ABSTRACT - Objective: To further characterize the capacity of lovastatin to prevent hippocampal neuronal loss after pilocarpine-induced statusepilepticus (SE) Method: Adult male Wistar rats were divided into four gro u p s : (A) control rats, received neither pilocarpine nor lovastatin (n=5); (B) control rats, received just lovastatin (n=5); (C) rats that received just pilocarpine (n=5); (D) rats that received pilocarpine and lovastatin (n=5). After pilo- carpine injection (350mg/kg, i.p.), only rats that displayed continuous, convulsive seizure activity were included in our study. Seizure activity was monitored behaviorally and terminated with an injection of diazepam (10 mg/kg, i.p.) after 4 h of convulsive SE. The rats treated with lovastatin received two doses of 20mg/kg via an oesophag- ic probe immediately and 24 hours after SE induction. Seven days after pilocarpine-induced SE, all the animals w e reperfused and their brains were processed for histological analysis through Nissl method. Results: The cell counts in the Nissl-stained sections perf o rmed within the hippocampal formation showed a significant cell loss in rats that received pilocarpine and presented SE (CA1= 26.8 ± 13.67; CA3= 38.1 ± 7.2; hilus= 43.8 ± 3.95) when c o m p a red with control group animals (Group A: CA1= 53.2 ± 9.63; CA3= 63.5 ± 13.35; hilus= 59.08 ± 10.24; Gro u p B: CA1= 74.3 ± 8.16; CA3= 70.1 ± 3.83; hilus= 70.6 ± 5.10). The average neuronal cell number of CA1 subfield of rats that present SE and received lovastatin (44.4 ± 17.88) was statically significant increased when compare d with animals that just presented SE. Conclusion: Lovastatin exert a neuro p rotective role in the attenuation of brain damage after SE.
Statusepilepticus (SE) induced by high doses of p i- locarpine in rats has received special attention, since this injury drive on a type of epilepsy in rodents, w h i c h re p roduce the main clinical and neuro p a t h o l o g i c a l f e a t u res of human temporal lobe epilepsy. When de- veloped in adult animals, this experimental model is able to produce long-lasting SE (acute period, 12h), a seizure - f ree period (silent period, 14 days) and spon- taneous re c u rrent seizures (chronic period), which a re associated to extensive cell loss in several brain s t ru c t u res and mossy fiber sprouting in the hippocam- pal form a t i o n 1 - 3 . The consequences of pilocarpine-in-
Since our patient was in a confused state and had stereotypic and myoclonic movements in his legs until he was sedated with propofol, the posi- tion of his head was changing rapidly. These posi- tion changes may have caused the drug to diffuse to the cephalic region. The probability of the drugs to diffuse into the cephalic region has also been men- tioned in a study and it has been recommended to elevate the head to a 10° angle in order to reduce the diffusion .In our patient, the stereotypical and myoclonic movements in the legs followed by the GTC seizure that occurred soon after the infu- sion of the bupivacaine into the vertebral space may point out that the drug may have spread towards the cephalic region and caused a GTC type of statusepilepticus.
9. Longo B, Romariz S, Blanco MM, Vasconcelos JF, Bahia L, Soares MBP, et al. Distribution and proliferation of bone marrow cells in the brain after pilocar- pine-induced statusepilepticus in mice. Epilepsia 2010;51(8):1628–32. 10. Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB. The great migration of
Introduction: Super-refractory statusepilepticus is defined as statusepilepticus that persists or recurs 24 hours after anaesthetic therapy onset or after its withdrawal. It is mostly found in intensive care units and carries high mortality but good long-term prognosis for those who survive. In contrast with the initial phases of statusepilepticus, treatment lacks strong scientific evidence and is mostly derived from case reports or small case series.
Estudos experimentais mostram evidências de que ratos adultos submetidos às convulsões neonatais apresentam mudanças morfológicas e cognitivas, exibindo também comportamento autista caracterizado pela baixa preferência pela novidade social, déficit de discriminação social e comportamento tipo ansioso. Porém, os mecanismos que respondem por estas alterações ainda não são conhecidos. Várias evidências demonstram que a ocitocina (OT) está presente em regiões importantes para reconhecimento social, tais como a amígdala medial e o hipocampo. Postulamos que a deficiência na sinalização mediada pela OT na rede neural relacionada com o cérebro social responda pelo prejuízo na sociabilidade e pelo aumento da emocionalidade subsequente à convulsão neonatal. Este trabalho tem como objetivo avaliar a memória de reconhecimento social e a expressão gênica da OT e do seu receptor (OTR) em animais submetidos ao statusepilepticus neonatal. Foram utilizados ratos Wistar machos adultos submetidos ao statusepilepticus no nono dia de vida (P9) pela administração da pilocarpina (350 mg/kg, ip) e os controles receberam salina 0.9% (0,1 mL/10 g). Em P90 foi avaliada a memória social pelo paradigma de habituação/desabituação. Ao fim dos testes comportamentais, os animais foram anestesiados e decapitados para a retirada das estruturas de estudo (amígdala, hipocampo, e hipotálamo). Posteriormente foi realizada a análise da expressão gênica da ocitocina e seu receptor nos tecidos citados, por meio da PCR em tempo real. No teste de memória social os animais experimentais apresentaram menor tempo de investigação social, indicativo de prejuízo no sistema de motivação/recompensa e prejuízo de habituação/desabituação, sugestivo de prejuízo na memória de reconhecimento social. A expressão gênica da ocitocina não diferiu entre os grupos nas estruturas analisadas, mas observou-se uma pequena redução na expressão gênica do receptor de ocitocina no hipocampo. Com isso conclui-se o statusepilepticus neonatal em ratos produz déficit na memória de reconhecimento social e do sistema de motivação / recompensa mesolímibico. O presente trabalho mostrou que animais submetidos ao statusepilepticus neonatal apresentam redução da exploração da novidade social, sugestivo de prejuízo no sistema de motivação/recompensa mesolímbico e da memória de reconhecimento social que pode estar relacionada a redução da expressão dos receptores da ocitocina no hipocampo.
Cognitive impairments are prominent sequelae of prolonged continuous seizures (statusepilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE- induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.
A epilepsia é uma doença multifatorial, multifacetada, que apresenta diferentes variações de gravidade de pessoa para pessoa, caracterizada pelo surgimento de crises espontâneas devido à hiperatividade neural. Dentre as epilepsias, a epilepsia do lobo temporal (ELT) é uma forma muito grave e comum, que compreende cerca de 40% de todos os casos, comumente refratária à medicação com um impacto substancial no processo cognitivo e no comportamento da pessoa afetada. A ELT é caracterizada pela presença de crises parciais complexas com início nas estruturas límbicas, parcialmente atribuídas à neuropatologia primária mais frequente, a esclerose hipocampal. Essa crise pode causar prejuízos cognitivos e comportamentais, associados a transtornos psiquiátricos, os quais o Transtorno do Déficit de Atenção e Hiperatividade (TDAH). Com objetivo de avaliar a atividade locomotora e exploratória em ratos jovens submetidos ao statusepilepticus. Ratos Wistar machos com idade de 25 dias pós-natal, receberam injeção intraperitoneal de pilocarpina (350mg/kg). Animais controle receberam solução salina. O modelo de indução por pilocarpina foi utilizado nessa pesquisa, tendo em vista que suas características histológicas, bioquímicas, eletrofisiológicas e comportamentais reproduzem de forma fidedigna as encontradas na ELT em humanos. Após a indução ao SE por pilocarpina os animais foram submetidos a testes comportamentais que tiveram início 5 dias após o SE e foram concluídos em 15 dias. Foram eles: o campo aberto e o labirinto em cruz elevado. O presente trabalho mostrou evidências que animais jovens submetidos ao statusepilepticus apresentam hiperatividade moderada com aumento da emocionalidade em um contexto ameaçador. A hiperatividade foi observada ao longo do tempo, quando os animais foram reapresentados a um ambiente com contexto neutro (campo aberto) ou imediatamente, quando expostos a um ambiente ameaçador (LCE). Os resultados observados neste estudo argumentam a favor da presença concomitante de TDHA no modelo de ELT. Mostra evidências que as alterações comportamentais se manifestam precocemente, antes mesmo da instalação das crises epilépticas comportamentais. Neste aspecto, abre-se uma janela de oportunidades para se buscar intervenções precoces que possam minimizar as consequências deletérias das crises convulsivas.
Primary central nervous system vasculitis (PCNV) is limited with central nervous system and rare vasculitis that mostly seen in middle-aged men. PCNV vasculitis is usually presented that headache, dementia, stroke and multifocal common neurological symptoms. PCNV especially involves small medium-sized leptomeningeal and cortical arteries. 43 years old male patient who have been progressive forgetfulness and headache for 3 years. He applied with recurrent that before starting right focal and than sprawling whole body which generalized tonic-clonic seizures to us. During management that he was transfered to the intensive care unit due to statusepilepticus (SE). Later than we found right hemiparesis, motor aphasia and right babinski positivity in neurologic examination. Diffusion restriction was revealed in left MCA territory in diffusion magnetic resonance imaging (MRI). EEG showed two types abnormality that a slow background ritm and epileptiform activity. Biochemistry of blood, complete blood count, blood sedimentation rate, CRP and markers of vasculitis were found in the normal range. Cerebral anjiography revealed that irregularities in the distal vascular areas and fusiform aneurysm at the top of basilar artery. He was consulted with rheumatology and diagnosed central nervous system vasculitis with the existing findings. Biopsy couldn't be taken from the brain to verify the diagnosis. Finally, we applied treatment that pulse steroid and cyclophosphamide to patient. This case has been presented due to emphasize that PCNV rarely may play a role in the etiology of recurrent stroke and statusepilepticus.
Epilepsy is a devastating disease, currently treated with medications, surgery or electrical stimulation. None of these approaches is totally effective and our ability to control seizures remains limited and complicated by frequent side effects. The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats. Hippocampal pyramidal neurons were transduced in vivo with a virus carrying an enhanced halorhodopsin (eNpHR), a yellow light activated chloride pump, and acute seizure progression was then monitored behaviorally and electrophysiologically in the presence and absence of illumination delivered via an optical fiber. Inhibition of those neurons with illumination prior to seizure onset significantly delayed electrographic and behavioral initiation of statusepilepticus, and altered the dynamics of ictal activity development. These results reveal an essential role of hippocampal excitatory neurons in this model of ictogenesis and illustrate the power of optogenetic approaches for elucidation of seizure mechanisms. This early success in controlling seizures also suggests future therapeutic avenues.
Grupo de animais normonutridos sem indução ao statusepilepticus pela pilocarpina – Grupo de 18 animais normonutridos, como descrito acima, foi administrado salina i.p., ao invés de pilocarpina. Noventa minutos após o a administração de salina foi injetado Diazepam NQ ? (20 mg/kg,.i.p.). Após um período cinco dias, os ratos foram monitorados por câmara filmadora, por um período de seis horas diariamente. Do grupo de 18 animais, em 6 foram realizadas cirurgias estereotáxicas, com implantação de eletrodo profundo e posterior avaliação do vídeo- EEG, seguida de perfusão e histologia para verificação dos sítios de registro. Aos 120 dias de vida um grupo de seis animais, dos 18 ratos tratados, foi submetido aos procedimentos, descritos abaixo, para realização da marcação histoquímica pelo Neo- Timm. Os animais restantes do grupo foram sacrificados aos 120 dias e submetidos aos demais ensaios biológicos.
Recent research data have shown that systemic administration of pyruvate and oxaloacetate causes an increased brain-to-blood glutamate efﬂux. Since increased release of glutamate during epileptic seizures can lead to excitotoxicity and neuronal cell death, we tested the hypothesis that glutamate scavenging mediated by pyruvate and oxaloacetate systemic administration could have a neuroprotective effect in rats subjected to statusepilepticus (SE). SE was induced by a single dose of pilocarpine (350 mg/kg i.p.). Thirty minutes after SE onset, a single dose of pyruvate (250 mg/kg i.p.), oxaloacetate (1.4 mg/kg i.p.), or both substances was administrated. Acute neuronal loss in hippocampal regions CA1 and hilus was quantitatively determined ﬁve hours after SE onset, using the optical fractionator method for stereological cell counting. Apoptotic cascade in the hippocampus was also investigated seven days after SE using caspase-1 and -3 activity assays. SE-induced neuronal loss in CA1 was completely prevented in rats treated with pyruvate plus oxaloacetate. The SE-induced caspase-1 activation was signiﬁcantly reduced when rats were treated with oxaloacetate or pyruvate plus oxaloacetate. The treatment with pyruvate and oxaloacetate caused a neuroprotective effect in rats subjected to pilocarpine-induced SE. ß 2010 Elsevier Ltd. Open access under the Elsevier OA license.
Objective: Nonconvulsive statusepilepticus (NCSE) is currently considered as one of the most frequent types of statusepilepticus (SE). The objective of the present study was to identify the natural history of the electrographical evolution of refractory NCSE and to establish the relationship between ictal patterns and prognosis. Methods: We analyzed, retrospectively, 14 patients with loss of consciousness and NCSE. The ictal patterns were classified as discrete seizures (DS), merging seizures (MS), continuous ictal discharges (CID), continuous ictal dis- charges with flat periods (CID-F), and periodic lateralized epileptiform discharges (PLEDs). Results: The ictal patterns were DS (n=7; 50.0%), PLEDs (n=3; 1.4%), CID (n=2; 14.3%), MS (n=1; 7.1%), and CID-F (n=1; 7.1%). Conclusions: NCSE electrographic findings are heterogeneous and do not follow a stereotyped sequence. PLEDs were related to a higher probability of neurological morbidity and mortality.
Case Report A case of an 18-year-old adolescent girl, with chlo- rpromazine therapy started for anxiety-phobic disorder was reported. Her personal history disclosed delayed psychomotor development. Shortly after the introduction of the neuroleptic chlorpromazine therapy in minimal daily dose (37.5 mg), she developed myoclonic statusepilepticus, confirmed by the EEG records. Frequent, symmetrical bilateral myoclonic jerks and altered behavior were associated with bilateral epileptiform dis-
The anterior nucleus of the thalamus (AN) has been suggested as a potential target for seizure modulation in animal models and patients with refractory epilepsy. We investigate whether microinjections of GABAergic agonists into the AN were protective against pilocarpine-induced generalized seizures and statusepilepticus (SE). Rats were treated with bilateral AN injections of muscimol (160 or 80 nmol), bicuculline (15 nmol), or saline (controls) 20 min prior to pilocarpine administration (350 mg/kg i.p.). Electrographic recordings were used to conﬁrm seizure activity. We found that pretreatment with AN muscimol 160 nmol increased the latency to seizures and SE by 2.5– 3.0-fold. This dose however was associated with side effects, particularly hypotonia. AN bicuculline was proconvulsant, whereas no major effect was observed after muscimol 80 nmol injections. The percentage of animals that developed SE was similar across groups. Overall, microinjection of high doses of muscimol into the AN delayed the occurrence of pilocarpine-induced seizures and SE but was not able to prevent these events.
The second author’s name is spelled incorrectly. The correct name is: Sylvain Barriere. The fourth author’s name also contains an additional space. The correct name is: Pierre-Pascal Lenck-Santini. The correct citation is: Flynn SP, Barriere S, Scott RC, Lenck-Santini P-P, Holmes GL (2015) StatusEpilepticus Induced Spontaneous Dentate Gyrus Spikes: In Vivo Cur- rent Source Density Analysis. PLoS ONE 10(7): e0132630. doi:10.1371/journal.pone.0132630
Administration of pilocarpine causes epilepsy in rats if status epilep- ticus (SE) is induced at an early age. To determine in detail the electrophysiological patterns of the epileptogenic activity in these animals, 46 Wistar rats, 7-17 days old, were subjected to SE induced by pilocarpine and electro-oscillograms from the cortex, hippocam- pus, amygdala, thalamus and hypothalamus, as well as head, rostrum and vibrissa, eye, ear and forelimb movements, were recorded 120 days later. Six control animals of the same age range did not show any signs of epilepsy. In all the rats subjected to SE, iterative spike-wave complexes (8.1 ± 0.5 Hz in frequency, 18.9 ± 9.1 s in duration) were recorded from the frontal cortex during absence fits. However, similar spike-wave discharges were always found also in the hippocampus and, less frequently, in the amygdala and in thalamic nuclei. Repetitive or single spikes were also detected in these same central structures. Clonic movements and single jerks were recorded from all the rats, either concomitantly with or independently of the spike-wave com- plexes and spikes. We conclude that rats made epileptic with pilo- carpine develop absence seizures also occurring during paradoxical sleep, showing the characteristic spike-wave bursts in neocortical areas and also in the hippocampus. This is in contrast to the well- accepted statement that one of the main characteristics of absence-like fits in the rat is that spike-wave discharges are never recorded from the hippocampal fields.
unilateral SE 47 , the most recent proposal for classifi- cation indicates that SE should be classified into only two categories, generalised and focal SE 48 . The first group should be further subclassified into generalised tonic–clonic, clonic, absence, tonic and myoclonic SE, while the focal SE would encompass epilepsia par- tialis continua of Kojevnikov, aura continua, limbic SE (psychomotor status) and finally, hemiconvulsive status with hemiparesis. This new proposal appears to be more adequate, however, we should still consider the fact that not all focal nonconvulsive SE can be in- cluded in the classical limbic SE.
Results: 29 children were admitted with 33 episodes of SE aged between nine months and five years, there were no differences in gender distribution (male 12, female: 17 - p = 0.46). The etiology of SE was febrile in 16 children, remote symptomatic in seven related to idiopathic / cryptogenic epilepsy in five children and not classifiable in one case. The mean follow-up was six years and four months. There were no deaths associated with SE. There was deterioration in neurological status in two children (8.7%). Epilepsy was diag- nosed following the SE in three (13%) children.