Experimental treatment options in absence epilepsy

Contains fulltext : 182124.pdf (preprint version ) (Open Access)Background: The benign character of absence epilepsy compared to other genetic generalized epilepsy syndromes has often hampered the search for new treatment options. Absence epilepsy is most often treated with ethosuximide or valproic acid. However, both drugs are not always well tolerated or fail, and seizure freedom for a larger proportion of patients remains to be achieved. The availability of genuine animal models of epilepsy does allow to search for new treatment options not only for absence epilepsy perse but also for other genetic - previously called idiopathic - forms of epilepsy. The recent discovery of a highly excitable cortical zone in these models is considered as a new therapeutic target area. Methods: Here, we provide an overview regarding the search for new therapeutical options as has been investigated in the genetic rodent models (mainly WAG/Rij and GAERS) including drugs and whether antiepileptogenesis can be achieved, various types of electrical and optogenetical invasive stimulations, different types of non-invasive stimulation and finally whether absence seizures can be predicted and prevented. Results: Many factors determine either the cortical and or thalamic excitability or the interaction between cortex and thalamus and offer new possibilities for new anti-absence drugs, among others metabotropic glutamatergic positive and negative allosteric modulators. The inhibition of epileptogenesis by various drugs with its widespread consequences seems feasible, although its mechanisms remain obscure and seems different from the anti-absence action. Surgical intervention on the cortical zone initiating seizures, either with radiosurgery using synchrotron-generated microbeams, or ablation techniques might reduce spike-and-wave discharges in the rodent models. High frequency electrical subcortical or cortical stimulation might be a good way to abort ongoing spike-and-wave discharges. In addition, possibilities for prevention with real-time EEG analyses in combination with electrical stimulation could also be a way to fully control these seizures. Conclusion: Although it is obvious that some of these treatment possibilities will not be used for absence epilepsy and/or need to be further developed, all can be considered as proof of principle and provide clear directives for further developments

Pump-Turbine Rotor-Stator Interactions in Generating Mode: Pressure Fluctuation in Distributor Channel

Investigation of the rotor-stator interactions of a reduced-scale model 0.19 ν= pump-turbine in generating mode is presented for the maximum discharge operating condition. This operating point is chosen in order to have the most important rotor-stator interactions. The numerical simulation of the unsteady flow is performed with CFX 5.7™ for a computing domain which is extended to the full pump-turbine from the spiral casing to the draft tube. A computing domain embracing the full geometry enables to minimize the errors, streaming focus the boundary conditions, the periodic interface or the pitch ratio of rotor-stator interface. It also allows considering the fully non uniformity of the in coming flow field from the spiral casing. The pressure measurements are performed with piezoresitive miniature pressure sensors located in the distributor channels. The pressure fluctuations for one distributor channel obtained from the numerical simulation present a very good agreement with experimental data. The numerical result analysis shows, how the pressure fluctuations at blade passage frequency (BPF) and its harmonics vary along a distributor channel of the pumpturbine. The maximum pressure amplitude of BPF occurs in the rotor-stator zone, but it decreases very fast backward to the stay vane. However, the pressure amplitude of the first harmonic corresponding to 2 times the blade passage frequency spreads to the spiral casing highlighting the -2 precessing diametrical mode resulting from the modulation of the interacting stationary and rotating flow field

Retinoic acid degradation shapes zonal development of vestibular organs and sensitivity to transient linear accelerations

Each vestibular sensory epithelium in the inner ear is divided morphologically and physio- logically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)- mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions

Progress and outlooks in a genetic absence epilepsy model (WAG/Rij)

Item does not contain fulltextThe WAG/Rij model is a well characterized and validated genetic animal epilepsy model in which the for absence epilepsy highly characteristic spike-wave discharges (SWDs) develop spontaneously. In this review we discuss first some older and many new studies, with an emphasis on pharmacological and neurochemical studies towards the role of GABA and glutamate and the ion channels involved in the pathological firing patterns. Next, new insights and highlights from the last 5-10 years of reaearch in WAG/Rij rats are discussed. First, early environmental factors modulate SWD characteristics and antiepileptogenesis is possible. Also new is that the classically assumed association between sleep spindles and SWDs seems no longer valid as an explanatory role for the occurrence of SWDs in the genetic rodent models. A role of cortical and thalamic glial cells has been revealed, indicating a putative role for inflammatory cytokines. Neurophysiologic and signal analytical studies in this and in another rodent model (GAERS) point towards a cortical site of origin, that SWDs do not have a sudden onset, and propose a more important role for the posterior thalamus than was previously assumed. Finally it is proposed that the reticular nucleus of the thalamus might be heterogeneous with respect to its role in propagation and maintenance of SWDs. The presence of a well-established cortical region in which SWDs are elicited allows for research towards new non-invasive treatment options, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). The first results show the feasibility of this new approach.18 p

Noninvasive transcranial direct current stimulation in a genetic absence model

Item does not contain fulltextThe proposed area of onset for absence epilepsy characteristic of spontaneously occurring spike and slow-wave discharges (SWDs) in the genetic absence rat model is the subgranular layer of the somatosensory cortex. Modulation of the hyperexcitable cortical foci by bilateral transcranial direct current stimulation (tDCS) might change the expression of SWDs. The effects of cathodal and anodal tDCS as well as cumulative effects of different intensities of repeated cathodal stimulation on EEG and behavior were examined. Cathodal tDCS reduced the number of SWDs during stimulation and affected the mean duration after stimulation both in an intensity-dependent manner. Behavior was changed after the highest stimulation intensity. Spectral analyses of the EEG during stimulation revealed an increase in sub-delta and delta frequency ranges, suggesting that cortical cells were hyperpolarized. Cathodal tDCS might be an effective non-invasive tool to decrease cortical excitability, presumably in focal zone in this genetic model

Being asleep while walking around? Modulation of thalamocortical oscillations in TRIP8B, an auxiliary subunit for HCN channels

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