1. CD8+ T cell-mediated epileptic neurodegeneration in limbic encephalitis associated with glutamic acid decarboxylase autoantibodies

G. Widman, A. Schulte-Mecklenbeck, J. A. Witt, A. Dik, J. Pitsch, K. S. Golombeck, J. Wagner, C. Mönig, C. Strippel, A. Johnen, T. Kuhlmann, H. Wiendl, C. E. Elger, S. G. Meuth, C. Helmstaedter, C. C. Gross, A. J. Becker, N. Melzer (Münster, Bonn; Germany)

Background: Autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) have been described in patients with a chronic slowly progressive form of non-paraneoplastic autoimmune limbic encephalitis (LE). Due to the intracellular localization of the target antigen GAD65, direct pathogenic effects of autoantibodies have been questioned. We therefore hy-pothesized a pathogenic role for T cells in GAD65-autoantibody associated LE.
Methods: We investigated the immune cell profile in 10 patients with typical GAD65-autoantibody-associated LE compared to 24 controls in a cross-sectional manner in both peripheral blood and cerebrospinal fluid by using multi-parameter flow cytometry and related these findings to structural cerebral changes on magnetic resonance imaging (MRI) and deficits upon neuropsychological testing. These data were linked to neuropathological findings in selective amygdalohippocampectomy specimen from 2 patients with GAD65 autoantibody-associated LE.
Results: We found elevated fractions of activated CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid of patients with GAD65-autoantibody-associated LE compared to controls. Intrathecal fractions of CD8+ T cells strongly correlated with hippocampal atrophy and memory dysfunction in patients with GAD65-autoantibody-associated LE. Antigen-experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin-expressing CD8+ T cells found attached mainly to small interneurons but also to large principal neurons together with wide-spread neuronal degeneration in hippocampi of patients with GAD65-autoantibody-associated LE.
Conclusion: Our data suggest a pathogenic effect of CD8+ T cells in GAD65-auto-antibody associated LE which should be considered when designing selective immunotherapies in these patients.

2. Development of the Epilepsy Monitoring Unit Comfort Questionnaire (EMUCQ)

A. Egger-Rainer, E. Trinka, S. Lorenzl (Salzburg; Austria)

Background: Some patients perceive the experience of hospitalization in an epilepsy monitoring unit (EMU) to be an uncomfortable one. In order to provide comfort-enhancing measures, nurses should assess comfort levels. For this purpose, Kolcaba developed the General Comfort Questionnaire (GCQ), which may be modified for setting-specific usage. The objective of this study was to develop an instrument to assess patient comfort during hospitalization in an EMU.
Methods: The GCQ was translated from American English into German following guidelines of the International Society for Pharmacoeconomics and Outcome Research (ISPOR). For use in an EMU, setting-specific items were added. Cognitive debriefing was conducted using cognitive interviews. Qualitative data analysis was based on the framework method. Experts assessed content validity.
Results: Three forward translations were done by Austrian native speakers with good command of the English language. The three versions were conflated to a single one. Back translation was done by an expert who grew up bilingual. For setting-specific modification, 12 items were added. Nine experts performed initial content validity rating. Based on the rating, 26 items remained unchanged, 12 items underwent revisions, and 14 items were omitted. Eight items were put aside for a follow-up rating in the context of cognitive debriefing. For this purpose, 25 patients participated in five rounds of cognitive interviews. According to the results, 27 items remained unchanged, 11 items were reworded, and six items were added. The final content validity rating showed item-content validity indices (I-CVI) between .33 and 1, and an average CVI on a scale level (S-CVI/ave) of .84.
Conclusion: Enhancing comfort is a fundamental nursing goal. The EMUCQ is a valuable tool to support the assessment of comfort levels. ISPOR guidelines proved to be useful when translating an instrument. Using cognitive interviews enhanced the understandability of items and supported modification of the GCQ. At present, S-CVI/ave value of the EMUCQ is acceptable. Further testing is necessary.

3. Language Lateralization in presurgical work-up: Improving the retest reliability of functional transcranial Doppler sonography

N. Conradi, A. Hermsen, K. Krause, I. Gorny, A. Haag, R. Scharf, P. Mross, S. Knake, F. Rosenow (Frankfurt, Marburg; Germany)

Background: Since its introduction functional transcranial Doppler sonography (fTCD) has been extensively applied in research and clinical settings and has by now become part of the presurgical evaluation routine of epilepsy patients. Because of its importance in planning neurosurgical interventions, the reproducibility of fTCD determining hemispheric language lateralization has to be assured.
Methods and Results: In the present study fTCD was performed twice in 61 patients suffering from temporal lobe epilepsy (TLE) using a standard word generation paradigm (Knake et al., 2006). Language lateralization was consistent between the two measurements in forty-six percent of patients. However, language lateralization of thirteen percent of patients switched sides in the second measurement. Patients with inconclusive lateralization were excluded from further analysis. Closer examination of the remaining patients (n=28) revealed significant correlations between silent word generation and speech period only for “non-switchers” and nearly no correlations for “switchers”, indicating doubts regarding appropriate task performance in the “switchers” group.
Thus, a second step to analyzing fTCD was added by rating the quality of measurements regarding (1) instruction-compliant task performance, (2) sufficient baseline period and (3) adequate increase in cerebral blood flow velocity (CBFV) during activation period. As expected, a Chi-Square-Test revealed a significantly lower quality of the first measurement in the “switchers” group compared to the “non-switchers” (p<0.000).
After implementing this second step by defining low quality measurements as inconclusive lateralization, the laterality indexes of the original sample (n=61) showed a significant retest reliability of r=.89 (p<0.000). A Wilcoxon-Test revealed a significant improvement in quality of the second measurement compared to the first (p=0.003).
Conclusion: Analyzing fTCD quantitatively (by using confidence intervals) and qualitatively (by rating the quality of measurements regarding instruction-compliance, baseline and increase in CBFV) improves the process of determining hemispheric language lateralization in TLE patients. By rejecting measurements with quantitatively significant laterality indexes but low quality in task performance, the risk of incorrect determination of hemispheric language lateralization is reduced, which has direct impact on further evaluation of neurosurgical interventions.

4. Distinctive epileptogenic networks for parietal operculum seizures

H. Wang, D. Olivier, Z. Wenjing (Beijing; China; Grenoble; France)

Background: Few studies have described the anatomo-clinical correlations in parietal operculum seizures (POS) and they are often regrouped into the categories of parietal lobe seizures or insular-opercular seizures The present study describes the electro-clinical features and epileptogenic networks of parietal operculum seizures investigated by intracerebral recordings using stereo-electroencephalography (SEEG)
Methods: The comprehensive presurgical evaluation data of seven drug-resistant epileptic patients with parietal operculum seizures were analyzed retrospectively. The SEEG recorded seizures were processed visually and quantitatively using Epileptogenicity Mapping (EM), which has been proposed to ergonomically quantify epileptogenicity of brain structures by adopting a neuroimaging approach.
Results: Six patients reported an initial specific sensation consisting of somatosensory or viscerosensitive symptoms. Ictal clinical signs were represented by frequent nocturnal hypermotor seizures and contralateral focal motor seizures, including facial and limbs tonic, tonic-clonic or dystonic seizures. Interictal and ictal scalp EEG provided lateralizing information in the majority of patients but the discharges were widely distributed over perisylvian or “rolandic-like” regions and the vertex. Furthermore, two subgroups of the epileptogenic networks organization within parietal operculum seizures could be distinguished by SEEG visually and quantitatively using EM approach: group 1 (mesial frontal-central networks), observed in 3 patients who mainly exhibited hypermotor seizures, and group 2 (perisylvian networks ), observed in 4 patients who mainly exhibited contralateral focal motor seizures.
Conclusion: This study indicated the parietal operculum seizures were characterized by initial specific somatosensory sensation followed by frequently nocturnal hypermotor seizures or contralateral focal motor seizures. The distinctive seizure semiology depended on two main epileptogenic networks organization respectively.

5. Alcohol-related seizures as a predictor of severe depression and alcohol dependence syndrome

E. Gūtmane, N. Sūna, A. Tomilova, L. Liepiņa (Riga; Latvia)

Background: Alcohol withdrawal seizures basically occur only in chronic heavy users of alcohol [A McKeon et al., 2007]. Co-morbid alcoholism and depression may promote suicidal thoughts and behaviour.
Materials and methods: A descriptive cross-sectional study design was used to analyse alcohol use habits, the prevalence of depression in patients with alcohol-related seizures (ARS) and alcohol dependence syndrome (ADS) and the impact of alcohol-related seizures on the severity and manifestations of depression. All patients were recruited to participate in survey between January 2016 and December 2016 in Latvia, using the Alcohol Use Disorder Identification Test (AUDIT) and the Hamilton Depression Rating Scale (HAM-D). The data were statistically analysed using the IBM SPSS 22. The study was approved by the Medical and Biomedical Research Ethics Committee of the Riga East Clinical University Hospital.
Results: In our study participated 110 patients- 60 with ARS and 50 with ADS. In ADS 44%(n=22) were women, 56%(n=28) men, in ARS group 28.3%(n=17) were women and 71.7%(n=43) men. In ADS 96% (n=48) suffered from depression regarding HAM-D scale, in ARS- 81.7% (n=49), p=0.02. Severe or very severe depression was observed in 16%(n=8) and 8%(n=4) of cases in ADS, in 11.7%(n=7) and 5%(n=3) of cases in ARS group (p=0.209). The mean HAM-D score in ADS group was 16.10(SD 0.876) and 13.22(SD 0.713) in ARS group (p=0.023). In ARS group more often was noted light or mild suicidal thoughts compared with ADS (23.3%(n=14) vs. 12%(n=6)), p=0.141) as well as there was more pronounced disturbances in daily activities and work- severe disturbances in 10%(n=6) of ARS group, but in none of ADS group(p=0.029). Mean AUDIT score in ADS group was 18.84 (min 6, max 30), in ARS group - 20.07 (min 6, max 36). Regarding severity of alcoholism, ARS group had tendency without statistical significant difference to have higher AUDIT scores meeting criteria of alcohol dependency (> 20 points)- 56.7 %(n=34) vs. 48%(n=24).
Conclusion: Alcohol dependence syndrome which demand narcologist consultation and appropriate treatment are often observed in patients with ARS and are linked to depression with particular pronounced suicidal thoughts compared with those, who have only alcohol dependence syndrome.

6. Non-compliance of patients with driving restrictions due to uncontrolled epilepsy

L. M. Willems, P. S. Reif, S. Knake, H. M. Hamer, C. Willems, G. Krämer, F. Rosenow, A. Strzelczyk (Erlangen, Frankfurt, Marburg; Germany; Zürich; Switzerland)

Epilepsies are a common and chronic neurological disorder characterized by sustained risk of recurrent seizures. Due to paroxysmal and often unpredictable occurrence of seizures, patients with uncontrolled epilepsy are subject to disease specific restrictions in daily life, such as their career choice or specific work limitations. According to German law and many other European and international guidelines, driving is strictly prohibited in patients with uncontrolled epilepsy to increase active and passive safety in public road traffic. Nevertheless, a relevant proportion of patients does not comply with these legal restrictions and drives on a regular basis.
For this study we analyzed a representative German cohort from 2008 with 305 patients with established epilepsy to identify the amount of patients driving without permission. The delay between data acquisition and publication was inevitable to avoid possible legal consequences. Approximately 15% of the 205 patients with uncontrolled epilepsy reported to drive on a regular basis. As significant risk factors a permanent employment, freelance-work the absence of a relevant disability and living alone were identified, which underlines the already existing evidence for the importance of a possible restricted access to labor market as motive for disregarding legal driving restrictions.
In our opinion, a specialized and generally available social counseling with a special focus on vocational and career guidance is urgently needed to improve the compliance with epilepsy caused driving restrictions and the underlying causes for violating these rules.

7. Sternberg’s canal, rare cause of temporal lobe epilepsy –our experience

V. Sulentic, S. Nankovic, Z. Poljakovic, Z. Petelin-Gadze, G. Mrak, P. Nimac, A. Bujan Kovac (Zagreb; Croatia)

Background: Sternberg's canal is result of incomplete closure of the sphenoidal sinus during fetal and child development, forming a rare abnormal lateral craniopharyngeal canal connecting the middle cranial fossa and sphenoidal sinus. Sternberg's canal is potential place for meningocele or encephalocele with temporal lobe herniation. The encephalocele can be acquired as a consequence of trauma or surgery or as a result of inflammatory process . In the presence of cerebrospinal fluid (CSF) leak or rhinorrhea through Sternberg's canal risk of meningitis, brain abscess, intracranial hypotension or benign intracranial hypertension is high. The association between meningoencephaloceles and epileptic seizures is rare but well reported in the literature.
Methods and Results: We present a case studies of six patients with Sternberg's canal meningoencephaloceles. All have semiology of temporal lobe epilepy. All of the patients conducted 3T MRI examinations according to a protocol to epilepsy patients. Two patients were surgically treated with good postoperative results and seizure free with reduction. The others are seizure free with two antiepileptic drugs in therapy.
Conclusion: Stermberg's canal encephaloceles with brain herniation can be cause of drug-resistant epilepsy and may be overlooked on standard neuroimaging. Surgical treatment, removal of the lesion, sometimes with limited resection with sparing of the amygdala and hippocampus can induce seizure freedom. Evaulation of epilepsy patients shood be guided by seizure semiology and electroclinical characteristics.

8. Propagation of seizures in a case of secondary somatosensory epilepsy studied by stereo-EEG

Q. Feng, Z. Wenjing (Beijing; China)

Background: The secondary somatosensory (S2)epilepsy is rare. Hypermotor seizures (HMS) are commonly characterized by complex movements involving the proximal segment of the limbs and trunk, and usually distinguished two types HMS1 and HMS2. HMS1 are mainly associated with the ventromesial frontal cortex, while HMS2 are primarily centered on the dorsal frontal cortex. We describe a S2 epilepsy featured by HMS2. Method The patient underwent a series of noninvasive and invasive examinations, including scalp video-EEG. high resolution MRI. FDG PET-CT. stereo-EEG (SEEG).
Results: Through SEEG, 16 habitual seizures characterized by HMS2 were recorded. And by the coregister of brain MRI and post-operation CT, the contacts which were especially important during interictal discharge and ictal onset were over the upper banker of right parietal opecular cortex and the posterior cortex of insular. So, our case’s SEEG result revealed a S2 ictal zone and an area of PCC soon affected. Stimulation to these contacts located at upper banker of right parietal opecular cortex also result from similar symptoms just like the special somatosensory aura. The incision of right S2 was performed and the patient was seizure free for nearly three years. The pathology was FCD Ⅱb.
Conclusion: Different from that HMS2 are of a more dorsal epileptogenic zone, our case is the first time about HMS of posterior origin, or rather, the S2 origin. However, we still have difficulties to identify whether the S2 seizure can directly produce hypermotor or discharge propagation to PCC result in hypermotor. For the posterior speculation, we cannot record discharges at other contacts except the S2 and PCC area. So we hardly establish the whole propagation network of HMS. So, we need more cases to analysis the anatomy-electrical-clinical features of S2 epilepsy.

9. Age-related MR-characteristics in patients with MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy)

T. Hartlieb, T. Pieper, H. Holthausen, P. Winkler, M. Kudernatsch, I. Blümcke, R. Coras, M. Staudt (Vogtareuth, Erlangen; Germany)

Background: Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a newly described, rare histopathologic entity detected in resected brain tissue of patients with refractory epilepsies (Schurr et al, Brain Pathology 2016). Here, we report age-related MR characteristics of MOGHE.
Methods: Retrospective analysis of 16 pediatric MOGHE patients (1.6 to 17.5 years) who received epilepsy surgery at our center.
Results: Analysis of high resolution MRI (3D-T2, 3D-FLAIR) revealed two main MR-subtypes:
Type I is characterized by increased laminar T2 signal at the cortico-medullary junction (laminar T2-hyperintensity), Type II by reduced cortico-medullary differentiation due to increased signal of the adjacent white matter, mimicking radiologic findings in FCD Type 1. One patient did not match the above mentioned criteria.
Distribution of subtypes in the MOGHE group was clearly age-related, with Type I occurring between 1.5 and 5 years (median 2.4 years) (14 MRIs) and type II between 3.4 and 15.9 years (median 9.3 years)(11 MRIs). In one patient MRI at the age of 2.7 years showed subtype I and had changed to subtype II by the age of 16 years. In other patient with 3 MRI’s between 1.6 and 2.9 years a decline of laminar T2-hyperintensities was observed.
In addition to the typical findings of MOGHE, histology revealed patchy areas of reduced myelination in the majority of patients with subtype I. (subtype referring to the last MRI before surgery).
Conclusion: MR characteristics in patients with MOGHE are clearly age-related and seem to change from subtype I (“infantile type”) to subtype II (“adult type”) probably due to maturational processes between 3 and 5 years.
Patchy areas of reduced myelination in histology apparently disappear during brain maturation, since they were no longer detectable in older patients and may therefore represent the histologic correlate of laminar T2-hyperintensities in Type I.
Sensitivity and specificity of laminar T2-hyperintensities for the radiologic diagnosis of MOGHE has to be elucidated.
Knowledge of MR characteristics of MOGHE and their age-related change can facilitate the diagnosis of this new challenging entity and might have an impact on surgical approach and therefore postoperative outcome.

10. SUDEP Counseling by Indian Neurologists

A. Diwan, G. Diwan (Nashik; India)

Objective: To examine the attitudes toward counseling about sudden unexpected death in epilepsy (SUDEP) and other epilepsy risk factors among Indian neurologists and neuropediatricians, and to determine factors responsible for not discussing SUDEP.
Methods: Web based questionnaires ( were sent via email to approximately 1200 neurologists through President, IAN (Indian Academy of Neurologists) to approximately 1200 neurologists in Dec 2016 and a reminder for the same was emailed after 4wks. Questions were asked regarding experience of SUDEP amongst treated epileptic patients; when and how often they discussed SUDEP, and its risk factors, and reasons for not discussing SUDEP.
Results: In total, 100 surveys were completed (76% adult neurologists, 15% Neurologists with additional epilepsy training, 5% pediatric neurologists and 4% non-neurologists (Intensivists/physicians). A minority of 6.06% reported that they counseled all of their patients(>90%) on SUDEP, 8.08% counseled most of their patients(50-90%), 20% sometimes(10-49%), 49.49% rarely(1-9%), and 16.16% reported not counseling about SUDEP at all. In contrast, 79.38% reported that they counseled all patients(>90%) about risks in daily life activities. Refractory epilepsy (72.16%) and non compliance for the medications (62.89%) were the most common reasons to counsel for SUDEP.
Conclusion: Very few neurologists discussed premature mortality due to SUDEP in their epileptic patients. At the same time, majority of these responders counseled for prevention of injuries in daily life e.g. falling from heights, working in hostile environment. Discomfort in discussing premature death due to SUDEP is related to many factors like lack of time, no definite preventive measures, fear of emotional reaction or adding anxiety to patients with poor benefit to risk ratio.

11. Quality of life in patients with post-stroke epilepsy and its determinants

Y. Winter, A. Müller, N. Daneshkhah, N. Galland, I. Kotulla, A. Krüger, S. Groppa (Mainz, Giessen, Marburg; Germany)

Background: Post-stroke epilepsy is an important complication of cerebrovascular disease. Only limited data on quality of (QoL) in patients with post-stroke epilepsy are available. We analysed QoL in patients with epilepsy after stroke and identified ist independent determinants.
Methods: We performed preliminary analysis of patients with post-stroke epilepsy who were recruited in two stroke registers (Mainz Stroke Register, MAINZ-STREG and Marburger Stroke Register, MARSTREG). Data collection inlcuded demographics, functional impairment (Barthel-Index), antiepileptic drugs (AEDs), depression (Geriatric Depression Scale) and health-related quality of life (EQ5D and EQ VAS). A multiple regression analysis was done for identification of QoL-determinants.
Results: The current analysis included data of 70 patients with post-stroke epilepsy. In comparison to patients without seizures, the QoL-values of patients with post-stroke epilepsy were markedly (EuroQol-VAS: 54.1±8.9 versus 65.8±9.5, p=0.02). The independent QoL-influencing factors were seizure frequency, depression and functional impairment (Barthel-Index). The adjustment of AEDs within 12 months after therapy start resulted in decrease of seizure frequency and reduction of complications, which led to improvement of QoL.
Conclusion: Post-stroke epilepsy is associated with decreased QoL in patients experienced stroke. In our analysis we identified factors influencing QoL in post-stroke epilepsy, which could improve the management of disease course. These factors include identification and treatment of depression, reduction of seizure frequency by adjustment of AEDs and introduction of rehabilitation programs for patients with post-stroke epilepsy.

12. Robot assisted Epilepsy Surgery: Accuracy comparing Leksell Frame vs Laser Scan Referencing based on MR or CT data

A. Spyrantis, A. Cattani, T. Woebbecke, A. Strzelczyk, F. Rosenow, V. Seifert, M. Kudernatsch, T. M. Freiman (Frankfurt, Vogtareuth; Germany)

Background: In robotic guided stereotaxic procedures, as implantation of intracerebral electroencephalography electrodes (sEEG), referencing the patients anatomy to the robot is the most crucial step. We will compare the accuracy of different referencing methods. First, computed tomography (CT) with stereotaxic frame, second, CT and laser scanning of the face and, third, magnetic resonance tomography (MR) and laser scanning.
Methods: In total, 171 sEEG electrodes were implanted in 19 patients assisted by the robotic surgery assistant (ROSA). Referencing was accomplished either by CT-based Leksell frame (n=49), CT-based laser scan of the face (n=60) or MR-based laser scan (n=62). Preoperative MR-based planning data was compared with the postoperative position of the sEEG-electrode in CT. The accuracy was determined by the target point error (TPE) and the entry point error (EPE) applying the Euclidian distance.
Results: In Leksell frame-based referencing, the TPE amounted to 2,28 mm, the EPE to 0,86 mm (n=49). CT based laser scan referencing resulted in a TPE of 2,41 mm and an EPE of 1,85 mm. Using the 3.0 T MR based laser scan for referencing, the mean TPE amounted to 3.51 mm, the mean EPE to 3,02 mm (n=56). The accuracy improved combining 1.5 T MRI with laser scan, the mean TPE dropped to 1.71 mm, the EPE 0.97 mm (n=6). Two clinically inapparent hemorrhages were detected in patients with CT based laser scan for referencing. No further complications were observed.
Conclusion: Robot-guided sEEG with Leksell frame based referencing is very accurate and can serve for high precision placement of electrodes. In contrast, 3.0 T MRI based laser scan referencing saves radiation for the patient and most trajectories can be reached by using alternative routes over less vessel dens brain areas.

13. Ictal head version - A truly focal sign?

T. Kovacevic-Preradoic, T. Mayer (Radeberg; Germany)

Background: The differentiation between the stringent dichotomy of focal and generalized epileptic seizures and syndromes still occupies a great number of physicians who counsel the patients suffering from epilepsy. Versive head movements have been described for lateralization and localization of seizure focus strongly suggestive of frontal and temporal lobe origin; two most common epilepsy entities considered for epilepsy surgery. Forced head turning can occur also in idiopathic generalized epilepsy (IGE) and may not necessarily indicate focal epilepsy.
Methods: We retrospectively reviewed video and EEG studies of 9 adolescent patients with head version prior to generalized tonic-clonic seizures who have been seen in our center in the last six months. Six of them had diagnosis of a focal epilepsy of unknown etiology because of the irregularities in interictal EEG as well as focal onset (head version) of generalized tonic-clonic seizure. Most of them were treated with Oxcarbazepine, Topiramat or Lamotrigine, some with Levetiracetam, without effect. All patients demonstrated forced head version, including turning to the right and left on consecutive seizures. Four of them showed another seizures such as complex absences or unilateral clonic movement.
Results: All patients fulfilled criteria for some IGE, but none of them could be classified as an ILAE-conform syndrome. No epilepsy risk factors could be found. 8/9 had irregular EEGs with regional and generalized interictal epileptiform discharges; one patient had normal EEG, inclusive sleep deprivation.
Conclusion: Head version is the most important focal sign in our patient cochort with IGE. Despite certain focal semiological elements and EEG irregularities, we suggest to consider an IGE first in otherwise healthy adolescent patients with generalized tonic-clonic seizures only and head version as initial manifestation.

14. Invasive EEG-electrodes in presurgical evaluation of epilepsies:
Systematic analysis of implantation, monitoring and explantation related complications and review of literature

L. M. Willems, P. S. Reif, K. M. Klein, A. Spyrantis, A. Cattani, T. Freiman, V. Seifert, S. Schubert-Bast, M. Wagner, S. J. You, F. Rosenow, A. Strzelczyk (Frankfurt; Germany)

Introduction: Stereo-electroencephalography (sEEG) is a diagnostic procedure for patients with refractory focal epilepsies that is performed at specialized epilepsy centers to localize and define the epileptogenic zone. In contrast to grid-electrodes, sEEG-electrodes are implanted using minimal-invasive operation techniques without large craniotomies. Previous studies provide good evidence that sEEG-implantation is a safe and effective procedure, however complications in asymptomatic patients after explantation may be underreported. The aim of this analysis is to provide systematic imaging data following implantation and explantation.
Results: We analysed 18 consecutive patients (mean age 30.5, range 12-46; 61.1% female) undergoing invasive presurgical video-EEG-monitoring via sEEG electrodes (n=167 implanted electrodes) over a period of 2.5 years with robot assisted implantation. There were no neurological deficits reported after implantation or explantation in any of the enrolled patients. Post-implantation imaging showed a subclinical subarachnoidal haemorrhage in one patient, further workup revealed an unknown factor VII deficiency. During video-EEG monitoring no injuries or status epilepticus occurred, in one patient a seizure related asymptomatic cross break of two fixation screws was found and lead to revision surgery. Unspecific symptoms like headaches or low grade fever were present in 10 of 18 (55.6%) patients during the first days of video-EEG monitoring and were transient. Post-explantation imaging showed asymptomatic and limited bleeding close to 4 electrodes (4/167; 2.4%).
Conclusion: Overall, sEEG is a safe and well tolerated procedure. Systematic imaging after implantation and explantation help to identify clinically silent complications of sEEG. In literature complication rates are reported of up to 4.4 % in sEEG and in 49.9 % of subdural EEG, however systematic imaging after explantation was not used throughout the studies and might lead to underreporting of associated complications.

Industry Poster

15. Antiseizure Properties of Cannabidiol are Attenuated in the Absence of Transient Receptor Potential Vanilloid 1 Receptors

C. G. Stott, N. A. Jones, B. J. Whalley, R. A. Gray (Cambridge; UK)

Background: Cannabidiol (CBD) is significantly superior to placebo in reducing seizure frequency in Lennox-Gastaut and Dravet syndromes1,2. CBD acts as a transient receptor potential vanilloid 1 (TRPV1) agonist that rapidly desensitises TRPV1 in a concentration- and calcium-dependent fashion3. The effect of CBD on seizure threshold in the maximal electroshock seizure threshold test was evaluated in wild-type (WT) and TRPV1 knockout (KO) mice.
Methods: Mice (WT and KO) were given intraperitoneal CBD (10-200 mg/kg), vehicle, TRPV1 antagonist (capsazepine 10 mg/kg) or diazepam (2.5 mg/kg). A constant current stimulus was delivered via corneal electrodes, and mice were assessed for exhibition of tonic hind limb extension indicative of acute generalised seizures. The current required to produce maximal seizures in 50% of mice (CC50), and brain and plasma concentrations of CBD were measured.
Results: No significant difference was seen in CC50 between vehicle-treated WT and KO mice; both capsazepine and diazepam were effective in WT and KO mice (P<0.001 vs vehicle). Treatment with CBD (25-200 mg/kg) dose-dependently increased CC50 in WT mice vs vehicle (P<0.05-0.001), an effect which was markedly reduced or absent in KO mice. Brain exposure for CBD was consistent with concentrations required for TRPV1 activation and desensitisation. No significant difference in the brain and plasma CBD concentration was noted between WT and KO mice.
Conclusion: These data suggest that the anticonvulsant effects of CBD in acute, murine generalised seizures are in part mediated via TRPV1 receptor interaction.

Funding: GW Research Ltd


1 Cross JH, et al. Cannabidiol (CBD) reduces convulsive seizure frequency in Dravet Syndrome: results of a multi-centered, randomized, controlled study (GWPCARE1). 70th AES Annual Meeting, Houston, TX, USA, 2-6 December 2016 (Abst 2.362).
2 Thiele EA, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome: results of a multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE4). 70th AES Annual Meeting, Houston, TX, USA, 2-6 December 2016 (Abst 1.377).
3 Iannotti FA, et al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 2014; 19(5):1131-1141.

16. A Role of the Orphan G-protein Coupled Receptor in the Anti-epileptic Properties of Cannabidiol

M. Bazelot, E. C. Rosenberg, R. W. Tsien, B. J. Whalley, C. G. Stott, O. Devinsky (Cambridge, Reading; UK; New York; USA)

Background: The objective of these studies was to investigate whether modulation of orphan G-protein coupled receptor (GPR55)-mediated signalling by cannabidiol (CBD) contributes to its anti-epileptic effect.
Methods: Firstly, effects of CBD on GPR55-mediated increases in miniature excitatory postsynaptic currents (mEPSCs) were studied in brain slices from healthy and epileptic rats. Whole-cell patch-clamp recordings of hippocampal CA1 pyramidal neurons and interneurons were made, and changes in lysophosphatidylinositol (LPI)-mediated effects on mEPSCs were examined. Secondly, in vivo mouse models of acute seizure were used to assess the role of GPR55 expression in seizure events and the effect of altered GPR55-mediated signalling on the anticonvulsant potency of CBD.
Results: Mean (± standard error [SE]) amplitude of mEPSCs in epileptic slices (6.6±1.8 pA) was lower than that in non-epileptic tissue (14.9±5.6 pA, P<0.001), which confirmed previous results1. Mean (± SE) decay time constant was longer in epileptic tissue (11.2±2.4 ms) than in non-epileptic slices (14.5±0.9 ms, P<0.05), suggesting alterations in the postsynaptic amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Changes in mEPSC waveform in epileptic tissue were unaffected by CBD. The LPI effect was potentiated in epileptic CA1 pyramidal cells versus non-epileptic neurons, evoking a mean (± SE) 2.8±0.6 relative increase in mEPSC frequency (P<0.05); CBD fully inhibited this response. CBD significantly prevented pentylenetetrazol-induced death in GPR55 knockout mice but did not reduce tonic-clonic seizures.
Conclusion: Glutamatergic transmission at CA3-CA1 synapses is modified by epilepsy, potentially involving changes in AMPA receptor subunit composition. These findings provide evidence for an involvement of GPR55 receptors in the CBD mechanism of action in epilepsy.

Funding: GW Research Ltd


1 Sylantyev S, et al. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci USA 2013;110(13):5193-5198.

17. Maintained Safety and Efficacy of Cannabidiol in a Long-term Open-label Trial in Patients with Lennox-Gastaut Syndrome (GWPCARE5)

M. Mazurkiewicz-Bełdzińska, E. Marsh, J. Halford, B. Gunning, D. Checketts, C. Roberts, E. Thiele (Gdansk; Poland; Philadelphia, Charleston, Boston; USA; Zwolle; The Netherlands; Cambridge; UK)

Background: Cannabidiol (CBD) significantly reduced seizures associated with Lennox-Gastaut syndrome (LGS) and was generally well tolerated in the Phase 3 randomised placebo-controlled trials GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690). We present a prespecified interim analysis (cutoff 3 November 2016) of the open-label extension (OLE) of these trials designed to assess the long-term safety and efficacy of add-on CBD to existing anti-epileptic drug (AED) treatment in children and adults with LGS.
Methods: Patients who completed either of two Phase 3, 14-week, double-blind, randomised, controlled trials (GWPCARE3 and GWPCARE4) could enter this OLE (GWPCARE5; NCT02224573). Patients received a plant-derived pharmaceutical formulation of CBD oral solution for ≤2 years. Primary endpoint: safety. Secondary endpoints: drop and total seizure frequency; Subject/Caregiver Global Impression of Change (S/CGIC).
Results: In total, 366/368 (99%) patients with LGS who completed a core study were enrolled in the OLE; 67 had withdrawn, 22 owing to adverse events (AEs). Mean age: 15.9 years; 33% ≥18 years; 54% male. Patients took a median of three concomitant AEDs. Baseline median seizure frequency/28 days: 80 for drop seizures, 168 for total seizures. Mean (range) modal dose: 23 (2.5-30) mg/kg/day. Median (range) exposure: 263 (3-430) days. AEs occurred in 92% of patients (treatment related 58%); most were mild to moderate. Most common (≥10%) AEs: diarrhoea, somnolence, convulsion, pyrexia, decreased appetite, vomiting and upper respiratory tract infection. Some elevations in transaminases were reported. Serious AE incidence: 26% (treatment related 6%). There were four deaths; none were deemed treatment related by the investigator(s). When analysed in 12-week intervals over 48 weeks, median reductions in monthly seizure frequency were (min-max) 48%-60% for drop seizures and 48%-58% for total seizures. Improvements in overall condition (S/CGIC) were reported at Weeks 24 and 48 by approximately 88% of patients/caregivers.
Conclusion: Long-term add-on CBD treatment was generally well tolerated with an AE profile comparable to that observed previously. Reductions in drop and total seizure frequency and improvements in overall condition were maintained through 48 weeks.

Funding: GW Research Ltd