Animal models for mesiotemporal lobe epilepsy: The end of a misunderstanding?

The fact that epilepsy consists in multiple heterogeneous syndromes with different etiologies and different symptoms is insufficiently taken into account in current animal models. This is in particular the case when modeling mesiotemporal lobe epilepsy (MTLE) for which clinical, electrophysiological, histological and pharmacological features have been well described in the clinic but only partially reproduced in most rodent models. In this review, we report the data of our recent survey of european neurologists with expertise in epilepsy. The answers of 82 of them (out of 258) indicated that seizures with mild behavioral signs, hippocampal sclerosis and focal discharges were the three most critical features to be considered when developing an animal model of MTLE. We then examined how these features are reproduced in three different types of animal models of MTLE depending on their induction: (i) generalized convulsive status epilepticus; (ii) hyperthermic seizures in immature animals and (iii) focal status epilepticus. Among them, only rodent models resulting from the induction of a focal status epilepticus appear to present most characteristics of human MTLE.

Revisiting hippocampal sclerosis in mesial temporal lobe epilepsy according to the "two-hit" hypothesis.

Hippocampal sclerosis (HS) is the most common neuropathological pattern observed in pharmacoresistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy syndrome. However, its pathophysiological mechanisms and neuropathological consequences on seizures remain mostly unresolved. The new international classification of hippocampal sclerosis aims at standardizing its description to allow comparisons between different clinical studies. However, several aspects are not considered in this classification (granule cell dispersion, sprouting, glial modifications…). In this chapter, we discuss these different features associated with hippocampal sclerosis in perspective with the "two-hit" hypothesis and propose mechanisms that could be involved in the modulation of some specific neuropathological aspects like early life stress, hyperthermic seizures, brain lesions or hormonal modifications.

Influence of hypothermia on the prognostic value of early EEG in full-term neonates with hypoxic ischemic encephalopathy.

OBJECTIVE: To determine the prognostic value of early electroencephalograms (EEG) in full-term neonates suffering from hypoxic ischemic encephalopathy (HIE) exposed to whole-body hypothermia (cooled group), compared to neonates treated conventionally (control group). METHODS: The study included all term neonates born at Grenoble Hospital between 2000 and 2006 with symptoms of HIE. The first two EEGs were reviewed retrospectively and classified according to current electrophysiological criteria. In the cooled group, EEGs were recorded with a mean body temperature of 33°C. Neurological outcome was correlated with EEG pattern. RESULTS: An EEG inactive or paroxysmal pattern was associated with death in 60% of the controls, while all survivors had neurological sequels. In the cooled group, this EEG pattern was only predictive of death in 40% while survivors had normal examination at 1 year of age. Mild abnormalities on the first EEG correlated with a good prognosis in both groups. The second EEG had a high predictive value, particularly in the cooled group. Persistence of inactivity at 3 days after birth was always associated with death. CONCLUSIONS: After HIE, the first two EEGs are good prognostic indicators, also in the cooled group. Strong discontinuity in the EEG observed on the first hours after hypothermia induction can be associated with a good outcome. SIGNIFICANCE: Early Stage 4 EEGs recorded during the hypothermia may not always indicate a poor prognosis in HIE.

Novel mutations in pyridoxine-dependent epilepsy.

PURPOSE: Pyridoxine-Dependent Epilepsy (PDE) is a rare autosomal recessive disease with neonatal seizures resistant to conventional anti-epileptic drugs. This metabolic disease has to be diagnosed early and treated to improve outcome. We report on two new mutations that open new prenatal prospects and suggest a new diagnostic procedure. CASE REPORT: We describe PDE in a neonate carrying two novel mutations in the ALDH7A1 gene: c.[852_856delCTTAG] + [1230C > A]; p.[(Phe410Leu)] + p.[(Leu285CysfsX26)]. This case also illustrates that diagnosis could have been made without any pyridoxine withdrawal, thanks to the measurement of biomarkers. The patient was successfully treated with pyridoxine supplementation and currently shows normal neurological development.

[Assessment of a hypothermia protocol implementation for hypoxic-ischemic encephalopathy in term newborns]. / Évaluation d'un protocole de prise en charge de l'encéphalopathie anoxo-ischémique du nouveau-né par hypothermie.

BACKGROUND: A whole-body hypothermia protocol for term infants with hypoxic-ischemic encephalopathy (HIE) was implemented in our network in May 2004. The main objective of this study was to assess the feasibility of the protocol. The impact on the outcome was also assessed. METHODS: Monocentric retrospective study of all term infants admitted for HIE after the implementation of the protocol. The feasibility of the protocol was evaluated by its observance during the first 72 h. The neurodevelopmental outcome at 12 months of age of this population was compared with a historical control group. RESULTS: Twenty-five children were included. The protocol was not correctly applied for 8 children. The target temperature (33-34°C) was not reached for 3 infants. Four infants were admitted after 6h of age. In 1 infant, HIE was not diagnosed at admission. In the 17 patients with a good protocol observance, rectal temperature fell to the target temperature on average at 6.4h of age. The long-term follow-up rate was improved after the implementation of the protocol (100 % versus 92 % before protocol implementation). Death or neurodevelopmental disability occurred in 40 % during the protocol period versus 87 % before protocol implementation (p<0.01). CONCLUSIONS: The main limiting factor for implementation of whole-body hypothermia in infants with HIE is admission delay. The follow-up and the rate of death or disability in infants with HIE improved after implementing the protocol.

[Epileptic seizure and migraine visual aura: revisiting migralepsy]. / Aura visuelle migraineuse et crise épileptique: la migralepsie revisitée.

INTRODUCTION: The term of "migralepsy" has been proposed to define migraine-triggered epileptic seizures. Although already reported in the literature for more than fifty years, a number of observations remain debatable because of possible confusion between migraine and epileptic seizure clinical manifestations, including hemifield visual hallucinations, digestive signs and severe headache. OBSERVATION: We report on the case of a young patient suffering from both diseases, in whom a visual aura preceded either migraine attacks or epileptic generalized tonic-clonic seizure. Subtle modification in the primitive visual hallucination, which suddenly contained colored figures and was accompanied by fear before a prolonged loss of contact, suggested a continuum between migraine aura and epileptic seizure in this patient. Brain MRI was normal and EEG showed some sharp waves in the right posterior area. CONCLUSION: The presence of a neurophysiological continuum between migrainous aura and epileptic seizure is supported by this observation of "migralepsy". Recent findings from genetic and epidemiological studies further support this link.

[Temporal disconnection as an alternative treatment for intractable temporal lobe epilepsy: techniques, complications and results]. / Déconnexion du lobe temporal dans les épilepsies temporales pharmacorésistantes: techniques, complications et résultats.

Temporal lobe epilepsy (TLE) is the most common form of intractable partial epilepsy in adults. Surgery (lobectomy or amygdalohippocampectomy) is effective in most patients. However, some complications can occur and brain shift, hematoma into the post operative cavity and occulomotor nerve palsy have been reported due to the surgical technic. We report the technique, safety and efficacy of temporal disconnection in nonlesional TLE. Forty-seven patients (18 males, 29 females; handedness: 12 left, 33 right; aged 35 years+/-10; mean duration of epilepsy: 24+/-10 years) underwent temporal disconnection (20 left, 27 right) guided by neuronavigation. Sixteen patients (35 %) underwent additional presurgical evaluation with SEEG. The outcome was assessed using Engel's classification. At the two-year follow-up, 85 % of the patients were seizure-free (Engel I), 26 (58 %) of whom were Ia. Postoperative persistent morbidity included mild hemiparesis (n=1), mild facial paresis (n=1), quadranopsia (n=23) and hemianopia (n=1). Verbal memory worsened in 13 % of cases when the disconnection was performed in the dominant lobe. MRI follow-up showed two cases of nonsymptomatic thalamic or pallidal limited ischemias, two cases of temporal horn-cystic dilatation, one requiring surgical reintervention without sequelae. There was one case of postoperative phlebitis. In the seizure-free patient group, postoperative EEG showed interictal temporal spikes at three months, one year and two years located in the anterior temporal region. Temporal disconnection is effective, prevents the occurrence of subdural cyst and hematomas in the temporal cavity, prevents the occurrence of oculomotor palsy, and limits the occurrence of quadranopsia. However, comparative studies are required to evaluate temporal disconnection as an alternative to lobectomy in nonlesional TLE.

A novel microdialysis probe designed for clinical use: potential analytical and therapeutic applications.

Significant obstacles to the use of microdialysis in the clinic for diagnostic or therapeutic purposes include the production of dedicated entry port through the skull and the formation of a tract by the insertion of a probe into the parenchyma. We have developed a microdialysis probe that is minimally invasive and can be combined with an intracranial pressure probe, recording electrode, or other intracranial probe, that is minimally invasive. Yet the surface area of this probe is very high, permitting high recovery efficiencies even at relatively high flow rates. This probe design makes possible minimally invasive measurement of the peroxidation product, uric acid, and excitatory amino acids, two analytes that increase in experimental traumatic brain injury in animals. Moreover, its large surface area makes therapeutic applications of microdialysis probes in the brain potentially feasible. A pilot evaluation of the ability of microdialysis to have therapeutic benefit in limiting experimental excitotoxin lesions induced in rat striatum by N-methyl-D-aspartate (NMDA) is reported.

Effects of putative cognition enhancers on the NMDA receptor by [3H]MK801 binding.

Piracetam, aniracetam, and D-cycloserine were tested for their ability to reduce inhibition of [3H]MK801 (dizocilpine) binding by 100 microM kynurenate. Piracetam (100 microM-1 mM) failed to reduce inhibition by kynurenate but stimulated [3H]MK801 binding in the absence of kynurenate. In contrast, D-cycloserine (30 microM-1 mM) and aniracetam markedly reduced this inhibition by kynurenate. Thus, cognition enhancers might function via at least some subtypes of NMDA receptors.

Modulation of platelet thromboxane and malonaldehyde by dietary vitamin E and linoleate.

Thromboxane (TXB2) and malonaldehyde (MDA) production by thrombin-stimulated washed platelet were evaluated in rats fed 6 combinations of dietary vitamin E (0, 100, 1000 ppm) and linoleate (6.5 and 17.0 en%) for 23 weeks. The molar ratio of MDA:TXB2 was consistently near 3 in all groups studied. In animals receiving the lower linoleate diets, TXB2 and MDA synthesis were inversely related to the dietary vitamin E concentrations and the levels of MDA and TXB2 were positively correlated (r = 0.99) with decreasing vitamin E in the diet. High dietary linoleate (17.0 en%), independent of vitamin E status, reduces TXB2 and MDA synthesis. The importance of dietary antioxidant on platelet prostanoid synthesis is discussed.