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Startseite > Forschung > Publikationen / Publications > Kadish

Dr. Kadish

2020

Kadish, N. E., Riedel, C., Stephani, U., & Wiegand, G. (2020). Developmental outcomes in children/adolescents and one adult with tuberous sclerosis complex (TSC) and refractory epilepsy treated with everolimus. Epilepsy Behav., 111, 107182. PMID:32535369, doi:10.1016/j.yebeh.2020.107182.

This prospective observational study focuses on developmental outcomes in the treatment of tuberous sclerosis complex (TSC) with everolimus (EVO). Fourteen children/adolescents aged 1.7–13.07 and one adult aged 31 years, all with TSC and refractory epilepsy participated. All were treated with EVO for 3–70 months (md: 37). Development/adaptive functioning were evaluated at baseline with follow-up in 11 patients; all patients were assessed during the course of treatment. Our exploratory analyses included factors contributing to developmental impairment and change from baseline to last evaluation. The majority of patients showed severe developmental impairment (86%). Patients with a higher age at inclusion, duration of epilepsy, and number of previous antiepileptic drugs (AEDs) showed lower developmental levels. Earlier onset of epilepsy and a higher number of current AEDs were associated with worse adaptive functioning. At their last examination, four patients were seizure-free (27%), and four experienced a reduction of seizures > 50% (27%). With treatment, (slight) increase was seen in absolute values of developmental age (DA) regarding both development and adaptive functioning. Yet, when accounting for age, decrease was seen in both assessments. While developmental disorders were prominent, we observed an overall progression at a slower pace. Despite a positive effect on seizure occurrence, treatment with EVO did not reverse developmental problems in the observation period of this study.

Splittgerber, M., Suwelack, J. H., Kadish, N. E.*, & Moliadze, V.*. (2020). The Effects of 1 mA tACS and tRNS on Children/Adolescents and Adults: Investigating Age and Sensitivity to Sham Stimulation. Neural Plast., 2020, 1–14. PMID:32855633, doi:10.1155/2020/8896423.

The aim of this study was to investigate the effect of transcranial random noise (tRNS) and transcranial alternating current (tACS) stimulation on motor cortex excitability in healthy children and adolescents. Additionally, based on our recent results on the individual response to sham in adults, we explored this effect in the pediatric population. We included 15 children and adolescents (10–16 years) and 28 adults (20–30 years). Participants were stimulated four times with 20 Hz and 140 Hz tACS, tRNS, and sham stimulation (1 mA) for 10 minutes over the left M1 HAND . Single-pulse MEPs (motor evoked potential), short-interval intracortical inhibition, and facilitation were measured by TMS before and after stimulation (baseline, 0, 30, 60 minutes). We also investigated aspects of tolerability. According to the individual MEPs response immediately after sham stimulation compared to baseline (Wilcoxon signed-rank test), subjects were regarded as responders or nonresponders to sham. We did not find a significant age effect. Regardless of age, 140 Hz tACS led to increased excitability. Incidence and intensity of side effects did not differ between age groups or type of stimulation. Analyses on responders and nonresponders to sham stimulation showed effects of 140 Hz, 20 Hz tACS, and tRNS on single-pulse MEPs only for nonresponders. In this study, children and adolescents responded to 1 mA tRNS and tACS comparably to adults regarding the modulation of motor cortex excitability. This study contributes to the findings that noninvasive brain stimulation is well tolerated in children and adolescents including tACS, which has not been studied before. Finally, our study supports a modulating role of sensitivity to sham stimulation on responsiveness to a broader stimulation and age range.

Wagner, K., Gau, K., Metternich, B., Geiger, M. J., …, Kadish, N. E., …, & Foit, N. A. (2020). Effects of hippocampus-sparing resections in the temporal lobe: Hippocampal atrophy is associated with a decline in memory performance. Epilepsia, 61(4), 725–734. PMID:32162320, doi:10.1111/epi.16473.

Objective: In patients with temporal lobe epilepsy (TLE) with a nonlesional and nonepileptogenic hippocampus (HC), in order to preserve functionally intact brain tissue, the HC is not resected. However, some patients experience postoperative memory decline, possibly due to disruption of the extrahippocampal memory network and secondary hippocampal volume (HV) loss. The purpose of this study was to determine the extent of hippocampal atrophy ipsilateral and contralateral to the side of the surgery and its relation to memory outcomes. Methods: Hippocampal volume and verbal as well as visual memory performance were retrospectively examined in 55 patients (mean age ± standard deviation [SD] 30 ± 15 years, 25 female, 31 left) before and 5 months after surgery within the temporal lobe that spared the entire HC. HV was extracted based on prespecified templates, and resection volumes were also determined. Results: HV loss was found both ipsilateral and contralateral to the side of surgery (P <.001). Postoperative left HV loss was a significant predictor of postoperative verbal memory deterioration after left-sided surgery (P <.01). Together with the preoperative verbal memory performance, postoperative left HV explained almost 60% of the variance (P <.0001). However, right HV was not a clear predictor of visual memory performance. Larger resection volumes were associated with smaller postoperative HV, irrespective of side of surgery (left: P <.05, right: P <.01). Significance: A disruption of the memory network by any resection within the TL, especially within the language-dominant hemisphere, may lead to HC atrophy and memory decline. These findings may further improve the counseling of patients concerning their postoperative memory outcome before TL resections sparing the entire HC.

2019

El Sayed Hussein Jomaa, M., Van Bogaert, P., Jrad, N., Kadish, N. E., …, Siniatchkin, M., …, & Humeau-Heurtier, A. (2019). Multivariate improved weighted multiscale permutation entropy and its application on EEG data. Biomed. Signal Process. Control, 52, 420–428. doi:10.1016/j.bspc.2018.08.004.

This paper introduces an entropy based method that measures complexity in non-stationary multivariate signals. This method, called Mutivariate Improved Weighted Multiscale Permutation Entropy (mvIWMPE), has two main advantages: (i) it shows lower variance for the results when applied on a wide range of multivariate signals; (ii) it has good accuracy quantifying complexity of different recorded states in signals and hence discriminating them. mvIWMPE is based on two previously introduced permutation entropy algorithms, Improved Multiscale Permutation Entropy (IMPE) and Multivariate Weighted Multiscale Permutation Entropy (mvWMPE). It combines the concept of coarse graining from IMPE and the introduction of the weight of amplitudes of the signals from mvWMPE. mvIWMPE was validated on both synthetic and human electroencephalographic (EEG) signals. Several synthetic signals were simulated: mixtures of white Gaussian noise (WGN) and pink noise, chaotic and convergent Lorenz system signals, stochastic and deterministic signals. As for real signals, resting-state EEG recorded in healthy and epileptic children during eyes closed and eyes open sessions were analyzed. Our method was compared to multivariate multiscale, multivariate weighted multiscale and multivariate improved multiscale permutation entropy methods. Performance on synthetic as well as on EEG signals showed more undeviating results and higher ability for mvIWMPE discriminating different states of signals (chaotic vs convergent, WGN vs pink noise, stochastic vs deterministic simulated signals, and eyes open vs eyes closed EEG signals). We herein proposed an efficient method to measure the complexity of multivariate non-stationary signals. Experimental results showed the accuracy and the robustness (in terms of variance) of the method.

Kadish, N. E., Bast, T., Reuner, G., Wagner, K., …, & Ramantani, G. (2019). Epilepsy Surgery in the First 3 Years of Life: Predictors of Seizure Freedom and Cognitive Development. Neurosurgery, 84(6), E368—-E377. PMID:30137548, doi:10.1093/neuros/nyy376.

BACKGROUND: Although the majority of children undergoing epilepsy surgery are younger than 3 yr at epilepsy manifestation, only few actually receive surgical treatment in early childhood. Past studies have, however, suggested that earlier intervention may correlate with superior developmental outcomes. OBJECTIVE: To identify predictors for long-term seizure freedom and cognitive development following epilepsy surgery in the first 3 yr of life and determine the appropriate timing for surgical treatment in this age group. METHODS: We retrospectively analyzed the data of 48 consecutive children aged 1.1 ± 0.7 yr at surgery. RESULTS: Final surgeries comprised 52% hemispherotomies, 13% multilobar, and 35% intralobar resections. Etiology included cortical malformations in 71%, peri- or postnatal ischemic lesions in 13%, and benign tumor or tuberous sclerosis in 8% each. At last follow-up (median 4.3, range 1-14.3 yr), 60% of children remained seizure-free: 38% had discontinued antiepileptic drugs. Intralobar lesionectomy resulted more often in seizure control than multilobar or hemispheric surgery. Postsurgical seizure freedom was determined by the completeness of resection. Early postsurgical seizures were key markers of seizure recurrence. Presurgical adaptive and cognitive developmental status was impaired in 89% children. Longer epilepsy duration and larger lesion extent were detrimental to presurgical development, which, in turn, determined the postsurgical developmental outcome. CONCLUSION: Our study demonstrates that epilepsy surgery in very young children is safe as well as efficient regarding long-term seizure freedom and antiepileptic drug cessation in selected candidates. Longer epilepsy duration is the only modifiable predictor of impaired adaptive and cognitive development, thus supporting early surgical intervention.

Kortuem, V., Kadish, N. E., Siniatchkin, M., & Moliadze, V. (2019). Efficacy of tRNS and 140 Hz tACS on motor cortex excitability seemingly dependent on sensitivity to sham stimulation. Exp. Brain Res., 237(11), 2885–2895. PMID:31482197, doi:10.1007/s00221-019-05640-w.

This study investigates the effect of corticospinal excitability during sham stimulation on the individual response to transcranial non-invasive brain stimulation (tNIBS). Thirty healthy young adults aged 24.2 ± 2.8 S.D. participated in the study. Sham, as well as 1 mA of tRNS and 140 Hz tACS stimulation were applied for 10 min each at different sessions. The effect of each stimulation type was quantified by recording TMS-induced, motor evoked potentials (MEPs) before (baseline) and at fixed time points after stimulation (T0, T30, T60 min.). According to the individual response to sham stimulation at T0 in comparison to baseline MEPs, subjects were regarded as responder or non-responder to sham. Following, MEPs at T0, T30 and T60 after verum or sham stimulation were assessed with a repeated measures ANOVA with the within-subject factor stimulation (sham, tRNS, 140 Hz tACS) and the between-subjects factor group (responder vs non-responder). We found that individuals who did not show immediately changes in excitability in sham stimulation sessions were the ones who responded to active stimulation conditions. On the other hand, individuals who responded to sham condition, by either increases or decreases in MEPS, did not respond to active verum stimulation. This result suggests that the presence or lack of responses to sham stimulation can provide a marker for how individuals will respond to tRNS/tACS and thus provide an explanation for the variability in interindividual response. The results of this study draw attention to the general reactivity of the brain, which can be taken into account when planning future studies using tNIBS.

2018

Brauer, H., Kadish, N. E., Pedersen, A., Siniatchkin, M., & Moliadze, V. (2018). No Modulatory Effects when Stimulating the Right Inferior Frontal Gyrus with Continuous 6 Hz tACS and tRNS on Response Inhibition: A Behavioral Study. Neural Plast., 2018, 1–11. PMID:30425735, doi:10.1155/2018/3156796.

Response inhibition is the cognitive process required to cancel an intended action. During that process, a “go” reaction is intercepted particularly by the right inferior frontal gyrus (rIFG) and presupplementary motor area (pre-SMA). After the commission of inhibition errors, theta activity (4–8 Hz) is related to the adaption processes. In this study, we intend to examine whether the boosting of theta activity by electrical stimulation over rIFG reduces the number of errors and the reaction times in a response inhibition task (Go/NoGo paradigm) during and after stimulation. 23 healthy right-handed adults participated in the study. In three separate sessions, theta tACS at 6 Hz, transcranial random noise (tRNS) as a second stimulation condition, and sham stimulation were applied for 20 minutes. Based on behavioral data, this study could not show any effects of 6 Hz tACS as well as full spectrum tRNS on response inhibition in any of the conditions. Since many findings support the relevance of the rIFG for response inhibition, this could mean that 6 Hz activity is not important for response inhibition in that structure. Reasons for our null findings could also lie in the stimulation parameters, such as the electrode montage or the stimulation frequency, which are discussed in this article in more detail. Sharing negative findings will have (1) positive impact on future research questions and study design and will improve (2) knowledge acquisition of noninvasive transcranial brain stimulation techniques.

Ramantani, G., Kadish, N. E., Mayer, H., Anastasopoulos, C., …, & Bast, T. (2018). Frontal Lobe Epilepsy Surgery in Childhood and Adolescence: Predictors of Long-Term Seizure Freedom, Overall Cognitive and Adaptive Functioning. Clin. Neurosurg., 83(1), 93–102. PMID:29106684, doi:10.1093/neuros/nyx340.

BACKGROUND: Although frontal lobe resections account for one-third of intralobar resections in pediatric epilepsy surgery, there is a dearth of information regarding long-term seizure freedom, overall cognitive and adaptive functioning. OBJECTIVE: To identify outcome predictors and defne the appropriate timing for surgery. METHODS: We retrospectively analyzed the data of 75 consecutive patients aged 10.0 ± 4.9 yr at surgery that had an 8.1 yr mean follow-up. RESULTS: Etiology comprised focal cortical dysplasia (FCD) in 71% and benign tumors in 16% cases. All patients but one had a magnetic resonance imaging-visible lesion. At last follow-up, 63% patients remained seizure-free and 37% had discontinued antiepileptic drugs. Presurgical predictors of seizure freedom were a shorter epilepsy duration, strictly regional epileptic discharges in electroencephalography (EEG), and an epileptogenic zone and/or lesion distant from eloquent cortex. Postsurgical predictors were the completeness of resection and the lack of early postoperative seizures or epileptic discharges in EEG. Higher presurgical overall cognitive and adaptive functioning was related to later epilepsy onset and to a sublobar epileptogenic zone and/or lesion. Following surgery, scores remained stable in the majority of patients. Postsurgical gains were determined by higher presurgical performance and tumors vs FCD. CONCLUSION: Our fndings highlight the favorable long-term outcomes following frontal lobe epilepsy surgery in childhood and adolescence and underline the importance of early surgical intervention in selected candidates. Early postsurgical relapses and epileptic discharges in EEG constitute key markers of treatment failure and should prompt timely reevaluation. Postsurgical overall cognitive and adaptive functioning is stable in most patients, whereas those with benign tumors have higher chances of improvement.

2016

Reuner, G., Kadish, N. E., Doering, J. H., Balke, D., & Schubert-Bast, S. (2016). Attention and executive functions in the early course of pediatric epilepsy. Epilepsy Behav., 60, 42–49. PMID:27179191, doi:10.1016/j.yebeh.2016.04.011.

Objective: Our prospective study aimed at exploring attention and executive functions in children with new-onset epilepsy prior to and during the early course of antiepileptic treatment. Sociodemographic and epilepsy-related factors were analyzed as potential predictors both of impaired cognitive functions as well as for changes in cognitive functioning in the early course of illness. Methods: From a total group of 115 children aged six to 17 years without major disabilities, 76 children were assessed longitudinally with a screening tool for attention and executive functions (EpiTrack Junior{\textregistered}). Sociodemographic variables (gender, age at epilepsy onset, need of special education) and epilepsy-related variables (etiology of epilepsy, semiology of seizures, number of seizures) were considered as potential predictors for impaired functions prior to treatment and for deterioration/amelioration in cognitive functions in the early course. Results: Attention and executive functions of children with new-onset epilepsy were significantly more often impaired when compared with a healthy population, but less often when compared with children with chronic epilepsy. The majority of children showed stable cognitive functioning in the early course of treatment. The risk of impaired cognitive functions was significantly heightened when etiology of epilepsy was unknown or not classifiable. The chance for improvement of functioning was lowered by having a genetic epilepsy, or an unknown semiology of seizures. Conclusions: Children with new-onset epilepsy are at high risk for impaired attention and executive functions even prior to antiepileptic treatment, especially when etiology of their epilepsy remains unclear. The high stability of cognitive functioning in the early course can be used in counseling of families who worry about negative side effects of drug treatment. Finally, a systematic assessment of cognitive functions in children with new-onset epilepsy is necessary to detect subtle deficits in the early course and adjust treatment accordingly.

Thome-Souza, S., Klehm, J., Jackson, M., Kadish, N. E., …, & Loddenkemper, T. (2016). Clobazam higher-evening differential dosing as an add-on therapy in refractory epilepsy. Seizure, 40, 1–6. PMID:27281712, doi:10.1016/j.seizure.2016.05.014.

Purpose Clobazam treatment tailored to the timing of patient's seizures may improve seizure control. We aim to describe the safety and efficacy of higher-evening differential dose of clobazam as add-on therapy in patients with night-time/early morning seizures. Method Differential dosing with higher evening dosing was started based on a high proportion of seizures (>80%) at nighttime (6 p.m. to 6 a.m.). Differential dosing was defined as providing more than 50% of the total daily dose of clobazam after 6 p.m. Results Twenty-seven patients were treated with clobazam differential dosing as an add-on therapy. The median age was 9.1 years, with 11 (40.7%) females and median of the first follow-up was 2.7 months. Patients with differential dosing tolerated a higher median total clobazam dose of 0.8 mg/kg/d at first follow-up, as compared to 0.6 mg/kg/d in controls. In differential dose, the median percentage of the total clobazam dose administered in the evening was 66.7%. Differential dose patients exhibited a median seizure reduction of 75% as compared to 50% in controls (p < 0.005). Patients with generalized seizures benefited the most from differential dosing with a 77.5% median seizure reduction, as compared to 50% in controls (p = 0.017). Conclusion Higher-evening differential dose of clobazam improved seizure control in patients with predominantly nighttime and early-morning seizures. Chronotherapy tailored to the patients' seizure susceptibility patterns may improve care in epilepsy patients as differential dosing may allow for higher overall treatment doses at times of greatest seizure susceptibility without increased side effects at other times.

2014

Klehm, J., Thome-Souza, S., Sánchez Fernández, I., Bergin, A. M., …, Kadish, N. E., …, & Loddenkemper, T. (2014). Clobazam: Effect on Frequency of Seizures and Safety Profile in Different Subgroups of Children With Epilepsy. Pediatr. Neurol., 51(1), 60–66. doi:10.1016/j.pediatrneurol.2014.01.025.
Ramantani, G., Kadish, N. E., Anastasopoulos, C., Brandt, A., …, & Bast, T. (2014). Epilepsy surgery for glioneuronal tumors in childhood: Avoid loss of time. Neurosurgery, 74(6), 648–657. PMID:24584135, doi:10.1227/NEU.0000000000000327.

BACKGROUND: In contrast to the abundance of seizure outcome reports in epilepsy surgery for glioneuronal tumors in childhood and adolescence, there is a dearth of information regarding cognitive outcomes. OBJECTIVE: To investigate the seizure and cognitive outcome of children and adolescents that underwent resective surgery for glioneuronal tumor-associated refractory epilepsy and determine their predictive factors. METHODS: We retrospectively analyzed the presurgical findings, resection types, and outcomes over 1.3 to 12.3 years (mean, 7.3) of 29 consecutive patients, who underwent resection in 2000 to 2011. The mean age at epilepsy onset was 7.9 years (range, 0-15.4), the mean age at surgery was 11.7 years (range, 2.6-17.3), and the mean epilepsy duration to surgery was 3.8 years (range, 0.3-15.3). Etiology comprised 13 dysembryoplastic neuroepithelial tumors and 16 gangliogliomas, with additional focal cortical dysplasia in 5 cases. RESULTS: Eighty-six percent of children were seizure free 12 months after surgery; at final follow-up, 76% remained seizure free and 62% had discontinued antiepileptic drugs. Gross total resection was related to significantly higher rates of seizure freedom. Higher presurgical cognitive functioning (full-scale IQ, verbal IQ) was related to shorter epilepsy duration to surgery independent of age at epilepsy onset, thus determining postsurgical functioning. Improvements in verbal IQ, performance IQ, and visual memory as well as a trend toward improvement in full-scale IQ were established after surgery. Despite individual losses in full-scale IQ, verbal or visual memory, no deterioration was noted in any cognitive variable on a group level. CONCLUSION: Completeness of resection predisposes to favorable outcomes regarding seizure alleviation. Whereas cognitive functioning deteriorates with time in glioneuronal tumor-related refractory epilepsy, surgery is linked to improvement rather than to deterioration on a group level. {\textcopyright}Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Ramgopal, S., Thome-Souza, S., Jackson, M., Kadish, N. E., …, & Loddenkemper, T. (2014). Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy. Epilepsy Behav., 37, 291–307. doi:10.1016/j.yebeh.2014.06.023.

Nearly one-third of patients with epilepsy continue to have seizures despite optimal medication management. Systems employed to detect seizures may have the potential to improve outcomes in these patients by allowing more tailored therapies and might, additionally, have a role in accident and SUDEP prevention. Automated seizure detection and prediction require algorithms which employ feature computation and subsequent classification. Over the last few decades, methods have been developed to detect seizures utilizing scalp and intracranial EEG, electrocardiography, accelerometry and motion sensors, electrodermal activity, and audio/video captures. To date, it is unclear which combination of detection technologies yields the best results, and approaches may ultimately need to be individualized. This review presents an overview of seizure detection and related prediction methods and discusses their potential uses in closed-loop warning systems in epilepsy.

Thome-Souza, S., Kadish, N. E., Ramgopal, S., Sánchez Fernández, I., …, & Loddenkemper, T. (2014). Safety and retention rate of rufinamide in 300 patients: A single pediatric epilepsy center experience. Epilepsia, 55(8), 1235–1244. PMID:25070475, doi:10.1111/epi.12689.

Summary Objective Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. Methods We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline. Results Three hundred patients with a median age of 9.1 years (range 0.4-29.6 years) were reviewed. Median follow-up was 9 months (range 1-37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3-28 months). Significance Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology. {\textcopyright}2014 International League Against Epilepsy.

2013

Doering, J. H., Reuner, G., Kadish, N. E., Pietz, J., & Schubert-Bast, S. (2013). Pattern and predictors of complementary and alternative medicine (CAM) use among pediatric patients with epilepsy. Epilepsy Behav., 29(1), 41–46. PMID:23933629, doi:10.1016/j.yebeh.2013.06.025.

Parents of pediatric patients with chronic conditions such as epilepsy increasingly opt for complementary and alternative medicine (CAM). However, data on the pattern and reasons of CAM use in childhood epilepsy are scarce. The objectives of this study were as follows: first, to characterize CAM use among pediatric patients with epilepsy by assessing its spectrum, prevalence, costs, and frequency of use; second, to evaluate the influence of CAM use on compliance and satisfaction with conventional care as well as to explore parent-child neurologist communication concerning CAM; and third, to investigate predictors of CAM use.A postal survey was administered to all parents of pediatric outpatients with epilepsy aged 6 to 12, who have received treatment at the neuropediatric outpatient clinic of the University Children's Hospital Heidelberg between 2007 and 2009.One hundred thirty-two of the 297 distributed questionnaires were suitable for inclusion in statistical analysis (44.7%). Forty-nine participants indicated that their children used CAM during the previous year (37.1%). Thirty different types of CAM were used, with homeopathy (55.1%), osteopathy (24.5%), and kinesiology (16.3%) being the most commonly named. A mean of 86€ (0€-500€) and 3. h (1. h-30. h) per month was committed to CAM treatment. Only 53% of the users informed their child neurologist of the additional CAM treatment, while 85.6% of all parents wished to discuss CAM options with their child neurologist. Seventy-five percent of users considered the CAM treatment effective. Among the participants most likely to seek CAM treatment are parents whose children show a long duration of epileptic symptoms, parents who make use of CAM treatment themselves, and parents who value a holistic and natural treatment approach.A substantial portion of pediatric patients with epilepsy receive CAM treatment. The high prevalence of use and significant level of financial and time resources spent on CAM indicate the high importance of these treatment options for parents. On the other hand, communication concerning CAM with the child neurologist is largely insufficient despite the wish to speak about CAM. Complementary and alternative medicine users' high compliance with conventional treatment and high perceived effectiveness of CAM support an integrative approach to CAM for pediatric patients with epilepsy. Our study implies that in addition to open parent-child neurologist communication, active inquiry on CAM treatments is necessary to enable informed decision making by parents and to establish the suitability of CAM treatment for the patient. Reliable predictors for CAM use, which allow for improved identification of patients with a high likelihood to receive CAM treatment, are the duration of the illness, use of CAM by the parents themselves, and the desire of the parents to receive a holistic and natural treatment for their child. {\textcopyright}2013 Elsevier Inc.

Kadish, N. E., Baumann, M., Pietz, J., Schubert-Bast, S., & Reuner, G. (2013). Validation of a screening tool for attention and executive functions (EpiTrack Junior®) in children and adolescents with absence epilepsy. Epilepsy Behav., 29(1), 96–102. PMID:23939033, doi:10.1016/j.yebeh.2013.06.004.

Objective: Our prospective study aimed at the validation of EpiTrack Junior, a neuropsychological screening tool for attention and executive functions in children with epilepsy. Methods: Twenty-two children with absence epilepsy aged 8-17. years underwent comprehensive neuropsychological evaluation including EpiTrack Junior and measures of intelligence, verbal and nonverbal memory, word fluency and visuoconstructive organization. Concurrent and discriminant validity of EpiTrack Junior subtests and total score as well as sensitivity and specificity of the total score were analyzed. Results: EpiTrack Junior total score was impaired in 59% of participants. Concurrent validity was demonstrated in 4/6 subtests and for the total score. Discriminant validity was shown with respect to verbal and nonverbal long-term memory. Sensitivity was higher than specificity and highest for the "working memory index". Conclusion: EpiTrack Junior is recommended as a sensitive and time-efficient screening tool for attention and executive functions in children with epilepsy. Impaired results should be followed up with detailed evaluation including information from the parents and school as well as counseling where indicated. {\textcopyright}2013 Elsevier Inc.

Ramantani, G., Kadish, N. E., Brandt, A., Strobl, K., …, & Bast, T. (2013). Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence. Epilepsia, 54(6), 1046–1055. PMID:23506137, doi:10.1111/epi.12140.

Summary Purpose To evaluate the seizure control and developmental outcomes after hemispherotomy for refractory epilepsy in childhood and to identify their predictive factors. Methods We retrospectively studied the clinical courses and outcomes of 52 children with refractory epilepsy who underwent hemispherotomy in the Epilepsy Center Freiburg between 2002 and 2011. Key Findings Mean age at epilepsy onset was 1.8 years (range 0-8 years) and mean age at surgery was 6.7 years (range 6 months-18 years). The underlying etiology was congenital in 22 (42%) children, acquired in 24 (46%), and progressive in 6 (12%). At final follow-up of 1-9.8 years (mean 3.3), 43 children (83%) were seizure-free. Seizure outcome was not correlated to etiology, with the exception of hemimegalencephaly that was linked to poor seizure control. Presurgical development was impaired in all but one child. Postsurgical development highly correlated with presurgical development. Patients with acquired or progressive etiology, later epilepsy onset, and subsequent later surgery exhibited higher presurgical developmental status that substantially determined postoperative developmental outcome. Improved postsurgical development was determined by acquired etiology and seizure freedom off antiepileptic drugs. Significance In our study, most of the selected children and adolescents achieved seizure freedom, including those with congenital etiology. Developmental outcomes, however, were superior in patients with acquired etiology and older age at surgery, underscoring that it is never too late to reap the benefits of this procedure in terms of both epilepsy and development. {\textcopyright}Wiley Periodicals, Inc. {\textcopyright}2013 International League Against Epilepsy.

Ramantani, G., Kadish, N. E., Strobl, K., Brandt, A., …, & Bast, T. (2013). Seizure and cognitive outcomes of epilepsy surgery in infancy and early childhood. Eur. J. Paediatr. Neurol., 17(5), 498–506. PMID:23602440, doi:10.1016/j.ejpn.2013.03.009.

Aims To investigate seizure and developmental outcomes following epilepsy surgery in very young children and determine their predictive factors. Methods We retrospectively reviewed the clinical data, surgical variables, and outcomes of 30 children under 3 years of age that underwent resection for refractory focal epilepsy in our institution in 2001-2011. Results Seizure onset was in the first year of life in 27 (90%) cases and mean age at surgery was 20 months (range 5-33.6). Pathology consisted of cortical malformations in 24 (80%) cases, glioneuronal tumour and infarction with or without cortical dysplasia in three (10%) cases each. Morbidity was comparable with older paediatric cohorts. At 1-11.6 year follow-up (mean 4.1) 21 of 30 (70%) children achieved seizure freedom (Engel I), six (20%) demonstrated worthwhile improvement (Engel II/III) and three (10%) did not benefit from surgery (Engel IV). Intralobar lesionectomy more often resulted in seizure freedom than multilobar or hemispheric surgery. The abundance of non-regional interictal and ictal EEG findings did not preclude seizure freedom. Presurgical developmental impairment was established in 25 of 28 (89%) children; its severity correlated with longer epilepsy duration and determined postoperative developmental outcome. Developmental progress was established in 26 out of 28 (93%) children following surgery, showing stabilized trajectories rather than catch-up. Conclusions Resective surgery in very young children is safe and effective in terms of seizure control and developmental progress. Our findings underline the importance of early intervention in order to timely stop seizures and their deleterious effects on the developing brain. {\textcopyright}2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights.

Wagner, K., Uherek, M., Horstmann, S., Kadish, N. E., …, & Schulze-Bonhage, A. (2013). Memory outcome after hippocampus sparing resections in the temporal lobe. J. Neurol. Neurosurg. Psychiatry, 84(6), 630–636. PMID:23345282, doi:10.1136/jnnp-2012-304052.

Background and objective: Epilepsy surgery within the temporal lobe of the language dominant hemisphere bears the risk of postoperative verbal memory decline. As surgical procedures have become more tailored, the question has arisen, which type of resection within the temporal lobe is more favourable for memory outcome. Since the hippocampus (HC) is known to play an essential role for long-term memory, we examined whether HC sparing resections help to preserve verbal memory functions. Methods: We retrospectively analysed neuropsychological data ( prior to and 1 year after surgery) of patients undergoing either HC sparing resections (HC-S, N=65) or resections including the hippocampus (HC-R, N=62). Results: Prior to surgery, the HC-R group showed worse memory performance as compared to HC-S patients. Both patient groups revealed further deterioration over time, but in verbal learning HC-R patients demonstrated a stronger decline. Predictors for verbal learning decline were left-sided surgery, better preoperative performance, higher age at surgery, hippocampus resection, and lower preoperative IQ. In patients with spared HC, resection of the left-sided parahippocampal gyrus was rather accompanied by a decline in verbal learning performance. For visual memory, better preoperative performance best predicted deterioration after surgery. Seizure outcome was comparable between the two groups (HC-S: 66%, HC-R: 65% Engel 1a). Conclusions: Temporal lobe resections within the language dominant hemisphere can be accompanied by a decline in verbal memory performance, even if the HC is spared. Yet, HC sparing surgery is associated with a benefit in verbal learning performance. These results can help when counselling patients prior to epilepsy surgery.

2011

Fritz, N. E., Fell, J., Burr, W., Axmacher, N., …, & Helmstaedter, C. (2011). Do surface DC-shifts affect epileptic hippocampal EEG activity? Epilepsy Res., 95(1-2), 136–143. PMID:21550209, doi:10.1016/j.eplepsyres.2011.03.012.

Despite considerable research on EEG-feedback of slow cortical potentials (SCPs) for seizure control in epilepsy, the underlying mechanisms and the direct effects on intracerebral pathological activity within the focal area remain unclear. Intrahippocampal EEG recordings from four patients with temporal lobe epilepsy and implanted electrodes were analyzed with regard to spike activity and power in 10 frequency bands (0.5-148. Hz) during SCP feedback based on surface recordings (position Cz). Trials with positive, negative and indifferent SCPs were contrasted. Three of the four patients showed changes in spike activity during SCPs, but these were inconsistent between patients, and resulted in increased and decreased activity in both positive and negative SCPs. Spectral analysis revealed that in all patients, positive surface shifts showed a bi-hemispheric higher power in the high-frequency activity above 40. Hz. Two patients showed a higher power also during negative shifts, both in high-frequency activity and one in most other frequency bands. Feedback-related power effects did not differ between focal and non-focal side. The inconsistent change in spiking activity and the lack of decrease of power in pathology associated frequency bands during SCPs show that these SCPs do not decrease pathological activity within the epileptic focus. A possible relation of higher power in high-frequency activity during positive SCPs to cognitive processes, such as memory functions, is discussed. {\textcopyright}2011 Elsevier B.V.

2008

Gleissner, U., Fritz, N. E., Von Lehe, M., Sassen, R., …, & Helmstaedter, C. (2008). The validity of the Child Behavior Checklist for children with epilepsy. Epilepsy Behav., 12(2), 276–280. PMID:18065270, doi:10.1016/j.yebeh.2007.10.013.

The validity of the Child Behavior Checklist (CBCL) for patients with epilepsy has been questioned, because several items may reflect seizure semiology rather than habitual behavior. This study compared a standard version of the CBCL with an adjusted version that excluded those ambiguous items. Participants were 58 pediatric patients with epilepsy who were assessed preoperatively and 1 year after successful surgical treatment. Before surgery, the adjusted version indicated significantly lower values for the scales Attention Problems, Thought Problems, and Total Problems than the standard version. After surgery, the difference between the standard and adjusted versions and the scores for the ambiguous items were unchanged, although all patients were completely seizure free at that time. Elevated scores on the ambiguous items thus probably reflect real behavioral problems and are not due to confusion with seizure semiology. The results support the CBCL as a valid assessment tool in children with epilepsy. {\textcopyright}2007 Elsevier Inc. All rights reserved.

Helmstaedter, C., Fritz, N. E., Kockelmann, E., Kosanetzky, N., & Elger, C. E. (2008). Positive and negative psychotropic effects of levetiracetam. Epilepsy Behav., 13(3), 535–541. PMID:18583196, doi:10.1016/j.yebeh.2008.05.012.

Objectives: The goals of this study were to observe behavioral changes in patients receiving levetiracetam (LEV), a newer antiepileptic drug (AED), and to answer the question of whether LEV exerts a specific effect on impulse control and aggression. Methods: We asked 288 consecutive patients with epilepsy on LEV (90% polytherapy, mean dose = 2689 mg) and 135 relatives whether LEV caused a positive or negative behavioral change. Forty-three patients on other AEDs served as a control group. Ratings were related to patient characteristics, efficacy, dose, drug load, bidirectional ratings of change in behavioral domains, and questionnaires on personality (Fragebogens zur Pers{\"{o}}nlichkeit bei zerebralen Erkrankungen) and impulsivity (Barratt Impulsiveness Scale-11). Results: LEV was rated as very effective by 40% of the patients. In contrast to only 9% of the controls, a considerable number of patients reported a behavioral change while taking LEV (12% very negative, 25% negative, 16% positive, 6% very positive). Negative ratings were due to loss of self-control, restlessness, sleep problems, and, most importantly, aggression. Positive ratings were due to increased energy, vigilance, and activation. Increases in psychomotor speed, concentration, and remote memory indicated subjectively experienced positive effects on cognition. The proxy reports indicated reliable self-reports. Reported change was not related to type of epilepsy, co-therapy, dose, drug load, or psychiatric history. Negative effects were, however, associated with poorer seizure control, mental retardation, indicators of an organic psychosyndrome, and nonplanning impulsiveness. Conclusion: The results indicate that LEV exerts a dose-independent stimulating effect that can be positive or negative. Aggression is a prominent feature. Lack of efficacy, mental retardation, and presumably also pre-intake disposition (organic psychosyndrome, impulsivity) may be helpful in predicting whether additional activation under LEV will be positive or negative. {\textcopyright}2008 Elsevier Inc. All rights reserved.

2007

Fell, J., Fritz, N. E., Burr, W., Ludowig, E., …, & Helmstaedter, C. (2007). Human neocortical and hippocampal near-DC shifts are interconnected. Hippocampus, 17(6), 413–419. PMID:17372976, doi:10.1002/hipo.20285.

Hippocampal DC shifts have been observed under various physiological and pathological conditions. Here, we studied the interconnection of slow shifts (0.01 Hz high-pass) in surface EEG and hippocampal shifts as emerging in an event-related EEG biofeedback paradigm. Hippocampal EEG activity was monitored by depth electrodes implanted in four epilepsy patients for presurgical evaluation. Trials were sorted according to the near-DC shifts occurring at the surface position Cz, which was the feedback electrode, into positive, indistinct (i.e., small or biphasic) and negative shifts. We found significant hippocampal near-DC shifts being positively or negatively correlated to the shifts in surface EEG in all four patients. The amplitudes of the hippocampal near-DC shifts were several times larger than the surface shifts. The polarity of the shifts appears to depend on the location of the electrode contacts with respect to the hippocampal subfields. The finding that neocortical and hippocampal near-DC shifts are interconnected may open new perspectives for the prediction and control of mediotemporal lobe seizures. {\textcopyright}2007 Wiley-Liss, Inc.

2006

Helmstaedter, C., Fritz, N. E., González Pérez, P. A., Elger, C. E., & Weber, B. (2006). Shift-back of right into left hemisphere language dominance after control of epileptic seizures: Evidence for epilepsy driven functional cerebral organization. Epilepsy Res., 70(2-3), 257–262. PMID:16624525, doi:10.1016/j.eplepsyres.2006.03.005.

Atypical, i.e. right hemisphere language dominance is frequently observed in early onset left hemisphere epilepsies. In left mesial temporal lobe epilepsy, where eloquent cortex is not directly involved, it is a matter of debate, to which degree atypical language dominance is driven not only by morphological lesions but also by epileptic dysfunction, and whether atypical dominance is hardwired or not. Taking this as the background this study evaluated the hypothesis that epilepsy driven atypical dominancy might be reversible when seizures are successfully controlled. This was evaluated in patients with left mesial temporal lobe epilepsy, who were atypically language dominant by means of language fMRI before surgery, and became seizure free after left selective amygdalo-hippocampectomy. Three out of 53 consecutive atypically dominant patients with chronic epilepsy fulfilled these criteria. Postoperative follow-up language fMRI indicated reversal of right into left dominance in one patient going along with unexpected losses in verbal memory performance. The two other patients experienced unchanged or even enhancement of the pre-existing dominance pattern, going along with consistent postoperative performance changes in cognition. The data thus provide supporting evidence that atypical language dominance can indeed be functionally driven and moreover that in at least some patients, right hemispheric language can shift-back to the left hemisphere when the driving factor, i.e. seizures, becomes successfully controlled. The results have clinical implications for outcome prediction after brain surgery in atypically dominant patients with epilepsy. However, further research in larger groups of atypically dominant patients is required to identify the conditions under which atypical dominance becomes hardwired and when not.

2005

Fritz, N. E., Glogau, S., Hoffmann, J., Rademacher, M., …, & Helmstaedter, C. (2005). Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy Behav., 6(3), 373–381. PMID:15820346, doi:10.1016/j.yebeh.2005.01.002.

Whereas the efficacy of the newer antiepileptic drugs (AEDs) is well established, there remain questions regarding their cognitive side effects. Therefore, we performed a comparative open randomized trial with TPM and TGB as add-on therapy, with particular consideration of cognition, mood, and health-related quality of life (HRQOL).