Transcranial focal electrical stimulation via concentric ring electrodes in freely moving cats: Antiepileptogenic and postictal effects

Transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCRE), tripolar TFS, is proposed to treat pharmacoresistant epilepsy. We determined the effect of tripolar TFS on electrical amygdaloid kindling (AK) in freely moving cats. Fifteen cats were bilaterally implanted with electrodes in the amygdala (AM) and prefrontal cortex and assigned to three groups: the control group, which only received AK; the tripolar TFS before AK group, in which TCREs were placed over the vertex and tripolar TFS (300 Hz, 200 μs biphasic equal charge, square pulses) was delivered for 40 min just prior to AK; and the tripolar TFS after AK group, in which the TCREs were placed over the temporal bone ipsilateral to the kindled AM, while tripolar TFS was administered for 2 min just after AK onset for 40 days, and, thereafter, only AK was applied. AK was applied daily until all animals reached kindling stage VI. A three concentric spheres finite element cat head model was developed to analyze the electric fields caused by tripolar TFS. Tripolar TFS after AK inhibited kindling development. Animals with tripolar TFS after AK remained at the focal seizure stages for 20 days after tripolar TFS cessation and required 80.0 ± 15.42 AK stimulations to reach stage VI, significantly higher than TFS before AK, and control (P \u3c .001). Tripolar TFS before AK did not show signs of protection against epileptogenesis. The finite modeling of tripolar TFS showed that the electric field is \u3e0.3 mV/mm at depths less than approximately 12.6 mm in the cat brain, which should be strong enough to alter brain activity. In conclusion, tripolar TFS applied via a TCRE over the ipsilateral temporal area significantly delayed AK. This taken together with other reports of tripolar TFS aborting seizures in acute seizure models suggests that tripolar TFS is a promising new modality that should be considered for further testing

Novel therapies for epilepsy in the pipeline

Despite the availability of many antiepileptic drugs (AEDs) (old and newly developed) and, as recently suggested, their optimization in the treatment of patients with uncontrolled seizures, more than 30% of patients with epilepsy continue to experience seizures and have drug-resistant epilepsy; the management of these patients represents a real challenge for epileptologists and researchers. Resective surgery with the best rates of seizure control is not an option for all of them; therefore, research and discovery of new methods of treating resistant epilepsy are of extreme importance. In this article, we will discuss some innovative approaches, such as P-glycoprotein (P-gp) inhibitors, gene therapy, stem cell therapy, traditional and novel antiepileptic devices, precision medicine, as well as therapeutic advances in epileptic encephalopathy in children; these treatment modalities open up new horizons for the treatment of patients with drug-resistant epilepsy

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

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application.

Status epilepticus (SE) is a life-threatening neurological emergency often refractory to available treatment options. It is a very heterogeneous condition in terms of clinical presentation and causes, which besides genetic, vascular and other structural causes also include CNS or severe systemic infections, sudden withdrawal from benzodiazepines or anticonvulsants and rare autoimmune etiologies. Treatment of SE is essentially based on expert opinions and antiepileptic drug treatment per se seems to have no major impact on prognosis. There is, therefore, urgent need of novel therapies that rely upon a better understanding of the basic mechanisms underlying this clinical condition. Accumulating evidence in animal models highlights that inflammation ensuing in the brain during SE may play a determinant role in ongoing seizures and their long-term detrimental consequences, independent of an infection or auto-immune cause; this evidence encourages reconsideration of the treatment flow in SE patients

Characterising gene regulation during epileptogenesis in different models of epilepsy

As epilepsy develops an enormous range of changes occurs in neurons. This process, epileptogenesis, involves complex spatiotemporal alterations of neuronal homeostasis and neural networks. The molecular mechanism of epileptogenesis remains obscure and gene regulation during the epileptogenic process dynamically controls various signalling and functional pathways which play an important role in defining the mechanisms of epilepsy. This thesis explores gene regulation in different in vitro models of seizure like activity, and further focuses on the temporal profiles of molecular changes during an in vivo model of epilepsy. We seek to identify important regulators of epileptogenesis which may be the targets for further study of the mechanism of epilepsy in human. The High-K+, Low-Mg2+, Kainic acid, and Pentylenetetrazole models were used to elicit seizure like activity in cortical neuronal cultures. The tetanus toxin (TeNT) model of focal neocortical epilepsy in rats was utilised to characterise gene regulation in different time points: acute, subacute and chronic stages (48-72 hours, 2 weeks, and 30 days after first spontaneous seizure, respectively). A set of candidate genes relevant to epilepsy was selected to analyse changes in mRNA expression during these in vitro and in vivo models. The mRNA expression of the different candidate genes reveals diverse regulatory behaviours in different models, as well as at different time points during the process of epileptogenesis. The cell culture model treated with Low-Mg2+ for 72 hours displayed the most similar mRNA expression profile to the in vivo model of TeNT neocortical epilepsy during subacute to chronic stages. Furthermore, in the in vivo model, GFAP, mTOR, REST, and SNAP-25 are all temporarily apparently up-regulated during epileptogenesis, while CCL2 is strongly up-regulated later when epilepsy is established. Transient down-regulation of BDNF in the acute stage, and the distinctly lower expression of GABRA5 in late stage suggest that this GABAergic signalling pathway may be down-regulated in the late phase of epileptogenesis. Our work highlights how different candidate genes are differentially regulated during epileptogenesis, and how the regulation of individual genes changes as epileptogenesis progresses

Cell therapy in models for temporal lobe epilepsy

SummaryFor patients with refractory epilepsy it is important to search for alternative treatments. One of these potential treatments could be introducing new cells or modulating endogenous neurogenesis to reconstruct damaged epileptic circuits or to bring neurotransmitter function back into balance. In this review the scientific basis of these cell therapy strategies is discussed and the results are critically evaluated. Research on cell transplantation strategies has mainly been performed in animal models for temporal lobe epilepsy, in which seizure foci or seizure propagation pathways are targeted. Promising results have been obtained, although there remains a lot of debate about the relevance of the animal models, the appropriate target for transplantation, the suitable cell source and the proper time point for transplantation. From the presented studies it should be evident that transplanted cells can survive and sometimes even integrate in an epileptic brain and in a brain that is subjected to epileptogenic interventions. There is evidence that transplanted cells can partially restore damaged structures and/or release substances that modulate existent or induced hyperexcitability. Even though several studies show encouraging results, more studies need to be done in animal models with spontaneous seizures in order to have a better comparison to the human situation