ILAE genetics commission conference report: molecular analysis of complex genetic epilepsies.
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Epilepsy↗
Biomedical subjects
G Avanzini
Publications and source records attributed to G Avanzini.
Epileptic phenotypes associated with mitochondrial disorders.
OBJECTIVE: To define the clinical and EEG features of the epileptic syndromes occurring in adult and infantile mitochondrial encephalopathies (ME). METHODS: Thirty-one patients with recurrent and apparently unprovoked seizures associated with primary ME were included in the study. Diagnosis of ME was based on the recognition of a morphologic, biochemical, or molecular defect. RESULTS: Epileptic seizures were the first recognized symptom in 53% of the patients. Many adults (43%) and most infants (70%) had nontypical ME phenotypes. Partial seizures, mainly with elementary motor symptoms, and focal or multifocal EEG epileptiform activities characterized the epileptic presentation in 71% of the patients. Generalized myoclonic seizures were an early and consistent symptom only in the five patients with an A8344G mitochondrial DNA point mutation with classic myoclonus epilepsy with ragged red fibers (MERRF) syndrome or "overlapping" characteristics. Photoparoxysmal EEG responses were observed not only in patients with typical MERRF, but also in adult patients with ME with lactic acidosis and strokelike episodes (MELAS), or overlapping phenotypes, and in one child with Leigh syndrome. CONCLUSIONS: Epilepsy is an important sign in the early presentation of ME and may be the most apparent neurologic sign of nontypical ME, often leading to the diagnostic workup. Except for those with an A8344G mitochondrial DNA point mutation, most of our patients had partial seizures or EEG signs indicating a focal origin.
Adolescent↗
Positive response to immunomodulatory therapy in an adult patient with Rasmussen's encephalitis.
Rasmussen's encephalitis (RE) is a rare and progressive neurologic condition of uncertain etiology that typically has a childhood onset. The authors describe a 45-year-old woman with adult-onset progressive aphasia, right hemiparesis, severe drug refractory epilepsy, and left cerebral hemisphere atrophy. High-dose corticosteroids and plasmapheresis were not effective. She improved with high-dose therapy with human IV immunoglobulin.
Brain↗
Neuroprotective effects of lamotrigine and remacemide on excitotoxicity induced by glutamate agonists in isolated chick retina.
The possible neuroprotective effects of two recently developed antiepileptic compounds, lamotrigine (LTG) and remacemide (REMA), against glutamate agonist-induced excitotoxicity have been investigated in the isolated chick embryo retina model. Retina segments from 15- or 16-day-old embryos were incubated in 1 ml of balanced salt solution, at 25 degrees C for 30 min, in the presence or absence of N-methyl-d-aspartate (NMDA), kainic acid (KA), or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (10 to 200 microM). LTG, REMA, and the active desglycinyl metabolite of REMA (d-REMA) (10-200 microM) were added separately 5 min before glutamate agonists. Retina damage was assessed after 24 h (i) by measuring LDH activity present in the medium, expressed as percentage of total retina LDH activity, and (ii) by histological analysis of retina specimens through scoring for the presence or absence of edema, necrosis, nuclear pyknosis, and cell layer damage. LTG, REMA, and d-REMA reduced LDH release produced by NMDA 58-70% in a dose-dependent manner, with d-REMA being the most potent (EC(50): d-REMA, 25.75 +/- 3.27 microM; REMA, 64.75 +/- 7.75 microM; LTG, 60.50 +/- 6.80 microM; P < 0.001). The drugs had less effect on the LDH release produced by AMPA and KA. Histological analysis confirmed these biochemical results, with all three compounds reducing edema and the number of necrotic and pyknotic nuclei in the ganglion layer. d-REMA provided almost complete protection of the ganglion cell layer against damage produced by NMDA. Combinations of d-REMA and LTG showed additive rather than potentiative effects against NMDA-induced cell injury. The present data provide pharmacological evidence that LTG, REMA, and d-REMA decrease glutamate agonist-induced excitotoxicity in isolated chick retina, findings that might have therapeutic implications for various neurological disorders.
Acetamides↗
Cortical reorganization and seizure generation in dysplastic cortex.
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Animals↗
Interictal spikes in focal epileptogenesis.
Interictal electroencephalography (EEG) potentials in focal epilepsies are sustained by synchronous paroxysmal membrane depolarization generated by assemblies of hyperexcitable neurons. It is currently believed that interictal spiking sets a condition that preludes to the onset of an ictal discharge. Such an assumption is based on little experimental evidence. Human pre-surgical studies and recordings in chronic and acute models of focal epilepsy showed that: (i) interictal spikes (IS) and ictal discharges are generated by different populations of neuron through different cellular and network mechanisms; (ii) the cortical region that generates IS (irritative area) does not coincide with the ictal-onset area; (iii) IS frequency does not increase before a seizure and is enhanced just after an ictal event; (iv) spike suppression is found to herald ictal discharges; and (v) enhancement of interictal spiking suppresses ictal events. Several experimental evidences indicate that the highly synchronous cellular discharge associated with an IS is generated by a multitude of mechanisms involving synaptic and non-synaptic communication between neurons. The synchronized neuronal discharge associated with a single IS induces and is followed by a profound and prolonged refractory period sustained by inhibitory potentials and by activity-dependent changes in the ionic composition of the extracellular space. Post-spike depression may be responsible for pacing interictal spiking periodicity commonly observed in both animal models and human focal epilepsies. It is proposed that the strong after-inhibition produced by IS protects against the occurrence of ictal discharges by maintaining a low level of excitation in a general condition of hyperexcitability determined by the primary epileptogenic dysfunction.
Action Potentials↗
Cortical myoclonus in Janz syndrome.
OBJECTIVE: To evaluate the characteristics of EEG paroxysms and the relationship between EEG spikes and ictal myoclonic jerks in patients with juvenile myoclonic epilepsy (JME). METHODS: Six patients with a typical form of JME entered the study and underwent computerized polygraphic recordings. In each patient, the inter-peak spike interval was measured on repeated EEG bursts, and jerk-locked back averaging was performed on ictal epochs using a time window including the 100 ms before and the 100-200 ms after the point at which the jerk-related EMG potential diverged from baseline. RESULTS: In all cases, the myoclonic jerks were associated with polyspike waves (PSW) complexes. The frequency of repeated spikes within the PSW complex ranged from 16 to 27 Hz. Jerk-locked averaging revealed a positive-negative EEG transient with maximal amplitude on the frontal leads, which preceded the myoclonic jerk by 10.25+/-0.96 ms. A delay of 9.50+/-1.73 ms was measured between the jerk-locked positive peak detected on the frontal EEG leads of the two hemispheres; a comparable time lag was observed between the onset of myoclonic jerks in the two deltoid muscles. CONCLUSIONS: Our data suggest that the ultimate mechanism responsible for ictal myoclonic jerks in JME is largely similar to that sustaining cortical myoclonus in more severe pathological conditions such as progressive myoclonus epilepsies, despite the different pathogenic substrate and triggering mechanisms.
Adolescent↗
Potentially epileptogenic dysfunction of cortical NMDA- and GABA-mediated neurotransmission in Otx1-/- mice.
Knockout Otx1 mice present a microcephalic phenotype mainly due to reduced deep neocortical layers and spontaneous recurrent seizures. We investigated the excitable properties of layer V pyramidal neurons in neocortical slices prepared from Otx1-/- mice and age-matched controls. The qualitative firing properties of the neurons of Otx1-/- mice were identical to those found in wild-type controls, but the proportion of intrinsically bursting (IB) neurons was significantly smaller. This is in line with the lack of the Otx1 gene contribution to the generation and differentiation of neurons destined for the deep neocortical layers, in which IB neurons are located selectively in wild-type rodents. The pyramidal neurons recorded in Otx1-/- mice responded to near-threshold electrical stimulation of the underlying white matter, with aberrant polysynaptic excitatory potentials often leading to late action potential generation. When the strength of the stimulus was increased, the great majority of the Otx1-/- neurons (78%) responded with a prominent biphasic inhibitory postsynaptic potential that was significantly larger than that observed in the wild-type mice, and was often followed by complex postinhibitory depolarizing events. Both late excitatory postsynaptic potentials and postinhibitory excitation were selectively suppressed by NMDA receptor antagonists, but not by AMPA antagonists. We conclude that the cortical abnormalities of Otx1-/- neocortex due to a selective loss of large projecting neurons lead to a complex rearrangement of local circuitry, which is characterized by an excess of N-methyl-d-aspartate-mediated polysynaptic excitation that is counteracted by GABA-mediated inhibition in only a limited range of stimulus intensity. Prominent postsynaptic inhibitory potentials may also act as a further pro-epileptogenic event by synchronizing abnormal excitatory potentials.
2-Amino-5-phosphonovalerate↗
Generalized epileptic disorders: an update.
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Animals↗
Protein kinase C-dependent modulation of Na+ currents increases the excitability of rat neocortical pyramidal neurones.
The effect of the protein kinase C (PKC) activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) on TTX-sensitive Na+ currents in neocortical pyramidal neurones was evaluated using voltage-clamp and intracellular current-clamp recordings. In pyramid-shaped dissociated neurones, the addition of OAG to the superfusing medium consistently led to a 30% reduction in the maximal peak amplitude of the transient sodium current (I(Na,T)) evoked from a holding potential of -70 mV. We attributed this inhibitory effect to a significant negative shift of the voltage dependence of steady-state channel inactivation (of approximately 14 mV). The inhibitory effect was completely prevented by hyperpolarising prepulses to potentials that were more negative than -80 mV. A small but significant leftward shift of INa,T activation was also observed, resulting in a slight increase of the currents evoked by test pulses at potentials more negative then -35 mV. In the presence of OAG, the activation of the persistent fraction of the Na+ current (INa,P) evoked by means of slow ramp depolarisations was consistently shifted in the negative direction by 3.9+/-0.5 mV, while the peak amplitude of the current was unaffected. In slice experiments, the OAG perfusion enhanced a subthreshold depolarising rectification affecting the membrane response to the injection of positive current pulses, and thus led the neurones to fire in response to significantly lower depolarising stimuli than those needed under control conditions. This effect was attributed to an OAG-induced enhancement of INa,P, since it was observed in the same range of potentials over which I(Na,P) activates and was completely abolished by TTX. The qualitative firing characteristics of both the intrinsically bursting and regular spiking neurones were unaffected when OAG was added to the physiological perfusing medium, but their firing frequency increased in response to slight suprathreshold depolarisations. The obtained results suggest that physiopathological events working through PKC activation can increase neuronal excitability by directly amplifying the I(Na,P)-dependent subthreshold depolarisation, and that this facilitating effect may override the expected reduction in neuronal excitability deriving from OAG-induced inhibition of the maximal INa, T peak amplitude.
Animals↗
Challenges for clinical neurophysiology.
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Cost Control↗
The role of the thalamus in vigilance and epileptogenic mechanisms.
OBJECTIVES: The most relevant results of studies on the anatomo-physiological substrate of the thalamic rhythmogenic mechanisms responsible for sleep spindles and spike-wave discharges are reviewed. METHODS: The reviewed experiments have been carried out in cats, rodents and other mammals with either in vivo or in vitro electrophysiological recording. RESULTS: The rhythmic bilateral and synchronous EEG activities underlying sleep spindles and spike-wave discharges have been found to be correlated with oscillatory patterns involving mutually interconnected cortical and thalamic neurons. These rhythmic patterns are generated in thalamic neurons when the membrane potential, which is modulated by aminergic and cholinergic systems, is set to a level where the low threshold calcium current is de-inactivated. The pacemaker structure responsible for the initiation of the thalamo-cortical oscillatory activities has been identified as the reticular thalamic nucleus, a GABAergic structure projecting exclusively to the other thalamic nuclei. Experiments carried out in GAERS (genetic absence epilepsy rat from Strasbourg) demonstrated in this rat model of inherited absence epilepsy an enhancement of the pacemaker properties of the thalamic nucleus, due to a genetically determined increase in the low threshold calcium current, which is responsible for the pathological synchronization underlying spike-wave discharges. CONCLUSIONS: Recent experiments confirm the longstanding hypothesis that spindles and spike-wave discharges share common mechanisms involving thalamo-cortical circuitry. Due to its unusual anatomic and functional organization the nucleus reticularis thalami plays a crucial role as pacemaker of these rhythmic EEG activities.
Animals↗
Quality of life and memory performance in patients with temporal lobe epilepsy.
OBJECTIVE: To explore the contribution of memory performance to quality of life (QOL) in patients with left or right temporal lobe epilepsy (TLE). SUBJECTS AND METHODS: Sixty-five patients with left or right TLE compiled the QOL in Epilepsy-89 Inventory (QOLIE-89), the State-Trait Anxiety Inventory (STAI) and the Hopelessness Scale (BDI) for self-evaluation of QOL and mood. Memory was assessed by tests of verbal and non-verbal memory and the Questionnaire of Memory Efficiency (QME). A neuropsychological battery was also administered to assess general intelligence, attention, visual perception, language, set shifting, word fluency and conceptual-motor tracking. RESULTS: On factor analysis, the neuropsychological battery and mood scales consisted of six factors (Memory, Mental Speed, Mood, Praxis, Sorting and Perception), while the QOLIE-89 consisted of five factors (Psychosocial Satisfaction, Epilepsy-Related Effects, Role, Physical Performance, Cognition). On regression analysis, overall QOLIE-89 score was predicted by the factor Mood and QME score. The QOLIE-89 factor Cognition was predicted by QME score and the Memory, Mental Speed, Perception and Praxis factors of the neuropsychological battery. CONCLUSION: In TLE patients self-reported memory, as assessed by QME, is an important predictor of QOL, and also correlates with performance on memory tests. This suggests that memory improvement by specific training may help to improve QOL in these patients.
Adolescent↗
Synaptic properties of neocortical neurons in epileptic mice lacking the Otx1 gene.
PURPOSE: The murine homeobox-containing Otx gene is required for correct nervous system and sense organ development. Otx1-/1 mice obtained by replacing Otx with the lac Z gene show developmental abnormalities of the cerebellum, mesencephalon, and cerebral cortex associated with spontaneous epileptic seizures (1). The epileptogenic mechanisms accounting for these seizures were investigated by means of electrophysiological recordings made from neocortical slices. METHODS: The 400-microm slices were prepared from the somatosensory cortex of Otx1-/- and Otx1+/+ mice, and the current clamp intracellular recordings were obtained from layer V pyramidal neurons by means of pipettes containing K+ acetate 1.5 mol/L and biocytin 2% (pH 7.3). RESULTS: Synaptic responses could be evoked in the neocortical pyramidal neurons by electrically stimulating the underlying white matter. gamma-Aminobutyric acid A/B-mediated inhibitory postsynaptic potentials were more pronounced in the Otx1-/- than in the control pyramidal neurons from the earliest postnatal period; multisynaptic excitatory postsynaptic potentials were significantly more expressed in the Otx1-/- mice also at the end of the first postnatal month, when they were only rarely encountered in controls. CONCLUSION: Excessive excitatory amino acid-mediated synaptic driving may lead to a hyperexcitable condition that is responsible for the epileptic manifestations occurring in Otx1-/- mice. This excess of excitation is not counteracted by well-developed gamma-aminobutyric acid activity, which seems to be involved in the synchronization of cell discharges. Our ongoing and more extensive comparative analysis of the mutants and controls should help to clarify the way in which the putative rearrangement taking place in Otx1-/- neocortex may lead to the excitatory hyperinnervation of layer V pyramidal neurons.
Animals↗
The concept of consciousness: a challenge for the neuroscientist.
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Arousal↗
Congenital malformations due to antiepileptic drugs.
To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.
Abnormalities, Drug-Induced↗
Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.
The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.
Anticonvulsants↗
Spectral properties of EEG fast activity ictal discharges associated with infantile spasms.
OBJECTIVE: The aim of this study was to evaluate the characteristics of the ictal EEG event accompanying infantile spasms. METHODS: Quantitative analysis was used, based on the application of a bivariate autoregressive (AR) parametric model; autospectra, coherence, phase functions and inter-hemispheric time differences were estimated on homologous EEG channels in 18 infants presenting with either cryptogenic or symptomatic West syndrome. RESULTS: The AR analysis of the 500 ms EEG epochs preceding spasm onset revealed the presence of a short discharge of fast activity restricted to a narrow frequency band in 13 of the 18 cases included in the study. The fast discharge peaked at 17.5+/-2.1 Hz, with rather low inter-hemispheric coherence values (0.52+/-0.17) and asymmetric amplitude on homologous EEG derivations. It persisted briefly after spasm onset, reaching a higher coherence value (0.71+/-0.16). The inter-hemispheric time difference, estimated in those cases with the coherence values significantly different from zero, ranged from 9.1 to 14.3 ms (11.4+/-1.9) in the epoch preceding spasm onset. CONCLUSION: The data obtained from the analysis of the ictal EEG events, compared with clinical and interictal EEG features, indicate that an asymmetric EEG pattern (mainly consisting of a rhythmic burst of fast activity) consistently preceded both symmetric and asymmetric spasms, thus suggesting a localized cortical origin of the ictal discharge giving rise to the spasms.
Age of Onset↗