during surgery for the purpose of determining the extent of the resection.

Adult↗

Extent of resection in temporal lobectomy for epilepsy. I. Interobserver analysis and correlation with seizure outcome.

The extent of resection was assessed in 45 temporal lobectomies for medically intractable epilepsy with mapped temporal lobe foci. Postoperative magnetic resonance imaging (MRI) in the coronal plane was used to quantify the extent of resection of superior lateral, inferior lateral, basal, and medial structures, including the amygdalohippocampal complex. A new 20-compartment model of the temporal lobe was used for this assessment. Blinded interobserver variability was minimal. Intraoperative measurements and maps routinely overestimated the actual extent of resection, especially of medial structures. One year after surgery, 70% of patients remained seizure-free (except for auras). Seizure-free outcome was accomplished despite varying degrees of resection, but was more likely achieved with more extensive resections in all compartments. Among patients with mesiobasal foci, seizure-free outcome correlated significantly with extent of resection of amygdalohippocampal complex. We conclude that assessment of extent of resection by postoperative MRI provides an objective basis of evaluating outcome after temporal lobectomy. It allows a rational approach to understanding of operative failures and is potentially useful in comparing efficacy of various surgical approaches.

Epilepsy↗

Gap junction gene expression in human seizure disorder.

Increased intercellular coupling has been implicated in contributing to the synchronization of discharges characteristic of epileptic foci. Using RNA blot analysis, the level of mRNA for the heart-type gap junction protein, connexin43, is shown to be elevated in samples of temporal lobe neocortex obtained at the time of surgical resection for intractable seizure disorder. Much lower levels of this mRNA are detectable in peritumoral temporal lobe tissue samples obtained during removal of cerebral tumors. However, in cases where the tumors had induced acute seizures, the level of connexin43 mRNA is higher than that detected in epileptic samples. Similar changes are observed for the mRNA for the liver-type gap junction protein, connexin32, although the observed differences are less dramatic. These findings indicate that there is an increase in the level of connexin mRNA in the temporal cortex of patients exhibiting seizure disorders, suggesting an increase in the synthesis of gap junction protein that may lead to an increase in intercellular coupling.

Adolescent↗

Ganglioglioma occurring with glioblastoma multiforme: separate lesions or the same lesion?

The authors report on the first such case of ganglioglioma and a malignant variant in the same individual without prior irradiation. Gangliogliomas are frequently encountered in children and young adults and have a predilection for the temporal lobes. Sporadic cases of malignant degeneration have been reported; however, most cases have undergone radiation or subtotal resection. A 45-year-old female was seen for speech abnormalities and symptoms referable to elevated intracranial pressure. The patient had no significant past medical history and no history of neurocutaneous disorders. Two separate lesions located in the posterior and anterior temporal lobes were found on imaging. At initial surgery, she underwent gross total resection of the anterior temporal tip ganglioglioma and cyst aspiration of the posterior temporal lobe lesion. The anterior temporal lesion was a ganglioglioma and did not recur. However, the posterior temporal lesion was identified as a malignant ganglioglioma/glioblastoma multiforme variant that recurred multiple times requiring several surgeries, radiation and chemotherapy. The occurrence of these distinct entities is uncommon in patients without a history of prior radiation treatment. Even rarer, is the occurrence of these separate intracranial lesions in a patient without a history of phacomatosis. For benign gangliogliomas, gross total resection can be curative; however, more aggressive variants may be resistant to multimodal therapies.

Antineoplastic Agents, Alkylating↗

Limbic and neocortical gliomas associated with intractable seizures: a distinct clinicopathological group.

The authors studied 65 patients with intractable seizures and glial tumors who were treated between 1978 and 1991. Most of the tumors were in the temporal (63%) or occipital lobe (18%) and were commonly found in limbic or perilimbic neocortical locations. The majority of these gliomas (83%) involved the gray matter of allocortex, neocortex, or transitional cortex. These tumors spanned a wide range of glial differentiation: Most (61%) were low-grade astrocytomas, but 17% were histologically malignant. However, their biological behavior was strikingly indolent, as suggested by a stable clinical history during many years of chronic seizures (mean, 15 yr). The median follow-up time since the onset of symptoms in these patients was 17.2 years, and only one patient in the entire series died from the tumor. The mainstay of the surgical treatment was resection of the gliomas to histologically confirmed, tumor-free margins. The resection was not guided by intraoperative electrocorticography. Of the 60 patients who had a postoperative follow-up of more than 1 year, 82% were seizure free. Of the 31 patients who had auras with their seizures, 87% did not retain their auras postoperatively. Of the patients who were rendered seizure free, only one patient continued to have auras. Failure in seizure control was associated with an incomplete resection of the lesion. In patients with temporal lobe tumors, seizure outcome was not significantly related to the extent of medial temporal resection. It is suggested that limbic and perilimbic gliomas associated with intractable seizures constitute a distinct clinicopathologic group of glial tumors that involve the gray matter, arise in a young host, and exhibit stable biological behavior over many years. Surgical treatment that includes complete resection of these tumors can achieve excellent seizure control.

Adolescent↗

Genetically engineered cells with regulatable GABA production can affect afterdischarges and behavioral seizures after transplantation into the dentate gyrus.

Intractable seizures originating in the mesial temporal lobe can often be controlled by resection. An alternative to removing hippocampal tissue may be transplantation of GABA-producing cells. Neural cell transplantation has been performed in hundreds of patients, including some with temporal lobe epilepsy. This study evaluates the seizure-suppressing capabilities of engineered GABA-producing cells transplanted into the dentate gyrus. Immortalized neurons were engineered to produce GABA under the control of doxycycline. The cells were characterized for GABA production in vitro and for their ability to raise GABA concentrations in vivo. Cells were transplanted bilaterally into the dentate gyrus of rats and tested in two separate paradigms. Afterdischarge thresholds and durations were tested with granule cell stimulation, and the development of behavioral seizures, induced by daily electrical stimulation of the major excitatory input pathway into the dentate gyrus, was assessed in the presence, or the absence, of doxycycline. GABA production was under the tight control of doxycycline. Cells engineered to produce GABA raised tissue GABA concentrations in the hippocampus compared with non GABA-producing cells, and this was abolished when doxycycline was administered. GABA-producing cells raised the threshold, and shortened the duration of hippocampal afterdischarges elicited by granule cell stimulation. Lastly, the appearance of stage 5 seizures was slowed in the kindling paradigm, compared with a group that received non-GABA-producing cells, and compared with a group that received GABA-producing cells but was administered doxycycline. This study shows that targeted hippocampal implants of genetically engineered cells have the potential to raise GABA levels and to affect seizure development. The ability to suppress the production of GABA, and to modulate the physiological effects of the transplanted cells provides an important level of experimental control. These techniques, combined with stem cell technology, may advance cell-based therapies for epilepsy and other diseases of the CNS.

Amino Acids↗

Ganglioglioma: a correlative clinicopathological and radiological study of ten surgically treated cases with follow-up.

Gangliogliomas are rare benign tumors of the central nervous system containing neoplastic ganglion and low grade glial cells. In studying 10 surgically treated cases, we evaluated the clinical, pathological, radiological, and immunocytochemical features, with follow-up. Ranging from 18 to 58 years in age, 7 patients were women, and 3 were men. The most common presenting symptom was seizure. Computed tomographic scan showed a low density enhancing mass in 8 and calcification in 5. Six had minimally abnormal vascularity on angiography. Seven patients had total and 3 had subtotal resections of the tumor. The temporal lobe was the location of the tumor in 6 cases. All of the cases met the histological criteria of Russell and Rubinstein for ganglioglioma. Four patients received postoperative radiotherapy because of subtotal resection or aggressive histological makeup. On follow-up, from 2.5 to 7 years, 8 patients are alive and tumor-free, and 7 are also seizure-free. Two died after operation: one immediately and the other of a glioblastoma that developed 5 years later. Our study confirms that ganglioglioma is a distinct histological entity, anatomically localized, with characteristic clinical and radiological findings and long term survival. Aggressive histological makeup is not a definite indication of malignant potential. The definitive role of follow-up radiotherapy for this tumor needs further study. Malignant evolution is rare, but warrants follow-up.

Adolescent↗

Volumetric stereotaxy and the supratentorial occipitosubtemporal approach in the resection of posterior hippocampus and parahippocampal gyrus lesions.

OBJECTIVE: Resection of intracranial tumors in the posterior hippocampus and the parahippocampal gyrus can be associated with significant morbidity because of the parenchymal resection and the cortical retraction often required in gaining access to this infrequently explored region. With the use of image guidance, the occipitosubtemporal (OST) approach requires neither lateral cortical resection nor the placement of brain retractors to gain surgical access to the posterior hippocampus and the parahippocampal gyrus, and this approach is associated with a high rate of gross total tumor resection. METHODS: The computer-assisted volumetric stereotactic OST approach was used to resect 40 posterior hippocampus and parahippocampal gyrus tumors in 34 consecutive patients during an 8-year period. Patient, radiographic, and surgical outcome data were collected retrospectively. RESULTS: The series included operations in 25 men and 15 women, and the patients' average age was 40.3 years (range, 15-69 yr). Twenty-five of the 40 procedures were performed to remove lesions in the dominant hemisphere, and previous craniotomies for resection had been performed in 12 of 40 cases. In 38 of 40 cases, histopathological analysis revealed a glial neoplasm, and 50% of these tumors were high-grade lesions. Preoperatively, 23 patients were neurologically intact before 40 procedures, whereas visual field deficits were noted in 7 patients, mild hemiparesis was documented in 4 patients, and other neurological deficits were present in 9 patients. An excellent outcome (Glasgow Outcome Scale Grade 5) was noted after 38 (95%) of the 40 computer-assisted volumetric stereotactic OST procedures. Permanent postoperative hemiparesis (Glasgow Outcome Scale Grade 4) occurred after one procedure, and a second patient, despite being neurologically unchanged postoperatively and despite having had an optimal tumor resection, died on postoperative Day 33 (Glasgow Outcome Scale Grade 1). Complete resection of the preoperatively defined tumor volume was noted on postoperative gadolinium-enhanced magnetic resonance imaging examinations after 39 (97.5%) of the 40 procedures. The average duration of clinical follow-up was 15.9 months (range, 0.5-67 mo). CONCLUSION: We think that the OST approach is well suited to the resection of tumors in the posterior hippocampus and the parahippocampal gyrus. By allowing the neurosurgeon to avoid unnecessary brain resection and retraction, this approach reduces the risk of injury to important lateral temporal and occipital lobe cortex and tracts. In addition, the resection of a posterior hippocampus or parahippocampal gyrus mass with the OST approach relieves temporal horn entrapment. Computer-assisted volumetric stereotaxy helps the neurosurgeon to maintain precise spatial and anatomic orientation and accurately delineates the margin between the tumor and the surrounding neural tissue.

Adolescent↗

Tumors of Heschl's gyrus: report of two cases.

OBJECTIVE AND IMPORTANCE: The clinical presentation and treatment of patients with lesions involving Heschl's gyrus is reported. Intraoperative bipolar cortical stimulation mapping of Heschl's gyrus has not been previously reported. Only monopolar stimulation of this region (with potential electrical recruitment of large areas of surrounding cortex) has been undertaken. CLINICAL PRESENTATION: Two patients with intrinsic brain tumors located in Heschl's gyrus, in the hemisphere dominant for speech, presented with interictal or ictal auditory changes. INTERVENTION: Craniotomies were performed with the patients awake and with intraoperative bipolar cortical stimulation mapping of language cortex and of Heschl's gyrus. CONCLUSION: In contrast to previous studies using monopolar cortical stimulation, auditory changes were not elicited by stimulation. In one of the patients, a persistent interictal ringing sound stopped abruptly during lesion resection. Neither patient had essential temporal lobe language cortex near the lesion. Lesions in Heschl's gyrus can be identified by clinical presentation and magnetic resonance imaging. Based on topographic anatomy, cytoarchitecture, and functional mapping data, these lesions may be resectable without language or auditory mapping, although further experience will be necessary to confirm this observation.

Adult↗

Mesial temporal lobe epilepsy: a proton magnetic resonance spectroscopy study and a histopathological analysis.

OBJECT: Proton magnetic resonance (MR) spectroscopy imaging of the ratio of N-acetylaspartate (NAA) to creatine (Cr) has proved efficacious as a localizing tool in demonstrating the metabolic changes associated with temporal lobe epilepsy. To analyze the significance of these MR spectroscopy findings further, the authors explored the relationship between regional alterations in the NAA/Cr ratio in hippocampi measured preoperatively and histopathological findings in hippocampi resected in patients with intractable mesial temporal lobe epilepsy (MTLE). METHODS: Twelve patients in whom the diagnosis of MTLE had been made and 12 healthy volunteers with no known history of neurological disease underwent high-resolution 1H MR spectroscopy imaging of NAA and Cr (0.64 cm3 nominal voxel resolution) in five voxels spanning the anteroposterior length of the hippocampus. The authors correlated the NAA/Cr ratio with neuropathological findings in resected hippocampi, specifically glial fibrillary acidic protein (GFAP) immunoreactivity and pyramidal neuronal loss. A linear regression analysis of the ipsilateral NAA/Cr ratio revealed a statistically significant relation to the extent of hippocampal neuronal loss in only the CA2 sector (correlation coefficient [r] = -0.66, p < 0.03). The ipsilateral NAA/Cr ratio displayed significant regressions with GFAP immunoreactivity from all the CA sectors (r values ranged from -0.69 and p < 0.01 for the CA4 sector to -0.88 and p < 0.001 for the CA2 sector) except for the CA1. The extent of neuronal cell loss in every hippocampal subfield (r = 0.71-0.74, p < 0.007), except the CA2 (p = 0.08), correlated to the extent of neuronal cell loss in the dentate gyrus. There was no significant relationship between the duration or frequency of seizures and the mean ipsilateral NAA/Cr ratio; however, the mean density of GFAP-immunopositive cells correlated with seizure frequency (p < 0.03). CONCLUSIONS: The NAA/Cr ratio may not measure the full extent of hippocampal neuronal cell loss. The significant association of the NAA/Cr ratio with the GFAP immunoreactivity of most CA sectors indicates that the NAA/Cr ratio may provide a more accurate measurement of recent neuronal injury caused by epileptic activity. The coupling between neuronal impairment and astroglial GFAP expression may indicate the close association between neuronal and glial dysfunction in patients with epilepsy.

Adult↗

Cortical motion deafness.

The extent to which the auditory system, like the visual system, processes spatial stimulus characteristics such as location and motion in separate specialized neuronal modules or in one homogeneously distributed network is unresolved. Here we present a patient with a selective deficit for the perception and discrimination of auditory motion following resection of the right anterior temporal lobe and the right posterior superior temporal gyrus (STG). Analysis of stimulus identity and location within the auditory scene remained intact. In addition, intracranial auditory evoked potentials, recorded preoperatively, revealed motion-specific responses selectively over the resected right posterior STG, and electrical cortical stimulation of this region was experienced by the patient as incoming moving sounds. Collectively, these data present a patient with cortical motion deafness, providing evidence that cortical processing of auditory motion is performed in a specialized module within the posterior STG.

Acoustic Stimulation↗

Persistence of the typical spike-wave EEG pattern after surgical excision of a temporal lobe astrocytoma and apical lobectomy.

This is a report on a patient with intractable 'primary' generalized seizures and typical spike-wave EEG patterns, in whom an unexpected temporal lobe astrocytoma was detected by MRI studies. Clinical and electrophysiological studies were performed before and after surgical excision of the tumor and apical temporal lobectomy in an attempt to determine whether 'primary' generalized seizures and EEG patterns and the temporal lobe tumor were only coincident neurological disorders or were indeed related. Before resection, the patient consistently showed a typical spike-wave EEG pattern with no background and paroxysmal activities suggestive of 'secondary' bilateral synchrony in 10 consecutive conventional EEG recordings; neither spontaneous interictal nor ictal ECoG activities suggested focal temporal lobe epileptogenesis. After resection, the patient showed increased pentylenetetrazol (PTZ) convulsive threshold, and reduction in the number of 'primary' generalized seizures, although typical spike-wave EEG discharges persisted. These observations suggest that 'primary' generalized seizures, EEG patterns and the temporal tumor were physiopathologically interrelated, and that both reticulocortical and corticoreticular mechanisms may participate together in the genesis of 'primary' generalized clinical and EEG activities.

Adult↗

[Microscopic disorders of cortical development of the brain and its etiopathogenic importance for detection in patients with temporal epilepsy associated with hippocampal sclerosis].

Hippocampal sclerosis represents a common structural basis of temporal lobe epilepsy. However, the etiological factors and mechanisms leading to its development still remain unexplained. In our study, we present neuropathological findings in the resected hippocampus and the pole of the temporal lobe in 15 patients with hippocampal sclerosis. "Initial precipitating injuries" that are thought to cause the development of hippocampal sclerosis (febrile seizures in early childhood, head injury or meningoencephalitis) were present in the history of 12 patients. In the remaining 3 cases, no predisposing factors were found. Attention was paid to the histopathological identification of disturbed neuronal migration and differentiation in the temporal lobe. These defects were observed in 7 cases; in three of these, no predisposing factors were stated in the patients' histories. We suggest that in these cases, hippocampal sclerosis arises due to previously undetected disorders of cortical development. A latent neocortical malformation may also contribute to the development of hippocampal sclerosis in patients with an initial precipitating injury in anamnensis. Histopathological examination of resected epileptic brain tissue can provide insights into the individual pathogenesis of epileptic disorders, especially by the detection of microscopic disorders of cortical development.

Adolescent↗

Cerebral metastases in pleural mesothelioma: case report and review of the literature.

A case of malignant mesothelioma metastatic to the brain is described. A 52-year old woman, with no known exposure to asbestos, presented with a biphasic mesothelioma of the left parietal pleura. Following resection, the thorax was irradiated with 4000 cGy, and all symptoms subsided. Three months later, a left temporal lobe tumor was diagnosed and subsequently resected. Despite neurological improvement, she died 10 days post-operatively from constrictive pericardial disease. The authors have reviewed the 54 reported cases of brain metastases from mesothelioma and have noted that the histologic appearance of brain metastases from mesothelioma may be similar to glioblastoma multiforme. Because brain metastasis from mesothelioma is rare, procedures to clarify the nature of the tumor should be performed.

Brain Neoplasms↗