Accepted Manuscript Treatment of pediatric epilepsy in Poland Dorota Dunin-Wąsowicz, Maria Mazurkiewicz-Bełdzińska, Barbara Steinborn, James Wheless, Sergiusz Jóźwiak PII:
S1090-3798(15)00007-0
DOI:
10.1016/j.ejpn.2014.12.023
Reference:
YEJPN 1867
To appear in:
European Journal of Paediatric Neurology
Received Date: 7 September 2014 Revised Date:
9 December 2014
Accepted Date: 31 December 2014
Please cite this article as: Dunin-Wąsowicz D, Mazurkiewicz-Bełdzińska M, Steinborn B, Wheless J, Jóźwiak S, Treatment of pediatric epilepsy in Poland, European Journal of Paediatric Neurology (2015), doi: 10.1016/j.ejpn.2014.12.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Treatment of pediatric epilepsy in Poland Dorota Dunin-Wąsowicza, Maria Mazurkiewicz-Bełdzińskab, Barbara Steinbornc, James Whelessd, e Sergiusz Jóźwiak a a
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Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland b Department of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Poland c Chair, Department of Developmental Neurology, Poznań University of Medical Sciences, Poland d University of Tennessee Health Science Center, Memphis, TN, USA e Le Bonheur Children’s Hospital, Memphis, TN, USA
Category of manuscript: original research
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Corresponding author Sergiusz Jóźwiak a Full address: Department of Neurology and Epileptology; The Children’s Memorial Health Institute; Al. Dzieci Polskich 20; 04-730 Warsaw; Poland. Telephone number: +48 22 8157447 Email: [email protected].
Running title: Treatment of pediatric epilepsy. Polish Expert Opinion, 2012. List of respondents:
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Artemowicz Barbara, Białystok Bańdo Bożena, Kraków Biegański Grzegorz, Poznań Brzozowski Edmund, Olsztyn Bugaj Grażyna, Poznań Chrościńska-Krawczyk Magdalena, Lublin Ciarka Roman, Kołobrzeg Czyżyk Elżbieta, Rzeszów Jabłecka-Deja Halina, Katowice Domańska-Pakieła Dorota, Warszawa Dudzińska Magdalena, Chorzów Emich-Widera Ewa, Katowice Gergont Aleksandra, Kraków Gniatkowska-Nowakowska Anna, Kielce Gołębiewska Mirosława, Dziekanów Leśny Gucwa-Piotrowska Grażyna, Kraków Hibner Elżbieta, Łódź Hnatyszyn Grażyna, Szczecin Kemnitz Paweł, Poznań Kleist Teresa, Chorzów Kochanowska Iwona, Szczecin Koncewicz Renata, Lublin Krajnik Anna, Warszawa Krause Małgorzata, Wrocław Kroczka Sławomir, Kraków
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Kubarek Grażyna, Tarnów Kuzior-Pławiak Małgorzata, Wrocław Kużel Marek, Wejherowo Łobodzińska-Młynarczyk Elżbieta, Olsztyn Matheisel Agnieszka, Gdańsk Melnyk Aleksandra, Gdańsk Mermer-Kutek Danuta, Olsztyn Milecka Grażyna, Poznań Natwora-Gołąbek Beata, Kielce Piasecka-Frąc Elżbieta, Chorzów Pilarska Ewa, Gdańsk Służewski Wojciech, Poznań Sokołowska Dorota, Łódź Strzelecka Joanna, Warszawa Surmacz Jolanta, Katowice Szczepanik Elżbieta, Warszawa Szwed-Białożyt Barbara, Katowice Ujma-Czapska Barbara, Wrocław Wątróbska Stanisława, Rzeszów Wendorff Janusz, Łódź Wesołowska Marzenna, Bydgoszcz Witkowska-Gęsicka Iwona, Toruń Zacharzewska Joanna, Białystok Zielnik Aleksander, Katowice
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ACCEPTED MANUSCRIPT Abstract
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Background: The many types of childhood epilepsies make the diagnosis and treatment difficult and the outcomes frequently poor. Furthermore, there are few clinical trials in pediatric epilepsy that provide useful results to guide daily practice. Therefore for pediatric neurologists expert opinion may be useful. Aims: To provide an overview of current practice in Poland and compare results with European and US clinical guidelines. Methods: Polish specialists in pediatric neurology were asked to participate in a survey about paediatric epilepsy. The focus of the questions was on the overall strategy and treatment options for different syndromic diagnoses. The survey was developed and performed according to a previous European survey (Wheless et al. 2007). Results: Fifty-one Polish specialists, working in academic or clinical settings, completed the questionnaire. They limited combination therapy to two or three antiepileptic drugs. Valproate was the treatment of choice for myoclonic, generalized tonic-clonic seizures and Lennox-Gastaut syndrome. For infantile spasms caused by tuberous sclerosis and of symptomatic aetiology, vigabatrin was treatment of choice; valproate and ACTH were other first line options. Valproate and ethosuximide were chosen for childhood absence epilepsy and valproate for juvenile absence epilepsy. Carbamazepine was the first-line treatment option for benign partial epilepsy of childhood with centrotemporal spikes and complex partial seizures. In the treatment of juvenile myoclonic epilepsy for males valproate, for females lamotrigine were chosen. Conclusion: Polish pediatric neurologists agreed on the majority of questions. Their views reflect the clinical utility and availability of treatment options in Poland. Results may provide direction for clinicians.
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Keywords: Poland, pediatric epilepsy, children, antiepileptic drugs, seizure
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ACCEPTED MANUSCRIPT Introduction Epilepsy and epileptic syndromes are among the most common neurological disorders in childhood and adolescence with a prevalence of 5.3–8.8 per 1,000 in children below 13 years of age1. Compared with adult epilepsies, childhood epilepsies present a much more heterogeneous group of conditions, each characterized by varied diagnostic criteria, and frequently specific management requirements and different outcomes.
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In recent years, many new antiepileptic drugs (AEDs) have been brought to the market, five between 2009 and 2011 alone in the US2. At present there are 24 AEDs, as well as vagus nerve stimulation (VNS) approved for use in the treatment of epilepsy by the Food and Drug Administration in the United States2. Improvements in neurosurgical techniques have also made the surgical treatment of patients with refractory partial seizures more effective and safer. Ketogenic diet and its modifications are offered in increasing number of centres worldwide3,4. Even with this increasing number of new therapies, 30–35% of patients suffer from drug-resistant epilepsy. Expanding therapeutic options present a challenge to the physician in terms of choosing the optimal therapeutic agent for an individual patient. This situation has necessitated the development of therapeutic guidelines to assist the physician in the decision-making process.
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Guidelines from the Therapeutics and Technology Assessment Subcommittee and Quality Standard Subcommittee of the American Academy of Neurology and the American Epilepsy Society practice parameters for the use of new AEDs were first published in 20045 and are currently being updated.
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In 2006, the International League Against Epilepsy (ILAE) for the first time published evidence-based treatment guidelines for initial monotherapy based on an extensive review of the literature from 1940 to 20056. The authors analysed results from 50 randomized controlled trials and 7 metaanalyses. This document noted an alarming lack of well-designed, randomized controlled trials, especially in children. Results of only four trials were classified as class I evidence and two as class II evidence6. Remaining studies were classified as class III or IV evidence. Thus, the strongest recommendation (level A) in childhood epilepsy was available only in partial-onset seizures (oxcarbazepine). In other types of childhood epilepsies only low level of evidence were available (level C). Despite the ever-growing body of evidence in the medical literature regarding the treatment of epilepsy, many routine clinical questions remain unanswered or only partially answered.
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An update published in 2013 including 64 randomized studies and 11 meta-analyses - up to 2012. There were only 3 additional studies with class I evidence. The change in childhood epilepsy therapy was level A evidence for valproate and ethosuximide in absence epilepsy. The authors once again reported their concern over the general lack of high level evidence studies in children7. Very few of the clinical trials on these common childhood epilepsies have compared different treatments with each other. Moreover, many controlled trials do not include childhood epilepsies or epilepsy syndromes (e.g. juvenile absence epilepsy, neonatal seizures, juvenile myoclonic epilepsy). Thus, neuropaediatricians must very often rely on their own medical judgment to select the ‘best’ treatment option for an individual patient. Physicians look to their colleagues and to expert opinion to help ‘fill the gaps’ left by randomized clinical trials. The lack of therapeutic guidelines in paediatric epilepsies provided by recognized professional organizations results in attempts to provide physicians with practical information established by expert opinion groups. Results of expert opinion surveys may reflect many additional variables that are not considered in large randomized trials focused primarily on AED-related aspects, particularly on effectiveness and
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ACCEPTED MANUSCRIPT safety. Expert opinion statements also reflect country-specific variables such as national registration, reimbursement, and insurance coverage. The first such paediatric survey was completed by a group of 39 specialists in the United States in 2004-20058. The recommendations represented the first use of the expert consensus survey method in the field of paediatric epilepsy. A similar survey was performed in 2007 with a group of 42 Western European paediatric epileptologists8.
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In the present study we summarize the therapeutic choices of Polish paediatric neurologists in similar clinical situations. It is the first such study from the Central and Eastern European countries. The recommendations resulting from this survey should not be seen as clinical guidelines, but the therapeutic preferences of Polish paediatric neurologists. It provides information on how individual patient variables, labelled indications and Poland-specific reimbursement issues influence decisions on treatment strategies and drug selection.
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Methods
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Polish specialists in pediatric neurology were asked to participate in this survey. The specialists were identified by regional consultants who indicated physicians with substantial expertise in epilepsy therapy. The number of specialists from each region was relative to the number of pediatric neurologists practicing there. No honorarium was provided. The survey was conducted with the support of UCB Pharma.
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The survey was developed on the basis of a previously published European survey9. It was designed to address key decision/selection points in the management of epilepsy and seizures in pediatric patients in Poland. It should be noted that not all of the drugs listed in the survey questions are fully available or reimbursed in Poland. Some products available in Europe can be imported to Poland on demand. Survey questions were prepared in Polish and also supplemented for emerging AEDs.
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There were a total of 35 questions on approximately 650 treatment options for following conditions: symptomatic myoclonic and generalized tonic-clonic seizures (GTCS), complex partial seizures, neonatal seizures, infantile spasms, Lennox-Gastaut syndrome (LGS), febrile seizures, benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy; BECTS), absence epilepsy, juvenile myoclonic epilepsy (JME), newly diagnosed epilepsy in the emergency department and status epilepticus (SE).
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For each of the syndromic diagnoses, specific cases were presented and specialists were asked about the overall treatment strategy followed by their choice of specific treatment9. For the first part, (questions 1–9) specialists were asked to identify the order (steps) in which they would prefer/recommend certain treatment strategies. For example, if monotherapy was selected as the first step and subsequently failed, respondents were asked to identify the next best option. Since more than one treatment option might be considered at any step, ‘ties’ were permitted. For the next part (question 10–35) specialists were asked to use a modified RAND 9-point scale to rate utility of specific treatment choices for the given patient cases. For many of these questions, a ‘Don’t Know’ option was included so that the respondents would not feel compelled to rate an option if they did not have knowledge of, or experience with it. The results for each question indicate how many specialists rated each option (N). Except where indicated, specialists were instructed to assume the parents/guardians of the child will be amenable to all possible therapies. They were also instructed to assume that each treatment will be increased to the limit of clinical tolerability before new treatment is initiated. 5
ACCEPTED MANUSCRIPT Data analysis for options scored on the rating scale
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The mean, standard deviation (SD), and 95% confidence intervals (CI) as well chi-square testing were performed as described in Wheless et al., 20079. Consensus was defined as a non-random distribution of scores by chi-square test. A categorical rating of first (usually appropriate), second (equivocal), or third line (usually not appropriate) was designated as described in Wheless et al., 20079 ‘Usually appropriate’ or ‘first line‘. First-line treatments are those that the specialists identified as extremely or usually appropriate for the given clinical setting (options rated ‘7, 8, or 9’). Treatment of choice is a first-line therapy that was rated extremely appropriate (‘9’) by at least 50% of the specialists. ‘Equivocal’ or ‘second line’. Second-line therapies are reasonable options in instances when the usually appropriate or first-line agent is contraindicated or fails (options rated ‘4, 5, 6’). Failure can be due to poor efficacy, short- or long-term side effects, or an idiosyncratic reaction. ‘Usually not appropriate’ or ‘third line’. Third-line therapies are usually not appropriate (for the given scenario); however this is not the same as saying that they should not be used. Instead, these therapies might be considered if others are contraindicated or have already failed to produce complete seizure control. In case of random distribution of responses by chi-square it was not possible to design results to one of three categories. It indicated a lack of consensus.
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ACCEPTED MANUSCRIPT Results Survey response The questionnaire was sent to 70 specialists; it was completed and returned by 51 (73%), between January 2012 and April 2012. The majority of the specialists worked in an academic clinical or research setting.
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Symptomatic myoclonic and generalized tonic-clonic seizures
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For each of the following conditions, results are presented in three stages: the overall treatment strategy, treatment selection for the condition and comment. For each question, editors provide information on the interpretation of the results, factors influencing the treatment decisions and alignment with practice and guidelines described in Europe and US. Detailed results of the survey are provided in Supplementary Materials. Also in Supplementary Materials there are comments, remarks and general medication recommendations for each surveyed condition syndrome. Main findings describing practice in Poland are summarized in Table 1.
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Questions asked for general strategy for treating 2-years old or 12-years old child with myoclonic and generalized tonic-clonic seizures and mental retardation. Nearly all specialists indicated monotherapy as a first step, with alternative monotherapy as the next step, before trying combination therapy (Suppl. 1A, 1C). For a child of any age valproate was treatment of choice and in case of 12-years old patient topiramate was rated as another first-line treatment (Suppl. 1B, 1D). For patients with isolated generalized tonic-clonic seizures of any age valproate was treatment of choice and lamotrigine was an alternative first-line therapy for 12-years old child (Suppl. 1E, 1F). Complex partial seizures
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For children with either non-lesional cryptogenic complex partial seizures or right-sided mesial temporal sclerosis and complex partial seizures responders suggested three different trials of monotherapy before trying two or three trials of a combination of 2 antiepileptic drugs (Supp. 2A, 2B). If seizures continued to be refractory, they then suggested a combination of 3 antiepileptic drugs and evaluation for surgery (Suppl. 2B). For initial monotherapy carbamazepine was chosen as treatment of choice and oxcarbazepine and valproate as other first-line options. In case of lack of efficacy or intolerance of initial monotherapy with carbamazepine or oxcarbazepine, valproate and levetiracetam were selected as the next treatment choices. In case of failure of treatment with phenytoin, carbamazepine was treatment of choice for second monotherapy; oxcarbazepine, valproate and levetiracetam were rated as usually appropriative (other first line options after carbamazepine) (Suppl. 2C). Neonatal seizures
Treatment of neonatal seizures and even status epilepticus is often controversial and difficult. There is no standard approach for treatment of neonatal status epilepticus, which is likely why different options were chosen. Intravenous (IV), intramuscular (IM) and rectal benzodiazepines were rated as first line therapy. If this was not successful, experts would then give a second dose of the same benzodiazepine. In third step they would use a different IV or IM antiepileptic drug follow by its second dose and using different IV, IM, rectal benzodiazepines (Suppl. 3A). After stopping neonatal seizures experts continue treatment for a mean of 10.5 weeks. Among the available agents experts rated IV phenobarbital as treatment of choice and IV diazepam as sometimes appropriate (first line). In case of suboptimal control after trial with benzodiazepine, IV phenobarbital was selected as treatment of choice for next option (Suppl. 3B). 7
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For a 6-month-old diagnosed with infantile spasms (West Syndrome) experts endorsed minimum two trials of monotherapy before using following combinations with 2 and finally with 3 antiepileptic drugs (Suppl. 4A). Choosing specific medication for initial monotherapy of infantile spasm secondary to tuberous sclerosis complex (Supp. 4B) or of symptomatic in etiology (Suppl. 4C) experts indicated vigabatrin as treatment of choice and ACTH or valproate as usually appropriate initial monotherapy options. Lennox-Gastaut syndrome
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At least two monotherapy trials were considered before starting therapy combination therapies with 2 antiepileptic drugs (Supp. 5A). Considering initial monotherapy experts rated valproate as treatment of choice and topiramate as another first line therapy. If patient did not respond to lamotrigine or topiramate monotherapy valproate was still treatment of choice and topiramate or lamotrigine were alternative first line treatments respectively. In case of failure of treatment with valproate initial monotherapy experts rated topiramate as usually appropriate second line monotherapy (Suppl. 5B). Febrile seizures
For infants acute treatment of a prolonged febrile seizure or cluster of febrile seizures rectal diazepam was treatment of choice. In case of preventive therapy for infant with recurrent febrile generalized tonic-clonic seizures valproate was treatment of choice (Suppl. 6A). Benign childhood epilepsy with centro-temporal spikes
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Carbamazepine was rated as the treatment of choice for benign childhood epilepsy with centrotemporal spikes. Oxcarbazepine and valproate were selected as alternative first line options (Suppl. 7A). Absence epilepsy
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Valproate was treatment of choice both for childhood and juvenile absence epilepsy (Suppl. 8A, 8B). Ethosuximide was another treatment of choice for childhood absence epilepsy (Suppl. 8A). In case of failure of initial treatment of childhood absence epilepsy with ethosuximide valproate was rated as treatment of choice (Suppl. 8A). In case of failure of valproate in juvenile absence epilepsy experts selected lamotrigine as second line treatment of choice. Juvenile myoclonic epilepsy
For newly diagnosed male with juvenile myoclonic epilepsy treatment of choice was valproate (Suppl. 9A). In case of female lamotrigine was drug of choice when valproate and levetiracetam were rated as another first line options (Suppl. 9B). Newly diagnosed epilepsy in the emergency department For a 6-years old patient arriving to emergency department after 2 or 3 seizures, when decision is made to start treatment the panel selected valproate as treatment of choice (suppl. 10A). Status epilepticus 8
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Most of experts indicated use of IV, IM or rectal benzodiazepine in the case of convulsive status epilepticus in a 4-year-old child and following second course of the same benzodiazepine in case of lack of response. If these do not work different IV, IM or rectal benzodiazepine should be used and treatment should be repeated if seizures occur. In last steps were IV or IM antiepileptic drugs and drug coma (Suppl. 11A). For initial therapy of all types of status epilepticus (generalized tonic-clonic, absence, complex partial status epilepticus) experts indicated IV diazepam as treatment of choice for initial therapy (Suppl. 11B, 11C, 11D). In case of generalized tonic-clonic status epilepticus rectal diazepam and IV phenytoin (Suppl. 11B) and in case of absence status epilepticus IV valproate (Suppl. 11C) were selected as treatment of choice. Selecting second line treatment in case of failure of initial benzodiazepine, panel indicated as treatment of choice IV valproate of generalized tonic-clonic and absence status epilepticus (Suppl. 11B, 11C). Other first line treatments in this situation for generalized tonic-clonic status were IV phenytoin and IV phenobarbital (Suppl. 11B). In case of failure of treatment with benzodiazepine of complex partial status epilepticus iv phenytoin and IV valproate were rated as usually appropriate (Suppl. 11D).
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ACCEPTED MANUSCRIPT Discussion Since 1990, many new, better tolerated and easier-to-use AEDs have been introduced. The efficacy of the newer and classic AEDs is comparable, and the proportion of patients with drug-resistant seizures remains high. Guidelines summarizing clinical observations and trials are different in the US and Europe, and many AEDs continue to be used off-label. The paucity of trials with high class of evidence is another reason that antiepileptic therapeutic regimens should be individualized and tailored to the patient’s needs, and the treating physician’s experience.
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Expert consensus methods have been established for many years. Locally performed surveys provide a perspective on regional conditions, habits and standards of therapy; they also shed light on areas where there is lack of clear consensus. For this reason we compared the results of our survey with those of the US and European surveys, which were conducted using the same methodology. The level of agreement among the three panels was generally high and no substantial differences were identified. Despite different reimbursement policies for AEDs in Poland, their direct or on demand accessibility in certain cases, the results of this study based on the general knowledge and routine practice of specialists in Poland can provide additional useful insights. General comments and medication recommendations about treatment strategies and selection are discussed for particular conditions in detail in supplementary materials for this article.
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In this study we attempted to highlight the differences and similarities between the practice of Polish and European doctors. Levetiracetam is widely used as initial therapy in patients with generalized seizures, but in Poland only valproate is reimbursed as first line treatment in this indication. Lamotrigine may be more suitable for partial-onset, but not generalized seizures10. According to published recommendations the panel chose polytherapy with two or three AEDs, but not with four AEDs in patients with refractory epilepsy. Newer AEDs licensed for pediatric population are reimbursed for Polish patients in case of refractory epilepsy. Most of AEDs rated as treatment of choice are reimbursed in Poland for newly diagnosed epilepsy, however alternative first line options in many cases are not reimbursed in Poland, and this limits use, eg. oxcarbazepine for CPS and BECTS, topiramate fot LGS and myoclonic and generalized tonic-clonic seizures. Vigabatrin was the treatment of choice in infantile spasms and partial-onset seizures in TSC. In symptomatic infantile spasms vigabatrin was also chosen as a first line treatment, followed by valproate and ACTH. Zonisamide, used frequently in Japan, and rectal lorazepam are not available in Poland.
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Valproate and ethosuximide were the drugs of choice for children presenting with absence epilepsy. In contrast to European recommendations9, ethosuximide was considered more frequently than lamotrigine as first-line therapy in absence epilepsy. Interestingly, it is in line with recent ILAE recommendations, which supports the use of ethosuximide and valproate (level A evidence). Lamotrigine has only level C evidence7. For the treatment of children with BECTS, the majority of the specialists in our survey opted for carbamazepine rather than valproate which was treatment of choice in the European survey9. Both drugs have ILAE level C evidence in BECTS7. Not surprisingly, given its safety profile, phenytoin was not chosen. However, IV phenytoin is still widely used for the treatment of neonatal seizures. Valproate and lamotrigine were chosen more frequently for the treatment of children JME; the use of levetiracetam however may be underestimated in this indication. There were no differences between Polish and European specialists in their choices for the treatment of children presenting with convulsive SE. Since buccal benzodiazepines are not available in Poland, they could not be adequately rated in this survey for SE. In case of neonatal seizures estimation the duration of treatment depends mainly on factors such as neuroimaging and EEG results. Blood analysis and metabolic screening results remains also valuable. Treatment with AEDs could be necessary even 10
ACCEPTED MANUSCRIPT after an acute event of neonatal seizures and pediatric neurologists are aware that therapy with AEDs should be as short as possible.
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There are no randomized clinical trials comparing pharmacological with non-pharmacological treatment options for pediatric epilepsy. Non-pharmacological treatment of refractory epilepsy is very important, but it is frequently used only as the last step in the therapeutic process. Nonpharmacological therapeutic options such as epilepsy surgery, VNS and ketogenic diet may also improve the quality of life of patients with epilepsy. Resective surgery may be especially useful and important for the treatment of children presenting with mesial temporal sclerosis and complex partial seizures. In Poland, resective surgery is rather uncommon in comparison with other EU countries and the US. Ketogenic diet was not chosen either as an early therapeutic option by the panel in this survey; however, recently there are trends toward re-evaluation of this option3,4,11.
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Overall, there was strong agreement regarding the treatment of epileptic seizures in our panel, especially for partial-onset seizures – carbamazepine and oxcarbazepine were recommended by the panel and by other groups7,9. Despite this consensus, oxcarbazepine can not be used in Poland as first line treatment of newly diagnosed partial onset epilepsy, due to current reimbursement restrictions. Our survey also showed that epilepsy surgery is not often recommended in Poland, unlike other European countries9. This may reflect the lack of access to comprehensive epilepsy centers who can perform pre-surgical evaluations in children. There is a limited number of such centers in Poland, compared to the population and estimated needs. The ketogenic diet as add-on therapy was also chosen very rarely. It is a reason of limited access to experienced dieticians and lack of reimbursement of ketogenic diet therapy. From 3 to 4 centers use ketogenic diet in epilepsy therapy in Poland. AEDs choices were not so clear cut for the treatment of patients presenting with idiopathic generalized epilepsies; effective therapies listed were valproate, lamotrigine and topiramate.
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Despite widespread information about AEDs and types of seizures, the selection of the best therapeutic options for individual patients in clinical practice may often be challenging. This is especially the case for pediatric cases, where very few randomized, controlled clinical trials have been conducted. This study reveals how experts can use their knowledge of the epilepsy syndromes, seizure types, and local formulary and reimbursement to come up with practice recommendations that are helpful to their colleagues. While this data is very helpful to physicians practicing in Poland, and may help in getting other therapies into Poland, where a need is recognized, based on the results of this survey. This may not fit every country in central and eastern Europe. We suggest they would benefit from evaluating their own formularies, and then perhaps doing a similar survey. Ultimately, it would be ideal if the experts recommendations were the basis on a randomized trial to determine what are the best practices, as that performed by Marson et al for the UK10. In this survey, we sought the opinion of panel of Polish pediatric neurologists to gain insight into and develop a consensus on the best treatment practices for children with epilepsy. While the results of this exercise should not replace guidelines, it provides valuable information that could contribute to the decision-making process. Furthermore, it should be emphasized that treatment regimens for each patient should be individualized. Clinicians should use their personal experience and guidelines as well as the knowledge from their peers to ensure they choose the best therapeutic strategy for their patients.
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ACCEPTED MANUSCRIPT Table 1. Main treatment options for pediatric epilepsy syndromes voted for by the panel of Polish pediatric epilepsy specialists.
Syndrome/condition
Treatments of choice and first line treatments
Symptomatic myoclonic and generalized tonicclonic seizures
Valproate treatment of choice, topiramate as alternative first-line therapy.
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For first monotherapy carbamazepine was treatment of choice and oxcarbazepine or valproate were first line options, For second monotherapy after trial with carbamazepine or oxcarbazepine, valproate and levetiracetam were first line treatments,
Neonatal seizures
For second monotherapy after trial with phenytoin, carbamazepine was treatment of choice and oxcarbazepine, valproate and levetiracetam as first line options. IV phenobarbital as treatment of choice and IV diazepam as first line therapy, In case of suboptimal control of seizures after benzodiazepine therapy IV phenobarbital was treatment of choice, Vigabatrin as treatment of choice, with valproate and ACTH as other first-line options Valproate as treatment of choice and topiramate as first line option for initial monotherapy,
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Complex partial seizures
Infantile spasms
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Valproate as treatment of choice second monotherapy after failure of initial monotherapy with lamotrigine or topiramate. Lamotrigine or topiramate as alternative first line options for second monotherapy after failure of initial monotherapy with topiramate or lamortigine, respectively,
Lennox-Gastaut syndrome
Topiramate as first line second monotherapy choice after failure of valproate trial, Rectal diazepam as acute treatment of choice , Valproate as preventive treatment of choice
Febrile seizures Benign childhood epilepsy with centrotemporal spikes
Carbamazepine as drug of choice as initial monotherapy, valproate and oxcarbazepine as first line agents
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Childhood absence epilepsy Valproate and ethosuximide drugs of choice for first monotherapy, Valproate as second monotherapy treatment of choice after ethosuximide failure,
Absence epilepsy
Juvenile absence epilepsy Valproate drug of choice for first monotherapy, Lamotrigine as second monotherapy treatment of choice after valproate failure,
Female patients Lamotrigine drug of choice for first monotherapy, levetiracetam or valproate as another first line treatment
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Juvenile myoclonic epilepsy
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Male patients Valproate drug of choice for first monotherapy,
Newly diagnosed epilepsy in the emergency department
Valproate as drug of choice
Generalized tonic-clonic status epilepticus IV diazepam and rectal diazepam as treatment of choice After failure of initial benzodiazepine IV valproate as treatment of choice and IV phenytoin and phenobarbital as other first line alternatives,
Status epilepticus
Absence status epilepticus IV valproate and IV diazepam as treatments of choice, After failure of initial benzodiazepine IV valproate as treatment of choice, Complex partial status epilepticus IV diazepam as treatment of choice and rectal diazepam or IV phenytoin as alternative first line therapies, After failure of initial benzodiazepine IV phenytoin or IV valproate as first line treatments
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ACCEPTED MANUSCRIPT Acknowledgments The authors gratefully acknowledge the specialists for their contribution to the study. The authors thank Marcin Balcerzak and Anna Juś (UCB Pharma, Warsaw, Poland) for support in preparation and distribution of questionnaires, data management and analysis, preparation of figures, and editorial support in preparation of this publication. The authors thank Azita Tofighy (UCB Pharma, Brussels, Belgium) for reviewing the manuscript for English language. All costs associated with publication were funded by UCB Pharma, Brussels, Belgium.
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2. Sirven JI, Noe K, Hoerth M, Drazkowski J, Antiepileptic drugs 2012: recent advances and trends. Mayo Clin Proc 2012; 87(9): 879-889.
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3. Kossoff EH, Caraballo RH, du Toit T, et al., Dietary therapies: a worldwide phenomenon. Epilepsy Res 2012; 100(3): 205-209. 4. Jozwiak S, Kossoff EH, Kotulska-Jozwiak K. Dietary treatment of epilepsy: rebirth of an ancient treatment. Neurol Neurochir Pol 2011; 45(4): 370-378.
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5. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new –onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004; 45(5): 401-409. 6. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE Treatment Guidelines: Evidence-based Analysis of Antiepileptic Drug Efficacy and Effectiveness as Initial Monotherapy for Epileptic Seizures and Syndromes. Epilepsia 2006; 47(7): 1094-1120.
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7. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54(3): 551-63. 8. Wheless JW, Clarke DF, Carpenter A, Treatment of pediatric epilepsy: Expert opinion, 2005. J Child Neurol 2005; 20(1): S1-S56. 9. Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion. Epileptic Disord 2007; 9(4): 353-412. 10. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369(9566): 1016-26. 11. Kossoff EH, Zupec-Kania BA, Rho JM. Ketogenic diets: an update for child neurologists. J Child Neurol 2009; 24(8): 979-988.
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Treatment of pediatric epilepsy in Poland Supplementary materials Dorota Dunin-Wąsowicza, Maria Mazurkiewicz-Bełdzińskab, Barbara Steinbornc, James Whelessd, e Sergiusz Jóźwiak a a
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Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland Department of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Poland c Chair, Department of Developmental Neurology, Poznań University of Medical Sciences, Poland d University of Tennessee Health Science Center, Memphis, TN, USA e Le Bonheur Children’s Hospital, Memphis, TN, USA
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How to interpret the survey results
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A categorical rating of first (usually appropriate), second (equivocal), or third line (usually not appropriate) was designated as described in Wheless et al., 20071 and are explained below: ‘Usually appropriate’ or ‘first line‘. First-line treatments are those that the specialists identified as extremely or usually appropriate for the given clinical setting (options rated ‘7, 8, or 9’).
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Treatment of choice is a first-line therapy that was rated extremely appropriate (‘9’) by at least 50% of the specialists.
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‘Equivocal’ or ‘second line’. Second-line therapies are reasonable options in instances when the usually appropriate or first-line agent is contraindicated or fails (options rated ‘4, 5, 6’). Failure can be due to poor efficacy, short- or long-term side effects, or an idiosyncratic reaction. ‘Usually not appropriate’ or ‘third line’. Third-line therapies are usually not appropriate (for the given scenario); however this is not the same as saying that they should not be used. Instead, these therapies might be considered if others are contraindicated or have already failed to produce complete seizure control. No consensus. Random distribution of responses by chi-square indicates a lack of consensus.
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Results should be interpreted as described in Wheless et al. 20071. For the questions with the 9-point rating scale, a bar chart depicts the CI for each item, while tables list the numeric values for each item. A number of graphic conventions are used to present results for questions rated on the 9-point scale. A horizontal bar represents the CI for each option. Where the bars for two options do not overlap, there is a statistically significant difference between the mean scores of the two options. ’Usually appropriate’ or ‘first-line’ therapies are indicated with the darkest shaded bars; ‘equivocal’ or ‘second-line’ items are indicated with medium-shaded bars; ‘usually not appropriate’ or ‘third line’ CI bars are lightly shaded. The CI box in black color with white dots indicates items that were rated as ‘treatments of choice’ within the first-line category, that is, options rated as extremely appropriate by at least 50% of the experts, or a ‘9.’ A clear (unshaded) bar indicates items on which consensus was not reached. A table on the right side of each chart presents the numeric values for each option: the number of respondents who rated each option (N), the mean score (Avg), SD, and percentage of experts who rated the option as treatment of choice, first, second, or third line.
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1.
Symptomatic myoclonic and generalized tonic-clonic seizures
1A. Overall strategy
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Case: A 2-year-old child with developmental delay is diagnosed with myoclonic and generalized tonicclonic seizures and has not been treated yet.
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Comment: For this case, nearly all (98%) specialists indicated monotherapy as a first step, with alternative monotherapy as the next step. This may require further discussion. It may be difficult to apply alternative monotherapy in a child who has experienced two types of seizures from the beginning; it is possible that in real life dual therapy will be used, even if it is just a transition to the alternative monotherapy. Of course the results reflect how we would wish to treat the patient, not necessary how we really will. On the other hand, it is important to note that there is no solid evidence that alternative monotherapy will result in better outcomes that adjunctive therapy after failure of first drug2. The next steps were another adjunctive therapy trial, ketogenic diet but not as monotherapy. VNS was recommended by only a small number of experts, even though there is evidence in the literature for a beneficial effect of VNS in generalized seizures3.
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Figure 1. Treatment choices for a healthy 2-year-old child with developmental delay diagnosed with myoclonic and generalized tonic-clonic seizures.
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1B. Treatment selection Case: A 2-year-old child with developmental delay is diagnosed with myoclonic and generalized tonicclonic seizures. The child is starting therapy for the first time.
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Figure 2. Treatment choices for a healthy 2-year-old child with developmental delay diagnosed with myoclonic and generalized tonic-clonic seizures.
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Comment: For this 2-year-old, valproate was rated as treatment of choice by 94% of respondents, 16% and 13% also suggested levetiracetam and topiramate, respectively, as initial monotherapy. Levetiracetam and topiramate were rated by 65% and 63% of experts, respectively, as second-line treatment.
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Both clobazam and clonazepam were described as a sometimes appropriate first line therapy. Not surprisingly, there was a lack of consensus on lamotrigine and it was not as well recommended as the other options. It may be a more suitable drug for patients with partial onset seizures4.
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1C. Overall strategy
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Case: A 12-year-old male with mental impairment is diagnosed with myoclonic and generalized tonicclonic seizures and has not been treated yet.
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Comment: In the case of this patient all respondents indicated monotherapy as a first step, than similarly as in the previous case, alternative monotherapy followed by combination therapy. Twenty-one (38%) selected the ketogenic diet as add-on therapy starting from step four. This reflects an understanding and the increased role of dietary treatments for children with epilepsy, especially those with developmental delay5.
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Figure 3. Treatment choices for a 12-year-old male with mental disability diagnosed with myoclonic and generalized tonic-clonic seizures.
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1D. Treatment selection Case: A healthy 12-year-old male with mental impairment is diagnosed with myoclonic and generalized tonic-clonic seizures. The child is starting therapy for the first time.
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Figure 4. Treatment choices for a healthy 12-year-old male with mental disabilities diagnosed with myoclonic and generalized tonic-clonic seizures.
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Comment: For this older patient, the ratings were quite similar as those for the younger child. Topiramate was rated as an another first-line treatment, and levetiracetam, lamotrigine, clonazepam and clobazam, as second line options. This could be due to greater experience with topiramate since it is has been on the market longer, and it has been proven successful, especially in drug resistant generalized epilepsies6,7. All therapies in first and second-line therapies were broad spectrum AEDs.
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1E. Treatment selection Case: A 1-year-old child is diagnosed with symptomatic generalized tonic-clonic seizures. Assume you begin with monotherapy.
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Figure 5. Treatment choices for a 1-year-old child diagnosed with symptomatic generalized tonic-clonic seizures.
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Comment: Valproate was selected as the most appropriate drug by all respondents for first line monotherapy. Among newer generation drugs, use of levetiracetam was equivocal (second-line), and lamotrigine and topiramate inconclusive. The ILAE subcommission of AED Guidelines underlined lack of class A and B evidence in case of children with generalized tonic-clonic seizures8. Valproate has been used for many years, and newer AEDs (even those with less frequent sides effects) are not so popular as initial monotherapy.
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1F. Treatment selection Case: A 12-year-old child is diagnosed with symptomatic generalized tonic-clonic seizures. Assume you begin with monotherapy.
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Figure 6. Treatment choices for a 12-year-old child diagnosed with symptomatic generalized tonic-clonic seizures.
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Comment: Almost all specialists selected valproate as treatment of choice and lamotrigine as other first line treatment. Options selected for second-line therapy were topiramate or levetiracetam. This choice indicates greater confidence about using newer generation AEDs in older children, despite lack of high class evidence in the entire pediatric age spectrum8. It is not surprising that respondents chose valproate so frequently. Newer AEDs e.g. topiramate and levetiracetam mentioned as second-line therapy are also well-known alternatives in this clinical situation.
General medication recommendations for symptomatic myoclonic and generalized tonic-clonic seizures Valproate was selected for the initial treatment of children 1–12 years of age with GTC seizures. However, as the next option, lamotrigine, topiramate and levetiracetam were recommended for adolescents. Many respondents did not think levetiracetam was useful as initial treatment of a 1-year old infant, but some recommend it as second line therapy.
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2. Complex partial seizures 2A. Overall strategy
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Case: A healthy 8-year-old child is diagnosed with non-lesional cryptogenic complex partial seizures and has not been treated yet.
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Comment: At step one, the entire panel proposed using monotherapy. Monotherapy is recommended as the first therapeutic step for both in children and adults with epilepsy 1,9-11. In the event of unsuccessful monotherapy, 48 respondents suggested trying another monotherapy. Additional trials of monotherapy were recommended by 30 respondents and combination therapy with two AEDs was proposed as fourth step by 27. About half (26/51) of respondents recommended a combination of two AEDs as second choice. Additional trial of dual therapy was the next step of antiepileptic therapy as recommended by 19 respondents. Combination, or polytherapy should only be considered when attempts at monotherapy have not resulted in seizure freedom. Rational polytherapy is often needed for about 50% of patients who do not achieve satisfactory seizure control with a single AED12. Treatment with a combination of three AEDs was chosen only by 16 physicians in fourth, fifth and sixth steps. The next combination of three AEDs was indicated rarely (4/51) as a fourth or sixth step. The probability of becoming seizure free declines by 75% after using three AEDs10,12. Evaluation for epilepsy surgery was proposed by only one expert as the third or fourth step and by 11/51 in sixth step. In the previously published European expert opinion, evaluation for surgery was suggested as step 4 or 51. Epilepsy surgery is not performed frequently in Poland, given the lack of specialist centers. Ketogenic diet as add-on therapy was also chosen rarely ( 1/51). However, use of the ketogenic diet as part of the of the treatment plan for childhood epilepsy is increasing13-15. No one in the panel recommended using the ketogenic diet at the beginning of treatment. Figure 7. Treatment choices for a healthy 8-year-old child diagnosed with non-lesional cryptogenic complex partial seizures.
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2B Overal strategy
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Case: A healthy 9-year-old child presents with right-sided mesial temporal sclerosis and complex partial seizures and has not been treated yet.
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Comment: For this child all respondents selected monotherapy at first step. At step two, 39/51 suggested using second monotherapy. Opinion was divided for the third step, just as in the European survey1. Twenty specialists advised combination therapy with two AEDs and 14 another monotherapy. At third step, 18% of European specialists proposed pre-surgical evaluation1, whereas 50% of Polish specialists recognized evaluation of epilepsy surgery at sixth step. Surgical evaluation for the treatment of childhood epilepsies is needed in Poland, since resective surgery has been shown to be beneficial for some children with focal brain lesions and is carried out in many parts of the world16. All together 39/51 took into account this type of epilepsy therapy. In a case of mesial temporal sclerosis, after failure of antiepileptic therapy, evaluation for surgery is needed and recommended16,17. At step four, 1/5 of experts proposed polytherapy (combination of two AEDs). The fifth step – another dual therapy – was proposed by a third of Polish specialists. Combination therapy with three AEDs was rare and noted by three specialists only. Six specialists proposed using the ketogenic diet as add-on treatment only. As with European specialists, VNS was not considered a useful option1.
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Figure 8. Treatment choices for a healthy 9-year-old child presenting with right-sided mesial temporal sclerosis and complex partial-onset seizures.
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2C. Treatment selection Case: A healthy 6-year-old child with normal cognitive and neurological function is diagnosed with cryptogenic complex partial seizures. The patient is starting therapy for the first time.
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Figure 9. Treatment choices for a healthy, cognitively, and neurologically normal 6-year-old child diagnosed with cryptogenic complex partial-onset seizures.
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Comment: Carbamazepine was chosen as initial therapy by 94% of specialists; a choice consistent with recommendations by the National Institute for Health and Care Excellence (NICE) in the UK18. Oxcarbazepine as initial monotherapy was chosen by 87% and valproate by 76%. The same proposals were made by European specialists1. Levetiracetam, lamotrigine, topiramate and phenytoin were second line choices. The choice of initial AED seemed to be difficult due to the discrepancy between recommendation and reimbursement status of these drugs in Poland. Both lamotrigine and topiramate were sometimes described as appropriate as first line therapy. According to NICE guidance, lamotrigine should be used as first line drug in focal seizures in children18. Approximately 50% of respondents chose lamotrigine as an appropriate or good as a first line drug. Phenytoin, vigabatrin, clonazepam and clobazam were recommended as a second or third line drug, as in NICE guidance18 and their choice is likely related to their side effect profile20. Gabapentin, phenobarbital, zonisamide, tiagabine, eslicarbazepine, ketogenic diet, pregabaline, VNS, lacosamide, felbamate, rufinamide, methsuximide, ethosuximide, retigabine were pointed out as usually not suitable. Some are not registered in Poland for the treatment of children while some are not the reimbursed. The older AEDs are efficacious as an initial therapy but some of newer the AEDs should be considered as a first choice for monotherapy in children20, as proposed by the respondents.
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In the case described above, assume the first treatment you choose is carbamazepine . The child has no or poor response, or the drug was poorly tolerated. Assume you would next choose a second monotherapy trial. Rate the appropriateness of each of the following treatments as a second monotherapy.
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Figure 10. Second-line treatment choices following suboptimal control of seizures with carbamazepine in a child with cryptogenic complex partial-onset seizures.
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Comment: If carbamazepine therapy is not effective as first choice, respondents suggested using valproate or levetiracetam as second monotherapy. European specialists also chose valproate, as well as lamotrigine and topiramate1. Lamotrigine, oxcarbazepine or topiramate were rated by respondents as equivocal. Topiramate was suggested by NICE as a drug for add on therapy18. Results on phenytoin and vigabatrin as drugs ‘sometimes useful’ were inconclusive. Clonazepam, clobazam and gabapentin were proposed as usually not appropriate AEDs. Remaining drugs were rated as not appropriate in this situation.
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In the case described above, assume the first treatment you choose is phenytoin. The child has no/little reduction in seizures or the drug was poorly tolerated. Rate the appropriateness of each of the following treatments as a second monotherapy.
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Figure 11. Second-line treatment choices following suboptimal control of seizures with phenytoin in a child with with cryptogenic complex partial-onset seizures.
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Comment: If the first AED, phenytoin, was not effective, carbamazepine was chosen as the preferred second monotherapy was oxcarbazepine was rated as ‘usually appropriate’ and valproate and levetiracetam were rated as ‘suitable’ similar to the previous European survey1. Topiramate and lamotrigine were suggested as second-line.
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In the case described above, assume the first treatment you choose is oxcarbazepine. The child has no/little reduction of seizures or a limited response or the drug was poorly tolerated. Rate the appropriateness of each of the following treatments as a second monotherapy.
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Figure 12. Second-line treatment choices following suboptimal control of seizures with oxcarbazepine in a child with with cryptogenic complex partial-onset seizures.
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Comment: If oxcarbazepine was not effective as first monotherapy, respondents gave favorable rating for the use of valproate or levetiracetam. Lamotrigine, topiramate, carbamazepine and phenytoin were assessed as usually appropriate. A clear position for vigabatrin was not identified. Similarly, results for benzodiazepines (clonazepam and clobazam) gabapentin and zonisamide were equivocal. Remaining AEDs, VNS and the ketogenic diet were assessed as inappropriate as second monotherapy.
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General medication recommendations for complex partial seizures Monotherapy was identified as the best choice in the first step of treatment for children with complex partial seizures, followed by second monotherapy in the event of poor response to the first. The use of single-drug therapy as a second choice is a good option and proposed by many recommendations18,20. Monotherapy is highly recommended as the first step in the treatment of both children and adults 1,9-11. Carbamazepine, oxcarbazepine and valproate were rated to be the best choice for first monotherapy. As a second monotherapy, levetiracetam, valproate or lamotrigine were rated as usually appropriate drugs. Phenytoin was not chosen as a second line drug in complex partial seizures. Respondents opted for combination therapy as the next step of antiepileptic therapy. This study showed that epilepsy surgery is not often recommended in Poland unlike other European countries1. Ketogenic diet as add-on therapy was also chosen very rarely. Epilepsy surgery and non-pharmacological therapies should be options in the treatment of drug resistant epilepsy13-15.
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3. Neonatal seizures 3A. Overall strategies
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Case: An infant is delivered at 38 weeks gestation and has onset of seizures that it is suspected to be due to hypoxic-ischemic encephalopathy. The infant is now intubated, is having intermittent seizures, and has not yet been treated.
Comment: Intravenous (IV), intramuscular (IM) and rectal benzodiazepines (BDZs) were rated as the first line therapy. There is no standard approach for treatment of neonatal status epilepticus, what is likely why different options were chosen. Treatment of neonatal seizures and even status epilepticus may be controversial and difficult. BDZs are widely used along with intravenous phenytoin.
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Figure 13. Treatment choices for an infant delivered at age 38 weeks gestation presenting with seizures that are suspected to be due to hypoxic-ischemic encephalopathy.
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Case: The neonatal seizures stopped after the acute event. The infant is now 2 weeks old and is approaching hospital discharge. How long do you continue treatment for neonatal seizures? Mean = 10.5 weeks (Range: 0 – 24 weeks, N=36)
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Comment: Estimating the duration of treatment after neonatal seizures depends on factors such as neuroimaging and EEG results. However, pediatric neurologists are aware that therapy with AEDs after neonatal seizures should be as short as possible.
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3B. Treatment selection Case: For the case above, please rate the appropriateness of the following treatment options.
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Figure 14. Treatment choices for an infant delivered at 38 weeks gestation, with onset of seizures suspected to be due to hypoxic-ischemic encephalopathy.
Case: Assume the first agent used was a BDZ, administered to its maximum dose. It has failed to stop the neonatal seizures. Rate the appropriateness of the following treatments.
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Figure 15. Treatment choices following suboptimal control of neonatal seizures with maximum dose benzodiazepine.
General medication recommendations for neonatal seizures Treatment of neonatal seizures is controversial and may be difficult21,22. Furthermore, there is no standard protocol on how and when neonatal seizures should be treated. Among the available agents IV phenobarbital was selected most frequently as the drug of choice. This is also every day practice in Polish neonatal departments. However, in this survey specialists selected IV diazepam as another first-line therapeutic regimen. When phenobarbital is not effective, IV phenytoin is used. Polish specialists also recommended treatment with oral phenobarbital for 10.5 weeks. In previously US and European studies , the period of treatment after neonatal seizures with oral phenobarbital was 3–4 months. Prolonged treatment may have a negative effect on the developing brain, as phenobarbital and phenytoin have
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been shown to cause neuronal apoptosis in animal models23. Moreover, prolonged treatment after neonatal seizures does not prevent seizures later on in life24. When initial treatment with an IV BDZ was not successful, specialists chose IV phenobarbital or phenytoin as second-line therapy. This is in agreement with results of the, US and European surveys. Emerging evidence indicates levetiracetam25 and bumetanide26 may be beneficial in the treatment of neonatal seizures; however, more data are required.
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4. Infantile spasms 4A. Overall strategies
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Case: A healthy 6-month-old is diagnosed with infantile spasms (West Syndrome) and has not been treated.
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Comment: All specialists endorsed a trial of monotherapy at step 1. At step 2, opinion was divided, with 65% of specialists (34/51) selecting another trial of monotherapy, while 31% (16/51) selected combination therapy with two AEDs. At step 3, 24% of respondents (12/51) still favored continued trials of monotherapy, while 67% (34/51) favored the use of a combination therapy with two AEDs antiepileptic drugs. At step 4, the majority endorsed multiple drug therapy, with 63% (32/51) favoring the use of two AEDs antiepileptic drugs and 22% (11/51) favoring a combination of three. At this stage, 12% of respondents endorsed use of ketogenic diet as mono- or add-on therapy. Thus, drug therapy is suggested in the first 4 steps of the treatment of infantile spasms. However, an existing practice parameter from the Child Neurology Society and the American Academy of Neurology concluded that adrenocorticotropic hormone (ACTH) is probably effective and that vigabatrin is possible effective27, whereas no other medications were considered effective. Data from the 4-year follow up of the United Kingdom Infantile Spasms Study (UKISS) study indicated that there were no significant differences in long-term outcomes between the two treatment groups28. In the absence of an agreed therapeutic strategy in infantile spasms the use of the ketogenic diet29–31 or epilepsy surgery30,32 have also been proposed; however these suggestions were not endorsed by our specialists.
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Figure 16. Treatment choices for a healthy 6-month-old child diagnosed with infantile spasms.
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4B. Treatment selection
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Case: A healthy 6-month-old is diagnosed with infantile spasms secondary to tuberous sclerosis complex (TSC) and is starting therapy for the first time. Assume that you begin with monotherapy.
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Figure 17. Treatment choices for a healthy 6-month-old infant diagnosed with infantile spasms secondary to tuberous sclerosis.
Comment: Specialists rated vigabatrin as treatment of choice for infantile spasms if the etiology is TSC, with ACTH and valproate as other appropriate first-line options. While further evidence is deemed necessary by Cochrane reviewers27 and the practice parameter of the American Academy of Neurology
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and the Child Neurology Society (AAN/CNS)27, this rating of vigabatrin as treatment of choice by our specialists is consistent with findings from many open-label clinical trials35–36.
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It should be also stressed that recent recommendations on the management of TSC-associated epilepsy by European experts strongly endorse the use of vigabatrin as a treatment of choice in both infantile spasms and partial seizures in infants with TSC37. There is increasing evidence that treatment with vigabatrin of electrographic seizures (demonstrated by EEG) in the first 2 years of life may significantly improve cognitive outcome and decrease the probability of drug-resistant epilepsy in infants with TSC38.
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4C. Treatment selection
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Case: An otherwise healthy 8-month-old is diagnosed with infantile spasms that are symptomatic in etiology. The male infant was a product of a 28-week gestational pregnancy and suffered a grade 4 intraventricular hemorrhage. He has a gastrostomy tube in place because of severe gastroesophageal reflux and significant dysphagia. He is also cortically blind and has severe developmental delay.
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Figure 18. Treatment choices for a healthy 8-month-old infant diagnosed with infantile spasms following a grade 4 intraventricular hemorrhage.
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Comment: Specialists rated vigabatrin as treatment of choice for infantile spasms that are symptomatic in etiology, with valproate and ACTH as other first-line options. The position on prednisone and topiramate was unclear. The specialists’ endorsement of vigabatrin is not consistent with the American Academy of Neurology and the Child Neurology Society (AAN/CNS) 2004 practice parameter35. However, this parameter has been recently modified by US Infantile Spasms Working Group (ISWG), which recommended both vigabatrin and ACTH as the only proven first–line treatments in infantile spasms39. High-dose prednisolone has shown promise but further evidence is required39. Also, a recent Cochrane Review documented sufficient evidence for both Vigabatrin and ACTH as first–line medications for infantile spasms33. The UKISS found that hormonal therapy was significantly more likely than vigabatrin to cause cessation of spasms and resolution of hypsarrhythmia by day 14 of treatment40. However, the follow up study of this cohort at 4 years, did not demonstrate any difference between the treatments in spasm control or neurodevelopment, except in the group of infants with no identified underlying etiology28,41. Considering this long-term outcome, the possible side effects of hormonal therapy, and the ease of initiating treatment with vigabatrin may explain why specialists chose vigabatrin as the treatment of choice in
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symptomatic infantile spasms. Even if topiramate42,43 and zonisamide44,45 have shown benefit in this specific population in open-label studies, the lack of controlled studies accounts for their lower ratings. General Medication recommendations for infantile spasms
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For a healthy 6-month-old child with infantile spasms respondents opted for 1–2 trials of monotherapy before trying combinations of AEDs. Multiple trials of medication were endorsed before considering a ketogenic diet or evaluation for epilepsy surgery for the treatment of infantile spasms. In choosing specific medications, respondents selected vigabatrin as treatment of choice for spasms irrespective of their etiology. For spasms that are symptomatic in etiology, valproate and ACTH were regarded as alternative monotherapies.
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5. Lennox-Gastaut syndrome 5A. Overall strategy
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Case: A healthy 4-year-old female is diagnosed with Lennox-Gastaut syndrome consisting of frequent astatic seizures and only occasional generalized tonic-clonic and atypical absence seizures and has not been treated yet.
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Comment: All specialists endorsed monotherapy at step 1 for the initial therapy of this child with LGS. Opinion was divided at step 2; 39% of specialists recommended another trial of monotherapy, while 53% recommended combination therapy with two AEDs. At step 3, 62.5% supported use of second combination therapy while only 14% of respondents recommended another monotherapy. At step 4 and 5 the majority opted for combination therapy with mainly two AEDs. At step six, 24 (43%) specialists voted for the ketogenic diet as a treatment option, This is in line with recently published paper46. However, ideally, it should have been recommended earlier. VNS and pre-surgical evaluation did not reach the level of 10% of the indications. This is probably due to the costs of the procedure and lack of controlled studies in this specific syndrome47.
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Valproate, topiramate and lamotrigine were the most frequently chosen drugs, followed by benzodiazepines (clonazepam and clobazam) and the ketogenic diet. Only the ketogenic diet overtook the benzodiazepines in the situation when valproate was unsuccessful as the first drug. It is worth noting that rufinamide, felbamate, zonisamide were not recommended by our panel for LGS. This may be due to the registration and reimbursement situation in Poland where none of the aforementioned drugs are in common use; therefore, lack of experience with those drugs could have influenced the results.
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Figure 19. Treatment choices for a healthy 4-year-old female diagnosed with Lennox-Gastaut syndrome.
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5B. Treatment selection Case: A healthy 6-year-old child has LGS with infrequent generalized tonic-clonic and atypical absence seizures but multiple daily astatic seizures. The patient is being treated for the first time.
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Figure 20. Treatment choices for a healthy 6-year-old child with Lennox-Gastaut syndrome presenting with infrequent generalized tonic-clonic and atypical absence seizures but multiple daily astatic seizures.
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Case: Assume that the first treatment you select is valproate. The child has little or no reduction in seizures, or the medication is poorly tolerated. Rate the appropriateness of each of the following treatments as second monotherapy.
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Figure 21. Second-line treatment choices following suboptimal control of seizures with valproate in a child with Lennox-Gastaut syndrome.
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Case: Assume that the first treatment you select is lamotrigine. The child has little or no reduction in seizures, or the medication is poorly tolerated. Rate the appropriateness of each of the following treatments as second monotherapy.
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Figure 22. Second-line treatment choices following suboptimal control of seizures with lamotrigine in a child with Lennox-Gastaut syndrome.
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Case: Assume that the first treatment you select is topiramate. The child has little or no reduction in seizures, or the medication is poorly tolerated. Rate the appropriateness of each of the following treatments as second monotherapy.
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Figure 23. Second-line treatment choices following suboptimal control of seizures with topiramate in a child with Lennox-Gastaut syndrome.
General Medication recommendations for Lennox-Gastaut syndrome
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For a child with LGS who has astatic, rare tonic-clonic seizures and atypical absence seizures, the majority of respondents considered one to two trials of monotherapy before trying one or more combinations of two AEDs. Interestingly the ketogenic diet was rated as equivalent as multiple trials of medication (more than 2 drugs in treatment). VNS and preoperative investigations were seen as less favorable than multiple drug regimens. In choosing specific medications, the panel agreed on valproate as treatment of choice; topiramate was also chosen as first-line therapy. Lamotrigine was the most frequently chosen second-line treatment option. In the event of poor response to valproate, topiramate was the next option, followed by lamotrigine or levetiracetam. This choice may reflect the results of a national study with lamotrigine as a secondary treatment after carbamazepine or valproate failure48. If the first line was lamotrigine with no improvement, the next choice was valproate, then topiramate. The parallel situation was observed when topiramate was first line treatment with no improvement – next steps were valproate, then lamotrigine. Interestingly levetiracetam was in all of these situations recommended as the fourth drug in line (high second-line therapy).
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6. Febrile seizures 6A. Treatment selection
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Case: A healthy 12-month-old infant has experienced a first generalized tonic-clonic febrile seizure. The parents are anxious and ask for treatment to be initiated acutely in the event of recurrent, prolonged febrile seizures or a cluster of febrile seizures.
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Figure 24. Choices for preventive therapy for a healthy 12-month-old infant presenting with a first generalized tonic-clonic febrile seizure.
Case: A healthy 12-month-old infant is diagnosed with recurrent febrile generalized tonic-clonic seizures. The infant has had five generalized tonic-clonic seizures, all associated with fever since age 6 months. The parents request preventive therapy for his febrile seizures. The child is being treated for the first time. Rate the appropriateness of each of the following options for monotherapy.
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Figure 25. Choices for preventive therapy for a healthy 12-month-old infant diagnosed with recurrent febrile generalized tonic-clonic seizures.
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General Medication recommendations for febrile seizures The drug of choice for the treatment of prolonged febrile seizures was rectal diazepam. This is not surprising, given that in Poland rectal diazepam is used frequently in febrile seizures. Rectal lorazepam and nasal midazolam are not available in Poland. Even though intravenous midazolam is accessible in Polish hospitals, it could not be recommended for outpatient practice. The panel indicated that valproate should be considered for preventive treatment of febrile seizures; other AEDs were not deemed suitable. Similar results were obtained in the US and European surveys.
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7. Benign childhood epilepsy with centro-temporal spikes 7A. Treatment selection
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Case: A healthy 8-year-old is diagnosed with BECTS. The child has had several seizures such that the parents wish to start therapy for the first time. Please keep in mind the epilepsy syndrome the child has and rate the appropriateness of each of the following options for monotherapy.
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Figure 26. Treatment choices for a healthy 8-year-old child diagnosed with benign childhood epilepsy with centro-temporal spikes (benign rolandic epilepsy of childhood).
General medication recommendations for benign childhood epilepsy with centro-temporal spikes
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For the aforementioned case (previously untreated 8-year-old child with BECTS) carbamazepine was rated as initial monotherapy by 68% specialists and oxcarbazepine by 33%. Next, was valproate with 29% - there is data supporting the use of valproate in treatment of partial seizures49. This finding is not in agreement with that of the European survey where valproate was the treatment of choice for BECTS1. There was clear agreement on lamotrigine as a second-line drug, but not on levetiracetam . Again, these results may reflect the reimbursement situation in Poland where levetiracetam and lamotrigine are reimbursed for the treatment of patients with drug resistant epilepsies. Gabapentin, sulthiam, phenytoin, phenobarbital, zonisamide, tiagabine, eslicarbazepine, ketogenic diet, pregabalin, VNS, lacosamide, felbamate, rufinamide, methsuximide, ethosuximide, retigabine were rated as not usually appropriate. This is quite an interesting finding especially where phenytoin is concerned – it was pointed out as inappropriate for this type of patient – that may be due to the availability of newer drugs, such as oxcarbazepine which has led to a reduction in phenytoin use mainly due to its side effect profile50,51.
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8. Absence epilepsy 8A. Treatment Selection
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Case: A healthy 6-year-old is diagnosed with childhood absence epilepsy (absence seizures only). The patient is starting therapy for the first time. Please keep in mind the seizure type(s) the child is experiencing (within the syndrome diagnosis), and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 27. Treatment choices for a healthy 6-year-old child diagnosed with childhood absence epilepsy (absence seizures only).
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Assume that the first treatment you choose in case above is ethosuximide. The child either has had no reduction of seizures, a limited response, or the drug was poorly tolerated. Assume you choose a second monotherapy trial.
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Figure 29. Second-line treatment choices following suboptimal control of seizures with ethosuximide in a child with absence epilepsy.
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8B. Treatment Selection Case: A healthy 12-year-old is diagnosed with juvenile absence epilepsy (absence and generalized tonicclonic seizures). The patient is starting therapy for the first time. Please keep in mind the seizure type(s) the child is experiencing (within the syndrome diagnosis), and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 28. Treatment choices for a healthy 12-year-old child diagnosed with juvenile absence epilepsy (absence and generalized tonic-clonic seizures).
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Assume that the first treatment you choose in case above is valproate. The child either has had no reduction of seizures, a limited response, or the drug was poorly tolerated. Assume you choose a second monotherapy trial.
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Figure 30. Second-line treatment choices following suboptimal control of seizures with valproate in a child with juvenile absence epilepsy.
General Medication recommendations for absence epilepsies
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Childhood absence epilepsy For an untreated 6-year-old child, the drugs of choice were valproate and ethosuximide. Lamotrigine and levetiracetam were chosen less often as a first line treatment, and the specialists were uncertain where to rank them (lack of consensus). This is not in agreement with results of the European survey where valproate was rated as treatment of choice and lamotrigine was another first-line option. In Poland, ethosuximide was chosen more frequently than considered than lamotrigine in this clinical situation. No other AED reached the recommendation level for this type of seizure, indicating than when diagnosed, there is a clear choice for the treatment of childhood absence epilepsy. In the event of poor outcome with ethosuximide, the respondents all chose valproate as first line therapy followed by lamotrigine 56%, levetiracetam 37%, topiramate 19% and clonazepam 12%. This reflects the findings of the European survey1. Juvenile absence epilepsy For the patients with juvenile absence epilepsy, valproate was the drug of choice and if unsuccessful, lamotrigine reached the rating level for second line. The panel did not reach an agreement on the position of levetiracetam. Only 6% considered ethosuximide as a drug of choice in this syndrome. This may be due to known different disease course in this syndrome and the lack of benefit of ethosuximide in generalized tonic-clonic seizures, which occur more often in this type of absence syndrome.
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9. Juvenile myoclonic epilepsy (JME) 9A. Treatment selection
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Case: A healthy adolescent male is diagnosed with JME. The patient is being treated for the first time. Please keep in mind the epilepsy syndrome the adolescent has and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 31. Treatment choices for a healthy adolescent male diagnosed with juvenile myoclonic epilepsy.
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9B. Treatment selection
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Case: A healthy adolescent female is diagnosed with JME. The patient is being treated for the first time. Please keep in mind the epilepsy syndrome the adolescent has and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 32. Treatment choices for a healthy adolescent female diagnosed with juvenile myoclonic epilepsy.
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General medication recommendations for juvenile myoclonic epilepsy
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For adolescent males with JME the drug of choice was valproate followed by levetiracetam or lamotrigine (high second-line). The remaining AEDs, with the exception of topiramate ketogenic diet and VNS were rated as inappropriate. The choice of drug was different for the female patients reflecting the teratogenic effects of valproate and it is influence on the development of children born to mothers with epilepsy52. The drug of choice was lamotrigine, followed by valproate or levetiracetam. Recent trials have not shown show superiority of lamotrigine over valproate in treatment of JME53,54. The role of levetiracetam may be underestimated due to the relatively short time since its reimbursement in Poland.
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10. Newly diagnosed epilepsy in the emergency department 10A. Treatment selection
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Case: A healthy 6-year-old has just arrived in the emergency department, having had two or three seizures. Assume that the index of suspicion for seizure disorder is high; however, the type of seizure and/or epilepsy syndrome is unclear based on available information. The decision is made to start treatment. Please rate the appropriateness of the following treatments.
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Figure 33. Treatment choices for a healthy 6-year-old child who has just arrived in the emergency department, having had two or three seizures.
General medication recommendations for newly diagnosed epilepsy in the emergency department
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The drug of choice is valproate; second-line options include levetiracetam and lamotrigine. There is no agreement among the specialists regarding the usefulness of carbamazepine or topiramate. This choice is probably due to fact that valproate is considered a broad spectrum AED usually efficacious in most epileptic seizures (partial and generalized). Since the exact type of seizures is unclear the prudent option is valproate, which in contrast to carbamazepine has no potential to aggravate seizures19. Interestingly, the second line choice was levetiracetam; this shows increasing impact of this new broad spectrum AED with low potential for drug–drug interactions. Lamotrigine were also rated as useful in this clinical situation. Oxcarbazepine was positioned quite low as a drug of choice in this clinical situation – this could be due to the concern that it may aggravate generalized seizures.
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11. Status epilepticus 11A. Overall strategy
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Case: A 4-year-old child is in convulsive SE. No treatment has been started.
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Comment: the entire panel highly advised use of IV, IM or rectal benzodiazepine in the case of convulsive status epilepticus in a 4-year-old child. European specialists chose the same course of therapy1. These suggestions are in accordance with many recommendations in this topic 55,56,57. There were only two suggestions to use sublingual benzodiazepine at first step. In Poland access to this formulation is limited. The next step proposed by the panel was to repeat the second dose of the same IV, IM or rectal benzodiazepine. For the third step, opinion was divided. One group of specialists proposed using a different IV, IM or rectal benzodiazepine while the second group recommended and AED administered IV or IM. IV or IM AEDs (phenytoin, phenobarbital, valproate and levetiracetam) are recommended for established SE55. All specialists chose IV or IM AED at the fourth step and iatrogenic, drug-induced coma was proposed at the fifth step in refractory SE55,57.
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Figure 34. Treatment choices for a healthy 4-year-old child in convulsive status epilepticus.
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11B. Treatment selection Case: A healthy 4-year-old child is in generalized tonic-clonic SE. No treatment has been given yet. Assume that you begin with a single treatment, and assume each treatment is tried to maximum dose. Rate the appropriateness of each of the following treatments.
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Figure 35. Treatment choices for a healthy 4-year-old child in generalized tonic-clonic status epilepticus.
In the case above, (healthy 4-year-old in generalized tonic-clonic SE), assume administration of a benzodiazepine at maximum dose has failed to stop the convulsive SE. As in most clinical situations, a second agent must now be administered. Please rate the appropriateness of the following therapies.
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Figure 36. Treatment choices for a healthy 4-year-old child in generalized tonic-clonic status epilepticus, who has failed to respond to maximum dose.
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11C. Treatment selection
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Case: A healthy 8-year-old child is in absence SE. No treatment has been given yet. Assume the airway is protected. Please rate the appropriateness of the following therapies.
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Figure 37. Treatment choices for a healthy 8-year-old child in absence status epilepticus.
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In the case above (healthy 8-year-old in absence SE), assume administration of a benzodiazepine at maximum dose has failed to stop the absence SE. As in most clinical situations, a second agent must now be administered. Please rate the appropriateness of the following therapies. Again, assume that the patient’s airway is protected.
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Figure 38. Treatment choices for a healthy 8-year-old child in absence status epilepticus who has failed to respond to maximum dose benzodiazepine.
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11D. Treatment selection Case: A healthy 6-year-old child is in complex partial SE. No treatment has been given yet. Assume the airway is protected. Please rate the appropriateness of the following therapies.
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Figure 39. Treatment choices for a healthy 6-year-old in complex partial status epilepticus.
In the case above (6-year-old in complex partial SE), assume administration of a benzodiazepine at maximum dose has failed to stop the SE. As in most clinical situations, a second agent must now be administered. Please rate the appropriateness of the following treatments. Again, assume that the patient’s airway is protected.
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Figure 40. Treatment choices for a 6-year-old child in complex partial status epilepticus, who has failed to respond to maximum dose benzodiazepine.
General medication recommendations for status epilepticus Generalized tonic-clonic status epilepticus: The panel agreed on using IV diazepam in generalized tonic-clonic SE. Rectal diazepam was also rated as a first line treatment. European specialists and many others selected the same therapy in SE1,55-58. The next step proposed is to repeat the second dose of the same IV, IM or rectal benzodiazepine. The Polish panel rated the use of IV valproate as ‘usually appropriate’, while European specialists were equivocal1.
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IV lorazepam, midazolam, phenobarbital and phenytoin were rated as ‘appropriate’. There was uncertainty about the position of levetiracetam and fosphenytoin. Rectal use of other AEDs and sublingual lorazepam were rated as ‘not appropriate’. Lacosamide was regarded as not appropriate in such a case. There was no choice of the buccal formulation of benzodiazepines were not chosen by any of the respondents despite many studies supporting their efficacy and safety25,59. This is due to the unavailability of these agents in Poland. If the child fail to respond to a maximum dose of IV diazepam the panel chose IV valproate. The panel also rated IV phenytoin or phenobarbital as ‘usually appropriate’. Opinion on the use of IV midazolam, levetiracetam, IV diazepam and fosphenytoin appeared equivocal and without clear consensus among the specialists55-57. Rectal form of diazepam were on the border estimation as equivocal or not suitable. Sublingual lorazepam and IV lacosamide were rated ‘inappropriate’ – these medications are not licensed for use in Poland for SE .
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Absence status epilepticus: The entire panel rated IV valproate as the treatment of choice with IV diazepam or rectal diazepam as second-line therapy. European specialists chose IV diazepam at the same level as IV valproate or IV lorazepam, but did not rate rectal diazepam as highly useful1. The panel was equivocal in its view on the appropriateness of IV midazolam and lorazepam . Levetiracetam and phenobarbital were not chosen as first line drugs. Phenytoin, other rectal AEDs, fosphenytoin (not used in Poland) and lacosamide were rated as ‘not appropriate’.
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Complex partial status epilepticus: The panel rated IV diazepam as the treatment of choice in complex partial SE. The panel also rated rectal diazepam and IV phenytoin as possible first-line options and IV valproate as second-line therapy. The use of the following IV agents was rated as equivocal: lorazepam, midazolam, phenobarbital, and levetiracetam and equivocal were IV phenobarbital. The use of rectally administered agents, sublingual lorazepam and IV lacosamide was rated as ‘not appropriate’.
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If IV diazepam has not stopped the status epilepticus (complex partial) Polish experts proposed use of IV phenytoin (83% of them) or IV valproate (65%) as first-line therapies. It was similar to opinion (95% of them selected IV phenytoin)1. In contrast to the European specialists, the panel did not choose fosphenytoin as a first-line drug since it is not registered for use in Poland. The use IV phenobarbital or levetiracetam was estimated as equivocal partial). Valproate, phenobarbital and midazolam (IV) European experts estimated as equivocal or usually appropriate. Usually not appropriate in their opinion were rectal diazepam, sublingual lorazepam and rectal AEDs.
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References for Supplementary Materials 1. Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion. Epileptic Disord 2007; 9(4): 353-412
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27. Mackay MT, Weiss SK, Adams-Webber T, et al. American Academy of Neurology; Child Neurology Society. Practice parameter: Medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology 2004; 62(10): 1668-81.
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30. Wheless JW, Bourgeois BF, Choosing antiepileptic drugs for developmentally normal children with specific epilepsy syndromes and behavioral disorders. J Child Neurol. 2004; 19( 1): S39-S48.
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31. Hong AM, Turner Z, Hamdy RF, et al. Infantile spasms treated with the ketogenic diet: prospective single – centre experience in 104 consecutive infants. Epilepsia 2010; 51(8): 1403-7. 32. Chugani HT, Asano E, Sood S. Who are the ideal surgical candidates? Epilepsia 2010; 51(Suppl.1): 9496.
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33. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev 2008; 8(4): CD001770. 34. Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain Dev. 2001; 23(7): 649-53.
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35. Mackay M, Weiss S, Snead OC, 3rd. Treatment of infantile spasms: an evidence-based approach. Int Rev Neurobiol 2002; 49: 157-84. 36. Thiele EA. Managing epilepsy in tuberous sclerosis. J Child Neurol 2004; 19(9): 680-6.
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37. Curatolo P, Jozwiak S, Nabbout R, et al. Management of epilepsy associated with tuberous sclerosis complex (TSC): Clinical recommendations. Eur J Paediatr Neurol 2012; 16(6): 582-6. 38. Jozwiak S, Kotulska K, Domanska-Pakiela D, et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 2011; 15(5): 424-31. 39. Pellock JM, Hrachovy R, Shinnar S, Baram TZ, Bettis D, Dlugos DJ, Gaillard WD, Gibson PA, Holmes GL, Nordl DR, O'Dell C, Shields WD, Trevathan E, Wheless JW. Infantile Spasms: A U.S. consensus report. Epilepsia 2010; 51(10): 2175-2189.
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40. Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet 2004; 13-19;364(9447): 1773-8.
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43. Zhu X, Chen O, Zhang D, et al. A prospective study on the treatment of infantile spasms with first-line topiramate followed by low-dose ACTH. Epilepsy Res 2011; 93(2-3): 149-54.
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44. Yum MS, Ko TS, Zonisamide in West syndrome: an open label study. Epileptic Disord 2009; 11(4): 339-44. 45. Yanagaki S, Oguni H, Yoshii K, et al. Zonisamide for West syndrome: a comparison of clinical responses among different titration rate. Brain Dev 2005; 27(4): 286-90.
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46. Cross JH. The ketogenic diet in the treatment of Lennox-Gastaut syndrome. Dev Med Child Neurol 2012; 54(5): 394-5. 47. Lancman G, Virk M, Shao H, et al. Vagus nerve stimulation vs. corpus callosotomy in the treatment of Lennox-Gastaut syndrome: A meta-analysis. Seizure 2013; 22(1): 3-8.
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48. Jozwiak S, Terczyński A. Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients over 12 years with carbamazepine or valproate resistant epilepsy. Seizure 2000; 9 (7): 486-492.
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53. Mazurkiewicz-Bełdzińska M, Szmuda M, Matheisel A, et al. Long-term efficacy of valproate versus lamotrigine in treatment of idiopathic generalized epilepsies in children and adolescents. Seizure 2010; 19(3): 195-7.
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54. Bodenstein-Sachar H, Gandelman-Marton R, Ben-Zeev B, et al. Outcome of lamotrigine treatment in juvenile myoclonic epilepsy. Acta Neurol Scand 2011; 124(1): 22-7. 55. Mastrangelo M, Celato A. Diagnostic work-up and therapeutic options in management of pediatric status epilepticus. Word J Pediatr 2012; 8(2): 109-15.
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56. Ng Y-T, Maganti R. Status epilepticus in childhood. J Paediatr Child Health 2013; 49(6): 432-7.
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57. Riviello J, Claassen J, LaRoche S, et al. Treatment of Status Epilepticus: An International Survey of Experts. Neurocrit Care 2013; 18(2): 193-200. 58. Babl FE, Sheriff N, Borland M, et al. Emergency management of paediatric status epilepticus in Australia and New Zealand: practice patterns in the context of clinical practice guidelines. J Paediatr Child Health 2009; 45(9): 541-6.
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59. Ashrafi MR, Khosroshahi N, Karimi P, et al. Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children. Eur J Paediatr Neurol 2010; 14(5): 434-8
S1090-3798(15)00007-0
DOI:
10.1016/j.ejpn.2014.12.023
Reference:
YEJPN 1867
To appear in:
European Journal of Paediatric Neurology
Received Date: 7 September 2014 Revised Date:
9 December 2014
Accepted Date: 31 December 2014
Please cite this article as: Dunin-Wąsowicz D, Mazurkiewicz-Bełdzińska M, Steinborn B, Wheless J, Jóźwiak S, Treatment of pediatric epilepsy in Poland, European Journal of Paediatric Neurology (2015), doi: 10.1016/j.ejpn.2014.12.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Treatment of pediatric epilepsy in Poland Dorota Dunin-Wąsowicza, Maria Mazurkiewicz-Bełdzińskab, Barbara Steinbornc, James Whelessd, e Sergiusz Jóźwiak a a
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Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland b Department of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Poland c Chair, Department of Developmental Neurology, Poznań University of Medical Sciences, Poland d University of Tennessee Health Science Center, Memphis, TN, USA e Le Bonheur Children’s Hospital, Memphis, TN, USA
Category of manuscript: original research
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Corresponding author Sergiusz Jóźwiak a Full address: Department of Neurology and Epileptology; The Children’s Memorial Health Institute; Al. Dzieci Polskich 20; 04-730 Warsaw; Poland. Telephone number: +48 22 8157447 Email: [email protected].
Running title: Treatment of pediatric epilepsy. Polish Expert Opinion, 2012. List of respondents:
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Artemowicz Barbara, Białystok Bańdo Bożena, Kraków Biegański Grzegorz, Poznań Brzozowski Edmund, Olsztyn Bugaj Grażyna, Poznań Chrościńska-Krawczyk Magdalena, Lublin Ciarka Roman, Kołobrzeg Czyżyk Elżbieta, Rzeszów Jabłecka-Deja Halina, Katowice Domańska-Pakieła Dorota, Warszawa Dudzińska Magdalena, Chorzów Emich-Widera Ewa, Katowice Gergont Aleksandra, Kraków Gniatkowska-Nowakowska Anna, Kielce Gołębiewska Mirosława, Dziekanów Leśny Gucwa-Piotrowska Grażyna, Kraków Hibner Elżbieta, Łódź Hnatyszyn Grażyna, Szczecin Kemnitz Paweł, Poznań Kleist Teresa, Chorzów Kochanowska Iwona, Szczecin Koncewicz Renata, Lublin Krajnik Anna, Warszawa Krause Małgorzata, Wrocław Kroczka Sławomir, Kraków
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Kubarek Grażyna, Tarnów Kuzior-Pławiak Małgorzata, Wrocław Kużel Marek, Wejherowo Łobodzińska-Młynarczyk Elżbieta, Olsztyn Matheisel Agnieszka, Gdańsk Melnyk Aleksandra, Gdańsk Mermer-Kutek Danuta, Olsztyn Milecka Grażyna, Poznań Natwora-Gołąbek Beata, Kielce Piasecka-Frąc Elżbieta, Chorzów Pilarska Ewa, Gdańsk Służewski Wojciech, Poznań Sokołowska Dorota, Łódź Strzelecka Joanna, Warszawa Surmacz Jolanta, Katowice Szczepanik Elżbieta, Warszawa Szwed-Białożyt Barbara, Katowice Ujma-Czapska Barbara, Wrocław Wątróbska Stanisława, Rzeszów Wendorff Janusz, Łódź Wesołowska Marzenna, Bydgoszcz Witkowska-Gęsicka Iwona, Toruń Zacharzewska Joanna, Białystok Zielnik Aleksander, Katowice
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ACCEPTED MANUSCRIPT Abstract
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Background: The many types of childhood epilepsies make the diagnosis and treatment difficult and the outcomes frequently poor. Furthermore, there are few clinical trials in pediatric epilepsy that provide useful results to guide daily practice. Therefore for pediatric neurologists expert opinion may be useful. Aims: To provide an overview of current practice in Poland and compare results with European and US clinical guidelines. Methods: Polish specialists in pediatric neurology were asked to participate in a survey about paediatric epilepsy. The focus of the questions was on the overall strategy and treatment options for different syndromic diagnoses. The survey was developed and performed according to a previous European survey (Wheless et al. 2007). Results: Fifty-one Polish specialists, working in academic or clinical settings, completed the questionnaire. They limited combination therapy to two or three antiepileptic drugs. Valproate was the treatment of choice for myoclonic, generalized tonic-clonic seizures and Lennox-Gastaut syndrome. For infantile spasms caused by tuberous sclerosis and of symptomatic aetiology, vigabatrin was treatment of choice; valproate and ACTH were other first line options. Valproate and ethosuximide were chosen for childhood absence epilepsy and valproate for juvenile absence epilepsy. Carbamazepine was the first-line treatment option for benign partial epilepsy of childhood with centrotemporal spikes and complex partial seizures. In the treatment of juvenile myoclonic epilepsy for males valproate, for females lamotrigine were chosen. Conclusion: Polish pediatric neurologists agreed on the majority of questions. Their views reflect the clinical utility and availability of treatment options in Poland. Results may provide direction for clinicians.
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Keywords: Poland, pediatric epilepsy, children, antiepileptic drugs, seizure
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ACCEPTED MANUSCRIPT Introduction Epilepsy and epileptic syndromes are among the most common neurological disorders in childhood and adolescence with a prevalence of 5.3–8.8 per 1,000 in children below 13 years of age1. Compared with adult epilepsies, childhood epilepsies present a much more heterogeneous group of conditions, each characterized by varied diagnostic criteria, and frequently specific management requirements and different outcomes.
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In recent years, many new antiepileptic drugs (AEDs) have been brought to the market, five between 2009 and 2011 alone in the US2. At present there are 24 AEDs, as well as vagus nerve stimulation (VNS) approved for use in the treatment of epilepsy by the Food and Drug Administration in the United States2. Improvements in neurosurgical techniques have also made the surgical treatment of patients with refractory partial seizures more effective and safer. Ketogenic diet and its modifications are offered in increasing number of centres worldwide3,4. Even with this increasing number of new therapies, 30–35% of patients suffer from drug-resistant epilepsy. Expanding therapeutic options present a challenge to the physician in terms of choosing the optimal therapeutic agent for an individual patient. This situation has necessitated the development of therapeutic guidelines to assist the physician in the decision-making process.
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Guidelines from the Therapeutics and Technology Assessment Subcommittee and Quality Standard Subcommittee of the American Academy of Neurology and the American Epilepsy Society practice parameters for the use of new AEDs were first published in 20045 and are currently being updated.
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In 2006, the International League Against Epilepsy (ILAE) for the first time published evidence-based treatment guidelines for initial monotherapy based on an extensive review of the literature from 1940 to 20056. The authors analysed results from 50 randomized controlled trials and 7 metaanalyses. This document noted an alarming lack of well-designed, randomized controlled trials, especially in children. Results of only four trials were classified as class I evidence and two as class II evidence6. Remaining studies were classified as class III or IV evidence. Thus, the strongest recommendation (level A) in childhood epilepsy was available only in partial-onset seizures (oxcarbazepine). In other types of childhood epilepsies only low level of evidence were available (level C). Despite the ever-growing body of evidence in the medical literature regarding the treatment of epilepsy, many routine clinical questions remain unanswered or only partially answered.
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An update published in 2013 including 64 randomized studies and 11 meta-analyses - up to 2012. There were only 3 additional studies with class I evidence. The change in childhood epilepsy therapy was level A evidence for valproate and ethosuximide in absence epilepsy. The authors once again reported their concern over the general lack of high level evidence studies in children7. Very few of the clinical trials on these common childhood epilepsies have compared different treatments with each other. Moreover, many controlled trials do not include childhood epilepsies or epilepsy syndromes (e.g. juvenile absence epilepsy, neonatal seizures, juvenile myoclonic epilepsy). Thus, neuropaediatricians must very often rely on their own medical judgment to select the ‘best’ treatment option for an individual patient. Physicians look to their colleagues and to expert opinion to help ‘fill the gaps’ left by randomized clinical trials. The lack of therapeutic guidelines in paediatric epilepsies provided by recognized professional organizations results in attempts to provide physicians with practical information established by expert opinion groups. Results of expert opinion surveys may reflect many additional variables that are not considered in large randomized trials focused primarily on AED-related aspects, particularly on effectiveness and
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ACCEPTED MANUSCRIPT safety. Expert opinion statements also reflect country-specific variables such as national registration, reimbursement, and insurance coverage. The first such paediatric survey was completed by a group of 39 specialists in the United States in 2004-20058. The recommendations represented the first use of the expert consensus survey method in the field of paediatric epilepsy. A similar survey was performed in 2007 with a group of 42 Western European paediatric epileptologists8.
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In the present study we summarize the therapeutic choices of Polish paediatric neurologists in similar clinical situations. It is the first such study from the Central and Eastern European countries. The recommendations resulting from this survey should not be seen as clinical guidelines, but the therapeutic preferences of Polish paediatric neurologists. It provides information on how individual patient variables, labelled indications and Poland-specific reimbursement issues influence decisions on treatment strategies and drug selection.
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Methods
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Polish specialists in pediatric neurology were asked to participate in this survey. The specialists were identified by regional consultants who indicated physicians with substantial expertise in epilepsy therapy. The number of specialists from each region was relative to the number of pediatric neurologists practicing there. No honorarium was provided. The survey was conducted with the support of UCB Pharma.
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The survey was developed on the basis of a previously published European survey9. It was designed to address key decision/selection points in the management of epilepsy and seizures in pediatric patients in Poland. It should be noted that not all of the drugs listed in the survey questions are fully available or reimbursed in Poland. Some products available in Europe can be imported to Poland on demand. Survey questions were prepared in Polish and also supplemented for emerging AEDs.
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There were a total of 35 questions on approximately 650 treatment options for following conditions: symptomatic myoclonic and generalized tonic-clonic seizures (GTCS), complex partial seizures, neonatal seizures, infantile spasms, Lennox-Gastaut syndrome (LGS), febrile seizures, benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy; BECTS), absence epilepsy, juvenile myoclonic epilepsy (JME), newly diagnosed epilepsy in the emergency department and status epilepticus (SE).
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For each of the syndromic diagnoses, specific cases were presented and specialists were asked about the overall treatment strategy followed by their choice of specific treatment9. For the first part, (questions 1–9) specialists were asked to identify the order (steps) in which they would prefer/recommend certain treatment strategies. For example, if monotherapy was selected as the first step and subsequently failed, respondents were asked to identify the next best option. Since more than one treatment option might be considered at any step, ‘ties’ were permitted. For the next part (question 10–35) specialists were asked to use a modified RAND 9-point scale to rate utility of specific treatment choices for the given patient cases. For many of these questions, a ‘Don’t Know’ option was included so that the respondents would not feel compelled to rate an option if they did not have knowledge of, or experience with it. The results for each question indicate how many specialists rated each option (N). Except where indicated, specialists were instructed to assume the parents/guardians of the child will be amenable to all possible therapies. They were also instructed to assume that each treatment will be increased to the limit of clinical tolerability before new treatment is initiated. 5
ACCEPTED MANUSCRIPT Data analysis for options scored on the rating scale
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The mean, standard deviation (SD), and 95% confidence intervals (CI) as well chi-square testing were performed as described in Wheless et al., 20079. Consensus was defined as a non-random distribution of scores by chi-square test. A categorical rating of first (usually appropriate), second (equivocal), or third line (usually not appropriate) was designated as described in Wheless et al., 20079 ‘Usually appropriate’ or ‘first line‘. First-line treatments are those that the specialists identified as extremely or usually appropriate for the given clinical setting (options rated ‘7, 8, or 9’). Treatment of choice is a first-line therapy that was rated extremely appropriate (‘9’) by at least 50% of the specialists. ‘Equivocal’ or ‘second line’. Second-line therapies are reasonable options in instances when the usually appropriate or first-line agent is contraindicated or fails (options rated ‘4, 5, 6’). Failure can be due to poor efficacy, short- or long-term side effects, or an idiosyncratic reaction. ‘Usually not appropriate’ or ‘third line’. Third-line therapies are usually not appropriate (for the given scenario); however this is not the same as saying that they should not be used. Instead, these therapies might be considered if others are contraindicated or have already failed to produce complete seizure control. In case of random distribution of responses by chi-square it was not possible to design results to one of three categories. It indicated a lack of consensus.
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ACCEPTED MANUSCRIPT Results Survey response The questionnaire was sent to 70 specialists; it was completed and returned by 51 (73%), between January 2012 and April 2012. The majority of the specialists worked in an academic clinical or research setting.
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Symptomatic myoclonic and generalized tonic-clonic seizures
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For each of the following conditions, results are presented in three stages: the overall treatment strategy, treatment selection for the condition and comment. For each question, editors provide information on the interpretation of the results, factors influencing the treatment decisions and alignment with practice and guidelines described in Europe and US. Detailed results of the survey are provided in Supplementary Materials. Also in Supplementary Materials there are comments, remarks and general medication recommendations for each surveyed condition syndrome. Main findings describing practice in Poland are summarized in Table 1.
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Questions asked for general strategy for treating 2-years old or 12-years old child with myoclonic and generalized tonic-clonic seizures and mental retardation. Nearly all specialists indicated monotherapy as a first step, with alternative monotherapy as the next step, before trying combination therapy (Suppl. 1A, 1C). For a child of any age valproate was treatment of choice and in case of 12-years old patient topiramate was rated as another first-line treatment (Suppl. 1B, 1D). For patients with isolated generalized tonic-clonic seizures of any age valproate was treatment of choice and lamotrigine was an alternative first-line therapy for 12-years old child (Suppl. 1E, 1F). Complex partial seizures
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For children with either non-lesional cryptogenic complex partial seizures or right-sided mesial temporal sclerosis and complex partial seizures responders suggested three different trials of monotherapy before trying two or three trials of a combination of 2 antiepileptic drugs (Supp. 2A, 2B). If seizures continued to be refractory, they then suggested a combination of 3 antiepileptic drugs and evaluation for surgery (Suppl. 2B). For initial monotherapy carbamazepine was chosen as treatment of choice and oxcarbazepine and valproate as other first-line options. In case of lack of efficacy or intolerance of initial monotherapy with carbamazepine or oxcarbazepine, valproate and levetiracetam were selected as the next treatment choices. In case of failure of treatment with phenytoin, carbamazepine was treatment of choice for second monotherapy; oxcarbazepine, valproate and levetiracetam were rated as usually appropriative (other first line options after carbamazepine) (Suppl. 2C). Neonatal seizures
Treatment of neonatal seizures and even status epilepticus is often controversial and difficult. There is no standard approach for treatment of neonatal status epilepticus, which is likely why different options were chosen. Intravenous (IV), intramuscular (IM) and rectal benzodiazepines were rated as first line therapy. If this was not successful, experts would then give a second dose of the same benzodiazepine. In third step they would use a different IV or IM antiepileptic drug follow by its second dose and using different IV, IM, rectal benzodiazepines (Suppl. 3A). After stopping neonatal seizures experts continue treatment for a mean of 10.5 weeks. Among the available agents experts rated IV phenobarbital as treatment of choice and IV diazepam as sometimes appropriate (first line). In case of suboptimal control after trial with benzodiazepine, IV phenobarbital was selected as treatment of choice for next option (Suppl. 3B). 7
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For a 6-month-old diagnosed with infantile spasms (West Syndrome) experts endorsed minimum two trials of monotherapy before using following combinations with 2 and finally with 3 antiepileptic drugs (Suppl. 4A). Choosing specific medication for initial monotherapy of infantile spasm secondary to tuberous sclerosis complex (Supp. 4B) or of symptomatic in etiology (Suppl. 4C) experts indicated vigabatrin as treatment of choice and ACTH or valproate as usually appropriate initial monotherapy options. Lennox-Gastaut syndrome
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At least two monotherapy trials were considered before starting therapy combination therapies with 2 antiepileptic drugs (Supp. 5A). Considering initial monotherapy experts rated valproate as treatment of choice and topiramate as another first line therapy. If patient did not respond to lamotrigine or topiramate monotherapy valproate was still treatment of choice and topiramate or lamotrigine were alternative first line treatments respectively. In case of failure of treatment with valproate initial monotherapy experts rated topiramate as usually appropriate second line monotherapy (Suppl. 5B). Febrile seizures
For infants acute treatment of a prolonged febrile seizure or cluster of febrile seizures rectal diazepam was treatment of choice. In case of preventive therapy for infant with recurrent febrile generalized tonic-clonic seizures valproate was treatment of choice (Suppl. 6A). Benign childhood epilepsy with centro-temporal spikes
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Carbamazepine was rated as the treatment of choice for benign childhood epilepsy with centrotemporal spikes. Oxcarbazepine and valproate were selected as alternative first line options (Suppl. 7A). Absence epilepsy
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Valproate was treatment of choice both for childhood and juvenile absence epilepsy (Suppl. 8A, 8B). Ethosuximide was another treatment of choice for childhood absence epilepsy (Suppl. 8A). In case of failure of initial treatment of childhood absence epilepsy with ethosuximide valproate was rated as treatment of choice (Suppl. 8A). In case of failure of valproate in juvenile absence epilepsy experts selected lamotrigine as second line treatment of choice. Juvenile myoclonic epilepsy
For newly diagnosed male with juvenile myoclonic epilepsy treatment of choice was valproate (Suppl. 9A). In case of female lamotrigine was drug of choice when valproate and levetiracetam were rated as another first line options (Suppl. 9B). Newly diagnosed epilepsy in the emergency department For a 6-years old patient arriving to emergency department after 2 or 3 seizures, when decision is made to start treatment the panel selected valproate as treatment of choice (suppl. 10A). Status epilepticus 8
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Most of experts indicated use of IV, IM or rectal benzodiazepine in the case of convulsive status epilepticus in a 4-year-old child and following second course of the same benzodiazepine in case of lack of response. If these do not work different IV, IM or rectal benzodiazepine should be used and treatment should be repeated if seizures occur. In last steps were IV or IM antiepileptic drugs and drug coma (Suppl. 11A). For initial therapy of all types of status epilepticus (generalized tonic-clonic, absence, complex partial status epilepticus) experts indicated IV diazepam as treatment of choice for initial therapy (Suppl. 11B, 11C, 11D). In case of generalized tonic-clonic status epilepticus rectal diazepam and IV phenytoin (Suppl. 11B) and in case of absence status epilepticus IV valproate (Suppl. 11C) were selected as treatment of choice. Selecting second line treatment in case of failure of initial benzodiazepine, panel indicated as treatment of choice IV valproate of generalized tonic-clonic and absence status epilepticus (Suppl. 11B, 11C). Other first line treatments in this situation for generalized tonic-clonic status were IV phenytoin and IV phenobarbital (Suppl. 11B). In case of failure of treatment with benzodiazepine of complex partial status epilepticus iv phenytoin and IV valproate were rated as usually appropriate (Suppl. 11D).
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ACCEPTED MANUSCRIPT Discussion Since 1990, many new, better tolerated and easier-to-use AEDs have been introduced. The efficacy of the newer and classic AEDs is comparable, and the proportion of patients with drug-resistant seizures remains high. Guidelines summarizing clinical observations and trials are different in the US and Europe, and many AEDs continue to be used off-label. The paucity of trials with high class of evidence is another reason that antiepileptic therapeutic regimens should be individualized and tailored to the patient’s needs, and the treating physician’s experience.
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Expert consensus methods have been established for many years. Locally performed surveys provide a perspective on regional conditions, habits and standards of therapy; they also shed light on areas where there is lack of clear consensus. For this reason we compared the results of our survey with those of the US and European surveys, which were conducted using the same methodology. The level of agreement among the three panels was generally high and no substantial differences were identified. Despite different reimbursement policies for AEDs in Poland, their direct or on demand accessibility in certain cases, the results of this study based on the general knowledge and routine practice of specialists in Poland can provide additional useful insights. General comments and medication recommendations about treatment strategies and selection are discussed for particular conditions in detail in supplementary materials for this article.
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In this study we attempted to highlight the differences and similarities between the practice of Polish and European doctors. Levetiracetam is widely used as initial therapy in patients with generalized seizures, but in Poland only valproate is reimbursed as first line treatment in this indication. Lamotrigine may be more suitable for partial-onset, but not generalized seizures10. According to published recommendations the panel chose polytherapy with two or three AEDs, but not with four AEDs in patients with refractory epilepsy. Newer AEDs licensed for pediatric population are reimbursed for Polish patients in case of refractory epilepsy. Most of AEDs rated as treatment of choice are reimbursed in Poland for newly diagnosed epilepsy, however alternative first line options in many cases are not reimbursed in Poland, and this limits use, eg. oxcarbazepine for CPS and BECTS, topiramate fot LGS and myoclonic and generalized tonic-clonic seizures. Vigabatrin was the treatment of choice in infantile spasms and partial-onset seizures in TSC. In symptomatic infantile spasms vigabatrin was also chosen as a first line treatment, followed by valproate and ACTH. Zonisamide, used frequently in Japan, and rectal lorazepam are not available in Poland.
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Valproate and ethosuximide were the drugs of choice for children presenting with absence epilepsy. In contrast to European recommendations9, ethosuximide was considered more frequently than lamotrigine as first-line therapy in absence epilepsy. Interestingly, it is in line with recent ILAE recommendations, which supports the use of ethosuximide and valproate (level A evidence). Lamotrigine has only level C evidence7. For the treatment of children with BECTS, the majority of the specialists in our survey opted for carbamazepine rather than valproate which was treatment of choice in the European survey9. Both drugs have ILAE level C evidence in BECTS7. Not surprisingly, given its safety profile, phenytoin was not chosen. However, IV phenytoin is still widely used for the treatment of neonatal seizures. Valproate and lamotrigine were chosen more frequently for the treatment of children JME; the use of levetiracetam however may be underestimated in this indication. There were no differences between Polish and European specialists in their choices for the treatment of children presenting with convulsive SE. Since buccal benzodiazepines are not available in Poland, they could not be adequately rated in this survey for SE. In case of neonatal seizures estimation the duration of treatment depends mainly on factors such as neuroimaging and EEG results. Blood analysis and metabolic screening results remains also valuable. Treatment with AEDs could be necessary even 10
ACCEPTED MANUSCRIPT after an acute event of neonatal seizures and pediatric neurologists are aware that therapy with AEDs should be as short as possible.
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There are no randomized clinical trials comparing pharmacological with non-pharmacological treatment options for pediatric epilepsy. Non-pharmacological treatment of refractory epilepsy is very important, but it is frequently used only as the last step in the therapeutic process. Nonpharmacological therapeutic options such as epilepsy surgery, VNS and ketogenic diet may also improve the quality of life of patients with epilepsy. Resective surgery may be especially useful and important for the treatment of children presenting with mesial temporal sclerosis and complex partial seizures. In Poland, resective surgery is rather uncommon in comparison with other EU countries and the US. Ketogenic diet was not chosen either as an early therapeutic option by the panel in this survey; however, recently there are trends toward re-evaluation of this option3,4,11.
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Overall, there was strong agreement regarding the treatment of epileptic seizures in our panel, especially for partial-onset seizures – carbamazepine and oxcarbazepine were recommended by the panel and by other groups7,9. Despite this consensus, oxcarbazepine can not be used in Poland as first line treatment of newly diagnosed partial onset epilepsy, due to current reimbursement restrictions. Our survey also showed that epilepsy surgery is not often recommended in Poland, unlike other European countries9. This may reflect the lack of access to comprehensive epilepsy centers who can perform pre-surgical evaluations in children. There is a limited number of such centers in Poland, compared to the population and estimated needs. The ketogenic diet as add-on therapy was also chosen very rarely. It is a reason of limited access to experienced dieticians and lack of reimbursement of ketogenic diet therapy. From 3 to 4 centers use ketogenic diet in epilepsy therapy in Poland. AEDs choices were not so clear cut for the treatment of patients presenting with idiopathic generalized epilepsies; effective therapies listed were valproate, lamotrigine and topiramate.
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Despite widespread information about AEDs and types of seizures, the selection of the best therapeutic options for individual patients in clinical practice may often be challenging. This is especially the case for pediatric cases, where very few randomized, controlled clinical trials have been conducted. This study reveals how experts can use their knowledge of the epilepsy syndromes, seizure types, and local formulary and reimbursement to come up with practice recommendations that are helpful to their colleagues. While this data is very helpful to physicians practicing in Poland, and may help in getting other therapies into Poland, where a need is recognized, based on the results of this survey. This may not fit every country in central and eastern Europe. We suggest they would benefit from evaluating their own formularies, and then perhaps doing a similar survey. Ultimately, it would be ideal if the experts recommendations were the basis on a randomized trial to determine what are the best practices, as that performed by Marson et al for the UK10. In this survey, we sought the opinion of panel of Polish pediatric neurologists to gain insight into and develop a consensus on the best treatment practices for children with epilepsy. While the results of this exercise should not replace guidelines, it provides valuable information that could contribute to the decision-making process. Furthermore, it should be emphasized that treatment regimens for each patient should be individualized. Clinicians should use their personal experience and guidelines as well as the knowledge from their peers to ensure they choose the best therapeutic strategy for their patients.
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ACCEPTED MANUSCRIPT Table 1. Main treatment options for pediatric epilepsy syndromes voted for by the panel of Polish pediatric epilepsy specialists.
Syndrome/condition
Treatments of choice and first line treatments
Symptomatic myoclonic and generalized tonicclonic seizures
Valproate treatment of choice, topiramate as alternative first-line therapy.
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For first monotherapy carbamazepine was treatment of choice and oxcarbazepine or valproate were first line options, For second monotherapy after trial with carbamazepine or oxcarbazepine, valproate and levetiracetam were first line treatments,
Neonatal seizures
For second monotherapy after trial with phenytoin, carbamazepine was treatment of choice and oxcarbazepine, valproate and levetiracetam as first line options. IV phenobarbital as treatment of choice and IV diazepam as first line therapy, In case of suboptimal control of seizures after benzodiazepine therapy IV phenobarbital was treatment of choice, Vigabatrin as treatment of choice, with valproate and ACTH as other first-line options Valproate as treatment of choice and topiramate as first line option for initial monotherapy,
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Complex partial seizures
Infantile spasms
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Valproate as treatment of choice second monotherapy after failure of initial monotherapy with lamotrigine or topiramate. Lamotrigine or topiramate as alternative first line options for second monotherapy after failure of initial monotherapy with topiramate or lamortigine, respectively,
Lennox-Gastaut syndrome
Topiramate as first line second monotherapy choice after failure of valproate trial, Rectal diazepam as acute treatment of choice , Valproate as preventive treatment of choice
Febrile seizures Benign childhood epilepsy with centrotemporal spikes
Carbamazepine as drug of choice as initial monotherapy, valproate and oxcarbazepine as first line agents
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Childhood absence epilepsy Valproate and ethosuximide drugs of choice for first monotherapy, Valproate as second monotherapy treatment of choice after ethosuximide failure,
Absence epilepsy
Juvenile absence epilepsy Valproate drug of choice for first monotherapy, Lamotrigine as second monotherapy treatment of choice after valproate failure,
Female patients Lamotrigine drug of choice for first monotherapy, levetiracetam or valproate as another first line treatment
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Juvenile myoclonic epilepsy
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Male patients Valproate drug of choice for first monotherapy,
Newly diagnosed epilepsy in the emergency department
Valproate as drug of choice
Generalized tonic-clonic status epilepticus IV diazepam and rectal diazepam as treatment of choice After failure of initial benzodiazepine IV valproate as treatment of choice and IV phenytoin and phenobarbital as other first line alternatives,
Status epilepticus
Absence status epilepticus IV valproate and IV diazepam as treatments of choice, After failure of initial benzodiazepine IV valproate as treatment of choice, Complex partial status epilepticus IV diazepam as treatment of choice and rectal diazepam or IV phenytoin as alternative first line therapies, After failure of initial benzodiazepine IV phenytoin or IV valproate as first line treatments
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ACCEPTED MANUSCRIPT Acknowledgments The authors gratefully acknowledge the specialists for their contribution to the study. The authors thank Marcin Balcerzak and Anna Juś (UCB Pharma, Warsaw, Poland) for support in preparation and distribution of questionnaires, data management and analysis, preparation of figures, and editorial support in preparation of this publication. The authors thank Azita Tofighy (UCB Pharma, Brussels, Belgium) for reviewing the manuscript for English language. All costs associated with publication were funded by UCB Pharma, Brussels, Belgium.
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7. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54(3): 551-63. 8. Wheless JW, Clarke DF, Carpenter A, Treatment of pediatric epilepsy: Expert opinion, 2005. J Child Neurol 2005; 20(1): S1-S56. 9. Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion. Epileptic Disord 2007; 9(4): 353-412. 10. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369(9566): 1016-26. 11. Kossoff EH, Zupec-Kania BA, Rho JM. Ketogenic diets: an update for child neurologists. J Child Neurol 2009; 24(8): 979-988.
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Treatment of pediatric epilepsy in Poland Supplementary materials Dorota Dunin-Wąsowicza, Maria Mazurkiewicz-Bełdzińskab, Barbara Steinbornc, James Whelessd, e Sergiusz Jóźwiak a a
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Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland Department of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Poland c Chair, Department of Developmental Neurology, Poznań University of Medical Sciences, Poland d University of Tennessee Health Science Center, Memphis, TN, USA e Le Bonheur Children’s Hospital, Memphis, TN, USA
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How to interpret the survey results
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A categorical rating of first (usually appropriate), second (equivocal), or third line (usually not appropriate) was designated as described in Wheless et al., 20071 and are explained below: ‘Usually appropriate’ or ‘first line‘. First-line treatments are those that the specialists identified as extremely or usually appropriate for the given clinical setting (options rated ‘7, 8, or 9’).
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Treatment of choice is a first-line therapy that was rated extremely appropriate (‘9’) by at least 50% of the specialists.
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‘Equivocal’ or ‘second line’. Second-line therapies are reasonable options in instances when the usually appropriate or first-line agent is contraindicated or fails (options rated ‘4, 5, 6’). Failure can be due to poor efficacy, short- or long-term side effects, or an idiosyncratic reaction. ‘Usually not appropriate’ or ‘third line’. Third-line therapies are usually not appropriate (for the given scenario); however this is not the same as saying that they should not be used. Instead, these therapies might be considered if others are contraindicated or have already failed to produce complete seizure control. No consensus. Random distribution of responses by chi-square indicates a lack of consensus.
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Results should be interpreted as described in Wheless et al. 20071. For the questions with the 9-point rating scale, a bar chart depicts the CI for each item, while tables list the numeric values for each item. A number of graphic conventions are used to present results for questions rated on the 9-point scale. A horizontal bar represents the CI for each option. Where the bars for two options do not overlap, there is a statistically significant difference between the mean scores of the two options. ’Usually appropriate’ or ‘first-line’ therapies are indicated with the darkest shaded bars; ‘equivocal’ or ‘second-line’ items are indicated with medium-shaded bars; ‘usually not appropriate’ or ‘third line’ CI bars are lightly shaded. The CI box in black color with white dots indicates items that were rated as ‘treatments of choice’ within the first-line category, that is, options rated as extremely appropriate by at least 50% of the experts, or a ‘9.’ A clear (unshaded) bar indicates items on which consensus was not reached. A table on the right side of each chart presents the numeric values for each option: the number of respondents who rated each option (N), the mean score (Avg), SD, and percentage of experts who rated the option as treatment of choice, first, second, or third line.
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1.
Symptomatic myoclonic and generalized tonic-clonic seizures
1A. Overall strategy
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Case: A 2-year-old child with developmental delay is diagnosed with myoclonic and generalized tonicclonic seizures and has not been treated yet.
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Comment: For this case, nearly all (98%) specialists indicated monotherapy as a first step, with alternative monotherapy as the next step. This may require further discussion. It may be difficult to apply alternative monotherapy in a child who has experienced two types of seizures from the beginning; it is possible that in real life dual therapy will be used, even if it is just a transition to the alternative monotherapy. Of course the results reflect how we would wish to treat the patient, not necessary how we really will. On the other hand, it is important to note that there is no solid evidence that alternative monotherapy will result in better outcomes that adjunctive therapy after failure of first drug2. The next steps were another adjunctive therapy trial, ketogenic diet but not as monotherapy. VNS was recommended by only a small number of experts, even though there is evidence in the literature for a beneficial effect of VNS in generalized seizures3.
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Figure 1. Treatment choices for a healthy 2-year-old child with developmental delay diagnosed with myoclonic and generalized tonic-clonic seizures.
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1B. Treatment selection Case: A 2-year-old child with developmental delay is diagnosed with myoclonic and generalized tonicclonic seizures. The child is starting therapy for the first time.
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Figure 2. Treatment choices for a healthy 2-year-old child with developmental delay diagnosed with myoclonic and generalized tonic-clonic seizures.
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Comment: For this 2-year-old, valproate was rated as treatment of choice by 94% of respondents, 16% and 13% also suggested levetiracetam and topiramate, respectively, as initial monotherapy. Levetiracetam and topiramate were rated by 65% and 63% of experts, respectively, as second-line treatment.
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Both clobazam and clonazepam were described as a sometimes appropriate first line therapy. Not surprisingly, there was a lack of consensus on lamotrigine and it was not as well recommended as the other options. It may be a more suitable drug for patients with partial onset seizures4.
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1C. Overall strategy
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Case: A 12-year-old male with mental impairment is diagnosed with myoclonic and generalized tonicclonic seizures and has not been treated yet.
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Comment: In the case of this patient all respondents indicated monotherapy as a first step, than similarly as in the previous case, alternative monotherapy followed by combination therapy. Twenty-one (38%) selected the ketogenic diet as add-on therapy starting from step four. This reflects an understanding and the increased role of dietary treatments for children with epilepsy, especially those with developmental delay5.
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Figure 3. Treatment choices for a 12-year-old male with mental disability diagnosed with myoclonic and generalized tonic-clonic seizures.
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1D. Treatment selection Case: A healthy 12-year-old male with mental impairment is diagnosed with myoclonic and generalized tonic-clonic seizures. The child is starting therapy for the first time.
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Figure 4. Treatment choices for a healthy 12-year-old male with mental disabilities diagnosed with myoclonic and generalized tonic-clonic seizures.
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Comment: For this older patient, the ratings were quite similar as those for the younger child. Topiramate was rated as an another first-line treatment, and levetiracetam, lamotrigine, clonazepam and clobazam, as second line options. This could be due to greater experience with topiramate since it is has been on the market longer, and it has been proven successful, especially in drug resistant generalized epilepsies6,7. All therapies in first and second-line therapies were broad spectrum AEDs.
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1E. Treatment selection Case: A 1-year-old child is diagnosed with symptomatic generalized tonic-clonic seizures. Assume you begin with monotherapy.
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Figure 5. Treatment choices for a 1-year-old child diagnosed with symptomatic generalized tonic-clonic seizures.
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Comment: Valproate was selected as the most appropriate drug by all respondents for first line monotherapy. Among newer generation drugs, use of levetiracetam was equivocal (second-line), and lamotrigine and topiramate inconclusive. The ILAE subcommission of AED Guidelines underlined lack of class A and B evidence in case of children with generalized tonic-clonic seizures8. Valproate has been used for many years, and newer AEDs (even those with less frequent sides effects) are not so popular as initial monotherapy.
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1F. Treatment selection Case: A 12-year-old child is diagnosed with symptomatic generalized tonic-clonic seizures. Assume you begin with monotherapy.
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Figure 6. Treatment choices for a 12-year-old child diagnosed with symptomatic generalized tonic-clonic seizures.
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Comment: Almost all specialists selected valproate as treatment of choice and lamotrigine as other first line treatment. Options selected for second-line therapy were topiramate or levetiracetam. This choice indicates greater confidence about using newer generation AEDs in older children, despite lack of high class evidence in the entire pediatric age spectrum8. It is not surprising that respondents chose valproate so frequently. Newer AEDs e.g. topiramate and levetiracetam mentioned as second-line therapy are also well-known alternatives in this clinical situation.
General medication recommendations for symptomatic myoclonic and generalized tonic-clonic seizures Valproate was selected for the initial treatment of children 1–12 years of age with GTC seizures. However, as the next option, lamotrigine, topiramate and levetiracetam were recommended for adolescents. Many respondents did not think levetiracetam was useful as initial treatment of a 1-year old infant, but some recommend it as second line therapy.
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2. Complex partial seizures 2A. Overall strategy
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Case: A healthy 8-year-old child is diagnosed with non-lesional cryptogenic complex partial seizures and has not been treated yet.
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Comment: At step one, the entire panel proposed using monotherapy. Monotherapy is recommended as the first therapeutic step for both in children and adults with epilepsy 1,9-11. In the event of unsuccessful monotherapy, 48 respondents suggested trying another monotherapy. Additional trials of monotherapy were recommended by 30 respondents and combination therapy with two AEDs was proposed as fourth step by 27. About half (26/51) of respondents recommended a combination of two AEDs as second choice. Additional trial of dual therapy was the next step of antiepileptic therapy as recommended by 19 respondents. Combination, or polytherapy should only be considered when attempts at monotherapy have not resulted in seizure freedom. Rational polytherapy is often needed for about 50% of patients who do not achieve satisfactory seizure control with a single AED12. Treatment with a combination of three AEDs was chosen only by 16 physicians in fourth, fifth and sixth steps. The next combination of three AEDs was indicated rarely (4/51) as a fourth or sixth step. The probability of becoming seizure free declines by 75% after using three AEDs10,12. Evaluation for epilepsy surgery was proposed by only one expert as the third or fourth step and by 11/51 in sixth step. In the previously published European expert opinion, evaluation for surgery was suggested as step 4 or 51. Epilepsy surgery is not performed frequently in Poland, given the lack of specialist centers. Ketogenic diet as add-on therapy was also chosen rarely ( 1/51). However, use of the ketogenic diet as part of the of the treatment plan for childhood epilepsy is increasing13-15. No one in the panel recommended using the ketogenic diet at the beginning of treatment. Figure 7. Treatment choices for a healthy 8-year-old child diagnosed with non-lesional cryptogenic complex partial seizures.
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2B Overal strategy
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Case: A healthy 9-year-old child presents with right-sided mesial temporal sclerosis and complex partial seizures and has not been treated yet.
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Comment: For this child all respondents selected monotherapy at first step. At step two, 39/51 suggested using second monotherapy. Opinion was divided for the third step, just as in the European survey1. Twenty specialists advised combination therapy with two AEDs and 14 another monotherapy. At third step, 18% of European specialists proposed pre-surgical evaluation1, whereas 50% of Polish specialists recognized evaluation of epilepsy surgery at sixth step. Surgical evaluation for the treatment of childhood epilepsies is needed in Poland, since resective surgery has been shown to be beneficial for some children with focal brain lesions and is carried out in many parts of the world16. All together 39/51 took into account this type of epilepsy therapy. In a case of mesial temporal sclerosis, after failure of antiepileptic therapy, evaluation for surgery is needed and recommended16,17. At step four, 1/5 of experts proposed polytherapy (combination of two AEDs). The fifth step – another dual therapy – was proposed by a third of Polish specialists. Combination therapy with three AEDs was rare and noted by three specialists only. Six specialists proposed using the ketogenic diet as add-on treatment only. As with European specialists, VNS was not considered a useful option1.
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Figure 8. Treatment choices for a healthy 9-year-old child presenting with right-sided mesial temporal sclerosis and complex partial-onset seizures.
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2C. Treatment selection Case: A healthy 6-year-old child with normal cognitive and neurological function is diagnosed with cryptogenic complex partial seizures. The patient is starting therapy for the first time.
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Figure 9. Treatment choices for a healthy, cognitively, and neurologically normal 6-year-old child diagnosed with cryptogenic complex partial-onset seizures.
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Comment: Carbamazepine was chosen as initial therapy by 94% of specialists; a choice consistent with recommendations by the National Institute for Health and Care Excellence (NICE) in the UK18. Oxcarbazepine as initial monotherapy was chosen by 87% and valproate by 76%. The same proposals were made by European specialists1. Levetiracetam, lamotrigine, topiramate and phenytoin were second line choices. The choice of initial AED seemed to be difficult due to the discrepancy between recommendation and reimbursement status of these drugs in Poland. Both lamotrigine and topiramate were sometimes described as appropriate as first line therapy. According to NICE guidance, lamotrigine should be used as first line drug in focal seizures in children18. Approximately 50% of respondents chose lamotrigine as an appropriate or good as a first line drug. Phenytoin, vigabatrin, clonazepam and clobazam were recommended as a second or third line drug, as in NICE guidance18 and their choice is likely related to their side effect profile20. Gabapentin, phenobarbital, zonisamide, tiagabine, eslicarbazepine, ketogenic diet, pregabaline, VNS, lacosamide, felbamate, rufinamide, methsuximide, ethosuximide, retigabine were pointed out as usually not suitable. Some are not registered in Poland for the treatment of children while some are not the reimbursed. The older AEDs are efficacious as an initial therapy but some of newer the AEDs should be considered as a first choice for monotherapy in children20, as proposed by the respondents.
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In the case described above, assume the first treatment you choose is carbamazepine . The child has no or poor response, or the drug was poorly tolerated. Assume you would next choose a second monotherapy trial. Rate the appropriateness of each of the following treatments as a second monotherapy.
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Figure 10. Second-line treatment choices following suboptimal control of seizures with carbamazepine in a child with cryptogenic complex partial-onset seizures.
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Comment: If carbamazepine therapy is not effective as first choice, respondents suggested using valproate or levetiracetam as second monotherapy. European specialists also chose valproate, as well as lamotrigine and topiramate1. Lamotrigine, oxcarbazepine or topiramate were rated by respondents as equivocal. Topiramate was suggested by NICE as a drug for add on therapy18. Results on phenytoin and vigabatrin as drugs ‘sometimes useful’ were inconclusive. Clonazepam, clobazam and gabapentin were proposed as usually not appropriate AEDs. Remaining drugs were rated as not appropriate in this situation.
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In the case described above, assume the first treatment you choose is phenytoin. The child has no/little reduction in seizures or the drug was poorly tolerated. Rate the appropriateness of each of the following treatments as a second monotherapy.
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Figure 11. Second-line treatment choices following suboptimal control of seizures with phenytoin in a child with with cryptogenic complex partial-onset seizures.
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Comment: If the first AED, phenytoin, was not effective, carbamazepine was chosen as the preferred second monotherapy was oxcarbazepine was rated as ‘usually appropriate’ and valproate and levetiracetam were rated as ‘suitable’ similar to the previous European survey1. Topiramate and lamotrigine were suggested as second-line.
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In the case described above, assume the first treatment you choose is oxcarbazepine. The child has no/little reduction of seizures or a limited response or the drug was poorly tolerated. Rate the appropriateness of each of the following treatments as a second monotherapy.
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Figure 12. Second-line treatment choices following suboptimal control of seizures with oxcarbazepine in a child with with cryptogenic complex partial-onset seizures.
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Comment: If oxcarbazepine was not effective as first monotherapy, respondents gave favorable rating for the use of valproate or levetiracetam. Lamotrigine, topiramate, carbamazepine and phenytoin were assessed as usually appropriate. A clear position for vigabatrin was not identified. Similarly, results for benzodiazepines (clonazepam and clobazam) gabapentin and zonisamide were equivocal. Remaining AEDs, VNS and the ketogenic diet were assessed as inappropriate as second monotherapy.
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General medication recommendations for complex partial seizures Monotherapy was identified as the best choice in the first step of treatment for children with complex partial seizures, followed by second monotherapy in the event of poor response to the first. The use of single-drug therapy as a second choice is a good option and proposed by many recommendations18,20. Monotherapy is highly recommended as the first step in the treatment of both children and adults 1,9-11. Carbamazepine, oxcarbazepine and valproate were rated to be the best choice for first monotherapy. As a second monotherapy, levetiracetam, valproate or lamotrigine were rated as usually appropriate drugs. Phenytoin was not chosen as a second line drug in complex partial seizures. Respondents opted for combination therapy as the next step of antiepileptic therapy. This study showed that epilepsy surgery is not often recommended in Poland unlike other European countries1. Ketogenic diet as add-on therapy was also chosen very rarely. Epilepsy surgery and non-pharmacological therapies should be options in the treatment of drug resistant epilepsy13-15.
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3. Neonatal seizures 3A. Overall strategies
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Case: An infant is delivered at 38 weeks gestation and has onset of seizures that it is suspected to be due to hypoxic-ischemic encephalopathy. The infant is now intubated, is having intermittent seizures, and has not yet been treated.
Comment: Intravenous (IV), intramuscular (IM) and rectal benzodiazepines (BDZs) were rated as the first line therapy. There is no standard approach for treatment of neonatal status epilepticus, what is likely why different options were chosen. Treatment of neonatal seizures and even status epilepticus may be controversial and difficult. BDZs are widely used along with intravenous phenytoin.
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Figure 13. Treatment choices for an infant delivered at age 38 weeks gestation presenting with seizures that are suspected to be due to hypoxic-ischemic encephalopathy.
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Case: The neonatal seizures stopped after the acute event. The infant is now 2 weeks old and is approaching hospital discharge. How long do you continue treatment for neonatal seizures? Mean = 10.5 weeks (Range: 0 – 24 weeks, N=36)
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Comment: Estimating the duration of treatment after neonatal seizures depends on factors such as neuroimaging and EEG results. However, pediatric neurologists are aware that therapy with AEDs after neonatal seizures should be as short as possible.
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3B. Treatment selection Case: For the case above, please rate the appropriateness of the following treatment options.
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Figure 14. Treatment choices for an infant delivered at 38 weeks gestation, with onset of seizures suspected to be due to hypoxic-ischemic encephalopathy.
Case: Assume the first agent used was a BDZ, administered to its maximum dose. It has failed to stop the neonatal seizures. Rate the appropriateness of the following treatments.
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Figure 15. Treatment choices following suboptimal control of neonatal seizures with maximum dose benzodiazepine.
General medication recommendations for neonatal seizures Treatment of neonatal seizures is controversial and may be difficult21,22. Furthermore, there is no standard protocol on how and when neonatal seizures should be treated. Among the available agents IV phenobarbital was selected most frequently as the drug of choice. This is also every day practice in Polish neonatal departments. However, in this survey specialists selected IV diazepam as another first-line therapeutic regimen. When phenobarbital is not effective, IV phenytoin is used. Polish specialists also recommended treatment with oral phenobarbital for 10.5 weeks. In previously US and European studies , the period of treatment after neonatal seizures with oral phenobarbital was 3–4 months. Prolonged treatment may have a negative effect on the developing brain, as phenobarbital and phenytoin have
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been shown to cause neuronal apoptosis in animal models23. Moreover, prolonged treatment after neonatal seizures does not prevent seizures later on in life24. When initial treatment with an IV BDZ was not successful, specialists chose IV phenobarbital or phenytoin as second-line therapy. This is in agreement with results of the, US and European surveys. Emerging evidence indicates levetiracetam25 and bumetanide26 may be beneficial in the treatment of neonatal seizures; however, more data are required.
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4. Infantile spasms 4A. Overall strategies
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Case: A healthy 6-month-old is diagnosed with infantile spasms (West Syndrome) and has not been treated.
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Comment: All specialists endorsed a trial of monotherapy at step 1. At step 2, opinion was divided, with 65% of specialists (34/51) selecting another trial of monotherapy, while 31% (16/51) selected combination therapy with two AEDs. At step 3, 24% of respondents (12/51) still favored continued trials of monotherapy, while 67% (34/51) favored the use of a combination therapy with two AEDs antiepileptic drugs. At step 4, the majority endorsed multiple drug therapy, with 63% (32/51) favoring the use of two AEDs antiepileptic drugs and 22% (11/51) favoring a combination of three. At this stage, 12% of respondents endorsed use of ketogenic diet as mono- or add-on therapy. Thus, drug therapy is suggested in the first 4 steps of the treatment of infantile spasms. However, an existing practice parameter from the Child Neurology Society and the American Academy of Neurology concluded that adrenocorticotropic hormone (ACTH) is probably effective and that vigabatrin is possible effective27, whereas no other medications were considered effective. Data from the 4-year follow up of the United Kingdom Infantile Spasms Study (UKISS) study indicated that there were no significant differences in long-term outcomes between the two treatment groups28. In the absence of an agreed therapeutic strategy in infantile spasms the use of the ketogenic diet29–31 or epilepsy surgery30,32 have also been proposed; however these suggestions were not endorsed by our specialists.
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Figure 16. Treatment choices for a healthy 6-month-old child diagnosed with infantile spasms.
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4B. Treatment selection
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Case: A healthy 6-month-old is diagnosed with infantile spasms secondary to tuberous sclerosis complex (TSC) and is starting therapy for the first time. Assume that you begin with monotherapy.
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Figure 17. Treatment choices for a healthy 6-month-old infant diagnosed with infantile spasms secondary to tuberous sclerosis.
Comment: Specialists rated vigabatrin as treatment of choice for infantile spasms if the etiology is TSC, with ACTH and valproate as other appropriate first-line options. While further evidence is deemed necessary by Cochrane reviewers27 and the practice parameter of the American Academy of Neurology
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and the Child Neurology Society (AAN/CNS)27, this rating of vigabatrin as treatment of choice by our specialists is consistent with findings from many open-label clinical trials35–36.
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It should be also stressed that recent recommendations on the management of TSC-associated epilepsy by European experts strongly endorse the use of vigabatrin as a treatment of choice in both infantile spasms and partial seizures in infants with TSC37. There is increasing evidence that treatment with vigabatrin of electrographic seizures (demonstrated by EEG) in the first 2 years of life may significantly improve cognitive outcome and decrease the probability of drug-resistant epilepsy in infants with TSC38.
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4C. Treatment selection
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Case: An otherwise healthy 8-month-old is diagnosed with infantile spasms that are symptomatic in etiology. The male infant was a product of a 28-week gestational pregnancy and suffered a grade 4 intraventricular hemorrhage. He has a gastrostomy tube in place because of severe gastroesophageal reflux and significant dysphagia. He is also cortically blind and has severe developmental delay.
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Figure 18. Treatment choices for a healthy 8-month-old infant diagnosed with infantile spasms following a grade 4 intraventricular hemorrhage.
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Comment: Specialists rated vigabatrin as treatment of choice for infantile spasms that are symptomatic in etiology, with valproate and ACTH as other first-line options. The position on prednisone and topiramate was unclear. The specialists’ endorsement of vigabatrin is not consistent with the American Academy of Neurology and the Child Neurology Society (AAN/CNS) 2004 practice parameter35. However, this parameter has been recently modified by US Infantile Spasms Working Group (ISWG), which recommended both vigabatrin and ACTH as the only proven first–line treatments in infantile spasms39. High-dose prednisolone has shown promise but further evidence is required39. Also, a recent Cochrane Review documented sufficient evidence for both Vigabatrin and ACTH as first–line medications for infantile spasms33. The UKISS found that hormonal therapy was significantly more likely than vigabatrin to cause cessation of spasms and resolution of hypsarrhythmia by day 14 of treatment40. However, the follow up study of this cohort at 4 years, did not demonstrate any difference between the treatments in spasm control or neurodevelopment, except in the group of infants with no identified underlying etiology28,41. Considering this long-term outcome, the possible side effects of hormonal therapy, and the ease of initiating treatment with vigabatrin may explain why specialists chose vigabatrin as the treatment of choice in
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symptomatic infantile spasms. Even if topiramate42,43 and zonisamide44,45 have shown benefit in this specific population in open-label studies, the lack of controlled studies accounts for their lower ratings. General Medication recommendations for infantile spasms
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For a healthy 6-month-old child with infantile spasms respondents opted for 1–2 trials of monotherapy before trying combinations of AEDs. Multiple trials of medication were endorsed before considering a ketogenic diet or evaluation for epilepsy surgery for the treatment of infantile spasms. In choosing specific medications, respondents selected vigabatrin as treatment of choice for spasms irrespective of their etiology. For spasms that are symptomatic in etiology, valproate and ACTH were regarded as alternative monotherapies.
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5. Lennox-Gastaut syndrome 5A. Overall strategy
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Case: A healthy 4-year-old female is diagnosed with Lennox-Gastaut syndrome consisting of frequent astatic seizures and only occasional generalized tonic-clonic and atypical absence seizures and has not been treated yet.
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Comment: All specialists endorsed monotherapy at step 1 for the initial therapy of this child with LGS. Opinion was divided at step 2; 39% of specialists recommended another trial of monotherapy, while 53% recommended combination therapy with two AEDs. At step 3, 62.5% supported use of second combination therapy while only 14% of respondents recommended another monotherapy. At step 4 and 5 the majority opted for combination therapy with mainly two AEDs. At step six, 24 (43%) specialists voted for the ketogenic diet as a treatment option, This is in line with recently published paper46. However, ideally, it should have been recommended earlier. VNS and pre-surgical evaluation did not reach the level of 10% of the indications. This is probably due to the costs of the procedure and lack of controlled studies in this specific syndrome47.
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Valproate, topiramate and lamotrigine were the most frequently chosen drugs, followed by benzodiazepines (clonazepam and clobazam) and the ketogenic diet. Only the ketogenic diet overtook the benzodiazepines in the situation when valproate was unsuccessful as the first drug. It is worth noting that rufinamide, felbamate, zonisamide were not recommended by our panel for LGS. This may be due to the registration and reimbursement situation in Poland where none of the aforementioned drugs are in common use; therefore, lack of experience with those drugs could have influenced the results.
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Figure 19. Treatment choices for a healthy 4-year-old female diagnosed with Lennox-Gastaut syndrome.
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5B. Treatment selection Case: A healthy 6-year-old child has LGS with infrequent generalized tonic-clonic and atypical absence seizures but multiple daily astatic seizures. The patient is being treated for the first time.
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Figure 20. Treatment choices for a healthy 6-year-old child with Lennox-Gastaut syndrome presenting with infrequent generalized tonic-clonic and atypical absence seizures but multiple daily astatic seizures.
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Case: Assume that the first treatment you select is valproate. The child has little or no reduction in seizures, or the medication is poorly tolerated. Rate the appropriateness of each of the following treatments as second monotherapy.
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Figure 21. Second-line treatment choices following suboptimal control of seizures with valproate in a child with Lennox-Gastaut syndrome.
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Case: Assume that the first treatment you select is lamotrigine. The child has little or no reduction in seizures, or the medication is poorly tolerated. Rate the appropriateness of each of the following treatments as second monotherapy.
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Figure 22. Second-line treatment choices following suboptimal control of seizures with lamotrigine in a child with Lennox-Gastaut syndrome.
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Case: Assume that the first treatment you select is topiramate. The child has little or no reduction in seizures, or the medication is poorly tolerated. Rate the appropriateness of each of the following treatments as second monotherapy.
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Figure 23. Second-line treatment choices following suboptimal control of seizures with topiramate in a child with Lennox-Gastaut syndrome.
General Medication recommendations for Lennox-Gastaut syndrome
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For a child with LGS who has astatic, rare tonic-clonic seizures and atypical absence seizures, the majority of respondents considered one to two trials of monotherapy before trying one or more combinations of two AEDs. Interestingly the ketogenic diet was rated as equivalent as multiple trials of medication (more than 2 drugs in treatment). VNS and preoperative investigations were seen as less favorable than multiple drug regimens. In choosing specific medications, the panel agreed on valproate as treatment of choice; topiramate was also chosen as first-line therapy. Lamotrigine was the most frequently chosen second-line treatment option. In the event of poor response to valproate, topiramate was the next option, followed by lamotrigine or levetiracetam. This choice may reflect the results of a national study with lamotrigine as a secondary treatment after carbamazepine or valproate failure48. If the first line was lamotrigine with no improvement, the next choice was valproate, then topiramate. The parallel situation was observed when topiramate was first line treatment with no improvement – next steps were valproate, then lamotrigine. Interestingly levetiracetam was in all of these situations recommended as the fourth drug in line (high second-line therapy).
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6. Febrile seizures 6A. Treatment selection
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Case: A healthy 12-month-old infant has experienced a first generalized tonic-clonic febrile seizure. The parents are anxious and ask for treatment to be initiated acutely in the event of recurrent, prolonged febrile seizures or a cluster of febrile seizures.
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Figure 24. Choices for preventive therapy for a healthy 12-month-old infant presenting with a first generalized tonic-clonic febrile seizure.
Case: A healthy 12-month-old infant is diagnosed with recurrent febrile generalized tonic-clonic seizures. The infant has had five generalized tonic-clonic seizures, all associated with fever since age 6 months. The parents request preventive therapy for his febrile seizures. The child is being treated for the first time. Rate the appropriateness of each of the following options for monotherapy.
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Figure 25. Choices for preventive therapy for a healthy 12-month-old infant diagnosed with recurrent febrile generalized tonic-clonic seizures.
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General Medication recommendations for febrile seizures The drug of choice for the treatment of prolonged febrile seizures was rectal diazepam. This is not surprising, given that in Poland rectal diazepam is used frequently in febrile seizures. Rectal lorazepam and nasal midazolam are not available in Poland. Even though intravenous midazolam is accessible in Polish hospitals, it could not be recommended for outpatient practice. The panel indicated that valproate should be considered for preventive treatment of febrile seizures; other AEDs were not deemed suitable. Similar results were obtained in the US and European surveys.
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7. Benign childhood epilepsy with centro-temporal spikes 7A. Treatment selection
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Case: A healthy 8-year-old is diagnosed with BECTS. The child has had several seizures such that the parents wish to start therapy for the first time. Please keep in mind the epilepsy syndrome the child has and rate the appropriateness of each of the following options for monotherapy.
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Figure 26. Treatment choices for a healthy 8-year-old child diagnosed with benign childhood epilepsy with centro-temporal spikes (benign rolandic epilepsy of childhood).
General medication recommendations for benign childhood epilepsy with centro-temporal spikes
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For the aforementioned case (previously untreated 8-year-old child with BECTS) carbamazepine was rated as initial monotherapy by 68% specialists and oxcarbazepine by 33%. Next, was valproate with 29% - there is data supporting the use of valproate in treatment of partial seizures49. This finding is not in agreement with that of the European survey where valproate was the treatment of choice for BECTS1. There was clear agreement on lamotrigine as a second-line drug, but not on levetiracetam . Again, these results may reflect the reimbursement situation in Poland where levetiracetam and lamotrigine are reimbursed for the treatment of patients with drug resistant epilepsies. Gabapentin, sulthiam, phenytoin, phenobarbital, zonisamide, tiagabine, eslicarbazepine, ketogenic diet, pregabalin, VNS, lacosamide, felbamate, rufinamide, methsuximide, ethosuximide, retigabine were rated as not usually appropriate. This is quite an interesting finding especially where phenytoin is concerned – it was pointed out as inappropriate for this type of patient – that may be due to the availability of newer drugs, such as oxcarbazepine which has led to a reduction in phenytoin use mainly due to its side effect profile50,51.
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8. Absence epilepsy 8A. Treatment Selection
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Case: A healthy 6-year-old is diagnosed with childhood absence epilepsy (absence seizures only). The patient is starting therapy for the first time. Please keep in mind the seizure type(s) the child is experiencing (within the syndrome diagnosis), and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 27. Treatment choices for a healthy 6-year-old child diagnosed with childhood absence epilepsy (absence seizures only).
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Assume that the first treatment you choose in case above is ethosuximide. The child either has had no reduction of seizures, a limited response, or the drug was poorly tolerated. Assume you choose a second monotherapy trial.
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Figure 29. Second-line treatment choices following suboptimal control of seizures with ethosuximide in a child with absence epilepsy.
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8B. Treatment Selection Case: A healthy 12-year-old is diagnosed with juvenile absence epilepsy (absence and generalized tonicclonic seizures). The patient is starting therapy for the first time. Please keep in mind the seizure type(s) the child is experiencing (within the syndrome diagnosis), and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 28. Treatment choices for a healthy 12-year-old child diagnosed with juvenile absence epilepsy (absence and generalized tonic-clonic seizures).
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Assume that the first treatment you choose in case above is valproate. The child either has had no reduction of seizures, a limited response, or the drug was poorly tolerated. Assume you choose a second monotherapy trial.
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Figure 30. Second-line treatment choices following suboptimal control of seizures with valproate in a child with juvenile absence epilepsy.
General Medication recommendations for absence epilepsies
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Childhood absence epilepsy For an untreated 6-year-old child, the drugs of choice were valproate and ethosuximide. Lamotrigine and levetiracetam were chosen less often as a first line treatment, and the specialists were uncertain where to rank them (lack of consensus). This is not in agreement with results of the European survey where valproate was rated as treatment of choice and lamotrigine was another first-line option. In Poland, ethosuximide was chosen more frequently than considered than lamotrigine in this clinical situation. No other AED reached the recommendation level for this type of seizure, indicating than when diagnosed, there is a clear choice for the treatment of childhood absence epilepsy. In the event of poor outcome with ethosuximide, the respondents all chose valproate as first line therapy followed by lamotrigine 56%, levetiracetam 37%, topiramate 19% and clonazepam 12%. This reflects the findings of the European survey1. Juvenile absence epilepsy For the patients with juvenile absence epilepsy, valproate was the drug of choice and if unsuccessful, lamotrigine reached the rating level for second line. The panel did not reach an agreement on the position of levetiracetam. Only 6% considered ethosuximide as a drug of choice in this syndrome. This may be due to known different disease course in this syndrome and the lack of benefit of ethosuximide in generalized tonic-clonic seizures, which occur more often in this type of absence syndrome.
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9. Juvenile myoclonic epilepsy (JME) 9A. Treatment selection
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Case: A healthy adolescent male is diagnosed with JME. The patient is being treated for the first time. Please keep in mind the epilepsy syndrome the adolescent has and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 31. Treatment choices for a healthy adolescent male diagnosed with juvenile myoclonic epilepsy.
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9B. Treatment selection
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Case: A healthy adolescent female is diagnosed with JME. The patient is being treated for the first time. Please keep in mind the epilepsy syndrome the adolescent has and rate the appropriateness of each of the following treatments for monotherapy.
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Figure 32. Treatment choices for a healthy adolescent female diagnosed with juvenile myoclonic epilepsy.
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General medication recommendations for juvenile myoclonic epilepsy
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For adolescent males with JME the drug of choice was valproate followed by levetiracetam or lamotrigine (high second-line). The remaining AEDs, with the exception of topiramate ketogenic diet and VNS were rated as inappropriate. The choice of drug was different for the female patients reflecting the teratogenic effects of valproate and it is influence on the development of children born to mothers with epilepsy52. The drug of choice was lamotrigine, followed by valproate or levetiracetam. Recent trials have not shown show superiority of lamotrigine over valproate in treatment of JME53,54. The role of levetiracetam may be underestimated due to the relatively short time since its reimbursement in Poland.
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10. Newly diagnosed epilepsy in the emergency department 10A. Treatment selection
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Case: A healthy 6-year-old has just arrived in the emergency department, having had two or three seizures. Assume that the index of suspicion for seizure disorder is high; however, the type of seizure and/or epilepsy syndrome is unclear based on available information. The decision is made to start treatment. Please rate the appropriateness of the following treatments.
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Figure 33. Treatment choices for a healthy 6-year-old child who has just arrived in the emergency department, having had two or three seizures.
General medication recommendations for newly diagnosed epilepsy in the emergency department
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The drug of choice is valproate; second-line options include levetiracetam and lamotrigine. There is no agreement among the specialists regarding the usefulness of carbamazepine or topiramate. This choice is probably due to fact that valproate is considered a broad spectrum AED usually efficacious in most epileptic seizures (partial and generalized). Since the exact type of seizures is unclear the prudent option is valproate, which in contrast to carbamazepine has no potential to aggravate seizures19. Interestingly, the second line choice was levetiracetam; this shows increasing impact of this new broad spectrum AED with low potential for drug–drug interactions. Lamotrigine were also rated as useful in this clinical situation. Oxcarbazepine was positioned quite low as a drug of choice in this clinical situation – this could be due to the concern that it may aggravate generalized seizures.
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11. Status epilepticus 11A. Overall strategy
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Case: A 4-year-old child is in convulsive SE. No treatment has been started.
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Comment: the entire panel highly advised use of IV, IM or rectal benzodiazepine in the case of convulsive status epilepticus in a 4-year-old child. European specialists chose the same course of therapy1. These suggestions are in accordance with many recommendations in this topic 55,56,57. There were only two suggestions to use sublingual benzodiazepine at first step. In Poland access to this formulation is limited. The next step proposed by the panel was to repeat the second dose of the same IV, IM or rectal benzodiazepine. For the third step, opinion was divided. One group of specialists proposed using a different IV, IM or rectal benzodiazepine while the second group recommended and AED administered IV or IM. IV or IM AEDs (phenytoin, phenobarbital, valproate and levetiracetam) are recommended for established SE55. All specialists chose IV or IM AED at the fourth step and iatrogenic, drug-induced coma was proposed at the fifth step in refractory SE55,57.
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Figure 34. Treatment choices for a healthy 4-year-old child in convulsive status epilepticus.
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11B. Treatment selection Case: A healthy 4-year-old child is in generalized tonic-clonic SE. No treatment has been given yet. Assume that you begin with a single treatment, and assume each treatment is tried to maximum dose. Rate the appropriateness of each of the following treatments.
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Figure 35. Treatment choices for a healthy 4-year-old child in generalized tonic-clonic status epilepticus.
In the case above, (healthy 4-year-old in generalized tonic-clonic SE), assume administration of a benzodiazepine at maximum dose has failed to stop the convulsive SE. As in most clinical situations, a second agent must now be administered. Please rate the appropriateness of the following therapies.
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Figure 36. Treatment choices for a healthy 4-year-old child in generalized tonic-clonic status epilepticus, who has failed to respond to maximum dose.
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11C. Treatment selection
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Case: A healthy 8-year-old child is in absence SE. No treatment has been given yet. Assume the airway is protected. Please rate the appropriateness of the following therapies.
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Figure 37. Treatment choices for a healthy 8-year-old child in absence status epilepticus.
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In the case above (healthy 8-year-old in absence SE), assume administration of a benzodiazepine at maximum dose has failed to stop the absence SE. As in most clinical situations, a second agent must now be administered. Please rate the appropriateness of the following therapies. Again, assume that the patient’s airway is protected.
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Figure 38. Treatment choices for a healthy 8-year-old child in absence status epilepticus who has failed to respond to maximum dose benzodiazepine.
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11D. Treatment selection Case: A healthy 6-year-old child is in complex partial SE. No treatment has been given yet. Assume the airway is protected. Please rate the appropriateness of the following therapies.
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Figure 39. Treatment choices for a healthy 6-year-old in complex partial status epilepticus.
In the case above (6-year-old in complex partial SE), assume administration of a benzodiazepine at maximum dose has failed to stop the SE. As in most clinical situations, a second agent must now be administered. Please rate the appropriateness of the following treatments. Again, assume that the patient’s airway is protected.
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Figure 40. Treatment choices for a 6-year-old child in complex partial status epilepticus, who has failed to respond to maximum dose benzodiazepine.
General medication recommendations for status epilepticus Generalized tonic-clonic status epilepticus: The panel agreed on using IV diazepam in generalized tonic-clonic SE. Rectal diazepam was also rated as a first line treatment. European specialists and many others selected the same therapy in SE1,55-58. The next step proposed is to repeat the second dose of the same IV, IM or rectal benzodiazepine. The Polish panel rated the use of IV valproate as ‘usually appropriate’, while European specialists were equivocal1.
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IV lorazepam, midazolam, phenobarbital and phenytoin were rated as ‘appropriate’. There was uncertainty about the position of levetiracetam and fosphenytoin. Rectal use of other AEDs and sublingual lorazepam were rated as ‘not appropriate’. Lacosamide was regarded as not appropriate in such a case. There was no choice of the buccal formulation of benzodiazepines were not chosen by any of the respondents despite many studies supporting their efficacy and safety25,59. This is due to the unavailability of these agents in Poland. If the child fail to respond to a maximum dose of IV diazepam the panel chose IV valproate. The panel also rated IV phenytoin or phenobarbital as ‘usually appropriate’. Opinion on the use of IV midazolam, levetiracetam, IV diazepam and fosphenytoin appeared equivocal and without clear consensus among the specialists55-57. Rectal form of diazepam were on the border estimation as equivocal or not suitable. Sublingual lorazepam and IV lacosamide were rated ‘inappropriate’ – these medications are not licensed for use in Poland for SE .
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Absence status epilepticus: The entire panel rated IV valproate as the treatment of choice with IV diazepam or rectal diazepam as second-line therapy. European specialists chose IV diazepam at the same level as IV valproate or IV lorazepam, but did not rate rectal diazepam as highly useful1. The panel was equivocal in its view on the appropriateness of IV midazolam and lorazepam . Levetiracetam and phenobarbital were not chosen as first line drugs. Phenytoin, other rectal AEDs, fosphenytoin (not used in Poland) and lacosamide were rated as ‘not appropriate’.
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Complex partial status epilepticus: The panel rated IV diazepam as the treatment of choice in complex partial SE. The panel also rated rectal diazepam and IV phenytoin as possible first-line options and IV valproate as second-line therapy. The use of the following IV agents was rated as equivocal: lorazepam, midazolam, phenobarbital, and levetiracetam and equivocal were IV phenobarbital. The use of rectally administered agents, sublingual lorazepam and IV lacosamide was rated as ‘not appropriate’.
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If IV diazepam has not stopped the status epilepticus (complex partial) Polish experts proposed use of IV phenytoin (83% of them) or IV valproate (65%) as first-line therapies. It was similar to opinion (95% of them selected IV phenytoin)1. In contrast to the European specialists, the panel did not choose fosphenytoin as a first-line drug since it is not registered for use in Poland. The use IV phenobarbital or levetiracetam was estimated as equivocal partial). Valproate, phenobarbital and midazolam (IV) European experts estimated as equivocal or usually appropriate. Usually not appropriate in their opinion were rectal diazepam, sublingual lorazepam and rectal AEDs.
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References for Supplementary Materials 1. Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion. Epileptic Disord 2007; 9(4): 353-412
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2. Beghi E, Gatti G, Tonini C, Ben-Menachem E, et al. Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial. Epilepsy Res 2003; 57(1): 1-13.
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27. Mackay MT, Weiss SK, Adams-Webber T, et al. American Academy of Neurology; Child Neurology Society. Practice parameter: Medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology 2004; 62(10): 1668-81.
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28. Darke K, Edwards SW, Hancock E, et al. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomized trial. Arch Dis Child 2010; 95(5): 382-386. 29. Kossoff EH, Hedderick EF, Turner Z, et al. A case control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms. Epilepsia 2008; 49(9): 1504-9.
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30. Wheless JW, Bourgeois BF, Choosing antiepileptic drugs for developmentally normal children with specific epilepsy syndromes and behavioral disorders. J Child Neurol. 2004; 19( 1): S39-S48.
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31. Hong AM, Turner Z, Hamdy RF, et al. Infantile spasms treated with the ketogenic diet: prospective single – centre experience in 104 consecutive infants. Epilepsia 2010; 51(8): 1403-7. 32. Chugani HT, Asano E, Sood S. Who are the ideal surgical candidates? Epilepsia 2010; 51(Suppl.1): 9496.
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33. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev 2008; 8(4): CD001770. 34. Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain Dev. 2001; 23(7): 649-53.
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35. Mackay M, Weiss S, Snead OC, 3rd. Treatment of infantile spasms: an evidence-based approach. Int Rev Neurobiol 2002; 49: 157-84. 36. Thiele EA. Managing epilepsy in tuberous sclerosis. J Child Neurol 2004; 19(9): 680-6.
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37. Curatolo P, Jozwiak S, Nabbout R, et al. Management of epilepsy associated with tuberous sclerosis complex (TSC): Clinical recommendations. Eur J Paediatr Neurol 2012; 16(6): 582-6. 38. Jozwiak S, Kotulska K, Domanska-Pakiela D, et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 2011; 15(5): 424-31. 39. Pellock JM, Hrachovy R, Shinnar S, Baram TZ, Bettis D, Dlugos DJ, Gaillard WD, Gibson PA, Holmes GL, Nordl DR, O'Dell C, Shields WD, Trevathan E, Wheless JW. Infantile Spasms: A U.S. consensus report. Epilepsia 2010; 51(10): 2175-2189.
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40. Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet 2004; 13-19;364(9447): 1773-8.
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41. Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicenter randomized trial. Lancet Neurol 2005; 4(11): 712-7. 42. Kwon YS, Jun YH, Hong YJ, et al. Topiramate monotherapy in infantile spasm. Yonsei Med J. 2006; 47(4): 498-504.
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43. Zhu X, Chen O, Zhang D, et al. A prospective study on the treatment of infantile spasms with first-line topiramate followed by low-dose ACTH. Epilepsy Res 2011; 93(2-3): 149-54.
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44. Yum MS, Ko TS, Zonisamide in West syndrome: an open label study. Epileptic Disord 2009; 11(4): 339-44. 45. Yanagaki S, Oguni H, Yoshii K, et al. Zonisamide for West syndrome: a comparison of clinical responses among different titration rate. Brain Dev 2005; 27(4): 286-90.
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46. Cross JH. The ketogenic diet in the treatment of Lennox-Gastaut syndrome. Dev Med Child Neurol 2012; 54(5): 394-5. 47. Lancman G, Virk M, Shao H, et al. Vagus nerve stimulation vs. corpus callosotomy in the treatment of Lennox-Gastaut syndrome: A meta-analysis. Seizure 2013; 22(1): 3-8.
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48. Jozwiak S, Terczyński A. Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients over 12 years with carbamazepine or valproate resistant epilepsy. Seizure 2000; 9 (7): 486-492.
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49. Aldenkamp A, Vigevano F, Arzimanoglou A, Covanis A. Role of valproate across the ages. Treatment of epilepsy in children. Acta Neurol Scand Suppl. 2006; 184: 1-13. 50. Dorado P, López-Torres E, Peñas-Lledó EM, et al. Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms. Pharmacogenomics J. 2012 13(4):359-61. 51. Brigo F. Phenytoin is dead, long live phenytoin? Epilepsy Behav 2012; 24(1): 152. 52. Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol 2012; 11(9): 803-13.
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53. Mazurkiewicz-Bełdzińska M, Szmuda M, Matheisel A, et al. Long-term efficacy of valproate versus lamotrigine in treatment of idiopathic generalized epilepsies in children and adolescents. Seizure 2010; 19(3): 195-7.
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54. Bodenstein-Sachar H, Gandelman-Marton R, Ben-Zeev B, et al. Outcome of lamotrigine treatment in juvenile myoclonic epilepsy. Acta Neurol Scand 2011; 124(1): 22-7. 55. Mastrangelo M, Celato A. Diagnostic work-up and therapeutic options in management of pediatric status epilepticus. Word J Pediatr 2012; 8(2): 109-15.
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56. Ng Y-T, Maganti R. Status epilepticus in childhood. J Paediatr Child Health 2013; 49(6): 432-7.
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57. Riviello J, Claassen J, LaRoche S, et al. Treatment of Status Epilepticus: An International Survey of Experts. Neurocrit Care 2013; 18(2): 193-200. 58. Babl FE, Sheriff N, Borland M, et al. Emergency management of paediatric status epilepticus in Australia and New Zealand: practice patterns in the context of clinical practice guidelines. J Paediatr Child Health 2009; 45(9): 541-6.
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59. Ashrafi MR, Khosroshahi N, Karimi P, et al. Efficacy and usability of buccal midazolam in controlling acute prolonged convulsive seizures in children. Eur J Paediatr Neurol 2010; 14(5): 434-8
