Long-term evaluation of anterior thalamic deep brain stimulation for epilepsy in the European MORE registry.

OBJECTIVE: Short-term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) were reported for people with drug-resistant focal epilepsy (PwE). Because long-term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT-DBS. METHODS: In this multicenter registry, PwE with ANT-DBS were followed up for safety, efficacy, and battery longevity. Follow-up ended after 5 years or upon study closure. Clinical characteristics and stimulation settings were compared between PwE with no benefit, improvers, and responders, that is, PwE with average monthly seizure frequency reduction rates of ≥50%. RESULTS: Of 170 eligible PwE, 104, 62, and 49 completed the 3-, 4-, and 5-year follow-up, respectively. Most discontinuations (68%) were due to planned study closure as follow-up beyond 2 years was optional. The 5-year follow-up cohort had a median seizure frequency reduction from 16 per month at baseline to 7.9 per month at 5-year follow-up (p < .001), with most-pronounced effects on focal-to-bilateral tonic-clonic seizures (n = 15, 77% reduction, p = .008). At last follow-up (median 3.5 years), 41% (69/170) of PwE were responders. Unifocal epilepsy (p = .035) and a negative history of epilepsy surgery (p = .002) were associated with larger average monthly seizure frequency reductions. Stimulation settings did not differ between response groups. In 179 implanted PwE, DBS-related adverse events (AEs, n = 225) and serious AEs (n = 75) included deterioration in epilepsy or seizure frequency/severity/type (33; 14 serious), memory/cognitive impairment (29; 3 serious), and depression (13; 4 serious). Five deaths occurred (none were ANT-DBS related). Most AEs (76.3%) manifested within the first 2 years after implantation. Activa PC depletion (n = 37) occurred on average after 45 months. SIGNIFICANCE: MORE provides further evidence for the long-term application of ANT-DBS in clinical routine practice. Although clinical benefits increased over time, side effects occurred mainly during the first 2 years. Identified outcome modifiers can help inform PwE selection and management.

Ex Vivo Feedback Control of Neurotransmission Using a Photocaged Adenosine A1 Receptor Agonist.

We report the design, synthesis, and validation of the novel compound photocaged N6-cyclopentyladenosine (cCPA) to achieve precisely localized and timed release of the parent adenosine A1 receptor agonist CPA using 405 nm light. Gi protein-coupled A1 receptors (A1Rs) modulate neurotransmission via pre- and post-synaptic routes. The dynamics of the CPA-mediated effect on neurotransmission, characterized by fast activation and slow recovery, make it possible to implement a closed-loop control paradigm. The strength of neurotransmission is monitored as the amplitude of stimulus-evoked local field potentials. It is used for feedback control of light to release CPA. This system makes it possible to regulate neurotransmission to a pre-defined level in acute hippocampal brain slices incubated with 3 µM cCPA. This novel approach of closed-loop photopharmacology holds therapeutic potential for fine-tuned control of neurotransmission in diseases associated with neuronal hyperexcitability.

Recent Advances in the Use of Focused Ultrasound as a Treatment for Epilepsy.

Epilepsy affects about 1% of the population. Approximately one third of patients with epilepsy are drug-resistant (DRE). Resective surgery is an effective treatment for DRE, yet invasive, and not all DRE patients are suitable resective surgery candidates. Focused ultrasound, a novel non-invasive neurointerventional method is currently under investigation as a treatment alternative for DRE. By emitting one or more ultrasound waves, FUS can target structures in the brain at millimeter resolution. High intensity focused ultrasound (HIFU) leads to ablation of tissue and could therefore serve as a non-invasive alternative for resective surgery. It is currently under investigation in clinical trials following the approval of HIFU for essential tremor and Parkinson's disease. Low intensity focused ultrasound (LIFU) can modulate neuronal activity and could be used to lower cortical neuronal hyper-excitability in epilepsy patients in a non-invasive manner. The seizure-suppressive effect of LIFU has been studied in several preclinical trials, showing promising results. Further investigations are required to demonstrate translation of preclinical results to human subjects.

The European Academy of Neurology Brain Health Strategy: One brain, one life, one approach.

BACKGROUND AND PURPOSE: Brain health is essential for health, well-being, productivity and creativity across the entire life. Its definition goes beyond the absence of disease embracing all cognitive, emotional, behavioural and social functions which are necessary to cope with life situations. METHODS: The European Academy of Neurology (EAN) Brain Health Strategy responds to the high and increasing burden of neurological disorders. It aims to develop a non-disease-, non-age-centred holistic and positive approach ('one brain, one life, one approach') to prevent neurological disorders (e.g., Alzheimer's disease and other dementias, stroke, epilepsy, headache/migraine, Parkinson's disease, multiple sclerosis, sleep disorders, brain cancer) but also to preserve brain health and promote recovery after brain damage. RESULTS: The pillars of the EAN Brain Health Strategy are (1) to contribute to a global and international brain health approach (together with national and subspecialty societies, other medical societies, the World Health Organization, the World Federation of Neurology, patients' organizations, industry and other stakeholders); (2) to support the 47 European national neurological societies, healthcare and policymakers in the implementation of integrated and people-centred campaigns; (3) to foster research (e.g., on prevention of neurological disorders, determinants and assessments of brain health); (4) to promote education of students, neurologists, general practitioners, other medical specialists and health professionals, patients, caregivers and the general public; (5) to raise public awareness of neurological disorders and brain health. CONCLUSIONS: By adopting this 'one brain, one life, one approach' strategy in cooperation with partner societies, international organizations and policymakers, a significant number of neurological disorders may be prevented whilst the overall well-being of individuals is enhanced by maintaining brain health through the life course.

Chemogenetic Seizure Control with Clozapine and the Novel Ligand JHU37160 Outperforms the Effects of Levetiracetam in the Intrahippocampal Kainic Acid Mouse Model.

Expression of inhibitory designer receptors exclusively activated by designer drugs (DREADDs) on excitatory hippocampal neurons in the hippocampus represents a potential new therapeutic strategy for drug-resistant epilepsy. To overcome the limitations of the commonly used DREADD agonist clozapine, we investigated the efficacy of the novel DREADD ligand JHU37160 in chemogenetic seizure suppression in the intrahippocampal kainic acid (IHKA) mouse model for temporal lobe epilepsy (TLE). In addition, seizure-suppressing effects of chemogenetics were compared to the commonly used anti-epileptic drug (AED), levetiracetam (LEV). Therefore, an adeno-associated viral vector was injected in the sclerotic hippocampus of IHKA mice to induce expression of a tagged inhibitory DREADD hM4Di or only a tag (control) specifically in excitatory neurons using the CamKIIα promoter. Subsequently, animals were treated with LEV (800 mg/kg), clozapine (0.1 mg/kg), and DREADD ligand JHU37160 (0.1 mg/kg) and the effect on spontaneous seizures was investigated. Clozapine and JHU37160-mediated chemogenetic treatment both suppressed seizures in DREADD-expressing IHKA mice. Clozapine treatment suppressed seizures up to 34 h after treatment, and JHU37160 effects lasted for 26 h after injection. Moreover, both compounds reduced the length of seizures that did occur after treatment up to 28 h and 18 h after clozapine and JHU37160, respectively. No seizure-suppressing effects were found in control animals using these ligands. Chemogenetic seizure treatment suppressed seizures during the first 30 min after injection, and seizures remained suppressed during 8 h following treatment. Chemogenetics thus outperformed effects of levetiracetam (p < 0.001), which suppressed seizure frequency with a maximum of 55 ± 9% for up to 1.5 h (p < 0.05). Only chemogenetic and not levetiracetam treatment affected the length of seizures after treatment (p < 0.001). These results show that the chemogenetic therapeutic strategy with either clozapine or JHU37160 effectively suppresses spontaneous seizures in the IHKA mouse model, confirming JHU37160 as an effective DREADD ligand. Moreover, chemogenetic therapy outperforms the effects of levetiracetam, indicating its potential to suppress drug-resistant seizures.

Level of hM4D(Gi) DREADD Expression Determines Inhibitory and Neurotoxic Effects in the Hippocampus.

Selective neuromodulation using designer receptors exclusively activated by designer drugs (DREADDs) has become an increasingly important research tool, as well as an emerging therapeutic approach. However, the safety profile of DREADD expression is unknown. Here, different titers of adeno-associated viral (AAV) vector were administered in an attempt to vary total expression levels of the inhibitory DREADD hM4D(Gi) in excitatory hippocampal neurons. Male Sprague Dawley rats were injected with AAV2/7 encoding DREADD-mCherry, DREADD, or mCherry. Pronounced neuronal loss and neuroinflammatory reactions were observed after transduction with the high titer DREADD AAV, which also resulted in the highest DREADD expression levels. No such effects were observed in the mCherry control group, despite an equally high titer, nor in conditions where lower viral vector titers were injected. In the high titer DREADD conditions, dentate gyrus (DG) evoked potentials were inhibited on clozapine-induced activation of hM4D(Gi), while in low titer conditions DG evoked potentials were enhanced. Recordings of single neuronal activity nevertheless indicated a reduction in spontaneous firing of granule cell layer neurons. Our results indicate that prolonged, high levels of DREADD expression can have neurotoxic effects and that chemogenetic suppression of excitatory hippocampal neurons can paradoxically enhance DG evoked potentials.

Comparison of In Vivo and Ex Vivo Magnetic Resonance Imaging in a Rat Model for Glioblastoma-Associated Epilepsy.

Magnetic resonance imaging (MRI) is frequently used for preclinical treatment monitoring in glioblastoma (GB). Discriminating between tumors and tumor-associated changes is challenging on in vivo MRI. In this study, we compared in vivo MRI scans with ex vivo MRI and histology to estimate more precisely the abnormal mass on in vivo MRI. Epileptic seizures are a common symptom in GB. Therefore, we used a recently developed GB-associated epilepsy model from our group with the aim of further characterizing the model and making it useful for dedicated epilepsy research. Ten days after GB inoculation in rat entorhinal cortices, in vivo MRI (T2w and mean diffusivity (MD)), ex vivo MRI (T2w) and histology were performed, and tumor volumes were determined on the different modalities. The estimated abnormal mass on ex vivo T2w images was significantly smaller compared to in vivo T2w images, but was more comparable to histological tumor volumes, and might be used to estimate end-stage tumor volumes. In vivo MD images displayed tumors as an outer rim of hyperintense signal with a core of hypointense signal, probably reflecting peritumoral edema and tumor mass, respectively, and might be used in the future to distinguish the tumor mass from peritumoral edema-associated with reactive astrocytes and activated microglia, as indicated by an increased expression of immunohistochemical markers-in preclinical models. In conclusion, this study shows that combining imaging techniques using different structural scales can improve our understanding of the pathophysiology in GB.

Optimized Parameters for Transducing the Locus Coeruleus Using Canine Adenovirus Type 2 (CAV2) Vector in Rats for Chemogenetic Modulation Research.

INTRODUCTION: The locus coeruleus noradrenergic (LC-NA) system is studied for its role in various neurological and psychiatric disorders such as epilepsy and Major Depression Dissorder. Chemogenetics is a powerful technique for specific manipulation of the LC to investigate its functioning. Local injection of AAV2/7 viral vectors has limitations with regards to efficiency and specificity of the transduction, potentially due to low tropism of AAV2/7 for LC neurons. In this study we used a canine adenovirus type 2 (CAV2) vector with different volumes and viral particle numbers to achieve high and selective expression of hM3Dq, an excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD), for chemogenetic modulation of LC neurons. METHODS: Adult male Sprague-Dawley rats were injected in the LC with different absolute numbers of CAV2-PRSx8-hM3Dq-mCherry physical particles (0.1E9, 1E9, 5E9,10E9, or 20E9 pp) using different volumes (LowV = 3 nl × 300 nl, MediumV = 3 × 600 nl, HighV = 3 × 1200 nl). Two weeks post-injection, double-labeling immunohistochemistry for dopamine ß hydroxylase (DBH) and mCherry was performed to determine hM3Dq expression and its specificity for LC neurons. The size of the transduced LC was compared to the contralateral LC to identify signs of toxicity. RESULTS: Administration of Medium volume (3 × 600 nl) and 1E9 particles resulted in high expression levels with 87.3 ± 9.8% of LC neurons expressing hM3Dq, but low specificity with 36.2 ± 17.3% of hM3Dq expression in non-LC neurons. The most diluted conditions (Low volume_0.1E pp and Medium Volume_0.1E pp) presented similar high transduction of LC neurons (70.9 ± 12.7 and 77.2 ± 9.8%) with lower aspecificity (5.5 ± 3.5 and 4.0 ± 1.9%, respectively). Signs of toxicity were observed in all undiluted conditions as evidenced by a decreased size of the transduced LC. CONCLUSION: This study identified optimal conditions (Low and Medium Volume with 0.1E9 particles of CAV2-PRSx8-hM3Dq-mCherry) for safe and specific transduction of LC neurons with excitatory DREADDs to study the role of the LC-NA system in health and disease.

Attenuation of Hippocampal Evoked Potentials in vivo by Activation of GtACR2, an Optogenetic Chloride Channel.

AIM: GtACR2, a light-activated chloride channel, is an attractive tool for neural inhibition as it can shunt membrane depolarizations. In this study, we assessed the effect of activating GtACR2 on in vivo hippocampal CA1 activity evoked by Schaffer collateral (SC) stimulation. METHODS: Adult male Wistar rats were unilaterally injected with 0.5 µL of adeno associated viral vector for induction of GtACR2-mCherry (n = 10, GtACR2 group) or mCherry (n = 4, Sham group) expression in CA1 pyramidal neurons of the hippocampus. Three weeks later, evoked potentials (EPs) were recorded from the CA1 subfield placing an optrode (bipolar recording electrode attached to an optic fiber) at the injection site and a stimulation electrode targeting SCs. Effects of illumination parameters required to activate GtACR2 such as light power densities (LPDs), illumination delays, and light-pulse durations were tested on CA1 EP parameters [population spike (PS) amplitude and field excitatory postsynaptic potential (fEPSP) slope]. RESULTS: In the GtACR2 group, delivery of a 10 ms light-pulse induced a negative deflection in the local field potential which increased with increasing LPD. When combined with electrical stimulation of the SCs, light-induced activation of GtACR2 had potent inhibitory effects on CA1 EPs. An LPD of 160 mW/mm2 was sufficient to obtain maximal inhibition CA1 EPs. To quantify the duration of the inhibitory effect, a 10 ms light-pulse of 160 mW/mm2 was delivered at increasing delays before the CA1 EPs. Inhibition of EPs was found to last up to 9 ms after the cessation of the light-pulse. Increasing light-pulse durations beyond 10 ms did not result in larger inhibitory effects. CONCLUSION: Precisely timed activation of GtACR2 potently blocks evoked activity of CA1 neurons. The strength of inhibition depends on LPD, lasts up to 9 ms after a light-pulse of 10 ms, and is independent of the duration of the light-pulse given.

Long-term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy.

OBJECTIVE: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. METHODS: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. RESULTS: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. SIGNIFICANCE: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.

Development of a Rat Model for Glioma-Related Epilepsy.

Seizures are common in patients with high-grade gliomas (30-60%) and approximately 15-30% of glioblastoma (GB) patients develop drug-resistant epilepsy. Reliable animal models are needed to develop adequate treatments for glioma-related epilepsy. Therefore, fifteen rats were inoculated with F98 GB cells (GB group) and four rats with vehicle only (control group) in the right entorhinal cortex. MRI was performed to visualize tumor presence. A subset of seven GB and two control rats were implanted with recording electrodes to determine the occurrence of epileptic seizures with video-EEG recording over multiple days. In a subset of rats, tumor size and expression of tumor markers were investigated with histology or mRNA in situ hybridization. Tumors were visible on MRI six days post-inoculation. Time-dependent changes in tumor morphology and size were visible on MRI. Epileptic seizures were detected in all GB rats monitored with video-EEG. Twenty-one days after inoculation, rats were euthanized based on signs of discomfort and pain. This study describes, for the first time, reproducible tumor growth and spontaneous seizures upon inoculation of F98 cells in the rat entorhinal cortex. The development of this new model of GB-related epilepsy may be valuable to design new therapies against tumor growth and associated epileptic seizures.

A Feasibility Study to Investigate Chemogenetic Modulation of the Locus Coeruleus by Means of Single Unit Activity.

AIM: Selective chemogenetic modulation of locus coeruleus (LC) neurons would allow dedicated investigation of the role of the LC-NA pathway in brain excitability and disorders such as epilepsy. This study investigated the feasibility of an experimental set-up where chemogenetic modification of the brainstem locus coeruleus NA neurons is aimed at and followed by LC unit activity recording in response to clozapine. METHODS: The LC of male Sprague-Dawley rats was injected with 10 nl of adeno-associated viral vector AAV2/7-PRSx8-hM3Dq-mCherry (n = 19, DREADD group) or AAV2/7-PRSx8-eGFP (n = 13, Controls). Three weeks later, LC unit recordings were performed in anesthetized rats. We investigated whether clozapine, a drug known to bind to modified neurons expressing hM3Dq receptors, was able to increase the LC firing rate. Baseline unit activity was recorded followed by subsequent administration of 0.01 and 0.1 mg/kg of clozapine in all rats. hM3Dq-mcherry expression levels were investigated using immunofluorescence staining of brainstem slices at the end of the experiment. RESULTS: Unit recordings could be performed in 12 rats and in a total of 12 neurons (DREADDs: n = 7, controls: n = 5). Clozapine 0.01 mg/kg did not affect the mean firing rate of recorded LC-neurons; 0.1 mg/kg induced an increased firing rate, irrespective whether neurons were recorded from DREADD or control rats (p = 0.006). Co-labeling of LC neurons and mCherry-tag showed that 20.6 ± 2.3% LC neurons expressed the hM3Dq receptor. Aspecific expression of hM3Dq-mCherry was also observed in non-LC neurons (26.0 ± 4.1%). CONCLUSION: LC unit recording is feasible in an experimental set-up following manipulations for DREADD induction. A relatively low transduction efficiency of the used AAV was found. In view of this finding, the effect of injected clozapine on LC-NA could not be investigated as a reliable outcome parameter for activation of chemogenetically modified LC neurons. The use of AAV2/7, a vector previously applied successfully to target dopaminergic neurons in the substantia nigra, leads to insufficient chemogenetic modification of the LC compared to transduction with AAV2/9.

The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor.

Adenosine acts as an endogenous anticonvulsant and seizure terminator in the brain. Many of its anticonvulsive effects are mediated through the activation of the adenosine A1 receptor, a G protein-coupled receptor with a wide array of targets. Activating A1 receptors is an effective approach to suppress seizures. This review gives an overview of the neuronal targets of the adenosine A1 receptor focusing in particular on signaling pathways resulting in neuronal inhibition. These include direct interactions of G protein subunits, the adenyl cyclase pathway and the phospholipase C pathway, which all mediate neuronal hyperpolarization and suppression of synaptic transmission. Additionally, the contribution of the guanyl cyclase and mitogen-activated protein kinase cascades to the seizure-suppressing effects of A1 receptor activation are discussed. This review ends with the cautionary note that chronic activation of the A1 receptor might have detrimental effects, which will need to be avoided when pursuing A1 receptor-based epilepsy therapies.

Long-term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy.

OBJECTIVE: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. METHODS: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. RESULTS: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. SIGNIFICANCE: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Electroencephalography in epilepsy: look for what could be beyond the visual inspection.

Since its starting point in 1929, human scalp electroencephalography (EEG) has been routinely interpreted by visual inspection of waveforms using the assumption that the activity at a given electrode is a representation of the activity of the cerebral cortex under it, but such a method has some limitations. In this review, we will discuss three advanced methods to obtain valuable information from scalp EEG in epilepsy using innovative technologies. Authors who had previous publications in the field provided a narrative review. Spike voltage topography of interictal spikes is a potential way to improve non-invasive EEG localization in focal epilepsies. Electrical source imaging is also a complementary technique in localization of the epileptogenic zone in patients who are candidates for epilepsy surgery. Quantitative EEG simplifies the large amount of information in continuous EEG by providing a static graphical display. Scalp electroencephalography has the potential to offer more spatial and temporal information than the traditional way of visual inspection alone in patients with epilepsy. Fortunately, with the help of modern digital EEG equipment and computer-assisted analysis, this information is more accessible.

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.

Diagnostic accuracy of interictal source imaging in presurgical epilepsy evaluation: A systematic review from the E-PILEPSY consortium.

OBJECTIVE: Interictal high resolution (HR-) electric source imaging (ESI) and magnetic source imaging (MSI) are non-invasive tools to aid epileptogenic zone localization in epilepsy surgery candidates. We carried out a systematic review on the diagnostic accuracy and quality of evidence of these modalities. METHODS: Embase, Pubmed and the Cochrane database were searched on 13 February 2017. Diagnostic accuracy studies taking post-surgical seizure outcome as reference standard were selected. Quality appraisal was based on the QUADAS-2 framework. RESULTS: Eleven studies were included: eight MSI (n = 267), three HR-ESI (n = 127) studies. None was free from bias. This mostly involved: selection of operated patients only, interference of source imaging with surgical decision, and exclusion of indeterminate results. Summary sensitivity and specificity estimates were 82% (95% CI: 75-88%) and 53% (95% CI: 37-68%) for overall source imaging, with no statistical difference between MSI and HR-ESI. Specificity is higher when partially concordant results were included as non-concordant (p < 0.05). Inclusion of indeterminate test results as non-concordant lowered sensitivity (p < 0.05). CONCLUSIONS: Source imaging has a relatively high sensitivity but low specificity for identification of the epileptogenic zone. SIGNIFICANCE: We need higher quality studies allowing unbiased test evaluation to determine the added value and diagnostic accuracy of source imaging in the presurgical workup of refractory focal epilepsy.

Single-Cell Recordings to Target the Anterior Nucleus of the Thalamus in Deep Brain Stimulation for Patients with Refractory Epilepsy.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising treatment for patients with refractory epilepsy. However, therapy response varies and precise positioning of the DBS lead is potentially essential for maximizing therapeutic efficacy. We investigate if single-cell recordings acquired by microelectrode recordings can aid targeting of the ANT during surgery and hypothesize that the neuronal firing properties of the target region relate to clinical outcome. We prospectively included 10 refractory epilepsy patients and performed microelectrode recordings under general anesthesia to identify the change in neuronal signals when approaching and transecting the ANT. The neuronal firing properties of the target region, anatomical locations of microelectrode recordings and active contact positions of the DBS lead along the recorded trajectory were compared between responders and nonresponders to DBS. We obtained 19 sets of recordings from 10 patients (five responders and five nonresponders). Amongst the 403 neurons detected, 365 (90.6%) were classified as bursty. Entry into the ANT was characterized by an increase in firing rate while exit of the ANT was characterized by a decrease in firing rate. Comparing the trajectories of responders to nonresponders, we found differences neither in the neuronal firing properties themselves nor in their locations relative to the position of the active contact. Single-cell firing rate acquired by microelectrode recordings under general anesthesia can thus aid targeting of the ANT during surgery, but is not related to clinical outcome in DBS for patients with refractory epilepsy.

European trends in epilepsy surgery.

OBJECTIVE: Resective surgery is effective in treating drug-resistant focal epilepsy, but it remains unclear whether improved diagnostics influence postsurgical outcomes. Here, we compared practice and outcomes over 2 periods 15 years apart. METHODS: Sixteen European centers retrospectively identified 2 cohorts of children and adults who underwent epilepsy surgery in the period of 1997 to 1998 (n = 562) or 2012 to 2013 (n = 736). Data collected included patient (sex, age) and disease (duration, localization and diagnosis) characteristics, type of surgery, histopathology, Engel postsurgical outcome, and complications, as well as imaging and electrophysiologic tests performed for each case. Postsurgical outcome predictors were included in a multivariate logistic regression to assess the strength of date of surgery as an independent predictor. RESULTS: Over time, the number of operated cases per center increased from a median of 31 to 50 per 2-year period (p = 0.02). Mean disease duration at surgery decreased by 5.2 years (p < 0.001). Overall seizure freedom (Engel class 1) increased from 66.7% to 70.9% (adjusted p = 0.04), despite an increase in complex surgeries (extratemporal and/or MRI negative). Surgeries performed during the later period were 1.34 times (adjusted odds ratio; 95% confidence interval 1.02-1.77) more likely to yield a favorable outcome (Engel class I) than earlier surgeries, and improvement was more marked in extratemporal and MRI-negative temporal epilepsy. The rate of persistent neurologic complications remained stable (4.6%-5.3%, p = 0.7). CONCLUSION: Improvements in European epilepsy surgery over time are modest but significant, including higher surgical volume, shorter disease duration, and improved postsurgical seizure outcomes. Early referral for evaluation is required to continue on this encouraging trend.

Modeling of intracerebral interictal epileptic discharges: Evidence for network interactions.

OBJECTIVE: The interictal epileptic discharges (IEDs) occurring in stereotactic EEG (SEEG) recordings are in general abundant compared to ictal discharges, but difficult to interpret due to complex underlying network interactions. A framework is developed to model these network interactions. METHODS: To identify the synchronized neuronal activity underlying the IEDs, the variation in correlation over time of the SEEG signals is related to the occurrence of IEDs using the general linear model. The interdependency is assessed of the brain areas that reflect highly synchronized neural activity by applying independent component analysis, followed by cluster analysis of the spatial distributions of the independent components. The spatiotemporal interactions of the spike clusters reveal the leading or lagging of brain areas. RESULTS: The analysis framework was evaluated for five successfully operated patients, showing that the spike cluster that was related to the MRI-visible brain lesions coincided with the seizure onset zone. The additional value of the framework was demonstrated for two more patients, who were MRI-negative and for whom surgery was not successful. CONCLUSIONS: A network approach is promising in case of complex epilepsies. SIGNIFICANCE: Analysis of IEDs is considered a valuable addition to routine review of SEEG recordings, with the potential to increase the success rate of epilepsy surgery.