Development of robust discriminant equations for assessing subtypes of glioblastoma biopsies.

BACKGROUND: In the preceding decade, various studies on glioblastoma (Gb) demonstrated that signatures obtained from gene expression microarrays correlate better with survival than with histopathological classification. However, there is not a universal consensus formula to predict patient survival. METHODS: We developed a gene signature using the expression profile of 47 Gbs through an unsupervised procedure and two groups were obtained. Subsequent to a training procedure through leave-one-out cross-validation, we fitted a discriminant (linear discriminant analysis (LDA)) equation using the four most discriminant probesets. This was repeated for two other published signatures and the performance of LDA equations was evaluated on an independent test set, which contained status of IDH1 mutation, EGFR amplification, MGMT methylation and gene VEGF expression, among other clinical and molecular information. RESULTS: The unsupervised local signature was composed of 69 probesets and clearly defined two Gb groups, which would agree with primary and secondary Gbs. This hypothesis was confirmed by predicting cases from the independent data set using the equations developed by us. The high survival group predicted by equations based on our local and one of the published signatures contained a significantly higher percentage of cases displaying IDH1 mutation and non-amplification of EGFR. In contrast, only the equation based on the published signature showed in the poor survival group a significant high percentage of cases displaying a hypothesised methylation of MGMT gene promoter and overexpression of gene VEGF. CONCLUSION: We have produced a robust equation to confidently discriminate Gb subtypes based in the normalised expression level of only four genes.

[Intraoperative identification of the supplementary motor area in neurooncological surgery]. / Identificación intraoperatoria del área motora suplentaria en cirugía neurooncológica.

OBJECTIVES: The main objective of the present work was to identify, by means of intraoperative electrical stimulation, the supplementary motor area (SMA) region which is implicated in complex motor function. The functional prognostic relevance of the surgical preservation of this area was also analyzed. METHOD: Fifteen patients with tumors infiltrating the premotor cortex were selected. All patients were operated under awake conditions. Primary motor cortex was identified with intraoperative electrical stimulation (IES). To identify the SMA, patients were asked to do a finger opposition motor task with their hand contralateral to the lesion, that was blocked by electrically stimulating the premotor cerebral cortex. RESULTS: SMA was identified in all patients with IES. Complete surgical resection was achieved in 13 patients (86.6%) and subtotal in 2 patients (13.3%). SMA function was preserved in 14 patients (93.3%). In only one patient the SMA was partially resected because of tumor infiltration (6.6%). In the immediate postoperative period, 8 patients (53.3%) did not show changes in comparison to their preoperative clinical status, and 2 patients improved. At 6 months follow up, 5 patients (33.3%) were asymptomatic and 10 patients showed permanent deficits. In this last group, five patients (33.3%) showed mild deficits that did not interfere with a normal life. In the other 5 patients (33.3%), permanent deficits interfered with daily life activities: two patients presented severe hemiparesis 3/5 (same similar to their preoperative status with no improvement), one patient had motor aphasia, and two other patients (13.3%) showed permanent left SMA syndrome. In two patients with severe postoperative hemiparesis, tumor infiltration of primary motor cortex and piramidal pathway was observed; severe preoperative motor deficit (KPS <70) was associated with poor functional outcome. CONCLUSIONS: Intraoperative electrical cortical stimulation is useful to identify the SMA. Once identified, SMA preservation decreases the risk of postoperative symptoms and permanent SMA syndrome. When SMA is infiltrated by the tumor, radical resection may cause permanent neurological deficits, specially in the dominant hemisphere. Severe preoperative motor deficit was associated with poor outcome.

Intracranial meningiomatosis causing foster kennedy syndrome by unilateral optic nerve compression and blockage of the superior sagittal sinus.

The original description of the Foster Kennedy syndrome included the clinical triad of optic disc pallor in one eye, optic disc edema in the other eye, and reduced olfaction caused by space-occupying anterior fossa masses. The optic disc pallor was attributed to direct compression of the intracranial optic nerve, the optic disc edema to increased intracranial pressure from mass effect, and the reduced olfaction to direct compression of the olfactory nerve. We report a patient with the ophthalmic features of the Foster Kennedy syndrome from meningiomatosis. A meningioma compressed one optic nerve to cause impaired visual function. Convexity meningiomas compressed the superior sagittal sinus to impair cerebral venous drainage, increased intracranial pressure, and papilledema in the other eye. This is the first report of the Foster Kennedy syndrome caused by this mechanism.

Fibrinolytic therapy in spontaneous intraventricular haemorrhage: efficacy and safety of the treatment.

Intraventricular haemorrhage (IVH) is associated with a poor outcome. Simple external ventricular drainage has not modified the high morbidity and mortality of these patients. Our objective was to review our experience using intraventricular urokinase (UK) in treating patients with moderate to severe IVH. Prospective analysis of medical records of 14 patients diagnosed with spontaneous IVH who received ventriculostomy and intraventricular infusion of UK from January 2002 to December 2005. Patients with the following characteristics were included: 18-70 years of age, GCS between 5 and 14, and moderate to severe IVH (Graeb > or = 6) without simultaneous intraparenchymal haematoma > 30 ml. The final results were compared to historic control group (14 patients) treated between January 1999 to December 2001 with ventriculostomy alone. All 28 patients accomplished the inclusion criteria. Patient age, initial GCS and Graeb classification of IVH were similar in the two groups of treatment. There was higher ventriculostomy obstruction rate in the non-UK group (33.3 vs. 0%; p > 0.05), a higher rate of intracranial hypertension in the non-UK group (66.6 vs. 16.6%; p = 0.036) and a lower mortality rate in the UK group (25 vs. 58.3%, p > 0.05). There was no rebleeding associated with UK treatment. Intraventricular UK appears to be a safe treatment. It is effective in the prevention of catheter blockage, speeding the clearance of IVH, and it is associated with lower rate of intracranial hypertension and death.

[Complications of craniofacial resection in anterior skull base tumors]. / Complicaciones de la cirugía craneofacial en tumores de base craneal anterior

INTRODUCTION: The development of new radiographic techniques and the refinement of microsurgery and reconstructive surgery have been the responsible of the establishment of craniofacial resection (CFR) as the standard treatment of anterior skull base tumors. Overall complication rates varies from 24-56%, according to a review of recently published series. OBJECTIVES: To describe the complications of CFR in a series of 41 patients and to analyze the management and final outcome. MATERIAL AND METHODS: From 1990 to 2002, 41 patients underwent CFR for tumors involving the anterior cranial base. The extent of the tumor was always assessed with craniofacial CT-scan and MRI. The objective of the surgical treatment was to achieve "on block" removal of the tumor. RESULTS: The average age was 57 years with a male preponderance (63.4%). Squamous cell carcinoma was the most frequent histopathological type of tumor. The tumors were localized in paranasal sinuses in 78% of the cases. Bifrontal craniotomy was performed in 85.4% and unilateral orbitofrontal craniotomy in 14.6% of the cases. The area of facial resection included: ethmoidectomy (60.9%), ethmoido-sphenoidectomy (24.3%), maxillectomy (39%) and orbital exenteration (14.6%). The reconstruction of the floor of the anterior cranial fossa was performed using pedicled pericranial flap (100%), local (34.1%) or microvascular free flaps (21.9%) and split calvarian graft (19.5%). 20 patients (48.7%) developed post-operative complications, CSF leaks (12.1%) and meningitis (7.3%) being the most frequent major complications. The mortality rate was 7.3%. CONCLUSIONS: CFR has become the standard approach for anterior cranial base tumors. Despite its widespread application, the complication's rate ranges between 24-50% and the procedure carries a risk of significant morbidity and even mortality. Improvement of specific aspects of surgical technique and more refined reconstructive methods will decrease the number of complications.

Selective percutaneous thermocoagulation rhizotomy in essential glossopharyngeal neuralgia.

Percutaneous radiofrequency (rf) thermocoagulation of the inferior petrous ganglion of Andersch at the jugular foramen has been used to treat three patients with essential glossopharyngeal neuralgia. Two of these patients needed a second rf thermocoagulation, one within 1 week due to an incomplete result, and the other 8 months after the first procedure for recurrence of some neuralgic pain. Thus, a total of five rf thermocoagulations of the ganglion of Andersch have been performed. The patients are now pain-free and without significant side-effects. Deglutition and phonation have remained intact after each rf thermocoagulation. Glossopharyngeal selectivity was obtained by avoiding the risk of injury to the other nerves at the jugular foramen. The surgical technique involves precise x-ray control and constant monitoring of the blood pressure and electrocardiogram findings. Electrode misplacement of any spreading of current to the vagus nerve will be readily detected by bradycardia and hypotension during the physiological testing before a definite rf lesion takes place. This operative technique is described.

Pituitary apoplexy into nonadenomatous tissue: case report and review.

Pituitary apoplexy into nonadenomatous tissue is extremely rare. The authors describe a 20-year-old woman with symptomatic pituitary hemorrhage into an apparently intrasellar malignant teratoma, which caused headache, visual impairment, involvement of III, IV, VI, and 1st division of the V cranial nerves, and hypopituitarism. Diabetes insipidus had developed previously. Magnetic resonance scans had a high-intensity signal in the pituitary on T1- and T2-weighted images, and lack of the signal of the posterior pituitary. Transsphenoidal approach, radiotherapy, and chemotherapy management did not preclude a fatal outcome.

[Pituitary apoplexy: analysis of endocrine function in 17 cases]. / Apoplejía hipofisaria: análisis de la función endocrina en 17 casos.

BACKGROUND: From a neurological standpoint, pituitary apoplexy (PA) is a well defined syndrome. There are few systematic studies addressing pituitary hormone secretion after a PA episode. The aim of the present study was to assess the frequency and degree of endocrine dysfunction due to PA. METHODS: In 17 consecutive patients, the secretion of growth hormone (GH), the pituitary-adrenal axis status, thyrotropin (TSH), prolactin and gonadotropins (LH, FSH) were evaluated after the administration of insulin, thyrotropin releasing hormone (TRH) and gonadotropin-releasing hormone (LHRH) after an episode of PA. 20-90 days after surgery the measurements were repeated. Antidiuretic hormone (ADH) was measured by plasma/urine osmolality after water deprivation and, in some cases, by administration of hypertonic saline. RESULTS: The most commonly found deficiency was that of GH (84%), which in two cases resulted in cure of acromegaly, followed by that of LH (78%). Pituitary-adrenal dysfunction was improved in two patients after surgery. In all cases except one there was a reduced secretion of at least two hormones. If serum prolactin was reduced, the rest of pituitary function was usually impaired. In one case, permanent diabetes insipidus developed after PA. The prevalence of PA in pituitary adenomas was 9%. CONCLUSIONS: Pituitary hormone secretion after a PA episode is almost invariably impaired. This impairment may be reversed after surgery. Hypoprolactinemia is an indicator of pituitary hypofunction.

[Intraoperative cortical mapping in the surgical resection of low-grade gliomas located in eloquent areas]. / Estimulación cortical intraoperatoria en el tratamiento quirúrgico de los gliomas de bajo grado situados en áreas elocuentes.

INTRODUCTION: Surgical selection of patients harboring low-grade gliomas based on radiological criteria may be insufficient due to individual variability in eloquent areas location and to the fact that function can be preserved within infiltrated brain tissue. Brain stimulation mapping safety for patients with low-grade gliomas is evaluated, analyzing whether this technique modifies the extent of resection and minimizes postoperative deficits. MATERIAL AND METHODS: Twenty-five patients with lowgrade gliomas (II/IV WHO) located in eloquent areas underwent tumor resection with the aid of intraoperative mapping. Patients underwent surgery under local or general anesthesia depending on the neurological function to be explored. All procedures were performed from an oncological point of view, trying to achieve a radical tumor resection but stopping removal whenever functional tissue was found within or near the lesion. RESULTS: Total or subtotal resection was achieved in 16 patients (64%); in five cases (20%) resection was partial, and in the remaining (16%) only a biopsy was obtained. Tumors located in the supplementary motor area (SMA) or in the operculum were those which could be more often totally resected. Thirteen patients (52%) experienced neurological worsening immediately after surgery but eight of them had almost completely recovered six months after the procedure. CONCLUSIONS: Intraoperative functional mapping can optimize extent of resection minimizing permanent morbidity. Functional tissue can be found within the infiltrated brain and this must be considered in the presurgical planning. SMA and opercular tumors allow radical resection with low morbidity whereas insular tumors remain a challenge even with the aid of this technique.

[Spinal epidural hematomas. Prognostic factors in a series of 22 cases and a proposal for management]. / Revisión de 22 casos de hematomas epidurales espinales. Factores pronósticos y manejo terapéutico.

INTRODUCTION: Spontaneous and non-spontaneous spinal epidural hematoma (SEH) is a rare condition in neurosurgical practice. It presents as an acute spinal cord compression and usually requires emergent surgical decompression. Recently non-surgical treatment (corticoid therapy) has been proposed in selected cases of SEH with good neurological recovery. OBJECTIVES: To identify the prognostic factors of this condition. A treatment management based upon our results is proposed. MATERIAL AND METHODS: Between 1985 and 2001, 22 patients suffering SEH were treated at our Department. Age, sex, initial neurological condition (evaluated using the Frankel grading scale), surgical timing, radiological data such as location, extension and degree of radiological cord compression, anticoagulation or antiplatelet therapy, epidural anesthesia and previous spinal surgery were analyzed in order to find prognostic factors. Finally, conservative or surgical treatment as well as final neurological condition were also considered for the analysis. RESULTS: The average age was 69 years with a male preponderance (72.7%). Surgical decompression was done in 17 cases, most of them (11 cases) presenting with high neurological deficit (Frankel A-B). Conservative treatment was used on 5 patients. Operated patients showed a larger degree of neurological recovery. The incidence of post-operative complications was of 13%. CONCLUSIONS: This study shows the efficiency of SEH surgical evacuation performed within the first 24 hours, particularly when the patient presents a severe neurological deficit (Frankel A-B). Patients presenting minimal neurological involvement (Frankel D-E) can be managed successfully with conservative treatment.

[Cushing's disease in the 90's: a review]. / La enfermedad de Cushing en los años 90. Una revisión.

Since 1932 when Cushing's disease has been described, several important advances have been made in diagnosis and management. However several points remain obscure and there is no general agreement among authors. An accurate biological diagnosis is one of the difficulties found when we face a patient with hypercortisolism. In addition, corticotropin dependent syndrome should be distinguished from the independent one, as well as identifying the source of ACTH hypersecretion. The main problem in Cushing's disease is to localise the secreting adenoma and at the moment there is not any diagnostic method with absolute sensibility and specificity. Magnetic Resonance Imaging shows a sensibility of 77% and 87% especificity; inferior petrosal sinus sampling may help in localising the side, where the adenoma lies, although an appropriate technique is mandatory. New developing techniques, such as intraoperative doppler and assessment of ACTH levels in the peripituitary veins may help us in localising the source of ACTH hypersecretion. Sometimes the adenoma cannot be identified and a surgical exploration of the pituitary is required. If an adenoma is found, a 89% probility of curation has been reported; on the contrary, incomplete tumor removal, no tumor found at surgery, or the presence of the so-called corticotrop hyperplasia where followed of bad results and may explain the failed surgery. Then, hypofisectomy, hemi-hypofisectomy, radiotherapy, photon knife or gamma knife, may be of help in the control of this condition. We reviewed the recent literature and analysed the diagnostic strategies and teatments currently available for this illness. In addition we propose an algohritm for diagnosis and treatment and analyze our results in a consecutive series of 38 patients.

[Assessment of prognosis factors in the cure of Cushing's disease surgically treated via a +septotransphenoidal approach]. / Evaluación de los factores pronósticos en la curación de la enfermedad de Cushing intervenida por vía septotransesfenoidal.

INTRODUCTION: In Cushing's disease (CD) pituitary surgery or radiotherapy has been proposed by some authors, when plasmatic cortisol after surgery is not clearly low. AIM: To assess if the different prognostic factors, specially plasmatic cortisol seven days after surgery and/or hypocortisolism phase are predictive of the CD outcome. METHODS: From 1988, 11 women with CD underwent 13 transsphenoidal microsurgery, because two patients relapsed. The mean age of patients was 27 years (11-52). Plasmatic cortisol was measured seven days after pituitary surgery, and since 45 days, every three-six months, basal plasmatic cortisol and after ACTH and urinary free cortisol were determined. RESULTS: Follow-up evaluations ranged from 18-84 months (median, 38 months). After pituitary surgery in 13 cases the cumulative remission was 100%, two cases relapsed. In 10 cases plasmatic cortisol seven days after surgery was less than 137 nmol/l and in three cases higher than 137 nmol/l. Three cases did not presented hypocortisolism phase. The two patients who relapsed, one was after eight months of pituitary surgery an previously showed low plasmatic cortisol and the other relapse 25 months after pituitary surgery without low cortisol plasmatic levels. CONCLUSION: Remission in CD can happen either low or normal plasmatic cortisol levels seven days posttreatment or without hypocortisolism phase. Ours findings ascribe new importance to the different presentations after treatment of CD, and patients with these findings are not a risk for relapse and pituitary surgery or irradiation would not be early indicated.

Intrasurgical mapping of complex motor function in the superior frontal gyrus.

A lesion to the superior frontal gyrus (SFG) has been associated with long-lasting deficits in complex motor functions. The aim of this study was to analyze the functional role of the SFG by means of electrical cortical stimulation. Direct intraoperative electrical stimulation was used in a group of 21 subjects with lesions within or close to the SFG while they performed three motor tasks that require high skills or bimanual synergy. The results were compared to functional magnetic resonance imaging (fMRI). Ninety-four of the 98 (94.9%) labels identified were located on the convexity surface of the SFG and only four (4.1%) labels were located on the middle surface of the SFG. Areas of blockage of the three tasks were identified in six of the 12 (50%) hemispheres with lesions that had infiltrated the SFG, compared to all 10 of the 10 hemispheres (100%) with lesions that spared the SFG. The difference between these two proportions was statistically significant (P=0.015). fMRI activation was mainly located on the medial aspect of the SFG. We show that the convexity surface of the SFG has an important role in bilateral control of complex movements and in bimanual coordination. The infiltration of the posterior part of the SFG by a lesion disturbs some of the complex hand motor functions, which may be assumed by the contralesional homologous area. Finally, the current study emphasizes the discrepancies between fMRI and intraoperative electrical stimulation maps in complex hand motor function.

Proton MR spectroscopy provides relevant prognostic information in high-grade astrocytomas.

BACKGROUND AND PURPOSE: There is a large range of survival times in patients with HGA that can only be partially explained by histologic grade and clinical aspects. This study aims to retrospectively assess the predictive value of single-voxel (1)H-MRS regarding survival in HGA. MATERIALS AND METHODS: Pretreatment (1)H-MRS in 187 patients with HGA produced 180 spectra at STE (30 ms) and 182 at LTE (136 ms). Patients were dichotomized into 2 groups according to survival better or worse than the median. The spectra of the 2 groups were compared using the Mann-Whitney U test. The points on the spectrum with the most significant differences were selected for discriminating patients with good and poor prognosis. Thresholds were defined with ROC curves, and survival was analyzed by using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Four points on the spectrum showed the most significant differences: 0.98 and 3.67 ppm at STE; and 0.98 and 1.25 ppm at LTE (P between <.001 and .011). These points were useful for stratifying 2 prognostic groups (P between <.001 and .003, Kaplan-Meier). The Cox forward stepwise model selected 3 spectroscopic variables: the intensity values of the points 3.67 ppm at STE (hazard ratio, 2.132; 95% CI, 1.504-3.023), 0.98 ppm at LTE (hazard ratio, 0.499; 95% CI, 0.339-0.736), and 1.25 ppm at LTE (hazard ratio, 0.574; 95% CI, 0.368-0.897). CONCLUSIONS: (1)H-MRS is of value in predicting the length of survival in patients with HGA and could be used to stratify prognostic groups.

Non-invasive grading of astrocytic tumours from the relative contents of myo-inositol and glycine measured by in vivo MRS.

MRI and MRS are established methodologies for evaluating intracranial lesions. One MR spectral feature suggested for in vivo grading of astrocytic tumours is the apparent myo-lnositol (ml) intensity (ca 3.55 ppm) at short echo times, although glycine (gly) may also contribute in vivo to this resonance. The purpose of this study was to quantitatively evaluate the ml + gly contribution to the recorded spectral pattern in vivo and correlate it with in vitro data obtained from perchloric acid extraction of tumour biopsies. Patient spectra (n = 95) at 1.5T at short (20-31 ms) and long (135-136 ms) echo times were obtained from the INTERPRET MRS database (http://gabrmn.uab.eslinterpretvalidateddbl). Phantom spectra were acquired with a comparable protocol. Spectra were automatically processed and the ratios of the (ml + gly) to Cr peak heights ((ml + gly)/Cr) calculated. Perchloric acid extracts of brain tumour biopsies were analysed by high-resolution NMR at 9.4T. The ratio (ml + gly)/Cr decreased significantly with astrocytic grade in vivo between low-grade astrocytoma (A2) and glioblastoma multiforme (GBM). In vitro results displayed a somewhat different tendency, with anaplastic astrocytomas having significantly higher (ml + gly)/Cr than A2 and GBM. The discrepancy between in vivo and in vitro data suggests that the NMR visibility of glycine in glial brain tumours is restricted in vivo.

Early post-operative ACTH and cortisol as predictors of remission in Cushing's disease.

AIM: To study the value of early (24 h) post-operative ACTH and serum cortisol as predictors of remission after transsphenoidal surgery in Cushing's disease. METHODS: We prospectively studied 44 patients who underwent transsphenoidal surgery for Cushing's disease between 1997 and 2005. The mean follow-up period of patients after surgery was 49 months (19-102 months). The predictive value of clinical characteristics, pre-operative hormonal studies, radiological, surgical and histological findings, and post-operative hormonal studies were analysed. For the post-operative hormonal study plasma ACTH and serum cortisol were determined at 8.00 a.m. the day after surgery. RESULTS: After surgery, Cushing's disease remitted in 39 patients (89%) and persisted in 5 patients (11%). Three patients relapsed during the follow-up period. Only three study variables were predictive of persistence of Cushing's disease after surgery: the non identification of the adenoma in histology (an adenoma was found in 87% of the patients in remission, and in 20% of treatment failures, p = 0.01), the early post-operative plasma ACTH (patients in remission: 2 pmol/L (1.1-10.8 pmol/L), treatment failures: 8.2 pmol/L (1.1-12 pmol/L), p = 0.019), and the early post-operative serum cortisol (patients in remission: 128.4 nmol/L (27.6-4644 nmol/L), treatment failures: 797 nmol/L (606-1037 nmol/L), p = 0.003). ROC curves indicated that plasma ACTH < or = 7.55 pmol/L distinguished patients in remission from treatment failures with 80% sensitivity and 97.4% specificity, and serum cortisol < or = 585 nmol/L with 100% sensitivity and 90% specificity. CONCLUSIONS: Twenty-four hours after transsesphenoidal surgery for Cushing's disease, and without glucocorticoids replacement, patients with serum cortisol concentrations higher than 585 nmol/L, and/or plasma ACTH higher than 7.55 pmol/L, and/or those in which an adenoma is not identified in the histological study, have a high risk of treatment failure.

Intracranial retrograde dissemination in filum terminale myxopapillary ependymomas.

Myxopapillary ependymomas (ME) are considered benign tumours (WHO grade I) of the central nervous system with long term survival rates and a tendency to local recurrence. However an aggressive course has occasionally been described, leading to CSF dissemination and even systemic metastases. We describe the case of a 23-year-old man diagnosed with intracranial subarachnoid dissemination of a filum terminale ME three years after the initial diagnosis. We have performed a careful review of the literature on CSF dissemination in ME and finally propose treatment of these cases.

Imaging of giant pituitary adenomas.

We present five proven giant pituitary adenomas studied by CT and MRI, and review the clinical and imaging findings. Our aim was to examine the radiologic appearances and to search for criteria useful in distinguishing these tumors from other sellar and suprasellar tumours, mainly craniopharyngioma. The main differences from small adenomas were high prevalence of macrocysts, a more invasive behaviour and a clinical picture dominated by mass effect rather than endocrine disturbance. Factors supporting the diagnosis of pituitary adenoma in a giant intra- and suprasellar mass include: infrasellar extension, absence of calcification and presence of low-signal cysts on T1-weighted images.