Hélio Rubens Machado

MicroRNAs Differentially Expressed in ACTH-Secreting Pituitary Tumors

CONTEXT MicroRNAs (miRNAs) are small noncoding RNAs, functioning as antisense regulators of gene expression by targeting mRNA and contributing to cancer development and progression. More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites of the genome. OBJECTIVE The aim of the study was to analyze the differential expression of let-7a, miR-15a, miR-16, miR-21, miR-141, miR-143, miR-145, and miR-150 in corticotropinomas and normal pituitary tissue and verify whether their profile of expression correlates with tumor size or remission after treatment. MATERIAL AND METHODS ACTH-secreting pituitary tumor samples were obtained during transphenoidal surgery from patients with Cushing disease and normal pituitary tissues from autopsies. The relative expression of miRNAs was measured by real-time PCR using RNU44 and RNU49 as endogenous controls. Relative quantification of miRNA expression was calculated using the 2(-DeltaDeltaCt) method. RESULTS We found underexpression of miR-145 (2.0-fold; P = 0.04), miR-21 (2.4-fold; P = 0.004), miR-141 (2.6-fold; P = 0.02), let-7a (3.3-fold; P = 0.003), miR-150 (3.8-fold; P = 0.04), miR-15a (4.5-fold; P = 0.03), miR-16 (5.0-fold; P = 0.004), and miR-143 (6.4-fold; P = 0.004) in ACTH-secreting pituitary tumors when compared to normal pituitary tissues. There were no differences between miRNA expression and tumor size as well as miRNA expression and ratio of remission after surgery, except in patients presenting lower miR-141 expression who showed a better chance of remission. CONCLUSION Our results support the possibility that altered miRNA expression profile might be involved in corticotrophic tumorigenesis. However, the lack of knowledge about miRNA target genes postpones full understanding of the biological functions of down-regulated or up-regulated miRNAs in corticotropinomas.

Seizure outcome after surgery for epilepsy due to focal cortical dysplastic lesions

Neocortical development is a highly complex process encompassing cellular proliferation, neuronal migration and cortical organization. At any time this process can be interrupted or modified by genetic or acquired factors causing malformations of cortical development (MCD). Epileptic seizures are the most common type of clinical manifestation, besides developmental delay and focal neurological deficits. Seizures due to MCD are frequently pharmacoresistant, especially those associated to focal cortical dysplasia (FCD). Surgical therapy results have been reported since 1971, however, currently available data from surgical series are still limited, mainly due to small number of patients, distinct selection of candidates and surgical strategies, variable pathological diagnosis and inadequate follow-up. This study addresses the possibilities of seizure relief following resection of focal cortical dysplasia, and the impact of presurgical evaluation, extent of resection and pathological findings on surgical outcome. We included 41 patients, 22 adults and 19 children and adolescents, with medically intractable seizures operated on from 1996 to 2002. All were submitted to standardized presurgical evaluation including high-resolution MRI, Video-EEG monitoring and ictal SPECT. Post-surgical seizure outcome was classified according to Engels schema. Univariate and multivariate analysis were performed. Fifteen patients had temporal and 26 extratemporal epilepsies. Of the total 26 patients (63.4%) reached seizure-free status post-operatively. There was no correlation between outcome and age at surgery, duration of epilepsy, frequency of seizures, and pathological findings. There was, however, a clear correlation with topography of FCD (temporal versus extratemporal) and regional ictal EEG onset, on univariate as well as multivariate analysis.

Volumetric Evidence of Bilateral Damage in Unilateral Mesial Temporal Lobe Epilepsy

Summary:  Purpose: We sought to analyze the contralateral volumes of the temporal pole, posterior segment of the temporal lobe, amygdala, hippocampus, and parahippocampal gyrus in patients with temporal lobe epilepsy (TLE) due to histologically proven mesial temporal lobe sclerosis (MTLS), seizure free for ≥4 years of postsurgical follow‐up.

Gelastic seizures treated by resection of a hypothalamic hamartoma

A 7-year-old girl presented for evaluation of a peculiar kind of epilepsy. Her seizures began before 1 year of age and consisted of episodes of brief, uncontrolled and unprovoked laughter than with time progressed to include cursive, complex partial and generalized tonic-clonic seizures. Progressive impairment of cognitive functions was noted as well as precocious puberty. Neuroimaging examination disclosed a hypothalamic hamartoma. It was excised by a pterional approach, and no further seizures were noted. The authors propose direct surgery for the hypothalamic hamartoma as a treatment for this progressive syndrome.

Clinical features of patients with posterior cortex epilepsies and predictors of surgical outcome

Summary:  Purpose: Posterior cortex epilepsies (PCEs) encompass a group of epilepsies originating from the occipital, parietal, or occipital border of the temporal lobe, or from any combination of these regions. When their seizures are refractory to pharmacologic treatment, these patients are usually referred for surgery. The aim of our study was to analyze clinical characteristics of all PCE patients referred for surgery from 1994 to 2003, and to search for predictors of surgical outcome.

Surgical outcome in mesial temporal sclerosis correlates with prion protein gene variant.

Background: Mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) is the most common surgically remediable epileptic syndrome. Ablation of the cellular prion protein (PrPc) gene (PRNP) enhances neuronal excitability of the hippocampus in vitro and sensitivity to seizure in vivo, indicating that PrPc might be related to epilepsy. Objective: To evaluate the genetic contribution of PRNP to MTLE-HS. Methods: The PRNP coding sequence of DNA from peripheral blood cells of 100 consecutive patients with surgically treated MTLE-HS was compared to that from a group of healthy controls adjusted for sex, age, and ethnicity (n = 180). The presence of PRNP variant alleles was correlated with clinical and presurgical parameters as well as surgical outcome. Results: A variant allele at position 171 (Asn→Ser), absent in controls, was found in heterozygosis (Asn171Ser) in 23% of patients (p < 0.0001). The PRNP genotypes were not correlated with any clinical or presurgical data investigated. However, patients carrying the Asn171Ser variant had a five times higher chance of continuing to have seizures after temporal lobectomy (95% CI 1.65 to 17.33, p = 0.005) than those carrying the normal allele. At 18 months after surgery, 91.8% of patients with the normal allele at codon 171 were seizure free, in comparison to 68.2% of those carrying Asn171Ser (p = 0.005). Conclusions: The PRNP variant allele Asn171Ser is highly prevalent in patients with medically untreatable MTLE-HS and influences their surgical outcome. The results suggest that the PRNP variant allele at codon 171 (Asn171Ser) is associated with epileptogenesis in MTLE-HS.

Temporal lobe epilepsy surgery in children and adolescents: clinical characteristics and post-surgical outcome.

BACKGROUND AND PURPOSE Temporal lobe epilepsy (TLE) encompasses 10-20% of the cases of intractable epilepsy in pediatric patients. Mesial temporal sclerosis (MTS) can still be encountered in adolescent patients, but is rare in children under 5 years of age. In this paper we report on the surgical outcome of a series of TLE patients ranging in age from 1 to 18 years at the time of operation. PATIENTS AND METHODS Thirty-five patients (37 surgeries) with medically intractable TLE were operated upon between January 1996 and December 2002. The following variables were analyzed: age at surgery, age at epilepsy onset, history of an initial precipitating injury, etiology, seizure semiology, interictal and ictal EEG findings, surgical complications, and post-surgical seizure outcome. RESULTS There were 68.6% females and 31.3% males, and complex partial seizures (CPS) occurred in 86.5%. The most common etiology was MTS (40%) followed by isolated cortical developmental abnormalities (22.9%). In the age group up to 5 years, cortical development abnormalities predominated, and 71% of these children had multifocal interictal EEG. Patients older than 10 years had more frequently MTS (78.6%) and focal temporal interictal EEG abnormalities. Post-surgical seizure outcome showed that 88.5% of patients were in Engel classes I and II. CONCLUSIONS Adolescents with TLE had clinical features, electrographic findings, and seizure outcome similar to those observed in adult patients. However, younger children up to 5 years of age had distinct ictal semiology and different etiological, electrophysiological and outcome profiles, clearly suggesting that they behave as a special subgroup within the TLE.

Non-functioning pituitary adenomas: clinical feature, laboratorial and imaging assessment, therapeutic management and outcome

OBJECTIVE This study is an updated review of a Southeast Brazilian experience NFPA, emphasizing clinical features, laboratorial and imaging assessment, therapeutic management and outcome. DESIGN AND METHODS Retrospective study, in which 104 patients with NFPA were evaluated by the same team of endocrinologists and neurosurgeon. Patients underwent biochemical evaluation, radiological studies and visual field assessment. RESULTS Hypopituitarism and neuro-ophthalmological defects were observed in 89%. We observed GH deficiency (81.4%), hypogonadism (63.3%), adrenal hypofunction (59.5%), hypothyroidism (20.4%), high (38.5%) and low (16.7%) prolactin levels. Preoperative imaging classified 93% of the tumors as macroadenomas. Extra-sellar expansion was observed in 83.8%. Varying degrees of visual disturbance were observed in 74%. Primary treatment was transsphenoidal surgery (75%). Clinical control was achieved with one surgery in 37.5 % of patients. The majority of patients needed a second therapeutic approach, radiotherapy or other surgeries. Immunohistochemistry resulted negative for pituitary hormones in 43%. Improvement of neuro-ophthalmological symptoms was observed in 61% of the patients after treatment. CONCLUSIONS Our data confirm elevated prevalence of mass effect and hypopituitarism in patients harboring NFPA. Recurrence due to invasion or incomplete resection of the tumor is quite common, which frequently leads to a second therapeutic option.

Cysticercosis of the central nervous system: I. Surgical treatment of cerebral cysticercosis. A 23 years experience in the hospital das clínicas of Ribeirão Preto Medical School

Cysticercosis is the most frequent parasitosis of the nervous system and nowadays it is widespread through the world. Despite the development of anticysticercal drugs (praziquantel and albendazole), their efficacy is more marked in cases with parenchymal active cysts and they do not prevent complications such as hydrocephalus. Thus, many patients with neurocysticercosis require surgical intervention, generally of palliative nature, but that may occasionally produce a cure. The clinical outcome of 180 patients with cerebral cysticercosis who underwent surgical treatment form 1970 to 1993 was analyzed. Surgical treatment was performed to control increased ICP in 177 patients and due to local compression of cranial nerves or brainstem in five. Some patients had more than one surgical procedure, totalizing 287 interventions. Increased intracranial pressure (ICP) was caused by hydrocephalus in 91%, by intracranial mass lesion (tumoral form) in 6.2% and by pseudotumor cerebri (pseudotumoral form) in 2.8% of the case. Based on the pathophysiological mechanisms of intracranial hypertension identified through conventional CT-scan, ventriculography, cysternotomography, ventriculotomography and MRI, different surgical approaches were indicated. Patients with tumoral form were submitted to direct approach and cyst removal and generally they had benefits from this procedure. Patients with pseudotumoral form whose clinical treatment failure underwent decompressive craniectomies and had a poor outcome (40% of good results). Direct removal of ventricular/cisternal cysts and/or ventriculoatrial/peritoneal shunting (VA/VPS) was performed in patients with hydrocephalus. Removal of free ventricular cysts in patients who had no ependimitis/arachnoiditis generally allowed a good outcome. Patients with adherent cysts and inflammatory process needed a VA/VPS posteriorly and the outcome was not so good. One hundred thirty-two patients were submitted to VA/VPS (109 as the first procedure and 23 after another surgical treatment). The VA/VPS was effective to control increased ICP, despite many complications observed mainly during the two first postoperative years. After this period the surviving patients generally had a better outcome. The patients submitted to cyst removal due to local compression of cranial nerves/brainstem generally had good results. Based on the experience acquired with the management of these patients we present our recent policy for the treatment of patients with neurocisticercosis.

Surgically amenable epilepsies in children and adolescents: clinical, imaging, electrophysiological, and post-surgical outcome data

Background and purposeA large number of patients with epilepsy in the pediatric population have medically intractable epilepsy. In this age group seizures are usually daily or weekly, and response to antiepileptic therapy is poor, especially for those with neurological abnormalities and symptomatic epilepsies. However, several authors have already demonstrated similarly favorable long-term post-surgical seizure control when comparing pediatric and adult populations. In this article we aim to report the experience of the Ribeirão Preto Epilepsy Surgery Program in pediatric epilepsy surgery.Patients and methodsWe analyzed 107 patients with medically intractable epilepsy operated on between July 1994 and December 2002, considering age at surgery, seizure type, pathological findings, and seizure outcome. All data were prospectively collected according to protocols previously approved by the institution ethics committee.ResultsWe analyzed a total of 115 operations performed in 107 patients. There was no difference in sex distribution. Complex partial seizures occurred in 31.4% of the patients, followed by tonic seizures (25.9%), focal motor seizures (15.4%), and infantile spasms (13.3%). The most common etiologies were cortical developmental abnormalities (25.2%), tumors (16.8%), mesial temporal sclerosis (15.9%), Rasmussen syndrome (6.5%), and tuberous sclerosis (6.5%). Overall post-surgical seizure outcome showed 67.2% of the patients within Engel classes I and II, reaching 75.0% when patients with callosotomies were excluded.ConclusionsPost-surgical seizure control in the pediatric population is similar to that in adult patients, despite the fact that epilepsies in this age group are more frequently of extratemporal origin, suggesting that surgery should be considered in children as soon as intractability is determined.