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

Spreading depression als endogener antiepileptischer Mechanismus: Das Zusammenspiel in der Grenzzone zwischen Migräne und Epilepsie

Background: Migraine and epilepsy are comorbid neurological diseases that have an intriguing relationship as similar genetic mutations and external stimuli trigger both conditions. While the resemblance of their clinical presentation can thus make a diagnosis difficult, the same prophylactic drugs, in turn, decrease attack frequency in both migraine and epilepsy. Spreading depression/depolarization (SD) and epileptic seizures represent their pathophysiological correlates and are triggered by hyperexcitability. Cortical SD describes an abrupt mass depolarization that creeps along the hemisphere and silences electrical activity for several minutes. In contrast, epileptic seizures rapidly recruit adjacent tissue into a hyperexcitable state. Objectives: To investigate whether epileptic seizures trigger SD, what determines the occurrence of SDs, and to what extent SD contributes to suppression and limitation of seizures. Methods: Four chemoconvulsants were used to induce focal neocortical and generalized seizures in an in vivo mouse model. Wildtype CD1 mice (n = 165), familial hemiplegic migraine mutant (n = 14) and transgenic mice (n = 18) were used. Seizure intensity and spread were quantified by an electrocorticogram, while generalized seizures were examined via intrahippocampal recordings. SDs were simultaneously detected via a slow direct current shift and Intrinsic Optical Imaging (IOS) in the cortex and hippocampus. Cerebral blood volume was used as a surrogate of seizure activity and measured via IOS. The effects of spontaneous, chemically, and optogenetically induced SDs were examined. Results: Focal neocortical and generalized seizures triggered multiple SDs. Severe seizure intensity and generalization were related to SD occurrence. Tetrodotoxin confirmed seizures as the only trigger of SD. SDs exerted an antiseizure effect, thereby inhibiting seizure intensity and limiting its spread. Chemically and optogenetically induced SDs showed a similar antiseizure effect. A single SD was capable of limiting the recurrence of seizures. The results could be reproduced in all mice strains. Pretreatment of the cortex with an SD 5 and 30 minutes before applying the chemoconvulsant prevented seizure development. Vice versa, the blockage of SDs with MK-801 resulted in greater expansion of the seizures. Conclusions: SD might function as an endogenous defense mechanism to diminish the occurrence of epileptic activity. Following the seizure suppression, SD manifests as a migraine aura. The data supports the understanding of migraine and epilepsy as related disorders linked by cortical hyperexcitability that either result in SD or seizures. It allows for a nuanced view of SD’s role in neurological disease and facilitates the identification of new therapy concepts for migraine and epilepsy.Hintergrund: Migräne und Epilepsie sind komorbide neurologische Erkrankungen, die in einer engen Beziehung stehen, da sie durch die gleichen externen Einflüsse sowie genetischen Mutationen getriggert werden. Während ihre ähnliche klinische Präsentation eine Diagnose erschweren kann, reduziert die gleiche Medikation wiederum die Episodenfrequenz in beiden Erkrankungen. Die Netzwerk-Phänomene Spreading Depression/Depolarization (SD) und epileptische Anfälle stellen hier die pathophysiologischen Korrelate dar und stehen in einer engen wechselseitigen Beziehung: Beide Phänomene werden durch eine Hypererregbarkeit des Kortex getriggert. SD liegt einer abrupten und intensiven Massendepolarisation zugrunde, breitet sich langsam im Kortex aus und supprimiert dort für einige Minuten hirnelektrische Aktivität. Im Gegensatz dazu rekrutieren epileptische Anfälle mit ihrer schnellen Ausbreitung benachbartes Hirngewebe in einen übererregten Zustand. Zielsetzung: Es soll untersucht werden, inwieweit epileptische Anfälle SDs triggern, welche Charakteristika SD-induzierende Anfälle aufweisen und inwieweit SDs zur Abschwächung und Limitierung von Anfällen beitragen. Methoden: Vier pharmakologische Anfällsmodelle wurden genutzt, um fokale neokortikale Anfälle und generalisierte Anfälle zu erzeugen. Es wurden Wildtyp- (n=165), transgene (n=18) und FHM1-Mäuse (n=14) genutzt. Ein Elektrokortikogramm wurde abgeleitet, um die Intensität und Expansion der epileptischen Anfälle zu erfassen. Systemisch induzierte Anfälle wurden über elektrophysiologische Messungen im Hippocampus beurteilt. Das Auftreten von SDs wurde simultan über die langsame Gleichstrompotenzialänderung im Kortex und Hippocampus, sowie über Intrinsic Optical Imaging (IOS) registriert. Das zerebrale Blutvolumen als metabolisches Korrelat einer gesteigerten neuronalen Aktivität wurde ebenfalls über IOS beurteilt. Es wurden Effekte spontaner, chemisch und optogenetisch induzierter SDs quantifiziert. Ergebnisse: Fokale neokortikale und generalisierte Anfälle triggerten multiple SDs. Das Auftreten spontaner SDs korrelierte mit einer schwerwiegenderen Anfallsintensität und -generalisation. SDs übten einen antiepileptischen Effekt auf den Anfall aus und schwächten sowohl Intensität als auch eine Generalisation. Chemisch und optogenetisch induzierte SDs zeigten einen ebenso potenten antiepileptischen Effekt. Eine einzelne SD konnte ein Wiederauftreten des Anfalls verhindern. Die Ergebnisse konnten in allen Maus-Stämmen reproduziert werden. Eine Vorbehandlung des Kortex mit einer einzelnen SD fünf bzw. 30 Minuten vor Applikation der epileptogenen Substanz verhinderte die Bildung eines Anfalls. Eine Inhibition von SDs mit MK-801 führte umgekehrt zu einer ausgedehnteren Generalisation. Schlussfolgerung: SD als endogener antiepileptischer Mechanismus kann epileptische Anfälle ausbremsen, um dann klinisch als Aura in Erscheinung zu treten. Die Daten festigen die These, dass Migräne und Epilepsie zwei sich überschneidende Erkrankungen darstellen, bei denen die Übererregbarkeit des Kortex entweder eine SD oder Anfälle triggert. Dies erlaubt einen nuancierten Blick auf das Phänomen SD in neurologischen Erkrankungen und erleichtert die Identifikation neuer Therapie- Strategien bei Migräne und Epilepsie

Development and application of inhibitory luminopsins for the treatment of epilepsy

Optogenetics has shown great promise as a direct neuromodulatory tool for halting seizure activity in various animal models of epilepsy. However, light delivery into the brain is still a major practical challenge that needs to be addressed before future clinical translation is feasible. Not only does light delivery into the brain require surgically implanted hardware that can be both invasive and restrictive, but it is also difficult to illuminate large or complicated structures in the brain due to light scatter and attenuation. We have bypassed the challenges of external light delivery by directly coupling a bioluminescent light source (a genetically encoded Renilla luciferase) to an inhibitory opsin (Natronomonas halorhodopsin) as a single fusion protein, which we term an inhibitory luminopsin (iLMO). iLMOs were developed and characterized in vitro and in vivo using intracellular recordings, multielectrode arrays, and behavioral testing. iLMO2 was shown to generate hyperpolarizing outward currents in response to both external light and luciferase substrate, which was sufficient to suppress action potential firing and synchronous bursting activity in vitro. iLMO2 was further shown to suppress single-unit firing rate and local field potentials in the hippocampus of anesthetized and awake animals. Finally, expression of iLMO was scaled up to multiple structures of the basal ganglia to modulate rotational behavior of freely moving animals in a hardware-independent fashion. iLMO2 was further utilized to acutely suppress focal epileptic discharges induced by intracerebral injection of bicuculline and generalized seizures resulting from systemic administration of pentylenetetrazol. Inhibitory luminopsins have enabled the possibility of optogenetic inhibition of neural activity in a non-invasive and hardware-independent fashion. This work increases the versatility, scalability, and practicality of utilizing optogenetic approaches for halting seizure activity in vivo.Ph.D

Optimizing electrical brain stimulation for seizure disorders

University of Minnesota Ph.D. dissertation. March 2017. Major: Neuroscience. Advisor: Theoden Netoff. 1 computer file (PDF); x, 145 pages.Approximately 1% of the world population is afflicted with Epilepsy. For many patients, antiepileptic drugs do not fully control seizures. Electrical brain stimulation therapies have been effective in reducing seizure rates in some patients. While current neuromodulation devices provide a benefit to patients, efficacy can be improved by optimizing brain stimulation so that the therapy is tuned on a patient by patient basis. One optimization approach is to target deep brain regions that strongly modulate seizure prone regions. I will present data on the effects of stimulation of two different anatomical regions for seizure control, and establish my experimental platform for testing closed-loop algorithms. There are two general methods to implementing closed-loop algorithms to modulate neural activity: 1) Model-free algorithms that require a learning period to establish an optimal mapping between neural states and best therapeutic parameters, and 2) Model-based algorithms that use forward predictions of the neural system to determine the appropriate stimulation therapy to be administered. In this thesis, I will propose and test two closed-loop control schemes to control the brain activity to prevent epileptogenic activity while reducing stimulation energy. I will also present techniques to remove stimulation artifacts so that neural biomarkers can be measured while simultaneously applying stimulation. The methods I will present could potentially be implemented in next generation electrical brain stimulation hardware for seizure disorders and other neurological diseases

Design and performance assessment of a solid-state microcooler for thermal neuromodulation

It is well known that neural activity can be modulated using a cooling device. The applications of this technique range from the treatment of medication-resistant cerebral diseases to brain functional mapping. Despite the potential benefits of such technique, its use has been limited due to the lack of suitable thermal modulators. This paper presents the design and validation of a solid-state cooler that was able to modulate the neural activity of rodents without the use of large and unpractical water pipes. A miniaturized thermal control solution based exclusively on solid-state devices was designed, occupying only 5 mm × 5 mm × 3 mm, and featuring the potential for wireless power and communications. The cold side of the device was cooled to 26 °C, while the hot side was kept below 43 °C. This range of temperatures is compatible with brain cooling and efficient enough for achieving some control of neural activity.This work is supported by Foundation for Science and Technology (FCT) with the reference project PTDC/EEI-TEL/5250/2014, by FEDER funds through Projecto 3599 - Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas (3599-PPCDT) and by grant SFRH/BD/100649/2014