Publications by authors named "Susanne Schubert-Bast"

58 Publications

Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies.

J Neurol Neurosurg Psychiatry 2021 Apr 26. Epub 2021 Apr 26.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, and Chalfont Centre for Epilepsy, Gerrard Cross, UK

Objective: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy.

Methods: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management.

Results: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%).

Significance: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.
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http://dx.doi.org/10.1136/jnnp-2020-325932DOI Listing
April 2021

Prescription patterns of antiseizure drugs in Tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature.

Expert Rev Clin Pharmacol 2021 Apr 1. Epub 2021 Apr 1.

Epilepsy Center Kork, Clinic for Children and Adolescents, Kehl-Kork, Germany.

Objective: Understanding treatment patterns associated with rare diseases can inform clinical research and guide healthcare policy development. Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC.

Methods: We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence from persons with TSC worldwide.

Results: TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs.

Conclusions: The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.
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http://dx.doi.org/10.1080/17512433.2021.1911643DOI Listing
April 2021

Benefits, safety and outcomes of long-term video EEG monitoring in pediatric patients.

Eur J Paediatr Neurol 2021 Mar 10;32:29-35. Epub 2021 Mar 10.

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany; Department of Child Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.

Objective: To investigate benefits of in-hospital, long-term video EEG monitoring (LVEM) for pediatric patients, from a therapeutic perspective and from the perspectives of patients and their families.

Methods: A monocentric retrospective cohort study was conducted. Patients aged 0-18 years who underwent LVEM for epilepsy surgery eligibility, epilepsy syndrome clarification, or medication adjustment were evaluated regarding paroxysmal event type, change in seizure frequency and patients' benefits using a standardized evaluation protocol.

Results: A total of 163 (88 boys and 75 girls, mean age 10.9 years) pediatric patients underwent 178 LVEM sessions, with a mean duration of 5.4 days. The rate of habitual event detection was 69.1%. Epilepsy diagnosis was confirmed in 147 patients and excluded in 16 patients (9.8%). LVEM results altered the diagnosis of 37.4% of patients. Diagnosis remained unchanged in 49.1% of patients and was specified in 13.5% of patients. Epilepsy surgery was performed in 32 patients, and 64% of epilepsy patients deemed ineligible for epilepsy surgery underwent medication adjustments. Patients or their families found LVEM helpful in 75% of cases. Significant seizure reductions and improvements in the disease course were reported by 45% of epilepsy patients. Three episodes of non-convulsive status epilepticus occurred, representing 1.7% of admissions and 1.9% of patients diagnosed with epilepsy, while no injuries were observed.

Conclusions: LVEM is beneficial for pediatric patients from both a medical perspective and from the perspective of patients and their families, even if patients are ineligible for epilepsy surgery. LVEM is well-tolerated with a low risk of status epilepticus and injuries.
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http://dx.doi.org/10.1016/j.ejpn.2021.03.006DOI Listing
March 2021

Postoperative outcomes and surgical ratio at a newly established epilepsy center: The first 100 procedures.

Epilepsy Behav 2021 03 22;116:107715. Epub 2021 Jan 22.

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany.

Purpose: To describe the patients' characteristics, surgical ratio, and outcomes following epilepsy surgery at the newly established Epilepsy Center Frankfurt Rhine-Main.

Methods: We retrospectively studied the first 100 consecutive patients, including adult (n = 77) and pediatric (n = 23) patients, with drug-resistant epilepsy who underwent resective or ablative surgical procedures at a single, newly established epilepsy center. Patient characteristics, seizure and neuropsychological outcomes, histopathology, complications, and surgical ratio were analyzed.

Results: The mean patient age was 28.8 years (children 10.6 years, adults 34.2 years). The mean epilepsy duration was 11.9 years (children 3.9 years, adults 14.3 years), and the mean follow-up was 1.5 years. At the most recent visit, 64% of patients remained completely seizure free [Engel IA]. The rates of perioperative complications and unexpected new neurological deficits were 5%, each. The proportion of patients showing deficits in one or more cognitive domains increased six months after surgery and decreased to presurgical proportions after two years. Symptoms of depression were significantly decreased and quality of life was significantly increased after surgery. The surgical ratio was 25.3%.

Conclusion: Similar postsurgical outcomes were achieved at a newly established epilepsy center compared with long-standing epilepsy centers. The lower time to surgery may reflect a general decrease in time to surgery over the last decade or the improved accessibility of a new epilepsy center in a previously underserved area. The surgical ratio was not lower than reported for established centers.
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http://dx.doi.org/10.1016/j.yebeh.2020.107715DOI Listing
March 2021

Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies.

CNS Drugs 2021 Jan 21;35(1):61-83. Epub 2021 Jan 21.

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, Schleusenweg 2-16 (Haus 95), 60528, Frankfurt am Main, Germany.

Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient's lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%-68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%-78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat-OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a 'one size fits all' approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.
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http://dx.doi.org/10.1007/s40263-020-00784-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873005PMC
January 2021

Epidemiology, healthcare resource use, and mortality in patients with probable Lennox-Gastaut syndrome: A population-based study on German health insurance data.

Epilepsy Behav 2021 02 22;115:107647. Epub 2020 Dec 22.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany. Electronic address:

Objective: This retrospective study examined patients with probable Lennox-Gastaut syndrome (LGS) identified from German healthcare data.

Methods: This 10-year study (2007-2016) assessed healthcare insurance claims information from the Vilua Healthcare research database. A selection algorithm considering diagnoses and drug prescriptions identified patients with probable LGS. To increase the sensitivity of the identification algorithm, two populations were defined: all patients with probable LGS (broadly defined) and only those with a documented epilepsy diagnosis before 6 years of age (narrowly defined). This specific criterion was used as LGS typically has a peak seizure onset between age 3 and 5 years. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, hospitalization rate and length of stay (LOS), medication use, and mortality.

Results: In the final year of the study, 545 patients with broadly defined probable LGS (mean [range] age: 31.4 [2-89] years; male: 53%) were identified. Using the narrowly defined probable LGS definition, the number of patients was reduced to 102 (mean [range] age: 7.4 [2-14] years; male: 52%). Prevalence of broadly defined and narrowly defined probable LGS was 39.2 and 6.5 per 100,000 people. During the 10-year study, 208 patients with narrowly defined probable LGS were identified and followed up for 1379 patient-years. The mean annual cost of healthcare was €22,787 per patient-year (PPY); greatest costs were attributable to inpatient care (33%), home nursing care (13%), and medication (10%). Mean annual healthcare costs were significantly greater for those with prescribed rescue medication (45% of patient-years) versus those without (€33,872 vs. €13,785 PPY, p < 0.001). Mean (standard deviation [SD]) annual hospitalization rate was 1.6 (2.0) PPY with mean (SD) annual LOS of 22.7 (46.0) days. Annual hospitalization rate was significantly greater in those who were prescribed rescue medication versus those who were not (2.2 [2.3] vs. 1.1 [1.6] PPY, p < 0.001). The mean (SD) number of different medications prescribed was 11.3 (7.3) PPY and 33.8 (17.0) over the entire observable time per patient (OET); antiepileptic drugs only accounted for 2.1 (1.1) of the medications prescribed PPY and 3.8 (2.0) OET. Over the 10-year study period, mortality in patients with narrowly defined probable LGS was significantly higher than the matched control population (six events [2.88%] vs. oneevent [0.01%], p < 0.001).

Conclusion: Annual healthcare costs incurred by patients with probable LGS in Germany were substantial, and mostly attributable to inpatient care, home nursing care, and medication. Patients prescribed with rescue medication incurred significantly greater costs than those who were not. Patients with narrowly defined probable LGS had a higher mortality rate versus control populations.
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http://dx.doi.org/10.1016/j.yebeh.2020.107647DOI Listing
February 2021

Advantages of methohexital over amobarbital in determining hemispheric language and memory lateralization in the Wada test - A retrospective study.

Epilepsy Behav 2020 12 24;113:107551. Epub 2020 Nov 24.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt and Goethe University, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt am Main, Germany.

Objective: Due to supply shortage, amobarbital, the traditional anesthetic agent in Wada testing, was replaced by methohexital in many epilepsy centers. This study aimed to compare the two barbiturates to identify possible advantages or disadvantages of methohexital as compared to amobarbital with regard to the adequacy of language and memory testing during the Wada test.

Methods: Data from 75 patients with temporal lobe epilepsy who underwent bilateral Wada tests using either amobarbital (n = 53) or methohexital (n = 22) as part of presurgical work-up were analyzed retrospectively. The two subgroups were compared regarding hemispheric language and memory lateralization results and Wada testing characteristics, and the adequacy of language and memory testing was assessed.

Results: We observed shorter durations of motor-, speech-, and EEG recovery after each injection in patients receiving methohexital compared to amobarbital. In addition, significantly more items could be presented during effective hemispheric inactivation in the methohexital group. Moreover, significant correlations of Wada memory scores with standard neuropsychological memory test scores could be found in the methohexital group.

Significance: Our findings confirm that methohexital is not only equally suitable for Wada testing but has several advantages over amobarbital. Wada testing can be performed more efficiently and under more constant hemispheric inactivation using methohexital. Furthermore, the adequacy of language and memory testing during the Wada test might be affected by the anesthetic agent used.
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http://dx.doi.org/10.1016/j.yebeh.2020.107551DOI Listing
December 2020

Clinical spectrum and treatment outcome of 95 children with continuous spikes and waves during sleep (CSWS).

Eur J Paediatr Neurol 2021 Jan 24;30:121-127. Epub 2020 Oct 24.

Division of Paediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Electronic address:

Objective: Continuous spikes and waves during sleep (CSWS) is an epileptic encephalopathy characterized by generalised epileptiform activity and neurocognitive dysfunction. Causes and outcome are diverse and treatment is mainly empirical.

Methods: Retrospective descriptive analysis of clinical and EEG data of children with CSWS diagnosed between 1998 and 2018 at the University Hospital Heidelberg.

Results: Ninety-five children were included with a median age at diagnosis of 5.4 years. A structural/metabolic aetiology was found in 43.2%, genetic alterations in 17.9%, while it remained unknown in 38.9%. The proportion of patients with genetic aetiology increased from 10.3% (1998-2007) to 22.8% (2008-2018). On average, each patient received 5 different treatments. CSWS was refractory in >70% of cases, steroids and neurosurgery were most effective. No difference was observed between children with CSWS or Near-CSWS (Spike-Wave-Index 40-85%).

Conclusions: Our cohort confirms CSWS as an age-dependent epileptic encephalopathy. Structural brain abnormalities were most frequent, but genetic causes are increasingly identified. More specific criteria for the diagnosis and treatment goals should be elaborated and implemented based on evidence.

Significance: This study is the largest monocentric observational study on treatment effects in children with CSWS, providing data for diagnostic and therapeutic decisions.
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http://dx.doi.org/10.1016/j.ejpn.2020.10.010DOI Listing
January 2021

Multilobar Epilepsy Surgery in Childhood and Adolescence: Predictors of Long-Term Seizure Freedom.

Neurosurgery 2020 12;88(1):174-182

Medical Faculty, University of Freiburg, Freiburg im Breisgau, Germany.

Background: Although multilobar resections correspond to one-fifth of pediatric epilepsy surgery, there are little data on long-term seizure control.

Objective: To investigate the long-term seizure outcomes of children and adolescents undergoing multilobar epilepsy surgery and identify their predictors.

Methods: In this retrospective study, we considered 69 consecutive patients that underwent multilobar epilepsy surgery at the age of 10.0 ± 5.0 yr (mean ± SD). The magnetic resonance imaging revealed a lesion in all but 2 cases. Resections were temporo-parieto(-occipital) in 30%, temporo-occipital in 41%, parieto-occipital in 16%, and fronto-(temporo)-parietal in 13% cases. Etiologies were determined as focal cortical dysplasia in 67%, perinatal or postnatal ischemic lesions in 23%, and benign tumors in 10% of cases.

Results: At last follow-up of median 9 yr (range 2.8-14.8), 48% patients were seizure free; 33% were off antiepileptic drugs. 10% of patients, all with dysplastic etiology, required reoperations: 4 of 7 achieved seizure freedom. Seizure recurrence occurred mostly (80%) within the first 6 mo. Among presurgical variables, only an epileptogenic zone far from eloquent cortex independently correlated with significantly higher rates of seizure arrest in multivariate analysis. Among postsurgical variables, the absence of residual lesion and of acute postsurgical seizures was independently associated with significantly higher rates of seizure freedom.

Conclusion: Our study demonstrates that multilobar epilepsy surgery is effective regarding long-term seizure freedom and antiepileptic drug withdrawal in selected pediatric candidates. Epileptogenic zones-and lesions-localized distant from eloquent cortex and, thus, fully resectable predispose for seizure control. Acute postsurgical seizures are critical markers of seizure recurrence that should lead to prompt reevaluation.
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http://dx.doi.org/10.1093/neuros/nyaa368DOI Listing
December 2020

Therapeutic advances in Dravet syndrome: a targeted literature review.

Expert Rev Neurother 2020 10 16;20(10):1065-1079. Epub 2020 Aug 16.

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt , Frankfurt am Main, Germany.

Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments.

Areas Covered: This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies.

Expert Opinion: Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
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http://dx.doi.org/10.1080/14737175.2020.1801423DOI Listing
October 2020

Risk incidence of fractures and injuries: a multicenter video-EEG study of 626 generalized convulsive seizures.

J Neurol 2020 Dec 10;267(12):3632-3642. Epub 2020 Jul 10.

Center of Neurology and Neurosurgery, Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt, Schleusenweg 2-16 (Haus 95), 60528, Frankfurt am Main, Germany.

Objective: To evaluate the incidence and risk factors of generalized convulsive seizure (GCS)-related fractures and injuries during video-EEG monitoring.

Methods: We analyzed all GCSs in patients undergoing video-EEG-monitoring between 2007 and 2019 at epilepsy centers in Frankfurt and Marburg in relation to injuries, falls and accidents associated with GCSs. Data were gathered using video material, EEG material, and a standardized reporting form.

Results: A total of 626 GCSs from 411 patients (mean age: 33.6 years; range 3-74 years; 45.0% female) were analyzed. Severe adverse events (SAEs) such as fractures, joint luxation, corneal erosion, and teeth loosening were observed in 13 patients resulting in a risk of 2.1% per GCS (95% CI 1.2-3.4%) and 3.2% per patient (95% CI 1.8-5.2%). Except for a nasal fracture due to a fall onto the face, no SAEs were caused by falls, and all occurred in patients lying in bed without evidence of external trauma. In seven patients, vertebral body compression fractures were confirmed by imaging. This resulted in a risk of 1.1% per GCS (95% CI 0.5-2.2%) and 1.7% per patient (95% CI 0.8-3.3%). These fractures occurred within the tonic phase of a GCS and were accompanied by a characteristic cracking noise. All affected patients reported back pain spontaneously, and an increase in pain on percussion of the affected spine section.

Conclusions: GCSs are associated with a substantial risk of fractures and shoulder dislocations that are not associated with falls. GCSs accompanied by audible cracking, and resulting in back pain, should prompt clinical and imaging evaluations.
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http://dx.doi.org/10.1007/s00415-020-10065-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674387PMC
December 2020

Expectations and knowledge of cannabidiol therapy for childhood epilepsy - A German caregiver survey.

Epilepsy Behav 2020 10 6;111:107268. Epub 2020 Jul 6.

Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine University of Freiburg, Mathildenstraße 1, 79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Germany; Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, Canada.

Background: Cannabidiol (CBD) has gained popularity among parents of children with epilepsy, even before evidence of efficacy and safety was available. The aim of our survey was to gain information about parental attitude to CBD, as well as expectations and knowledge of CBD for treatment of their child's epilepsy.

Methods: A survey using an open-access online questionnaire for parents or caregivers of children with epilepsy within German-speaking countries from March to June 2019 was used.

Results: Of 378 complete questionnaires (mean age of children: 11.1 (standard deviation [SD] 7.4) years), 28% (n = 106) reported previous or current CBD treatment over a mean time of 17.31 months (SD: 19.74), whereas 72% had no personal experience with CBD. Treatment was proposed by parents and not by physicians in 83% of cases and was mainly carried out with prescription-only products (71%, n = 67). Nevertheless, 29% used unregulated, artisanal products. Of all parents with previous experience, n = 77 (73%) reported that they expected CBD to be more efficient than the common antiseizure drugs (ASDs) at the beginning. Forty-five percent reported that their expectations were not met during therapy. Consistently, lack of seizure reduction was the most common reason to discontinue CBD (12/26). Of those responders without CBD experience, 93% would consider CBD for their child. However, the self-reported level of information was considered to be poor or very poor regarding efficacy (76%, n = 177), tolerance (83%, n = 191), interaction with other medication (91%, n = 211), and potential long-term effects (87%, n = 212).

Conclusions: There is a huge interest in CBD but includes potentially unrealistic expectations of its efficacy and tolerance combined with a low level of information. Neuropediatricians should address parents of children with epilepsy regarding potential motivation and expectations of CBD. In addition, parental education, especially on interactions and potential side effects, is strongly recommended.
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http://dx.doi.org/10.1016/j.yebeh.2020.107268DOI Listing
October 2020

Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring.

CNS Drugs 2020 05;34(5):545-553

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, University Hospital Frankfurt, Schleusenweg 2-16, Haus 95, 60528, Frankfurt am Main, Germany.

Background: An efficient, well tolerated, and safe emergency treatment with a rapid onset of action is needed to prevent seizure clusters and to terminate prolonged seizures and status epilepticus.

Objectives: This study aimed to examine the efficacy, tolerability, and safety of intranasal midazolam (in-MDZ) spray in clinical practice.

Methods: In this retrospective, multicenter observational study, we evaluated all patients with peri-ictal application of in-MDZ during video-EEG monitoring at the epilepsy centers in Frankfurt and Marburg between 2 014 and 2017. For every patient, we analyzed the recurrence of any seizure or generalized tonic-clonic seizures after index seizures with and without in-MDZ administration. Treatment-emergent adverse events (TEAEs) were also evaluated.

Results: In-MDZ was used in 243 patients with epilepsy (mean age 35.5 years; range 5-76 years; 46.5% female) for treatment of 459 seizures. A median dose of in-MDZ 5 mg (i.e., two puffs; range 2.5-15 mg) was administered within a median time from EEG seizure onset until in-MDZ application of 1.18 min [interquartile range (IQR) 1.27], while median time from clinical seizure onset until in-MDZ administration was 1.08 min (IQR 1.19). In-MDZ was given within 1 min after EEG seizure onset in 171 seizures. An intraindividual comparison of seizures with and without application of in-MDZ was feasible in 171 patients, demonstrating that in-MDZ reduced the occurrence of any (Cox proportional-hazard model p < 0.001) and generalized tonic-clonic seizure (Cox proportional-hazard model p = 0.0167) over a period of 24 h. The seizure-free timespan was doubled from a median of 5.0 h in controls to a median of 10.67 h after in-MDZ administration. We additionally clustered in-MDZ administrations for the 119 patients who received in-MDZ more than once, comparing them with the index cases without in-MDZ. Even when considering subsequent seizures with in-MDZ administration, a patient receiving in-MDZ is still half as likely to incur another seizure in the upcoming 24 h as compared with when the same patient does not receive in-MDZ (hazard ratio 0.50; 95% CI 0.42-0.60; p < 0.01). In-MDZ was well tolerated without major adverse events. The most common side effects were irritation of the nasal mucosa [37 cases (8.1%)], prolonged sedation [26 cases (5.7%)], and nausea and vomiting [12 cases (2.6%)]. A decline in oxygen saturation was measured after 78 seizures (17%).

Conclusion: We conclude that in-MDZ is a safe and efficient treatment option to prevent short-term recurrence of seizures. In-MDZ can be administered very quickly by trained staff within 1-2 min after seizure onset. No major cardiocirculatory or respiratory adverse events were observed.
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http://dx.doi.org/10.1007/s40263-020-00720-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198639PMC
May 2020

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Seizure 2020 May 5;78:31-37. Epub 2020 Mar 5.

Neurocenter Bellevue, Zurich, Switzerland.

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".
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http://dx.doi.org/10.1016/j.seizure.2020.02.018DOI Listing
May 2020

Prone, lateral, or supine positioning at seizure onset determines the postictal body position: A multicenter video-EEG monitoring cohort study.

Seizure 2020 Feb 21;76:173-178. Epub 2020 Feb 21.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized and Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany; Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany. Electronic address:

Purpose: Most patients who die from sudden unexpected death in epilepsy (SUDEP) are found in the prone position. We evaluated whether changes in body position occur during generalized convulsive seizures (GCSs).

Method: GCSs in patients undergoing video-EEG-monitoring between 2007 and 2017 at epilepsy centers in Frankfurt and Marburg were analyzed in relation to changes in body position.

Results: A total of 494 GCSs were analyzed among 327 patients. At seizure onset, positions included supine (48.2 %), right lateral (19.0 %), left lateral (15.6 %), sitting or standing (14.0 %), and prone (3.2 %). Between seizure onset and the start of generalization, 57.5 % of participants altered body positions. During four seizures, patients adopted a prone position, while, in five seizures, patients moved from a prone position. Patients who experienced GCS onset while in a nonprone position had a 2.1 % risk of entering the prone position by the end of their seizure. In contrast, 56.2 % of those in an initial prone position remained so at the end of the GCS, with an odds ratio for maintaining that position of 60.2 (95 % confidence interval: 29.1-124.3; p < 0.001). The likelihood of ending up in the prone position post-GCS did not vary among patients with different nonprone starting positions (p = 0.147).

Conclusions: Seizures in prone position occur during sleep and the highest risk for postictal prone positioning appears to be being in the prone position at GCS onset. Epilepsy patients should therefore be advised to go to sleep in a supine or lateral position to reduce their SUDEP risk.
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http://dx.doi.org/10.1016/j.seizure.2020.02.008DOI Listing
February 2020

A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC).

Orphanet J Rare Dis 2020 01 21;15(1):23. Epub 2020 Jan 21.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.

Objective: This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs.

Methods: We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included.

Results: We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years.

Conclusions: TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.
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http://dx.doi.org/10.1186/s13023-019-1258-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975094PMC
January 2020

First clinical postmarketing experiences in the treatment of epilepsies with brivaracetam: a retrospective observational multicentre study.

BMJ Open 2019 11 4;9(11):e030746. Epub 2019 Nov 4.

Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.

Objectives: Brivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting.

Design: Retrospective, observational multicentre study.

Setting: We retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist.

Participants: Data of 615 epilepsy patients treated with BRV were included in the study.

Primary And Secondary Outcome Measures: Efficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X contingency tests and effect sizes were performed.

Results: Overall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV.

Conclusions: The present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.
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http://dx.doi.org/10.1136/bmjopen-2019-030746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858140PMC
November 2019

Intranasal midazolam as first-line inhospital treatment for status epilepticus: a pharmaco-EEG cohort study.

Ann Clin Transl Neurol 2019 12 4;6(12):2413-2425. Epub 2019 Nov 4.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.

Objective: We sought to evaluate the efficacy and tolerability of intranasal midazolam (in-MDZ) as first-line inhospital therapy in patients with status epilepticus (SE) during continuous EEG recording.

Methods: Data on medical history, etiology and semiology of SE, anticonvulsive medication usage, efficacy and safety of in-MDZ were retrospectively reviewed between 2015 and 2018. Time to end of SE regarding the administration of in-MDZ and ß-band effects were analyzed on EEG and with frequency analysis.

Results: In total, 42 patients (mean age: 52.7 ± 22.7 years; 23 females) were treated with a median dose of 5 mg of in-MDZ (range: 2.5-15 mg, mean: 6.4 mg, SD: 2.6) for SE. The majority of the patients suffered from nonconvulsive SE (n = 24; 55.8%). In total, 24 (57.1%) patients were responders, as SE stopped following the administration of in-MDZ without any other drugs being given. On average, SE ceased on EEG at 05:05 (minutes:seconds) after the application of in-MDZ (median: 04:56; range: 00:29-14:53; SD:03:13). Frequency analysis showed an increased ß-band on EEG after the application of in-MDZ at 04:07 on average (median: 03:50; range: 02:20-05:40; SD: 01:09). Adverse events were recorded in six patients (14.3%), with nasal irritations present in five (11.9%) and prolonged sedation occurring in one (2.6%) patient.

Conclusions: This pharmaco-EEG-based study showed that in-MDZ is effective and well-tolerated for the acute treatment of SE. EEG and clinical effects of in-MDZ administration occurred within 04:07 and 5:05 on average. Intranasal midazolam appears to be an easily applicable and rapidly effective alternative to buccal or intramuscular application as first-line treatment if an intravenous route is not available.
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http://dx.doi.org/10.1002/acn3.50932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917318PMC
December 2019

Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature.

Epilepsy Behav 2019 09 10;98(Pt A):88-95. Epub 2019 Jul 10.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany; Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany. Electronic address:

Objective: The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe.

Methods: Patient use of routine AEDs and emergency medications over 3-6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe.

Results: The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed.

Significance: This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3-6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.
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http://dx.doi.org/10.1016/j.yebeh.2019.06.021DOI Listing
September 2019

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.

Epilepsia 2019 08 27;60(8):1697-1710. Epub 2019 Jun 27.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.

Objective: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany.

Methods: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days).

Results: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001).

Significance: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.
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http://dx.doi.org/10.1111/epi.16099DOI Listing
August 2019

First clinical experience with the new noninvasive transfontanelle ICP monitoring device in management of children with premature IVH.

Neurosurg Rev 2020 Apr 11;43(2):681-685. Epub 2019 May 11.

Department of Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.

We previously introduced a novel noninvasive technique of intracranial pressure (ICP) monitoring in children with open fontanelles. Within this study, we describe the first clinical implementation and results of this new technique in management of children with hydrocephalus caused by intraventricular hemorrhage (IVH). In neonates with posthemorrhagic hydrocephalus (PHH), an Ommaya reservoir was implanted for initial treatment of hydrocephalus. The ICP obtained noninvasively with our new device was measured before and after CSF removal and correlated to cranial ultra-sonographies. Six children with a mean age of 27.3 weeks and mean weight of 1082.3 g suffering from PHH were included in this study. We performed an overall of 30 aspirations due to ventricular enlargement. Before CSF removal, the mean ICP was 15.3 mmHg and after removal of CSF the mean ICP measured noninvasively decreased to 3.4 mmHg, p = 0.0001. The anterior horn width (AHW), which reflects early expansion of the ventricles, was before and after CSF removal 15.1 mm and 5.5 mm, respectively, p < 0.0006. There was a strong correlation between noninvasively measured ICP values and sonographically obtained AHW, r = 0.81. Ultimately, all children underwent ventriculoperitoneal shunt procedures. This is the first study providing proof for a noninvasively ICP-based approach for management of posthemorrhagic hydrocephalus in newborn children.
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http://dx.doi.org/10.1007/s10143-019-01105-4DOI Listing
April 2020

Quality of life and correlating factors in children, adolescents with epilepsy, and their caregivers: A cross-sectional multicenter study from Germany.

Seizure 2019 Jul 29;69:92-98. Epub 2019 Mar 29.

Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany; Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany. Electronic address:

Purpose: To identify factors correlating with poorer quality of life (QoL) in children and adolescents with epilepsy and regarding QoL and depression of their caregivers in Germany.

Method: A cross-sectional multicenter study on QoL and depression was performed in two representative German states (Hessen and Schleswig-Holstein). Variance analysis, linear regression, and bivariate correlation were used to identify correlating factors for poorer QoL and symptoms of depression.

Results: Data from 489 children and adolescents (mean age 10.4 ± 4.2 years, range 0.5-17.8; 54.0% male) and their caregivers were collected. We identified missing seizure freedom (p = 0.046), concomitant diseases (p = 0.007), hospitalization (p = 0.049), recent status epilepticus (p = 0.035), living in a nursing home or with foster parents (p = 0.049), and relevant degree of disability (p = 0.007) to correlate with poorer QoL in children and adolescents with epilepsy. Poorer QoL of caregivers was associated with longer disease duration (p = 0.004), non-idiopathic (mainly structural-metabolic) epilepsy (p = 0.003), ongoing seizures (p = 0.003), concomitant diseases (p = 0.003), relevant disability (p = 0.003), or status epilepticus (p = 0.003) as well as with unemployment of the primary caretaker (p = 0.010). Symptoms of depression of caregivers were associated with non-idiopathic epilepsy (p = 0.003), concomitant diseases (p = 0.003), missing seizure freedom (p = 0.007), status epilepticus (p = 0.004), or a relevant disability (p = 0.004) of their ward. A poorer QoL value of the children and adolescents correlated with a poorer QoL value of the caregivers (p < 0.001).

Conclusions: Epilepsy shows a considerable impact on QoL and symptoms of depression. Early and effective therapy should focus on reduction of seizure frequency and the probability for developing status epilepticus. Furthermore, comprehensive care should pay attention at comorbidities, consequences of disability and dependency on others.
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http://dx.doi.org/10.1016/j.seizure.2019.03.016DOI Listing
July 2019

Burden and epidemiology of status epilepticus in infants, children, and adolescents: A population-based study on German health insurance data.

Epilepsia 2019 05 13;60(5):911-920. Epub 2019 Apr 13.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany.

Objective: Status epilepticus (SE) is an important medical emergency condition with particularly unfavorable outcome in refractory and superrefractory SE (SRSE). The economic impact of SE and especially of SRSE in the pediatric population remains unclear. We aimed to determine the burden of illness of SE in a pediatric patient population.

Methods: Insurance records for patients aged 0-18 years admitted between 2008 and 2015 were selected from a nationwide insurance research database utilizing International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes for SE (G41), epilepsy (G40), or febrile convulsions (R56). Patients were further classified based on admission to the intensive care unit and use of mechanical ventilation.

Results: The algorithm identified 11 693 seizure-related admissions and classified 4% as SE. Of these cases, 282 (60.4%) were classified by the algorithm as nonrefractory SE (NRSE), 125 (26.8%) as refractory SE (RSE), and 60 (12.8%) as SRSE. The crude SE incidence was 17.6/100 000, with NRSE being 11.4/100 000, RSE 3.9/100 000, and SRSE 2.3/100 000. SRSE incidence peaked in the 0- to 1-year-old age subgroup accounting for 48.3% of all pediatric SRSE admissions. The median length of stay (LOS) for all SE cases was 7 days, with median 44.5 days in SRSE, 5 days in NRSE, and 12 days in RSE. Mean admission costs for total SE were €15 880, with a mean expense for SRSE of €75 358, for NRSE of €4119, and for RSE of €13 864. The mean LOS for non-SE epilepsy admissions was 3 days, with mean costs of €2697 for epilepsy and €1614 for febrile convulsion admissions. There were no deaths in non-SE and NRSE admissions, whereas the overall mortality for SE was 3%, with 5.6% in RSE and 11.7% in SRSE.

Significance: Although cases classified as SE represented 4% of the seizure-associated admissions, they accounted for 22% of the overall costs. These costs were disproportionately represented by SRSE cases, which accounted for 62% of all SE-associated costs.
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http://dx.doi.org/10.1111/epi.14729DOI Listing
May 2019

Burden-of-illness and cost-driving factors in Dravet syndrome patients and carers: A prospective, multicenter study from Germany.

Eur J Paediatr Neurol 2019 May 28;23(3):392-403. Epub 2019 Feb 28.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany; Department of Neuropediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany.

Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany.

Methods: A validated 3-12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany.

Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months-33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis.

Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.
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http://dx.doi.org/10.1016/j.ejpn.2019.02.014DOI Listing
May 2019

[Acceptance, demand, reasons for consultation and outcome of counseling on epilepsy in Hesse and Lower Franconia].

Nervenarzt 2019 Aug;90(8):832-839

Epilepsiezentrum Frankfurt Rhein-Main, Zentrum der Neurologie und Neurochirurgie, Goethe-Universität Frankfurt, Schleusenweg 2-16, 60528, Frankfurt am Main, Deutschland.

Background And Aim: The diagnosis of epilepsy is often accompanied by relevant restrictions for patients, which may result in disease-specific daily problems that need targeted and professional counseling. Specialized epilepsy counseling services (ECS) were introduced in some German states since 1996 to provide an additional and independent service for epilepsy-related problems. The objective of this prospective, multicenter cohort study at six ECS was to determine and analyze the acceptance, demand and frequent reasons for consultation in Hesse and Lower Franconia.

Results: A total of 435 clients were enrolled during the 12-month observation period (June 2014-May 2015) of which 74.3% were adults (n = 323, mean age 40.3 ± 14.7 years, range 18-76 years, 51.7% female) and 25.7% children and adolescents (n = 112, mean age 9.4 ± 4.8 years, range 1-17 years, 52.7% female). The mean number of outpatient consultations per year was 2.5 (median 2.0, SD ± 2.8, range 1-20), whereby a general counseling on dealing with epilepsy (adults 55.7%, children and adolescents 51.8%), clarification and information about the disease (43.7% and 41.1%, respectively) and assistance in applying for support (39.0% and 46.4%, respectively) were the most frequent issues. The distance from the place of residence to the ECS was significantly shorter in Lower Franconia compared to Hesse (p < 0.002). Client satisfaction was high with a mean patient satisfaction questionnaire (ZUF-8) score of 29.0 (maximum score 32). Overall 96.4% of the clients rated the quality of counseling as good or very good and 96.6% would consider consulting the ECS again in case of new problems. In cases of threatened workplace, training position or situation at school, counseling helped to avoid negative consequences in 72.0% of cases.

Conclusion: The ECS are frequently used, appreciated and effective institutions for adults and children with epilepsy as well as for their caregivers. The ECS complements the existing comprehensive specialized outpatient and inpatient care for epilepsy in Germany; however, in view of their limited numbers and inhomogeneous allocation, the number and the availability of ECS should be expanded on the national level.
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http://dx.doi.org/10.1007/s00115-019-0676-8DOI Listing
August 2019

Counseling and social work for people with epilepsy in Germany: A cross-sectional multicenter study on demand, frequent content, patient satisfaction, and burden-of-disease.

Epilepsy Behav 2019 03 14;92:114-120. Epub 2019 Jan 14.

Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany; Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany. Electronic address:

Background: The diagnosis of epilepsy is accompanied by relevant personal, interpersonal, and professional restrictions for patients and their caregivers. Specialized epilepsy counseling services (ECS) have been introduced to inform, advise, and support patients with disease-related problems.

Aim And Scope: The objective of this cross-sectional, multicenter study was to determine the demand, typical content, and outcomes of ECS in children, adolescents, and adults in two adjacent German regions of Hessen and Lower Franconia. All ECS sites in these regions participated in 2014 and 2015, offering a total population of 7.5 million inhabitants.

Results: A total number of 435 patients [323 adults (74.3%), 51.7% female, mean age: 40.3 ± 14.7 years and 112 children/adolescents (25.7%), 52.7% female, mean age: 9.4 ± 4.6 years] were enrolled at six ECS sites. The most common reasons for counseling were general information needs (n = 304; 69.9%), administrative help (n = 208; 47.8%), problems with education or work (n = 176; 40.5%), and recreational activities (n = 119; 27.3%). In addition, 6.2% reported epilepsy-related questions on family planning as a specific reason for desiring counseling. Recommendation by the treating physicians was the most frequent reason for receiving counseling through ECS (62.5%), and most patients preferred to receive a personal consultation (73.1%). Patient satisfaction as measured by the ZUF-8 client satisfaction score was high with a mean of 29.7 points (standard deviation: ±2.7 points, median: 29.9 points), and 83.9% of patients said they would recommend ECS. Disease-related job loss or change in school was avoided in 72% of 82 patients. Suggestions for improvement of ECS included an extension of service hours (58.6%) and a better availability of more sites located nearby (32.8%).

Conclusion: Epilepsy counseling services are necessary, valued, and effective institutions for people with epilepsy complementing outpatient and inpatient care. To improve the care for people with epilepsy, access to and availability of ECS should be improved.
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http://dx.doi.org/10.1016/j.yebeh.2018.12.004DOI Listing
March 2019

Postmarketing experience with brivaracetam in the treatment of focal epilepsy in children and adolescents.

Epilepsy Behav 2018 Dec 31;89:89-93. Epub 2018 Oct 31.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany; Epilepsy Center Hessen and Department of Neurology, Philipps-University, Marburg, Germany; Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany. Electronic address:

Introduction: This multicenter, retrospective study aimed to evaluate the efficiency, retention, safety, and tolerability of brivaracetam (BRV) in children and adolescents with focal epilepsy.

Methods: All patients aged ≤17 years with focal epilepsy who started BRV in 2016 and 2017 were analyzed.

Results: Thirty-four patients (mean age: 12.2 years, range: 3-17 years, 56% female) were treated with BRV for 25 days to 24 months, with a total exposure time of 19.7 years. Overnight switch from levetiracetam (LEV) to BRV was performed in 20 patients at a median ratio of 10:1. Retention rate was 97% at three months, with only one patient reporting a discontinuation of BRV treatment. Further dropouts were reported in one patient after seven months and in two patients after one year of treatment, respectively. The median length of exposure to BRV was 180 days. Efficacy at three months was 47% (50% responder rate), with 10 patients (29%) reporting seizure freedom. A long-term 50% responder rate was present in 12 patients [35%; four patients seizure-free (12%)] for more than six months and in seven patients (21%; no seizure-free patients) for more than 12 months. Treatment-emergent adverse events were observed in 12% of patients, with the most common being sedation, somnolence, loss or gain of appetite, and psychobehavioral adverse events.

Conclusions: Use of BRV in children and adolescents seems to be safe and well-tolerated. The results with 50% responder rate of 47% are consistent with those from randomized controlled trials and postmarketing studies in adults. An immediate switch from LEV to BRV at a ratio of 10:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV and a switch to BRV can be considered in patients with LEV-induced adverse events.
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http://dx.doi.org/10.1016/j.yebeh.2018.10.018DOI Listing
December 2018

Epilepsy Surgery in the First 3 Years of Life: Predictors of Seizure Freedom and Cognitive Development.

Neurosurgery 2019 06;84(6):E368-E377

Medical Faculty, University of Freiburg, Freiburg, Germany.

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.
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http://dx.doi.org/10.1093/neuros/nyy376DOI Listing
June 2019