Alterations in Rat Hippocampal Glutamatergic System Properties after Prolonged Febrile Seizures.

Febrile seizures during early childhood may result in central nervous system developmental disorders. However, the specific mechanisms behind the impact of febrile seizures on the developing brain are not well understood. To address this gap in knowledge, we employed a hyperthermic model of febrile seizures in 10-day-old rats and tracked their development over two months. Our objective was to determine the degree to which the properties of the hippocampal glutamatergic system are modified. We analyzed whether pyramidal glutamatergic neurons in the hippocampus die after febrile seizures. Our findings indicate that there is a reduction in the number of neurons in various regions of the hippocampus in the first two days after seizures. The CA1 field showed the greatest susceptibility, and the reduction in the number of neurons in post-FS rats in this area appeared to be long-lasting. Electrophysiological studies indicate that febrile seizures cause a reduction in glutamatergic transmission, leading to decreased local field potential amplitude. This impairment could be attributable to diminished glutamate release probability as evidenced by decreases in the frequency of miniature excitatory postsynaptic currents and increases in the paired-pulse ratio of synaptic responses. We also found higher threshold current causing hind limb extension in the maximal electroshock seizure threshold test of rats 2 months after febrile seizures compared to the control animals. Our research suggests that febrile seizures can impair glutamatergic transmission, which may protect against future seizures.

Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy.

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.

Bone fractures from generalized convulsive seizures and status epilepticus-A systematic review.

OBJECTIVE: We present a systematic review of the literature regarding types and anatomic distribution of fractures in association with generalized convulsive status epilepticus (GCSE) and convulsive seizures in adult patients accompanied by an illustrative case of a patient with GCSE and diffuse postictal pain from underlying bone fractures. METHODS: The library search engines PubMed and EMBASE were screened systematically using predefined search terms. All identified articles written in English were screened for eligibility by two reviewers. The preferred reporting items for systematic reviews and meta-analyses guidelines were followed. RESULTS: The screening of 3145 articles revealed 39 articles meeting the inclusion criteria. Among all fractures, bilateral posterior fracture-dislocations of the shoulders were reported most frequently (33%), followed by thoracic and lumbar vertebral compression fractures (29%), skull and jaw fractures (8%), and bilateral femoral neck fractures (6%). Risk factors for seizure-related fractures are seizure severity, duration of epilepsy, the use of antiseizure drugs known to decrease bone density, and a family history of fractures. Based on these findings, a three-step screening procedure is proposed to uncover fractures in the postictal state. All studies were retrospective without standardized screening methods for seizure-associated fractures resulting in a very low level of evidence and a high risk of bias. SIGNIFICANCE: Posterior fracture-dislocations of the shoulders, thoracic and lumbar vertebral compression, fractures of the skull and jaw, and bilateral femoral neck fractures are most frequently reported. Preventive measures including bone densitometry, calcium/vitamin D supplementation, and bisphosphonate therapy should be reinforced in epilepsy patients at risk of osteoporosis. As long as the effect of standardized screening of fractures is not investigated, it is too early to integrate such a screening into treatment guidelines. In the meantime, clinicians are urged to heighten awareness regarding seizure-associated fractures, especially in patients with postictal pain, as symptoms can be unspecific and misinterpretation may impede rehabilitation.

Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo - in search of potential anti-epileptogenic strategies for temporal lobe epilepsy.

BACKGROUND: Previous studies in various rodent epilepsy models have suggested that mammalian target of rapamycin (mTOR) inhibition with rapamycin has anti-epileptogenic potential. Since treatment with rapamycin produces unwanted side effects, there is growing interest to study alternatives to rapamycin as anti-epileptogenic drugs. Therefore, we investigated curcumin, the main component of the natural spice turmeric. Curcumin is known to have anti-inflammatory and anti-oxidant effects and has been reported to inhibit the mTOR pathway. These properties make it a potential anti-epileptogenic compound and an alternative for rapamycin. METHODS: To study the anti-epileptogenic potential of curcumin compared to rapamycin, we first studied the effects of both compounds on mTOR activation, inflammation, and oxidative stress in vitro, using cell cultures of human fetal astrocytes and the neuronal cell line SH-SY5Y. Next, we investigated the effects of rapamycin and intracerebrally applied curcumin on status epilepticus (SE)-induced inflammation and oxidative stress in hippocampal tissue, during early stages of epileptogenesis in the post-electrical SE rat model for temporal lobe epilepsy (TLE). RESULTS: Rapamycin, but not curcumin, suppressed mTOR activation in cultured astrocytes. Instead, curcumin suppressed the mitogen-activated protein kinase (MAPK) pathway. Quantitative real-time PCR analysis revealed that curcumin, but not rapamycin, reduced the levels of inflammatory markers IL-6 and COX-2 in cultured astrocytes that were challenged with IL-1ß. In SH-SY5Y cells, curcumin reduced reactive oxygen species (ROS) levels, suggesting anti-oxidant effects. In the post-SE rat model, however, treatment with rapamycin or curcumin did not suppress the expression of inflammatory and oxidative stress markers 1 week after SE. CONCLUSIONS: These results indicate anti-inflammatory and anti-oxidant properties of curcumin, but not rapamycin, in vitro. Intracerebrally applied curcumin modified the MAPK pathway in vivo at 1 week after SE but failed to produce anti-inflammatory or anti-oxidant effects. Future studies should be directed to increasing the bioavailability of curcumin (or related compounds) in the brain to assess its anti-epileptogenic potential in vivo.

Pyridoxine deficiency in adult patients with status epilepticus.

An 8-year-old girl treated at our facility for superrefractory status epilepticus was found to have a low pyridoxine level at 5 µg/L. After starting pyridoxine supplementation, improvement in the EEG for a 24-hour period was seen. We decided to look at the pyridoxine levels in adult patients admitted with status epilepticus. We reviewed the records on patients admitted to the neurological ICU for status epilepticus (SE). Eighty-one adult patients were identified with documented pyridoxine levels. For comparison purposes, we looked at pyridoxine levels in outpatients with epilepsy (n=132). Reported normal pyridoxine range is >10 ng/mL. All but six patients admitted for SE had low normal or undetectable pyridoxine levels. A selective pyridoxine deficiency was seen in 94% of patients with status epilepticus (compared to 39.4% in the outpatients) which leads us to believe that there is a relationship between status epilepticus and pyridoxine levels.

Thalamic lesions: a radiological review.

BACKGROUND: Thalamic lesions are seen in a multitude of disorders including vascular diseases, metabolic disorders, inflammatory diseases, trauma, tumours, and infections. In some diseases, thalamic involvement is typical and sometimes isolated, while in other diseases thalamic lesions are observed only occasionally (often in the presence of other typical extrathalamic lesions). SUMMARY: In this review, we will mainly discuss the MRI characteristics of thalamic lesions. Identification of the origin of the thalamic lesion depends on the exact localisation inside the thalamus, the presence of extrathalamic lesions, the signal changes on different MRI sequences, the evolution of the radiological abnormalities over time, the history and clinical state of the patient, and other radiological and nonradiological examinations.

Post-seizure α-tocopherol treatment decreases neuroinflammation and neuronal degeneration induced by status epilepticus in rat hippocampus.

Vitamin E (as α-tocopherol, α-T) was shown to have beneficial effects in epilepsy, mainly ascribed to its antioxidant properties. Besides radical-induced neurotoxicity, neuroinflammation is also involved in the pathophysiology of epilepsy, since neuroglial activation and cytokine production exacerbate seizure-induced neurotoxicity and contribute to epileptogenesis. We previously showed that α-T oral supplementation before inducing status epilepticus, markedly reduces astrocytic and microglial activation, neuronal cell death and oxidative stress in the hippocampus, as observed 4 days after seizure. In order to evaluate the possibility that such a neuroprotective and anti-inflammatory effect may also provide a strategy for an acute intervention in epilepsy, in this study, seizures were induced by single intaperitoneal injection of kainic acid and, starting from 3 h after status epilepticus, rats were treated with an intraperitoneal bolus of α-T (250 mg/kg b.w.; once a day) for 4 days, that was the time after which morphological and biochemical analyses were performed on hippocampus. Post-seizure α-T administration significantly reduced astrocytosis and microglia activation, and decreased neuron degeneration and spine loss; these effects were associated with the presence of a lowered lipid peroxidation in hippocampus. These results confirm and further emphasize the anti-inflammatory and neuroprotective role of α-T in kainic acid-induced epilepsy. Moreover, the findings show that post-seizure treatment with α-T provides an effective secondary prevention against post-seizure inflammation-induced brain damages and possibly against their epileptogenic effects.

[A case of acute encephalitis with refractory repetitive partial seizures successfully controlled by very-high-dose phenobarbital therapy found in a boy].

We experienced a case of acute encephalitis with refractory, repetitive partial seizures (AERRPS) found in an 8-year-old boy. Convulsive status epilepticus developed at the onset, which was intractable to the treatment with intravenous thiopental sodium even at the maximum dose of 9 mg/kg/hr. Since the adverse effect developed, thiopental sodium was discontinued. Phenobarbital (PB) was administrated at a very high daily dose up to 80 mg/kg, reaching serum trough level of 250 µg/ml, which was markedly effective to the treatment. Because seizures reappeared during tapering the dosage of PB, potassium bromide (KBr) at a daily dose of 80 mg/kg was additionally administrated. PB was successfully tapered into a daily dose of 20 mg/kg with a trough serum level around 80 µg/ml. He recovered in motor functions, but had disturbance of memory and apneic seizures. A very-high-dose PB therapy in an early period may be helpful for the treatment of intractable convulsive status epilepticus.

Influence of neuropathology on convection-enhanced delivery in the rat hippocampus.

Local drug delivery techniques, such as convention-enhanced delivery (CED), are promising novel strategies for delivering therapeutic agents otherwise limited by systemic toxicity and blood-brain-barrier restrictions. CED uses positive pressure to deliver infusate homogeneously into interstitial space, but its distribution is dependent upon appropriate tissue targeting and underlying neuroarchitecture. To investigate effects of local tissue pathology and associated edema on infusate distribution, CED was applied to the hippocampi of rats that underwent electrically-induced, self-sustaining status epilepticus (SE), a prolonged seizure. Infusion occurred 24 hours post-SE, using a macromolecular tracer, the magnetic resonance (MR) contrast agent gadolinium chelated with diethylene triamine penta-acetic acid and covalently attached to albumin (Gd-albumin). High-resolution T1- and T2-relaxation-weighted MR images were acquired at 11.1 Tesla in vivo prior to infusion to generate baseline contrast enhancement images and visualize morphological changes, respectively. T1-weighted imaging was repeated post-infusion to visualize final contrast-agent distribution profiles. Histological analysis was performed following imaging to characterize injury. Infusions of Gd-albumin into injured hippocampi resulted in larger distribution volumes that correlated with increased injury severity, as measured by hyperintense regions seen in T2-weighted images and corresponding histological assessments of neuronal degeneration, myelin degradation, astrocytosis, and microglial activation. Edematous regions included the CA3 hippocampal subfield, ventral subiculum, piriform and entorhinal cortex, amygdalar nuclei, middle and laterodorsal/lateroposterior thalamic nuclei. This study demonstrates MR-visualized injury processes are reflective of cellular alterations that influence local distribution volume, and provides a quantitative basis for the planning of local therapeutic delivery strategies in pathological brain regions.

[Delirium caused by nonconvulsive status epilepticus]. / Nonkonvulsiver Status epilepticus als Ursache eines Delirs.

We report about a patient (66 years) who was referred to our psychiatric hospital because of a progressive confusional state with acute onset. The colleagues of the referring psychiatric hospital considered a first manic episode as the cause of the symptoms and under therapy with haloperidol the confusional state had shown a progression.The clinical examination's findings were a mild central facial paresis on the right side and a mild hemiparesis on the right side with elevated reflex levels.The patient was disoriented, he had cognitive and mnestic deficits. His reasoning was slowed, incoherent and perseverating. The patient had a slight euphoria.An EEG recording showed a continuous regional EEG-seizure pattern. In combination with the clinical symptoms we diagnosed a nonconvulsive status epilepticus. Under anticonvulsive treatment with Lorazepam and Valproic acid the status epilepticus sustended but a control EEG recording showed signs of a Valproate-encephalopathy. Under treatment with Topiramate symptoms ameliorated but due to a vascular dementia the patient still showed fluctuating symptoms of cognitive and mnestic disturbances.

Frontal motor seizure following non-convulsive status epilepticus in ring chromosome 20 syndrome.

The ring chromosome 20 syndrome is a rare syndrome characterized by intractable epilepsy with particular electro clinical features including episodes of prolonged confusional state and nocturnal frontal lobe seizures. We report a 17-year-old girl who had intractable epilepsy with frontal seizure and prolonged confusional state secondary to non-convulsive status epilepticus. The diagnosis of ring chromosome 20 was suspected and confirmed by karyotype. The cytogenetic study of CHRNA4 and KCNQ2 genes did not detect deletion in the ring chromosome 20. During video-EEG recording, this girl presented a non-convulsive status epilepticus that lasted more than 20 minutes followed by typical frontal lobe seizure. This association was not previously described, and was probably caused by chromosomal instability.

Social play impairment following status epilepticus during early development.

Neonatal status epilepticus (SE) disrupts prefrontal cortex and thalamus, brain regions related to social play. Juvenile play was evaluated using the "intruder-resident" paradigm following SE in 9-day-old Wistar pups of both genders. Quite interestingly, we demonstrated for the first time that neonatal SE produces social impairment in male rats, reduces locomotor activity in both genders and enhances self-grooming in female. Additional studies are necessary to clarify if these effects can impair social behavior across the life span.

Grafting of striatal precursor cells into hippocampus shortly after status epilepticus restrains chronic temporal lobe epilepsy.

Status epilepticus (SE) typically progresses into temporal lobe epilepsy (TLE) typified by complex partial seizures. Because sizable fraction of patients with TLE exhibit chronic seizures that are resistant to antiepileptic drugs, alternative therapies that are efficient for diminishing SE-induced chronic epilepsy have great significance. We hypothesize that bilateral grafting of appropriately treated striatal precursor cells into hippocampi shortly after SE is efficacious for diminishing SE-induced chronic epilepsy through long-term survival and differentiation into GABA-ergic neurons. We induced SE in adult rats via graded intraperitoneal injections of kainic acid, bilaterally placed grafts of striatal precursors (pre-treated with fibroblast growth factor-2 and caspase inhibitor) into hippocampi at 4 days post-SE, and examined long-term effects of grafting on spontaneous recurrent motor seizures (SRMS). Analyses at 9-12 months post-grafting revealed that, the overall frequency of SRMS was 67-89% less than that observed in SE-rats that underwent sham-grafting surgery and epilepsy-only controls. Graft cell survival was approximately 33% of injected cells and approximately 69% of surviving cells differentiated into GABA-ergic neurons, which comprised subclasses expressing calbindin, parvalbumin, calretinin and neuropeptide Y. Grafting considerably preserved hippocampal calbindin but had no effects on aberrant mossy fiber sprouting. The results provide novel evidence that bilateral grafting of appropriately treated striatal precursor cells into hippocampi shortly after SE is proficient for greatly reducing the frequency of SRMS on a long-term basis in the chronic epilepsy period. Presence of a large number of GABA-ergic neurons in grafts further suggests that strengthening of the inhibitory control in host hippocampi likely underlies the beneficial effects mediated by grafts.

Effect of levetiracetam on visual-spatial memory following status epilepticus.

Status epilepticus (SE) is often followed by severe cognitive impairment, including memory impairment. Previous studies have shown that SE is associated with impairment of single cells in the hippocampus that fire action potentials when the animal is in a specific location in space, the so-called place cells, and that place cell function correlates well with performance in tasks of visual-spatial memory. Place cell patterns therefore appear to be an excellent measure of spatial memory and may serve as a tool to assess seizure-induced impairment in memory. In this study we determined the relationship between visual-spatial memory and place cell function following SE. In addition, we determined if levetiracetam (LEV), an antiepileptic drug with a novel mechanism of action, can improve cognitive function and place cell firing patterns when administered following SE. SE was induced in adult male rats which were then randomized to post-SE treatment with LEV or normal saline (NS) treatment for 14 days. Non-SE control rats also were randomized to LEV or NS. Following discontinuation of LEV rats were tested for visual-spatial memory in the Morris water-maze and then underwent unit recording in the CA1 region of the hippocampus. Brains were then evaluated for cell loss and mossy fiber sprouting. SE was associated with severely impaired performance in the water-maze with SE rats demonstrating no learning over four days of testing. Paralleling this memory deficit was a marked disturbance in firing patterns of pyramidal neurons in CA1. Non-SE rats learned quickly over four days of water-maze testing and had normal pyramidal cell firing patterns. LEV had no major effects on water-maze performance or place cell function. Histopathological examination of the brains showed severe cell loss in CA1 in all of the SE rats with lesser degrees of injury in CA3 and the hilus. LEV treatment resulted in less histological damage in the hippocampus but had no effect on visual-spatial function or place cell physiology in either control or SE rats.

Literature review, case report, and expert discussion of prolonged refractory status epilepticus.

We report the case of a 30-year-old woman with severe, prolonged refractory status epilepticus requiring more than 6 months of iatrogenic coma. Opinions on prognosis and clinical management were solicited from a number of experienced neurointensivists and epileptologists at multiple time-points during the clinical course. The ensuing discussion, annotated with references, is presented here. Several experts commented on isolated cases of young patients with encephalitis requiring up to 2-3 months of iatrogenic coma, yet still having good outcomes. Treatments discussed include ketamine, gammaglobulin, plasmapheresis, steroids, adrenocorticotropic hormone, very high-dose phenobarbital, isoflurane, lidocaine, electroconvulsive therapy, ketogenic diet, hypothermia, magnesium, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, and neurosurgery. The patient eventually suffered a cardiac arrest but was resuscitated as requested by the family. Seizures then stopped, and the patient has remained in a persistent vegetative state since.

Estado epiléptico: clasificación y pronóstico neurológico / Status Epilepticus: classification and neurological prognosis

Introducción: El estado epiléptico (EE) es una emergencia en la infancia con alta morbimortalidad, el pronóstico está determinado por el tipo de EE, edad y precocidad de tratamiento. Objetivos: Clasificar los EE según etiología y tipo de crisis. Relacionarlos con la evolución neurológica. Pacientes y Método: Se analizan las variables: tipo EE según crisis y etiología, edad, sexo, neuroimágenes y morbimortalidad en 25 pacientes hospitalizados por EE, entre Enero 1998 y Diciembre 2003. Resultados: La mediana para edad fue 33 meses (2-120 meses), relación M/F de 14/11. La distribución según tipo de crisis fue: EE convulsivo 76 por ciento, EE no convulsivo 26 por ciento. Según etiología: Remota 44 por ciento, aguda 40 por ciento, febril 12 por ciento, idiopática 4 por ciento. No hubo mortalidad. La incidencia de secuelas en pacientes previamente sanos fue de 35 por ciento, las secuelas se relacionaron con la etiología y las alteraciones en neuroimágenes. Conclusiones: El EE más frecuente según tipo de crisis es el EE Convulsivo y según etiología el EE de etiología remota. El pronóstico del EE en pacientes sanos está determinado por la etiología.

[Three cases with severe motor and intellectual disabilities presenting the severest condition caused by prolonged non-convulsive status epilepticus].

Three patients with severe motor and intellectual disabilities presented deterioration of the activities of daily living, which was revealed to be caused by prolonged non-convulsive status epilepticus (NCSE). Their condition improved by the treatment with antiepileptics. Case 1, a 4-year-old girl with profound psychomotor retardation and past history of West syndrome of unknown etiology, became unable to sit and eat orally above age of two years. EEG showed continuous generalized slow spike and wave bursts indicating NCSE. Continuous intravenous infusion of midazolam abolished EEG abnormalities of NCSE, and she regained the ability of oral feeding. Case 2, a 3-year-old boy with Angelman syndrome and past history of West syndrome, presented decreased mental response, poor oral intake and somnolence. EEG showed continuous slow spike and wave bursts, indicating NCSE. High-dose phenobarbital therapy and continuous intravenous injection of vitamin B6 were effective, and remarkably improved his psychomotor activities. Case 3, a 3-year-old boy with Lennox-Gastaut syndrome, developed decreased psychomotor activity and loss of vocalization and walking. He could not sit by himself and became nearly bed-ridden. EEG showed very frequent generalized spike and wave bursts, showing NCSE. Continuous infusion of thiopental diminished NCSE, and he could walk again. Psychomotor deterioration in patients with severe motor and intellectual disabilities may be caused by NCSE, which should not be overlooked.

[Hypoxic encephalopathy and cortical laminar necrosis]. / Encefalopatía hipóxica y necrosis laminar cortical.

INTRODUCTION: Cortical laminar necrosis is characterized by destruction of the cerebral cortex, mainly of the third layer, in situations of reduced energy supply to the brain. The cerebral lesions caused are known through studies made at autopsies, but there are few descriptions in the literature of the neuroimaging changes. We report the case of a patient who suffered hypoxic encephalopathy secondary to prolonged status epilepticus, and in whom cerebral MR showed changes compatible with cortical laminar necrosis. CLINICAL CASE: A 16 year old girl who had been epileptic since infancy presented with a state of generalized tonic-clonic convulsions followed by coma. Three weeks later she was mute, had a blink reflect to threats and followed visual stimuli with eye movements but no voluntary motor or verbal response. She also showed generalized hypertonia and fine tremor of her arms, which she moved spontaneously with no asymmetry. After two months her clinical condition became stable. Cerebral MR at this time showed diffuse hypersignal of the cortex and basal ganglia in T2 and FLAIR sequences and hyposignal of the subcortical white matter associated with a marked hypersignal delimiting the grooves of convexity in T1 sequences. CONCLUSIONS: Situations of prolonged hypoxia, such as in status epilepticus, lead to necrosis of layers of the cerebral cortex. Clinically this is seen as the appearance of hypoxic encephalopathy and radiologically as characteristic alterations of neuroimaging known as cortical laminar necrosis.