Treatment issues for children with epilepsy transitioning to adult care

YEBEH-05102; No of Pages 8 Epilepsy & Behavior xxx (2016) xxx–xxx

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Treatment issues for children with epilepsy transitioning to adult care Rima Nabbout a,⁎, Carol S Camfield b, Danielle M Andrade c, Alexis Arzimanoglou d, Catherine Chiron e, Joyce A Cramer f, Jacqueline A French g, Eric Kossoff h, Marco Mula i, Peter R Camfield j a

Reference Centre for Rare Epilepsies, Pediatric Neurology, Necker-Enfants Malades Hospital, APHP, University of Paris Descartes, Inserm U1129, Paris, France Dalhousie University & IWK Health Center, Dalhousie University, Halifax, Nova Scotia, Canada Department of Medicine, University of Toronto Adult Epilepsy Genetics Program, University of Toronto, Toronto Western Hospital, Toronto, Canada d University Hospitals of Lyon (HCL) and DYCOG Team, Lyon Neuroscience Research Centre (CRNL), INSERM U1028, CNRS UMR 5292, Lyon, France e Pediatric Neurology, Necker-Enfants Malades Hospital, Inserm U1129, Paris, France f Yale University School of Medicine, New Haven, CT, USA g NYU Comprehensive Epilepsy Center, New York, NY, United States h Johns Hopkins University, Baltimore, MD, United States i Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, Department of Neuropsychiatry, South West London & St George's Mental Health Trust, Institute of Medical and Biomedical Sciences, St George's University of London, United Kingdom j Dalhousie University & IWK Health Center, Dalhousie University, Halifax, NS, Canada b c

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Article history: Received 3 November 2016 Accepted 6 November 2016 Available online xxxx Keywords: Adult Pediatric Transition Treatment Mental health Compliance

a b s t r a c t This is the third of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper focuses on treatment issues that arise during the course of childhood epilepsy and make the process of transition to adult care more complicated. Some AEDs used during childhood, such as stiripentol, vigabatrin, and cannabidiol, are unfamiliar to adult epilepsy specialists. In addition, new drugs are being developed for treatment of specific childhood onset epilepsy syndromes and have no indication yet for adults. The ketogenic diet may be effective during childhood but is difficult to continue in adult care. Regional adult epilepsy diet clinics could be helpful. Polytherapy is common for patients transitioning to adult care. Although these complex AED regimes are difficult, they are often possible to simplify. AEDs used in childhood may need to be reconsidered in adulthood. Rescue medications to stop prolonged seizures and clusters of seizures are in wide home use in children and can be continued in adulthood. Adherence/compliance is notoriously difficult for adolescents, but there are simple clinical approaches that should be helpful. Mental health issues including depression and anxiety are not always diagnosed and treated in children and young adults even though effective treatments are available. Attention deficit hyperactivity disorder and aggressive behavior disorders may interfere with transition and successful adulthood but these can be treated. For the majority, the adult social outcome of children with epilepsy is unsatisfactory with few proven interventions. The interface between pediatric and adult care for children with epilepsy is becoming increasingly complicated with a need for more comprehensive transition programs and adult epileptologists who are knowledgeable about special treatments that benefit this group of patients. © 2016 Elsevier Inc. All rights reserved.

This is the third and final paper based on a symposium held in Paris in June 2016 about transition from pediatric to adult care for young people with epilepsy. The first paper [1] reviews the basic biological, sociological, and psychological issues that surround transition and the second paper [2] reviews the outcome of childhood onset epilepsy from adolescence to young adulthood with emphasis on transition issues for different epilepsy syndromes. This third paper summarizes

⁎ Corresponding author. E-mail address: [email protected] (R. Nabbout).

issues that are important for successful transition related to drug and dietary therapy as well as psychiatric and psychosocial care. 1. Antiepileptic drugs used in pediatrics but rarely in adult medicine Most antiepileptic drugs (AEDs) have been developed in adults with focal seizures and then transferred for use in children. This transfer is typically valid for focal seizures but has been disappointing for some specific epilepsy syndromes with onset in infancy and childhood. There is a lack of both efficacy and pharmacological data (pharmacokinetics, pharmacodynamics) for children, particularly infants. However,

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Please cite this article as: Nabbout R, et al, Treatment issues for children with epilepsy transitioning to adult care, Epilepsy Behav (2016), http:// dx.doi.org/10.1016/j.yebeh.2016.11.008

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the methodology for introducing new AEDs is evolving with an occasional revolution when AEDs are first introduced for use in children. The following examples emphasize how a few drugs have been developed and registered for specific pediatric syndromes. Children receiving these AEDs will eventually transition to adult care at an age when there may not be much data about efficacy and pharmacokinetics. Stiripentol is currently approved in many countries for children only, as adjunctive therapy with valproate and clobazam in Dravet syndrome. This AED was developed first for focal seizures and failed to show efficacy in phase 3 trials in adults. An exploratory open trial in pediatric pharmacoresistant epilepsies helped to identify Dravet syndrome as a potential target. Finally, a randomized double-blind trial of stiripentol in children with Dravet syndrome established its utility [3]. Presently, this AED is licensed in many countries as an orphan drug specifically for Dravet syndrome in children. Children with Dravet syndrome often enter adolescence and adulthood with stiripentol as part of their medication regime. Long-term studies show that efficacy is maintained up to late adolescence, but follow-up data in adulthood are still scarce [4,5]. It seems likely that adult patients with newly-diagnosed Dravet syndrome will also benefit from stiripentol, not only for seizures but also for cognitive enhancement [6]; however, the optimal dose and potential interactions with other AEDs and other classes of drugs remain to be determined in adults. Vigabatrin was extensively used during the 1990s by adults with focal onset seizures, but its use has been markedly restricted due to retinal toxicity. Because this toxicity increases with the dose and duration of drug exposure, vigabatrin is currently a “third line” AED in adults with pharmacoresistant focal epilepsy. However, the specific efficacy of vigabatrin for infantile spasms, noted as early as 1990 [7], has meant that it continues to be the first-line treatment for infantile spasms, especially in patients with tuberous sclerosis complex due to a positive benefit-risk balance [8]. It is possible that vigabatrin-induced visual field defects occur more frequently in adults (36%) than in children (18%) [9] and infants (21%) [10]. The information in infants is based entirely on electroretinogram studies since visual field testing is not possible at this age. Cannabidiol use in epilepsy is very recent. Several small open studies suggested that it might be useful for pharmacoresistant pediatric epilepsy and epileptic encephalopathies. An open-label study of 137 patients with Dravet syndrome, Lennox-Gastaut syndrome, and other drug-resistant epilepsies in childhood suggested that “motor” seizures decreased by a median of 37% (CI 0–65%) over 13 weeks of treatment [11]. Preliminary results from randomized placebo-controlled trials in Dravet syndrome and Lennox-Gastaut syndrome suggest efficacy in both conditions [12]. Cannabidiol has been shown to be of some value in the adult treatment of pain and multiple sclerosis; however, optimal dose and drug interaction profile need to be more extensively studied. A possible interaction with clobazam (increased serum levels) through CYP450 inhibition has been reported but requires further evaluation. Other molecules to treat rare epilepsies are currently in phase 2 and phase 3 trials aiming to be registered as orphan drugs. As the pathophysiology of early-onset epilepsies is better understood, there will be encouragement to develop highly targeted therapies. It is likely that the first trials of these drugs will be in childhood. Therefore, in the future, youth with epilepsy transitioning from pediatric to adult care will increasingly be receiving AEDs that are not familiar to adult caregivers. 2. Antiepileptic drug treatment differences in children compared with adults The etiology of epilepsy that begins in childhood may be very different than in adult epilepsy, which raises an important question for transition - do different AEDs have different effects in children than adults [13,14]? Most randomized clinical trials of AEDs include patients with a restricted age range (such as age 4–16, age 16–65 or N 65 years), which makes it impossible to know relative drug effects at different ages. The famous SANAD (Standard And New Antiepileptic Drugs)

study randomized 1721 newly-diagnosed patients including children over 4 years of age up to the elderly [15]. The AEDs studied were carbamazepine, gabapentin, lamotrigine, and oxcarbazepine. Children (b16 years of age) were more likely to experience treatment failure than adults, but also more likely to experience a 12-month remission. There were no differences in rates of response between AEDs in children and adults. On the basis of numerous trials in focal epilepsies of the same AED showing no difference in effect between adult and pediatric trials, the European Medicines Agency (EMA) concluded: “Focal epilepsies in children older than 4 years of age have a similar clinical expression to focal epilepsies in adolescents and adults. In refractory focal epilepsies … the results of efficacy trials performed in adults could to some extent be extrapolated to children provided the dose is established …” [16]. More recently Dr. Jack Pellock and colleagues, in collaboration with the University of Maryland, performed a PK-PD analysis as part of the FDA critical path initiative, to determine if the serum exposures necessary to control seizures in adults produced a similar degree of seizure reduction in children [17]. On the basis of this analysis, the FDA determined that results of adjunctive clinical trials in focal epilepsy in adults can be extrapolated to children 4 years and older. Most “specific” AED safety issues occur in children more than adults. These include increased rash from lamotrigine, increased liver toxicity from valproate, and probably increased behavioral issues from levetiracetam, topiramate, gabapentin, pregabalin, and others. These issues will have resolved or have been avoided by late adolescence and therefore are not of special concern in the context of transition. In the USA, of eight new AEDs approved since 2004 (pregabalin, lacosamide, rufinamide, ezogabine, clobazam, perampanel, eslicarbazepine, brivaracetam) only two have pediatric indications (clobazam and rufinamide). As emphasized above, there are some AEDs in development where the goal will be approval for children before adults. These AEDs include cannabidiol for Dravet syndrome and Lennox-Gastaut syndrome, fenfluoramine for Dravet syndrome, triheptanoin for Glut1 deficiency, anavex-273 for Rett syndrome, and everolimus for tuberous sclerosis. If these and similar drugs are effective then there will be a new issue for transition – do they continue to work in adults? 3. Strategies to deal with AED polytherapies (rarely simplified prior to transfer in severe epilepsies) Not surprisingly, many of the epilepsy syndromes that begin in childhood and persist into adulthood are characterized by poor seizure control. Polytherapy is very common for these patients and at its best provides satisfactory seizure control without significant side effects. At its worst there are many seizures and sedation. In adult care, simplifying these complex medication regimes may be challenging. Based on clinical experience, we propose four strategies. First, it is important to confirm that the events described by the patient (or parents/caregivers) are indeed seizures. Some epilepsy syndromes are associated with only one seizure type that is very typical, stereotyped, and unchanging through the pediatric years. Other epilepsies may present with different seizure types as the infant/child grows which may be a source of confusion. For instance, patients with severe epilepsy with very early onset (especially with intellectual disability) may have seizures with very subtle manifestations such as pupil dilatation or facial flushing. After these subtle types of seizures disappear, parents and caregivers may still interpret autonomic signs as seizures in their teenage child. The adult epileptologist now caring for this patient should be aware of this misinterpretation. Other paroxysmal events may also be confused with seizures: mannerisms, agitation, screaming episodes, and aggressive outbursts (especially in patients with moderate/severe intellectual disability). Movement disorders (tremor, myo-clonus, dystonia) and sleep disorders, may also be mistaken for seizures [18,19]. VideoEEG may be challenging in these patients but very helpful to clearly define which activities are seizures, thereby AED polytherapies.

Please cite this article as: Nabbout R, et al, Treatment issues for children with epilepsy transitioning to adult care, Epilepsy Behav (2016), http:// dx.doi.org/10.1016/j.yebeh.2016.11.008

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Another potential cause for polytherapy is a failure to recognize psychogenic nonepileptic seizures (PNES). Although PNES occur in patients with severe intellectual disability, they are more frequent in patients with more normal intelligence but with other co-morbidities such as depression or anxiety. Psychogenic nonepileptic seizures may co-exist [20] with epileptic seizures - both problems need proper treatment; however, diagnosing PNES may well lead to a simplification of the AED regimen. Second, compliance and life-style factors should be reviewed. Teenagers are at high risk of non-compliance with medical treatment and may not take control of their treatment even though its importance has been stressed by the pediatric health care team. The adult neurologist must ensure that lack of compliance is not a cause of increased seizures and an overly complex AED regimen. Solutions to the issue of compliance are discussed below. Other factors that may lead to polytherapy are modifiable risks/life-style issues such as sleep deprivation, photic/pattern stimulation, excess alcohol or alcohol withdrawal and drug abuse. These issues may be especially significant for teenagers with “idiopathic” or genetic generalized epilepsies who move out of their parents' house and may not appreciate how their “new life style” affects their epilepsy. Third, successful surgery can lead to simplification of AED regimen or even AED withdrawal. Surgical efficacy and timing of AED withdrawal needs consideration. Five years after temporal lobectomy, one-third of patients remain seizure-free after AED withdrawal; one-third become seizure-free as long as AEDs are maintained; and one-third do not have a significant improvement. The ideal timing of AED withdrawal after surgery is under investigation but remains unclear. Extra-temporal surgeries have a more variable outcome. For instance, hemispherotomy can lead to permanent seizure freedom in up to 75% of cases, which makes it easier to simplify AED regimens. On the other hand, very tailored corticectomies have a lower success rate making AED simplification sometimes hazardous [21–25]. Once the issues listed above have been addressed, we suggest nine steps to simplify polytherapy. These are outlined in Table 1 [26–31]. If the nine strategies fail, other options are the ketogenic or modified Aitkin's diet, neurostimulation, and callosotomy. Reconsidering resective surgery that had been rejected during the pediatric years should be also an important option for patients with focal epilepsies. 4. Long-term effects of the ketogenic diet: how does this affect transition? Many pediatric epilepsy centers have a sizeable population of adolescents with refractory epilepsy who are treated with the ketogenic diet and are old enough to require transfer to adult care. In patients

Table 1 Suggestions for simplifying polytherapy during transition to adult care. 1. Identify any AED that could be aggravating the epilepsy such as carbamazepine in generalized, genetic epilepsies or sodium channel inhibitors in Dravet syndrome [9,10]. 2. Avoid combining drugs with similar mechanisms of action such as clobazam plus clonazepam or carbamazepine plus phenytoin plus lacosamide. 3. Be cautious about combinations of medications with competitive hepatic enzyme inhibition such as topiramate + phenytoin or with competitive protein binding such as lamotrigine + carbamazepine [9,11–14]. 4. Be cautious about certain combinations such as valproate with topiramate (may offset weight gain, but lead to increased neurotoxic side effects). 5. Use AED combinations that may have synergistic effects such as valproate + lamotrigine or levetiracetam + carbamazepine. 6. Use combinations of AEDs with different mechanisms of action such as clobazam + valproate. 7. Consider AEDs that address both seizures and co-morbidities such as topiramate for seizures and migraine. 8. Consider retrying AEDs that were not tolerated in the past. For example, a teenager may tolerate clobazam even though it caused agitation during infancy. 9. Consider using AEDs that are typically only used in pediatrics such as sulthiame or stiripentol for Dravet syndrome.

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with Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, and other conditions, the ketogenic diet may be extremely efficacious and associated with good general heath. Needless to say, their parents may not wish to stop the diet once they reach adulthood. Successful transition to adult epileptologists can be complicated, especially if the dietary therapies have proven to be the only acceptable way to achieve and maintain seizure control, and the adult neurologist is not familiar with how to manage this treatment. In addition, there are some long-term side effects of dietary therapies that should be included in the decision to continue diet treatment into adulthood, even though these concerns may not be fully recognized by some parents. In a series of 28 patients from Johns Hopkins Hospital on the ketogenic diet from 6 to 12 years, the most common long-term side effects were growth disturbance (82%), kidney stones (25%), and bone fractures (21%) [32]. Since these data were gathered, kidney stones are now prevented with the use of oral alkalinizing agents and encouraging fluids. Surprisingly, after 12 months on the diet, elevated cholesterol and triglycerides were normalized, mirroring past data [33]. Another study surveyed the 101 children who had discontinued the ketogenic diet a mean of 6 years prior [34]. Most of these children (or by then adults) reported good health with normal heights, weights, laboratory values, and without cardiac symptoms. Data from South Korea echoed these results in regards to catch-up growth in nearly all ketogenic diet patients within a year of treatment being discontinued [35]. Thus, growth disturbance is the most common proven long-term adverse effect of continued ketogenic diet therapy, but may resolve once the diet is stopped, provided that the diet is stopped while further growth is still possible. There are also some potential adverse effects of the ketogenic diet that are of uncertain prevalence. A study from Philadelphia in 2008 revealed an apparent decline in bone mineral density in children treated with the ketogenic diet over a 15-month period [36]. This led to concern in the ketogenic diet community, and the suggestion by many experts that Vitamin D, calcium, weight-bearing activities, and reduction of first-generation anticonvulsant drugs were very important for children on ketogenic diets. However, these suggestions are not universally accepted and a recent paper from Italy, albeit in only three children with GLUT-1 deficiency on the diet N5 years, noted no change in bone mineral content and density [37]. Lastly, the effects of dietary therapy on cardiac function are of concern due to the known short-term effects on lipid profiles. Two studies raised concern about the effects of the ketogenic diet on carotid distensibility (a marker of cardiovascular disease). The first study reported that carotid distensibility was significantly reduced in 23 children and adults treated with ketogenic diets compared to 20 control subjects with epilepsy without diet treatment [38]. None of the patients had symptoms of cardiac disease and the thickness of the coronary arteries was normal. The second study examined the carotid artery distensibility of 26 ketogenic diet patients after 12 months and 13 children after 24 months on the diet [39]. Similarly, distensibility but not arterial thickness decreased by 3 and 12 months of treatment. Surprisingly, by 24 months, distensibility had normalized, which suggests that this potentially negative effect was reversible. The chronic use of the ketogenic diet had no effects on valve velocity and function [40]. More studies are required to assess the true long-term effects of dietary therapy on cardiac function, especially for adults at higher risk. Hence, it is important to counsel families of older adolescents considering dietary therapy into adulthood about growth disturbance, bone density changes (albeit controversial), and cardiovascular abnormalities (still unknown). If the patient and family decide to continue the ketogenic diet, we believe that the ideal transition is to a center or physician with access to one of the growing number of adult epilepsy diet centers. These centers are motivated to keep patients on dietary therapy into adulthood. One study of 10 patients transitioning into adulthood on dietary therapy found a higher chance of continuing the diet if adolescents were referred to an adult epilepsy diet center versus

Please cite this article as: Nabbout R, et al, Treatment issues for children with epilepsy transitioning to adult care, Epilepsy Behav (2016), http:// dx.doi.org/10.1016/j.yebeh.2016.11.008

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a general adult neurologist or continuing in a pediatric ketogenic diet center [41]. 5. Rescue medications across age groups In the context of transition of children with epilepsy to adult care, there may be a need for reassessment of the value of “rescue” treatments for seizures. The concept is that selected patients with recurrent prolonged seizures or episodes of status epilepticus can have their seizures stopped in the community or at home. Patients who tend to have clusters of seizures may benefit from a rescue medication after a seizure. In addition, a few patients with predictable seizures may receive “prophylactic” medication to prevent seizures. Rescue medications were first introduced in children to control status epilepticus, prevent or stop prolonged seizures, and prevent clusters of breakthrough seizures. Prolonged seizures are relatively common in some epilepsy syndromes and of concern to families and physicians especially since they may evolve to status epilepticus. The first studies of rescue treatment involved rectal diazepam for acute repetitive seizures [42]. Next, a randomized trial for prolonged seizures in children suggested that buccal midazolam was at least as effective as rectal diazepam with a higher proportion of successfully stopped seizures (75% vs. 59%, p = ns) and a shorter time to response (average 6 min vs. 8 min, p = ns) [43,44]. In adults with serial seizures, two randomized trials were carried out at a single center for severe epilepsy. In one study, patients were randomized to rectal diazepam compared to placebo and in the other study oral diazepam was compared to placebo [45]. In both studies, there were statistically fewer recurrent seizures with diazepam than placebo. The response rate to rectal diazepam was 81% and oral diazepam 71% but since these were separate trials in patients with different characteristics, a comparison between the two routes of administration is not possible. Two studies suggested that oral clobazam was at least partially effective in adults with clustered seizures [46,47]. A meta analysis of 15 studies involving 1662 seizures in 1331 patients indicated that buccal and nasal midazolam had equal efficacy [48]. Finally, a large randomized trial of children and adults (n = 893) compared out-of-hospital administration of intramuscular midazolam versus intravenous lorazepam in patients with ongoing seizures [49]. The response rate for midazolam Table 2 First-line treatment for children, young people, and adults with prolonged or repeated generalized, convulsive (tonic–clonic, tonic or clonic) seizures in the community. From: NICE. 2012. https://www.nice.org.uk/guidance/cg137. • Give immediate emergency care and treatment to children, young people and adults who have prolonged (lasting 5 min or more) or repeated (three or more in an hour) convulsive seizures in the community. [2012] • Administer buccal midazolam as first-line treatment in children, young people and adults with prolonged or repeated seizures. Administer rectal diazepam if preferred or if buccal midazolam is not available. If intravenous access is already established and resuscitation facilities are available, administer intravenous lorazepam. [new 2012] • Only prescribe buccal midazolam or rectal diazepam or for use in the community for children, young people and adults who have had a previous episode of prolonged or serial convulsive seizures. [new 2012] • Treatment should be administered by trained clinical personnel or, if specified by an individually agreed protocol drawn up with the specialist, by family members or carers with appropriate training. [2004] • Care must be taken to secure the child's, young person's or adult's airway and assess his or her respiratory and cardiac function. [2004] • Depending on response to treatment, the person's situation and any personalized care plan, call an ambulance, particularly if: • the seizure is continuing 5 min after the emergency medication has been administered • the person has a history of frequent episodes of serial seizures or has convulsive status epilepticus, or this is the first episode requiring emergency treatment or • there are concerns or difficulties monitoring the person's airway, breathing, circulation or other vital signs. [new 2012]

was superior (73% vs. 63% p b 0.001). All of this information led to the 2012 NICE guideline shown in Table 2 [50]. As mentioned above, there are a few patients who can expect to have seizures at certain times. The most obvious group is women who have seizures at the time of menstruation (catamenial epilepsy). Clobazam 20–30 mg/day was superior to placebo in a double-blind cross-over study in 18 such patients [51]. Acetazolamide has been traditionally used for catamenial epilepsy, although the evidence for its efficacy is less well-established. Patients with reflex seizures (for example photosensitive seizures) may benefit from oral clobazam 10 mg before exposure to the provoking situation. This approach is pragmatic but has not been subjected to a randomized trial. Since pediatric patients coming to transition to adult care are very likely to have difficult-to-treat epilepsy with clusters of seizures or prolonged seizures, it is appropriate for many to continue rescue medications into adulthood. The existing evidence supports the concept that these rescue medications are equally effective in children and adults provided that the dose is adjusted for body weight. 6. Could we improve compliance with AED treatment? Adolescents and young adults are infamous for poor drug compliance (or adherence). The former US Surgeon General C. Everett Koop stated wisely “Drugs don't work in people who don't take them”. It is surprising that studies of compliance with a variety of medications have shown very similar results since the early 1990s. On average, people take 75% of medication as prescribed [52]. This has held true across many diseases and types of medications, no matter what the medication or potential adverse outcome of missed doses. There seems to be no consequence so severe that everyone with a given disorder takes every dose. Interestingly, overall intelligence is not related to good compliance [53]. Numerous studies show the ineffectiveness of health education. Many people have good knowledge about the link between disease control/management and medication, but still do not carry-through by taking all doses. In addition, attention to daily doses often decreases over time [54]. An essential step for successful transition from pediatric to adult care is for the adolescent to take responsibility for his/her medication. The main reason proposed for skipping doses of medications may be “forgetfulness” on a daily basis or during a disrupted schedule. This concept has led to the proposition of a simple system to teach individuals how best to take their medication (Medication Usage Skills for Effectiveness, MUSE) [55]. Only the person who is taking the medication can select the most convenient time and a personalized cue. The efficacy of this approach has been demonstrated in several studies; however, the person Table 3 Implications for transition. • Stiripentol, vigabatrin, and cannabidiol are examples of AEDs that are indicated for specific epilepsy syndromes but rarely used in adult care. Knowledge about their use in adults needs to increase. • Although AEDs for focal epilepsy are efficacious in both children and adults, a number of new treatments are being developed for childhood-onset epilepsy syndromes that will affect adult care. • Polytherapy is common for adolescents ready for transfer to adult care. Simplifying these complex AED regimes is an art. • There needs to be more opportunity for young adults to continue on the ketogenic diet even though there are uncertain long-term side effects. • Rescue medications are in wide use in pediatrics and may be continued in adulthood. • Adherence/compliance can be improved in adolescents. • Depression and anxiety disorders are likely under recognized in childhood-onset epilepsy but can be effectively treated. • Hyperactivity and aggression require careful assessment and treatment. • Social problems in adults with childhood-onset epilepsy are frequent and there are few proven interventions.

Please cite this article as: Nabbout R, et al, Treatment issues for children with epilepsy transitioning to adult care, Epilepsy Behav (2016), http:// dx.doi.org/10.1016/j.yebeh.2016.11.008

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must accept their diagnosis and need for treatment. Physicians and other healthcare providers need to specifically ask if the person is willing to take the medicine and only then proceed to teach them how to set time and personalized cues. A large part of medication compliance behavior is a personal commitment based on choice, coupled with acceptable tactics to do what is recommended. Diseases differ in requirements, ranging from one tablet daily for hypertension, to twice-daily dosing of many AEDs, or to exercise and insulin treatments for type 1 diabetes. People differ in their willingness to perform health-related tasks, which may change over time based on other priorities in their lives [56] and to make choices for which they are responsible, both actions and inactions. The available information suggests that the number of medications, knowledge of the disorder, cost of treatments, and other factors are not as important as a system for remembering to take doses. Of course, a larger number of daily doses increases the risk of forgetting doses [53]. When there are recurrent seizures or low AED blood levels, clinicians should consider teaching patients specific skills on how to improve medication management before altering doses or medications. The key is simply to ask the patient to identify a daily task that could be used as a reminder (cue) for each dose of medicine [55]. Cues may vary across different doses (AM, PM, and weekdays/weekends). At repeat visits, patients are asked how the cue(s) help them to remember doses. If not successful, the patient is asked to select another reminder. In order to be useful, cues must be selected by the patient, not the doctor, nurse or family. Cues may need to be adjusted over time because the perceived importance of taking the medication often diminishes over time. No technology is needed for this simple, easy-to-implement system but it likely needs to be carried out initially and then repeated during follow-up. Additional helpful techniques include transparent plastic 7-day pill boxes. Patients fill the box once a week and then take the doses daily. Seeing pills in yesterday's box indicates that doses were missed (personal data, J Cramer). Another approach is for the health care provider to check the dates of prescription refills to determine whether prescriptions are refilled as expected. This technique is likely less efficient than working with the patient directly but can point to individuals who need further work on selection of dose reminder cues and daily pill boxes.

7. Psychiatric and social aspects related to transition 7.1. Depression and anxiety are important in children with epilepsy Both children and adults with epilepsy are increasingly recognized as having cognitive, behavioral, and mental health co-morbidities that make important contributions to health and social function [57–60]. Several studies indicate that depression, anxiety, and attention problems can precede epilepsy by years. There is fairly convincing evidence that children with epilepsy have a high risk of depression [57,60]. A meta-analysis of the prevalence of depression in children with epilepsy identified 11 publications that reported prevalence between 4 and 40% [61]. The lowest rate was in a group of children with absence seizures. The majority of the other studies noted a prevalence between 20 and 30% with severity and duration of epilepsy being the most important determinants. A variety of neuroimaging data, especially fMRI studies, suggest that brain dysfunction in the limbic system contributes to the mental health problems, and may be sufficient under some conditions to cause significant depression or anxiety. For example, a study of adults with temporal lobe epilepsy found a close relationship between depression scores and the extent of magnetic resonance spectroscopic imaging abnormalities in the hippocampus [61]. Other variables did not predict depression including gender, duration of epilepsy and seizure frequency, number of AEDs, and work/driving social scale.

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Although the evidence is less well-developed in children compared to adults, systematic screening and early identification of mental health, behavioral, and cognitive problems should allow optimal interventions [62]. An observation study of adult neurologists seeing patients with epilepsy indicated that visits were very short (average 11.8 min) and a scant 30 s were devoted to issues of mood [63]. A simple screening questionnaire for depression is clearly needed to alert physicians to significant mood problems [62,64]. Screening can lead to important interventions. Treatment of depression with SSRI medications or cognitive behavioral therapy can show impressive improvements in mood over a few weeks [65]. There is no evidence that SSRIs exacerbate seizures and despite concerns, there is no clear evidence that any antidepressant increases the risk of suicide in children [66]. 7.2. Hyperactivity and aggressive behavior in childhood-onset epilepsy A prospective community-based study in children and adolescents with active epilepsy found that up to 40% have intellectual disabilities, one-third have attention deficit hyperactivity disorder (ADHD), and roughly 20% have autistic spectrum disorder [67]. Attention deficit hyperactivity disorder is 2 to 3 times more frequent in people with epilepsy compared to the general population and is usually characterized by more inattentive presentations and an equal male-to-female ratio [68]. A community-based survey in N1000 adult patients with epilepsy reported that ADHD-like symptoms are present in 1 out of 5 individuals and associated with depression, anxiety, drug-resistance, and poor quality of life [69]. The importance of ADHD should not be underestimated as 65% of children with a diagnosis of ADHD continue to be symptomatic during adulthood. In addition, ADHD is associated with an increased risk of alcohol and substance abuse, psychiatric hospitalizations, antisocial personality disorder, and mortality [70]. Diagnosis and management of aggressive behavior in epilepsy is often challenging. Aggressive behavior can occur post-ictally in the context of post-ictal psychoses where it has been reported in 23% of cases [71]. Aggressive behavior as an ictal phenomenon is extremely rare. Video-EEG studies document that ictal aggressive acts may sometimes appear orchestrated, but in reality they do not involve intricate skills or purposeful behaviors [72,73]. Five criteria have been suggested to determine whether a specific violent act was the result of an epileptic seizure: (a) an established diagnosis of epilepsy; (b) video-EEG documentation of epileptic automatisms; (c) video-EEG documentation of the aggressive behavior; (d) the aggressive act should be characteristic of the patient's habitual seizures; and (e) a clinical judgment should be made by the neurologist as to the possibility that the violent act was part of a seizure [74]. Available data clearly suggest that aggressive behavior in epilepsy is usually unrelated to seizures and nearly always occurs interictally. In patients with intellectual disabilities, aggressive behavior can be due to autistic spectrum disorder, poor frustration tolerance, or an AED side effect [75]. In patients with normal IQ it is important to identify an underlying psychiatric problem. According to the DSM-5, aggressive behavior is a key symptom of impulse-control or conduct disorders or the antisocial personality disorder. These disorders are all characterized by problems in emotional and behavioral self-control and often start during childhood. In impulsive control disorders, intermittent explosive disorder is of greatest concern. It is characterized by aggressive outbursts that should be impulse and/or anger based and must cause marked distress, cause impairment in either occupational or interpersonal functioning or be associated with negative financial or legal consequences. Antisocial personality disorder is defined by a pervasive pattern of disregard for the rights of other people that often manifests as hostility and/or aggression. It also starts during childhood with conduct disorder often a precursor. Similar to impulse control disorders, patients with antisocial personality disorder frequently act on impulsive urges without considering the consequences. A typical and

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distinguishing feature for antisocial personality disorder is the lack of genuine remorse for the harm they cause others. These patients become quite adept at feigning remorse when it is in their best interest to do so. It is not clear how often conduct disorder occurs in children with epilepsy. Antiepileptic drugs may deteriorate or trigger aggressive behavior in selected patients [76]. The association between aggressive behavior and the antiepileptic treatment should be well documented with a clear time relationship with the start/change of the drug. In addition, various risk factors may be pertinent including past psychiatric history, family psychiatric history, and alcohol and substance abuse [75]. Available data suggest that patients with epilepsy and ID are not generally more prone to develop psychiatric side effects of AEDs [77]; however, if patients have been disabled by frequent seizures and then suddenly become seizure-free without being sedated, the consequence may be an increased propensity to misbehave. This condition is known as the “release phenomenon” and can occur with several AEDs that are effective in controlling seizures with positive impact on cognition and less sedation. Management of aggressive behavior in epilepsy largely depends on the experience of the individual clinicians, as there is no single successful strategy and little pertinent literature. Carbamazepine and oxcarbazepine represent valuable options while GABAergic drugs should be avoided. In addition, valproate and lamotrigine may paradoxically decompensate impulsivity or aggressive behaviors especially in adolescents [75]. Atypical antipsychotics, particularly risperidone and aripiprazole, are effective in reducing irritability, stereotypy, and hyperactivity in patients with autistic spectrum disorder; however, metabolic adverse events, such as weight gain and dyslipidemia, need to be considered [78]. These medications are valuable options in patients with epilepsy as they are not associated with a significant increased risk of seizures [79]. 7.3. Identifying and intervening for social problems in adults with childhood onset epilepsy Significant social difficulties of adults with childhood-onset epilepsy have been noted in large case-controlled [80,81] and populationbased studies [82–84]. Those with intellectual disability (20% of all childhood-onset epilepsies) face special issues; however, 75% of those with normal intelligence have at least one serious adverse social problem, much greater than the general population. Reported social problems include: behavioral or psychiatric diagnoses, decreased education level, unemployment or underemployment, not being married, social isolation, and inadvertent pregnancy [82]. The Nova Scotia population-based cohort examined the social outcome of patients with childhood-onset epilepsy and normal intelligence at about age 30 years. Adverse social outcomes included no high school graduation, pregnancy outside a stable relationship lasting b 6 months, inability to name a single close friend, unemployment, a DSM psychiatric diagnosis other than ADHD, criminal conviction, never having a romantic relationship b3 months, and living alone [82]. Seventy-five percent of patients had ≥1 adverse social outcome with no difference between epilepsy syndromes except Rolandic epilepsy where the number of adverse outcomes was similar to the general population. Other studies have documented that long-term employment is unsatisfactory in up to 30–50% of adults with childhood-onset epilepsy [81,82]. Employment has been associated with normal IQ, diagnosis of epilepsy at N6 years of age, vocational education, seizure remission, and no episodes of status epilepticus. The Connecticut study documented that good seizure control and normal cognitive function predicted college education, employment, and having a driver's license. Childhood anxiety about peer/adult acceptance predicted unemployment [81–84]. The goal of a transition program is to allow as normal an adult outcome as possible. Are there any potential interventions to enhance the social environment of adolescents and young adults? Continuing care

by a physician with residency training in a “Med-Peds” program might be helpful [85]. This is a 4-year residency training program developed in the United States combining Pediatrics and Internal Medicine. Presently there are 75 Med-Peds programs with 8000 graduates who provide primary care in the community or as hospitalists for youth and young adults. Neuropsychological and psychological interventions for adolescents and adults with epilepsy were the subject of a Cochrane review [86]. Only two articles fulfilled criteria but both were of small sample size and differing methodologies, so Meta analysis was not possible. The review concluded that “No interventions were found that detail a means to help people with chronic or newly diagnosed epilepsy to manage their psychological problems.” Two publications about psychosocial outcome appear to establish the value of transition programs for youth with epilepsy. First, a tertiary Dutch transition clinic was described [87]. The first visit was a “carousel” of neurologist/psychologist, social worker, and educationalist/vocational counsellor followed by a multidisciplinary case-meeting. All patients had a comprehensive medical evaluation. Eighteen percent had a single visit followed by transfer to adult medical care, while 82% had 2–3 visits with 6 to 36 months of personalized advice and management. These interventions included advice about finances (2%), housing (9%), family support, separation, independence or identity (11%), social interaction and support (7%), psychological assistance (15%), education and vocational counsellor/training (15%), planning daily activities (27%), and social work assistance (39%). The following changes were noted: improved education/vocation (p = 0.01), evolution from unemployed (47%) to employment (63%), independence/separation/identity (p = 0.04) with 45% beginning to live independently from their parents with greater social participation. No change was reported for seizure frequency; however, there was less polytherapy, more patients stopped AEDs, and medication adherence improved. Second, the MOSES program (Efficacy of an Educational Treatment Program for patients with Epilepsy) was shown to improve social outcome [88]. MOSES includes a manual with nine units of ~ 14 lessons (60 min each). The units include: living with epilepsy, epidemiology, basic knowledge, diagnostics, therapy, self-control, prognosis, psychosocial aspects, and network. In a clinical trial at 22 centers in 3 countries, 242 youth and young adults were randomized to either the MOSES treatment group or a waiting list control group. Questionnaires were compared at randomization and 6 months after the educational course. Knowledge about epilepsy improved (p b 0.001) as did coping with epilepsy and communication with others (p b 0.004). There was no effect on epilepsy-specific measures or self-esteem but seizure outcome improved (p = 0.04), and more were satisfied with their therapy with fewer side effects (p = 0.014). Subjects noted high satisfaction with the MOSES intervention. It is possible to use the MOSES program in routine care in patients older than 15 years of age, regardless of epilepsy syndrome or the duration/severity of seizures. There are several interventions that have been shown to improve social outcome in people with ADHD or anxiety but without epilepsy. By extension, it is likely that these interventions could also be used for those with epilepsy. Attention deficit hyperactivity disorder has significant effects on long term social function. In a review of medication and parental social skills training programs for treatment of ADHD, 16 randomized trials involving N 5000 adolescents aged 12–18 years were included [89]. ADHD symptoms improved with extended-release methylphenidate, amphetamine, guanfacine, and atomoxetine. Psychosocial treatments incorporating behavior contingency, motivational enhancement, and academic, organizational, and social skills training techniques had inconsistent effects on ADHD symptoms but had benefit for academic and organizational skills. In a separate Cochrane review,11 randomized trials were reviewed that involved parent training of social skills for 5to 11-year-old children with ADHD as a standalone treatment or adjunct pharmacological treatment [90]. Unfortunately, there were no

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statistically significant effects either on social skills competences, teacher-rated general behavior, or on the ADHD symptoms. There were no similar trials in adolescents. A separate Cochrane review addressed medication for ADHD in adults. Randomized controlled clinical trials suggested that immediate-release methylphenidate or atomoxetine were efficacious [91]. A web-based program, Strongest Families Smart Website intervention (SFSW), could be a useful public health strategy for early intervention for child mental health problems [91]. This is a validated, effective intervention for mild to moderate disruptive behavior or anxiety in 4to 12-year-olds. It consists of an 11-session internet-assisted parent training program, weekly 45-minute telephone parental coaching of positive parenting strategies plus advice and the usual clinic standard care. A randomized trial compared the SFSW (n = 464) with a parental education program (n = 232) consisting of a brief internet introduction to positive parenting strategies and a single 45-minute call from a coach who provided positive parenting advice, plus standard clinical care [92]. The SFSW was found to be very effective. 8. Conclusion There is a tremendous revolution in our knowledge and treatment approaches in epilepsy. Implications for transition are summarized in table. Child epileptologists have been waiting for new drugs that are first tested in adults but now are beginning to see development of drugs and diets specific for pediatric-onset syndromes. In a perplexing way, these new approaches (drugs and diets) may be very unfamiliar to the adult physician who assumes the care responsibilities for adolescents and young adults with epilepsy. Pediatric epileptologists need to disseminate information about these specific therapies and to study their long-term effects and side effects. In addition, there is still much to do to improve the adherence/compliance behaviors in adolescents and young adults with epilepsy. As well, their psychiatric and social issues need to be more vigorously pursued. Transition clinics represent a unique opportunity to improve epilepsy care in adolescents and young adults to prevent morbidity and to promote independence and adherence to treatment. An efficient transition clinic should aim to identify and treat early-onset psychiatric and behavioral problems associated with epilepsy. Intellectual disability and major psychiatric problems complicate transition and suggest the need for close collaboration between neurologists, psychiatrists, residential home staff, and other professionals Table 3. Deciding when a young person is ready for transition has been made easier by several questionnaires such as the TRAQ scale [93]. Published generic transition programs for many chronic diseases of childhood would seem to be very useful as children with epilepsy “take charge” of their illness and personal health decisions and find their way to adult care. Conflict of interest Authors declare no conflict of interest. Acknowledgments We are grateful for the contribution of Dr. Frank Gillam to the section on Depression and Anxiety. This symposium was in part supported by an unrestricted educational grant from SHIRE. References [1] Camfield PR, Camfield CS, Busiah K, Cohen D, Pack A, Nabbout R. The transition from pediatric to adult care for youth with epilepsy: basic biological, sociological, and psychological issues. Epilepsy Behav 2016 this issue.

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Please cite this article as: Nabbout R, et al, Treatment issues for children with epilepsy transitioning to adult care, Epilepsy Behav (2016), http:// dx.doi.org/10.1016/j.yebeh.2016.11.008