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Hemispheric epilepsy is quite frequent in children, compared with adults, and encompasses pathological substrates as diverse as hemimegalencephaly, Rasmussen encephalitis, Sturge-Weber syndrome, and porencephaly, among others. These patients most often become pharmacoresistant and thus require surgical management. Although anatomical hemispherectomy is a possibility, the technique that is favored by most epilepsy surgery centers worldwide is functional hemispherotomy, which results in equivalent outcomes with fewer postoperative complications. Therefore, it is essential that pediatric epilepsy neurosurgeons become familiar with these techniques. The present video describes in detail all surgical aspects of the perisylvian hemispherotomy.
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We investigated the participation of the nucleus of the tractus solitarius (NTS) in tonicâclonic seizures and postictal antinociception control mediated by NMDA receptors, the role of NTS GABAergic interneurons and noradrenergic pathways from the locus coeruleus (LC) in these phenomena. The NTS-lateral nucleus reticularis paragigantocellularis (lPGi)-LC pathway was studied by evaluating neural tract tracer deposits in the lPGi. NMDA and GABAergic receptors agonists and antagonists were microinjected into the NTS, followed by pharmacologically induced seizures. The effects of LC neurotoxic lesions caused by DSP-4, followed by NTS-NMDA receptor activation, on both tonicâclonic seizures and postictal antinociception were also investigated. The NTS is connected to lPGi neurons that send outputs to the LC. Glutamatergic vesicles were found on dendrites and perikarya of GABAergic interneurons in the NTS. Both tonicâclonic seizures and postictal antinociception are partially dependent on glutamatergic-mediated neurotransmission in the NTS of seizing rats in addition to the integrity of the noradrenergic system since NMDA receptor blockade in the NTS and intrathecal administration of DSP-4 decrease the postictal antinociception. The GABAA receptor activation in the NTS decreases both seizure severity and postictal antinociception. These findings suggest that glutamatergic inputs to NTS-GABAergic interneurons, in addition to ascending and descending noradrenergic pathways from the LC, are critical for the control of both seizures and postictal antinociception.
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Bencilaminas , Locus Coeruleus , Receptores de N-Metil-D-Aspartato , Ratas , Animales , Locus Coeruleus/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Bulbo Raquídeo/metabolismo , Núcleo Solitario/metabolismo , Norepinefrina/metabolismo , Convulsiones/metabolismoRESUMEN
INTRODUCTION: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. OBJECTIVE: To identify methylation signatures in ACPs regarding clinical presentation and outcome. METHODS: Clinical and pathology data were collected from 35 ACP patients (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multi-dimensional scaling. Statistical associations between clusters and clinical features were achieved using Fisher's test and global biological process interpretations were aided by Gene Ontology enrichment analyses. RESULTS: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = 0.0006), hypomethylated in CpG Island (CGI), non-CGI sites, and globally (P < 0.001), and associated with greater tumor size (24.1 vs 9.5cm3, P = 0.04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell-adhesion, cytoskeleton organization, and cytokine binding, and also cell-type specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. CONCLUSION: Two clusters of ACP patients were consistently revealed by unsupervised machine learning methods, being one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.
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PURPOSE: Hydrocephalus is a brain disease prevalent in the pediatric population that presents complex pathophysiology and multiple etiologies. The best treatment is still ventricular shunting. Mechanical obstruction is the most frequent complication, but the resulting pathological effects are still unknown. OBJECTIVE: Evaluation and comparison of clinical, histopathological, and immunohistochemical aspects in the acute phase of experimental hydrocephalus induced by kaolin, after treatment with adapted shunt, and after shunt obstruction and posterior disobstruction. METHODS: Wistar rats aged 7 days were used and divided into 4 groups: control group without kaolin injection (n = 6), untreated hydrocephalic group (n = 5), hydrocephalic group treated with ventriculosubcutaneous shunt (DVSC) (n = 7), and hydrocephalic group treated with shunt, posteriorly obstructed and disobstructed (n = 5). The animals were submitted to memory and spatial learning evaluation through the Morris water maze test. The rats were sacrificed at 28 days of age and histological analysis of the brains was performed with luxol fast blue, in addition to immunohistochemical analysis in order to evaluate reactive astrocytosis, inflammation, neuronal labeling, and apoptotic activity. RESULTS: The group with shunt obstruction had worse performance in memory tests. Reactive astrocytosis was more evident in this group, as was the inflammatory response. CONCLUSIONS: Obstruction of the shunt results in impaired performance of behavioral tests and causes irreversible histopathological changes when compared to findings in the group with treated hydrocephalus, even after unblocking the system. The developed model is feasible and efficient in simulating the clinical context of shunt dysfunction.
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Hidrocefalia , Caolín , Niño , Humanos , Ratas , Animales , Ratas Wistar , Gliosis/patología , Hidrocefalia/cirugía , Encéfalo/patologíaRESUMEN
PURPOSE: Epilepsy surgery for pediatric drug-resistant epilepsy has been shown to improve seizure control, enhance patient and family QoL, and reduce mortality. However, diagnostic tools and surgical capacity are less accessible worldwide. The International Society Pediatric Neurosurgery (ISPN) has established a Pediatric Epilepsy Surgery Interest Group (PESIG), aiming to enhance global collaboration in research and educational aspects. The goals of this manuscript are to introduce PESIG and analyze geographical differences of epilepsy surgery and technology availability. METHODS: PESIG was established (2022) following an ISPN executive board decision. Using a standardized form, we surveyed the PESIG members, collecting and analyzing data regarding geographical distribution, and availability of various epilepsy treatment-related technologies. RESULTS: Two hundred eighty-two members registered in PESIG from 70 countries, over 6 continents, were included. We categorized the countries by GDP as follows: low, lower-medium, upper-medium, and high income. The most commonly available technology was vagus nerve stimulation 68%. Stereoelectroencephalography was available for 58%. North America had statistically significant greater availability compared to other continents. Europe had greater availability compared to Africa, Asia, and South (Latin) America. Asia had greater availability compared to Africa. High-income countries had statistically significant greater availability compared to other income groups; there was no significant difference between the other income-level subgroups. CONCLUSION: There is a clear discrepancy between countries and continents regarding access to epilepsy surgery technologies. This strengthens the need for collaboration between neurologists and neurosurgeons from around the world, to enhance medical education and training, as well as to increase technological availability.
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Epilepsia , Neurocirugia , Humanos , Niño , Neurocirugia/educación , Calidad de Vida , Opinión Pública , Procedimientos Neuroquirúrgicos , Epilepsia/cirugíaRESUMEN
OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. METHODS: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks. RESULTS: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality. SIGNIFICANCE: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.
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Epilepsia , Síndrome de Lennox-Gastaut , Estimulación del Nervio Vago , Niño , Masculino , Humanos , Lactante , Preescolar , Adolescente , Síndrome de Lennox-Gastaut/cirugía , Estudios Retrospectivos , Cuerpo Calloso/cirugía , Convulsiones/terapia , Síncope , Resultado del Tratamiento , Nervio VagoRESUMEN
The present article describes pathophysiological and clinical aspects of congenital malformations of the cerebral tissue (cortex and white matter) that cause epilepsy and very frequently require surgical treatment. A particular emphasis is given to focal cortical dysplasias, the most common pathology among these epilepsy-related malformations. Specific radiological and surgical features are also highlighted, so a thorough overview of cortical dysplasias is provided.
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Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Humanos , Malformaciones del Desarrollo Cortical/complicaciones , Epilepsia/etiología , Corteza Cerebral/diagnóstico por imagen , Imagen por Resonancia Magnética/efectos adversosRESUMEN
Hydrocephalus is a neurological condition with altered cerebrospinal fluid flow (CSF). The treatment is surgical and the most commonly used procedure is ventricle-peritoneal shunt. However, not all patients can undergo immediate surgery or achieve complete lesion reversal. Neuroprotective measures are valuable in such cases. It was evaluated whether the use of celecoxib, a selective inhibitor of COX-2, associated or not with ventricular-subcutaneous derivation, could offer benefits to the brain structures affected by experimental hydrocephalus. Seven-day-old male Wistar Hannover rats induced by intracisternal injection of kaolin 15% were used, divided into five groups with ten animals each: intact control (C), untreated hydrocephalus (H), hydrocephalus treated with celecoxib 20 mg/kg intraperitoneal (HTC), hydrocephalus treated with shunt (HTS) and hydrocephalus treated with shunt and celecoxib 20 mg/kg intraperitoneal (HTCS). Celecoxib was administered for 21 consecutive days, starting the day after hydrocephalus induction and continuing until the end of the experimental period. The surgery was performed seven days after inducing hydrocephalus. Multiple assessment methods were used, such as behavioral tests (water maze and open field), histological analysis (hematoxylin and eosin), immunohistochemistry (caspase-3, COX-2, and GFAP), and ELISA analysis of GFAP. The results of the behavioral and memory tests indicated that celecoxib improves the neurobehavioral response. The improvement can be attributed to the reduced neuroinflammation (p < 0.05), and astrogliosis (p < 0.05) in different brain regions. In conclusion, the results suggest that celecoxib holds great potential as an adjuvant neuroprotective drug for the treatment of experimental hydrocephalus.
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Gliosis , Hidrocefalia , Humanos , Ratas , Animales , Masculino , Ratas Wistar , Celecoxib/efectos adversos , Gliosis/tratamiento farmacológico , Gliosis/patología , Neuroprotección , Enfermedades Neuroinflamatorias , Ciclooxigenasa 2 , Hidrocefalia/tratamiento farmacológico , Hidrocefalia/patología , Inflamación/tratamiento farmacológicoRESUMEN
Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 µA, 100 Hz) applied for 15 s by deep brain stimulation (DBS) device 21 days after CCI. Either cobalt chloride (CoCl2 at 1.0 mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0 nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl2 administration in the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0 nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0 nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats.
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Hiperalgesia , Neuralgia , Ratas , Masculino , Animales , N-Metilaspartato/farmacología , Dimensión del Dolor , Ratas Wistar , Neuralgia/terapia , Receptores de N-Metil-D-Aspartato/metabolismo , Corteza Prefrontal/metabolismoRESUMEN
OBJECTIVE: Rasmussen Encephalitis (RE) is a rare inflammatory neurodegenerative disease associated with refractory seizures, hemiparesis, and cognitive deterioration, due to lateralized cortical atrophy. Hemispheric surgery (hemispherotomy) is the mainstay of treatment, but its unavoidable motor deficits and lack of long-term data regarding seizure outcomes can make patients and families apprehensive to undergo this procedure. The present study aimed at analyzing the results of surgical treatment for RE from a motor and epilepsy standpoint, and mitigate such concerns. METHODS: Clinical and operative data were retrospectively collected from medical records of pharmacoresistant patients treated with functional hemispherectomy at a tertiary reference center for epilepsy surgery, during a 24-year period (1996-2020). Variables such as age of epilepsy onset, seizure semiology, seizure frequency, immunomodulatory therapy, age at surgery, duration of epilepsy, surgical procedures and complications, number of medications used preoperatively and postoperatively were described and statistically analyzed. RESULTS: Forty-three (43) patients were included in this study. Mean age of epilepsy onset was 6.14 years, the average interval between epilepsy onset and hemispherotomy was 2.21 years. and the mean age at surgery was 8.28 years. Thirty patients (69.7%) were Engel I at their last follow-up, of whom 23 (56.4%) were Engel Ia, within a mean follow-up of 11.3 years. Duration of epilepsy, seizure frequency, and age at surgery, among others, did not correlate with seizure outcome, except the use of immunotherapy which led to worse outcomes (p < .05). Also, after surgery, motor functionality was significantly recovered (i.e., most patients returned to their previous status) with time. SIGNIFICANCE: This study tackled some issues regarding the surgical treatment of this disease, particularly showing that hemispherotomy is safe and leads to potentially recoverable disability of motor functions while providing high rates of effective and long-lasting seizure control; therefore, early surgical indication should be warranted once medical refractoriness has been established.
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Encefalitis , Epilepsia , Hemisferectomía , Enfermedades Neurodegenerativas , Niño , Humanos , Resultado del Tratamiento , Estudios Retrospectivos , Enfermedades Neurodegenerativas/complicaciones , Convulsiones/cirugía , Convulsiones/complicaciones , Hemisferectomía/efectos adversos , Encefalitis/complicacionesRESUMEN
Groups (Grp) 3 and 4 are aggressive molecular subgroups of medulloblastoma (MB), with high rates of leptomeningeal dissemination. To date, there is still a paucity of biomarkers for these subtypes of MBs. In this study, we investigated the clinical significance and biological functions of Musashi-1 (MSI1) in Grp3 and Grp4-MBs. First, we assessed the expression profile of MSI1 in 59 primary MB samples (15-WNT, 18-SHH, 9-Grp3, and 17-Grp4 subgroups) by qRT-PCR. MSI1 mRNA expression levels were also validated in an additional public dataset of MBs (GSE85217). The ROC curve was used to validate the diagnostic standards of MSI1 expression. Next, the potential correlated cell-cycle genes were measured by RNA-Seq. Cell cycle, cell viability, and apoptosis were evaluated in a Grp3/Grp4 MB cell line after knockdown of MSI1 and cisplatin treatment. We identified an overexpression of MSI1 with a high accuracy to discriminate Grp3/Grp4-MBs from non-Grp3/Grp4-MBs. We identified that MSI1 knockdown not only triggered transcriptional changes in the cell-cycle pathway, but also affected G2/M phase in vitro, supporting the role of knockdown of MSI1 in cell-cycle arrest. Finally, MSI1 knockdown decreased cell viability and sensitized D283-Med cells to cisplatin treatment by enhancing cell apoptosis. Based on these findings, we suggest that MSI1 modulates cell-cycle progression and may play a role as biomarker for Grp3/Grp4-MBs. In addition, MSI1 knockdown combined with cisplatin may offer a potential strategy to be further explored in Grp3/Grp4-MBs.
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OBJECTIVE: People with epilepsy are at an increased risk of experiencing executive dysfunction, particularly those with frontal lobe epilepsy (FLE). The literature has also demonstrated alterations in executive functioning (EF) in patients with temporal lobe epilepsy (TLE). However, few studies have examined the neuropsychological profile of posterior cortex epilepsy (PCE), and little attention has been given to cognitive impairments in the pediatric population with PCE. This study aims to investigate EF performance in children with drug-resistant PCE compared to patients with FLE and TLE. METHODS: We analyzed neuropsychological data from 217 patients aged 6-18 years who underwent preoperative evaluation for epilepsy surgery. The EF of patients with PCE was compared to patients with FLE and TLE. RESULTS: There was no significant difference in Full-Scale Intelligence Quotient (FSIQ) means between groups. However, we found a significant effect of brain region on the Coding task, in which patients with PCE and FLE performed worse than those with TLE (p = 0.034). We also observed performance differences between groups on the Stroop test (p = 0.005), with patients with PCE and FLE performing worse than the TLE group. SIGNIFICANCE: These findings suggest that children with PCE have alterations in their EF that are similar to the deficits found in FLE compared to patients with TLE. This emphasizes the importance of understanding the neuroanatomy of executive functions and the model of neural networks extending beyond the prefrontal cortex.
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Epilepsia del Lóbulo Frontal , Epilepsia del Lóbulo Temporal , Humanos , Niño , Función Ejecutiva , Pruebas Neuropsicológicas , Encéfalo , Lóbulo FrontalRESUMEN
ABSTRACT: A 15-year-old adolescent boy with left body epilepsia partialis continua, hemiparesis, and electroencephalogram abnormalities lateralized to the right hemisphere. MRI finding was small hyperintense signal in the left putamen. 18F-FDG PET showed focal glucose hypermetabolism in the right paracentral lobule and hypometabolism in the inferior right frontal and precentral gyri. One month later, a new MRI showed a hyperintense signal over the paracentral lobule. Biopsy on this region confirmed the diagnosis of Rasmussen encephalitis. This patient finally underwent right hemispherotomy and became seizure free. This case emphasize the PET as an important early tool for the diagnosis of Rasmussen encephalitis.
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Encefalitis , Fluorodesoxiglucosa F18 , Masculino , Adolescente , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encefalitis/complicaciones , Encefalitis/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVE: To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. METHODS: In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo. RESULTS: Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs). CONCLUSION: This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.
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Adenoma Hipofisario Secretor de ACTH , Adenoma , Neoplasias Hipofisarias , Humanos , Femenino , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Masculino , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Adenoma/genética , Adenoma/patología , Epigenoma , Transcriptoma , Estudios Retrospectivos , Estudios Transversales , Adenoma Hipofisario Secretor de ACTH/genética , Hormona Adrenocorticotrópica/genéticaRESUMEN
BACKGROUND AND AIMS: The dysgranula parts of the posterior insular cortex (PIC) stimulation (PICS) has been investigated as a new putative cortical target for nonpharmacologic therapies in patients with chronic and neuropathic pain (NP). This work investigates the neural bases of insula neurostimulation-induced antinociception and glutamatergic neurochemical mechanisms recruited by the PICS in animals with neuropathy. MATERIALS AND METHODS: Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham procedure ("false operated"). Either the Cascade Blue 3000 MW lysine-fixable dextran (CBD) or the biotinylated dextran amine 3000 MW (BDA) neural tract tracer was microinjected into the PIC. The electrical PICS was performed at a low frequency (20 µA, 100 Hz) for 15 seconds by a deep brain stimulation device. PIC N-methyl-D-aspartate (NMDA) receptors (NMDAR) blockade with the selective antagonist LY235959 (at 2, 4, and 8 nmol/200 nL) followed by PICS was investigated in rats with CCI. RESULTS: PIC sends projections to the caudal pontine reticular nucleus, alpha part of the parvicellular reticular nucleus, dorsomedial tegmental area, and secondary somatosensory cortex (S2). PICS decreased both mechanical and cold allodynia in rats with chronic NP. Blockade of NMDAR in the PIC with LY235959 at 8 nmol attenuated PICS-produced antinociception. CONCLUSION: Neuroanatomic projections from the PIC to pontine reticular nuclei and S2 may contribute to chronic NP signaling. PICS attenuates the chronic NP, and the NMDA glutamatergic system in the PIC may be involved in PICS-induced antinociception in rodents with NP conditions.
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N-Metilaspartato , Neuralgia , Humanos , Ratas , Masculino , Animales , N-Metilaspartato/uso terapéutico , Hiperalgesia/terapia , Corteza Insular , Ratas Wistar , Neuralgia/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/uso terapéuticoRESUMEN
PURPOSE: We aimed to analyze the potential for postoperative (PO) medication suspension and reduction, emphasizing passive withdrawal. METHODS: Retrospective study of patients under 18 years old submitted to surgical treatment for pharmacoresistant epilepsy and classified as Engel I during the first year of PO follow-up. Therapeutic management was evaluated through discontinuation or reduction of medications, both in terms of the number of ASM prescribed and in daily maintenance dosages in mg/kg. RESULTS: ASM withdrawal started in the first year PO and occurred in 1.2% of cases, with a significant yearly reduction in the number of ASM during follow-up (p < 0.001). A comparison of the most commonly used ASM in daily mg/kg between the preoperative period (preop) and PO showed a reduction of ASM maintenance dosages during PO. Even though recurrence of seizures was observed 5 years after surgery, 125 patients (85%) were still classified as Engel I, albeit a higher number of ASM per patient was observed. Most patients showed no changes in cognitive and adaptive behavior evaluation between preop and PO, even in those who were able to reduce ASM. CONCLUSION: Significant reduction observed both in the number and daily maintenance dosages of ASM following each year of PO may be an indirect measure of the effectiveness of epilepsy surgery.
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Anticonvulsivantes , Epilepsia , Humanos , Niño , Adolescente , Estudios Retrospectivos , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/efectos adversos , Resultado del Tratamiento , Epilepsia/tratamiento farmacológico , Epilepsia/cirugía , Procedimientos NeuroquirúrgicosRESUMEN
Hydrocephalus is defined as the accumulation of cerebrospinal fluid in the brain ventricles. The usual treatment of hydrocephalus is surgical (shunt), but not all patients can undergo treatment immediately after diagnosis. Thus, neuroprotective measures were tested to minimize the tissue damage involved. Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which has shown a neuroprotective action in neurodegenerative diseases. This study aimed to evaluate the neuroprotective response of memantine in animals treated with or without a ventricular-subcutaneous shunt. Seven-day-old male Wistar rats induced by intracisternal injection of kaolin were used, divided into five groups: intact control (n = 10), hydrocephalic (n = 10), hydrocephalic treated with memantine (20 mg/kg/day) (n = 10), hydrocephalic treated with shunt (n = 10), hydrocephalic treated with shunt and memantine (20 mg/kg/day) (n = 10). Memantine administration was started on the day after hydrocephalus induction and continued until the last day of the experimental period, totaling 21 consecutive days of drug application. The CSF shunt surgery was performed seven days after hydrocephalus induction. Behavioral tests (open field, and modified Morris water maze), histological, and immunohistochemical evaluations were performed. Treatment with memantine resulted in significant improvement (p < 0.05) in sensorimotor development, preservation of spatial memory, reduction of astrocytic reaction in the corpus callosum, cortex, and germinal matrix. When associated with the shunt, it has also been shown to reduce the cell death cascade. It is concluded that memantine is a promising adjuvant drug with beneficial potential for the treatment of lesions secondary to hydrocephalus.
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Gliosis , Hidrocefalia , Memantina , Animales , Masculino , Ratas , Muerte Celular , Gliosis/tratamiento farmacológico , Gliosis/patología , Hidrocefalia/tratamiento farmacológico , Hidrocefalia/patología , Memantina/uso terapéutico , Ratas Wistar , Receptores de N-Metil-D-AspartatoRESUMEN
Objectives: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations. Design: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions. Methods: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths. Results: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs. Conclusions: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.
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Craneofaringioma , Telómero , beta Catenina , Adolescente , Niño , Craneofaringioma/genética , Estudios Transversales , Humanos , Mutación , Estudios Retrospectivos , Telómero/ultraestructura , Vía de Señalización Wnt , beta Catenina/genéticaRESUMEN
Hydrocephalus is characterized by the accumulation of CSF within the cerebral ventricles and the subarachnoid space. Ventricular volume can progressively increase and generate serious damage to the nervous system, with cerebral hypoxia/ischemia as one of the most important factors involved. Hyperbaric oxygen therapy (HBOT) improves oxygen supply to tissues, which can reduce the progression of lesions secondary to ventricular enlargement. We evaluated whether HBOT associated with CSF diversion can promote neuroprotective effects to structures damaged by ventriculomegaly and understand its role. Seven-day-old male Wistar Hannover rats submitted to hydrocephalus by intracisternal injection of 15% kaolin were used. The animals were divided into six groups, with ten animals in each: control, control associated with hyperbaric therapy, hydrocephalic without treatment, hydrocephalic treated with hyperbaric oxygen therapy, hydrocephalic treated with CSF deviation, and hydrocephalic treated with hyperbaric oxygen therapy associated with CSF deviation. To assess the response to treatment, behavioral tests were performed such as modified Morris water maze and object recognition, evaluation by transcranial ultrasonography, histology by Hematoxylin-Eosin and Luxol Fast Blue, immunohistochemistry for GFAP, Ki-67, Caspase-3, COX-2, NeuN and SOD1, and biochemical ELISA assay for GFAP and MBP. The results show that the association of treatments exerts neuroprotective effects such as neurobehavioral improvement, preservation of periventricular structures, antioxidant effect, and reduction of damage resulting from ischemia and the neuroinflammatory process. We conclude that HBOT has the potential to be used as an adjuvant treatment to CSF deviation surgery in experimental hydrocephalus.
Asunto(s)
Hidrocefalia , Oxigenoterapia Hiperbárica , Fármacos Neuroprotectores , Animales , Hidrocefalia/terapia , Masculino , Neuroprotección , Ratas , Ratas WistarRESUMEN
The neuroprotective effect of Edaravone in young hydrocephalic rats associated with a CSF derivation system was evaluated. The drug has already been shown to be beneficial in experimental hydrocephalus, but the combination of this drug with shunt surgery has not yet been investigated. Fifty-seven-day-old Wistar rats submitted to hydrocephalus by injection of kaolin in the cisterna magna were used and divided into five groups: control (n = 10), hydrocephalic (n = 10), hydrocephalic treated with Edaravone (20 mg/kg/day) (n = 10), hydrocephalic treated with shunt (n = 10) and hydrocephalic treated with shunt and Edaravone (n = 10). Administration of the Edaravone was started 24 h after hydrocephalus induction (P1) and continued until the experimental endpoint (P21). The CSF shunt surgery was performed seven days after hydrocephalus induction (P7). Open-field tests, histological evaluation by hematoxylin and eosin, immunohistochemistry by Caspase-3 and GFAP, and ELISA biochemistry by GFAP were performed. Edaravone reduced reactive astrogliosis in the corpus callosum and germinal matrix (p < 0.05). When used alone or associated with CSF shunt surgery, the drug decreased the cell death process (p < 0.0001) and improved the morphological aspect of the astroglia (p < 0.05). The results showed that Edaravone associated with CSF bypass surgery promotes neuroprotection in young hydrocephalic rats by reducing reactive astrogliosis and decreasing cell death.