Mathieu Sprengers

A decade of experience with deep brain stimulation for patients with refractory medial temporal lobe epilepsy

In this study, we present long-term results from patients with medial temporal lobe (MTL) epilepsy treated with deep brain stimulation (DBS). Since 2001, 11 patients (8M) with refractory MTL epilepsy underwent MTL DBS. When unilateral DBS failed to decrease seizures by > 90%, a switch to bilateral MTL DBS was proposed. After a mean follow-up of 8.5 years (range: 67-120 months), 6/11 patients had a ≥ 90% seizure frequency reduction with 3/6 seizure-free for > 3 years; three patients had a 40%-70% reduction and two had a < 30% reduction. In 3/5 patients switching to bilateral DBS further improved outcome. Uni- or bilateral MTL DBS did not affect neuropsychological functioning. This open study with an extended long-term follow-up demonstrates maintained efficacy of DBS for MTL epilepsy. In more than half of the patients, a seizure frequency reduction of at least 90% was reached. Bilateral MTL DBS may herald superior efficacy in unilateral MTL epilepsy.

The systemic kainic acid rat model of temporal lobe epilepsy: Long-term EEG monitoring

Animal models reproducing the characteristics of human epilepsy are essential for the elucidation of the pathophysiological mechanisms. In epilepsy research there is ongoing debate on whether the epileptogenic process is a continuous process rather than a step function. The aim of this study was to assess progression of epileptogenesis over the long term and to evaluate possible correlations between SE duration and severity with the disease progression in the kainic acid model. Rats received repeated KA injections (5mg/kg) until a self-sustained SE was elicited. Continuous depth EEG recording started before KA injection and continued for 30 weeks. Mean seizure rate progression could be expressed as a sigmoid function and increased from 1 ± 0.2 seizures per day during the second week after SE to 24.4 ± 6.4 seizures per day during week 30. Seizure rate progressed to a plateau phase 122 ± 9 days after SE. However, the individual seizure rate during this plateau phase varied between 14.5 seizures and 48.6 seizures per day. A circadian rhythm in seizure occurrence was observed in all rats. Histological characterization of damage to the dentate gyrus in the KA treated rats confirmed the presence of astrogliosis and aberrant mossy fiber sprouting in the dentate gyrus. This long-term EEG monitoring study confirms that epileptogenesis is a continuous process rather than a step function.

Neurostimulation for epilepsy.

Abstract Neurostimulation is an emerging treatment for neuropsychiatric disorders. Various neurostimulation modalities for epilepsy have been developed or are currently being investigated for efficacy and safety. Electrical stimulation of the tenth cranial nerve or vagus nerve stimulation (VNS) is indicated in patients with refractory epilepsy who are unsuitable candidates for epilepsy surgery or who have had insufficient benefit from such a treatment. For intracranial neurostimulation, stimulation electrodes are inserted into intracerebral targets in ‘deep brain stimulation’ (DBS) or placed over the cortical convexity for ‘cortical stimulation’ (CS) to administer electrical pulses to central nervous system structures. Several epilepsy centers around the world have recently reinitiated trials with DBS in different intracerebral structures such as the thalamus, the subthalamic nucleus, the caudate nucleus and medial temporal lobe structures. Also CS is being investigated in a multicenter trial and incorporated in a so called closed-loop system (the Responsive neurostimulator system, RNS). This bookchapter focuses on the mechanism of action, safety and efficacy of VNS and the different targets being investigated with DBS and CS.

Responsive neurostimulation in epilepsy

Various neurostimulation modalities have emerged in the field of epilepsy. Despite the fact that delivery of an electrical current to the hyperexcitable epileptic brain might, at first, seem contradictory, neurostimulation has become an established therapeutic option with a promising efficacy and adverse effects profile. In “responsive” neurostimulation the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or even prevent an upcoming seizure. The design of technology required for responsive stimulation is more challenging compared with devices for open-loop neurostimulation. The achievement of therapeutic success is dependent on adequate sensing and stimulation algorithms and a fast coupling between both. The benefits of delivering current only at the time of an approaching seizure merit further investigation. Current experience with responsive neurostimulation in epilepsy is still limited, but seems promising.

Clinical vagus nerve stimulation paradigms induce pronounced brain and body hypothermia in rats

Vagus nerve stimulation (VNS) is a widely used neuromodulation technique that is currently used or being investigated as therapy for a wide array of human diseases such as epilepsy, depression, Alzheimers disease, tinnitus, inflammatory diseases, pain, heart failure and many others. Here, we report a pronounced decrease in brain and core temperature during VNS in freely moving rats. Two hours of rapid cycle VNS (7s on/18s off) decreased brain temperature by around [Formula: see text]C, while standard cycle VNS (30[Formula: see text]s on/300[Formula: see text]s off) was associated with a decrease of around [Formula: see text]C. Rectal temperature similarly decreased by more than [Formula: see text]C during rapid cycle VNS. The hypothermic effect triggered by VNS was further associated with a vasodilation response in the tail, which reflects an active heat release mechanism. Despite previous evidence indicating an important role of the locus coeruleus-noradrenergic system in therapeutic effects of VNS, lesioning this system with the noradrenergic neurotoxin DSP-4 did not attenuate the hypothermic effect. Since body and brain temperature affect most physiological processes, this finding is of substantial importance for interpretation of several previously published VNS studies and for the future direction of research in the field.

Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy

&NA; See Lenck‐Santini (doi:10.1093/awx205) for a scientific commentary on this article. Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast‐spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy.

Disruption, but not overexpression of urate oxidase alters susceptibility to pentylenetetrazole‐ and pilocarpine‐induced seizures in mice

There is a continuous drive to find new, improved therapies that have a different mechanism of action in order to help diminish the sizable percentage of persons with pharmacoresistant epilepsy. Uric acid is increasingly recognized as contributing to the pathophysiology of multiple disorders, and there are indications that uric acid might play a role in epileptic mechanisms. Nevertheless, studies that directly investigate its involvement are lacking. In this study we assessed the susceptibility to pentylenetetrazole‐ and pilocarpine‐induced seizures in mice with genetically altered uric acid levels by targeting urate oxidase, which is the enzyme responsible for uric acid breakdown. We found that although disruption of urate oxidase resulted in a decreased susceptibility to all behavioral end points in both seizure models, overexpression did not result in any alterations when compared to their wild‐type littermates. Our results suggest that a chronic increase in uric acid levels may result in decreased brain excitability.

Closed loop neurostimulation for epilepsy

Various neurostimulation modalities have emerged in the field of epilepsy. Despite the fact that delivery of an electrical current to the hyperexcitable epileptic brain might, at first, seem contradictory, neurostimulation has become an established therapeutic option with a promising efficacy and adverse effects profile. In “responsive” neurostimulation the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or prevent an upcoming seizure. The design of technology required for responsive stimulation is more challenging compared to devices for open-loop neurostimulation. The achievement of therapeutic success is dependent on adequate sensing and stimulation algorithms and a fast coupling between both. The benefits of delivering current only at the time of an approaching seizure merit further investigation. Current experience with responsive neurostimulation in epilepsy is still limited, but seems promising.

Diepe hersenstimulatie (DHS) en corticale stimulatie (CS) als behandeling voor refractaire epilepsie: systematische review en meta-analyse

SamenvattingDiepe hersenstimulatie (DHS) en corticale stimulatie (CS) vormen mogelijke alternatieve behandelingsopties voor refractaire epilepsiepatiënten die, ondanks een optimale behandeling, niet volledig en/of blijvend aanvalsvrij zijn. Om de evidentie rond de doeltreffendheid en veiligheid van DHS en CS adequater te kunnen inschatten, verrichtten we een systematische review en meta-analyse waarbij alleen gerandomiseerde gecontroleerde studies (randomized controlled trials, RCT’s) voor inclusie in aanmerking kwamen. Onderzochte uitkomstparameters waren: aanvalsvrijheid, 50 % responder rate (dit is het aandeel patiënten met een aanvalsreductie van 50 % of meer), aanvalsfrequentie, bijwerkingen gerelateerd aan de stimulatie en/of de neurochirurgische ingreep, neuropsychologische uitkomst en levenskwaliteit. Van vijf verschillende stimulatiedoelwitten (targets) werd DHS of CS eerder in RCT’s geëvalueerd: de nuclei anteriores thalami, de nucleus centromedianus thalami, de cortex cerebelli, de hippocampus, en responsieve stimulatie van de ictale aanvangszone. Per stimulatiedoelwit konden niet meer dan één tot drie RCT’s worden geïdentificeerd. Bij de meeste RCT’s was de steekproefgrootte beperkt en beliep de geblindeerde evaluatieperiode slechts één tot drie maanden. Er is evidentie van hoge kwaliteit dat DHS van de nuclei anteriores thalami en responsieve stimulatie van de ictale aanvangszone bij patiënten met (multi)focale epilepsie leiden tot een matige reductie van de aanvalsfrequentie, naast evidentie van matige kwaliteit voor een soortgelijk effect met DHS van de hippocampus bij patiënten met epilepsie vanuit de temporale kwab. Er is geen evidentie voor een significante impact op aanvalsvrijheid, 50 % responder rate of levenskwaliteit na stimulatie met een duur van één tot drie maanden. DHS van de nuclei anteriores thalami is geassocieerd met een toename van subjectieve geheugenklachten en zelfgerapporteerde depressie. Responsieve stimulatie van de ictale aanvangszone lijkt goed te worden verdragen. Er is onvoldoende evidentie om uitspraken te doen over de bijwerkingen van DHS van de hippocampus en de doeltreffendheid en veiligheid van cerebellaire CS en DHS van de nucleus centromedianus thalami. Er is behoefte aan meer, grote en goed opgezette RCT’s waarin onderzoek wordt gedaan naar DHS en CS.

Invasive brain stimulation in the treatment of epilepsy

Invasive brain stimulation has emerged as an alternative treatment for refractory epilepsy patients and an increasing number of trials evaluating its efficacy and safety have been published. Various brain structures have been targeted, including the cerebellum, the anterior and centromedian thalamic nucleus, the hippocampus, the ictal onset zone and the subt halamic and caudate nucleus. The rationale for each of these targets and the results obtained in open-label and randomized controlled trials (RCTs) are discussed, with particular emphasis on two large RCTs that investigated open-loop anterior thalamic deep brain stimulation and responsive stimulation of the ictal onset zone. We conclude that promising results have been published for most targets, mainly in open-label trials, and that more RCTs are needed.