What Do We Need to Know About Transition/Transfer Programs and What Sort of Research Will Answer the Questions?

Despite an increasing literature, there are many unanswered questions about transition to adult care for youth with chronic disorders. This paper questions the definition and components of optimal transition programs, their effectiveness and costs. Few transition programs have been comprehensively evaluated and effectiveness studies are usually based on a historical control group. Transition clinics for neurological disorders are described but not evaluated. Studies in diabetes, renal transplant, and rheumatologic disorders provide the best available evidence, albeit limited, of the value of transition clinics/programs. A few studies have addressed the cost of transition clinics and suggest that the incremental costs of the clinic are recouped by reduced medical costs in adult care. There is room for a great deal more research about transition.

Self-reported quality of life and degree of youth-parent agreement: A long-term follow-up of childhood-onset epilepsy.

OBJECTIVE: To prospectively delineate self-reported health-related quality of life (HRQOL) of adolescents and young adults (AYAs) 8 and 10 years after an epilepsy diagnosis and evaluate the degree of AYA-parent agreement in ratings of AYA's HRQOL. METHODS: Data came from the Health-Related Quality of Life in Children with Epilepsy Study (HERQULES), a 10-year longitudinal study of children, aged 4-12 years, with newly diagnosed epilepsy. Epilepsy-specific HRQOL was self-reported by AYA 8 and 10 years after diagnosis and by parents at multiple time points throughout the 10-year follow-up. Measurers of HRQOL over time were analyzed using a linear mixed-effect model approach. AYA-parent agreement was evaluated using intraclass correlation coefficient (ICC) and Bland-Altman plots. RESULTS: A total of 165 AYAs participated at long-term follow-up. There was considerable heterogeneity among AYA's HRQOL, and as a group, there was no significant change in HRQOL from the 8- to 10-year follow-up. Household income at the time of diagnosis, seizure control at follow-up, and a history of emotional problems (anxiety/depression) were independent predictors of HRQOL at follow-up. AYA-parent agreement on AYA's HRQOL was moderate (ICC 0.62, 95% CI 0.51-0.71), although considerable differences were observed at the individual level. AYA-parent agreement varied with AYA's and parent's age, seizure control, and family environment. SIGNIFICANCE: In the long-term after a diagnosis of epilepsy, AYAs report stable HRQOL over time at the group level, although notable individual differences exist. Seizure control, anxiety/depression, and family environment meaningfully impact AYA's long-term HRQOL. AYA and parent reports on HRQOL are similar at the group level, although they cannot be used interchangeably, given the large individual differences observed.

Trajectories of quality of life 10 years following a diagnosis of epilepsy in childhood.

OBJECTIVE: This study estimated trajectories of health-related quality of life (HRQOL) over a 10-year period among children newly diagnosed with epilepsy. We also modeled the characteristics of children, parents, and families associated with each identified trajectory. METHODS: Data came from the HERQULES (Health-Related Quality of Life in Children With Epilepsy Study), a Canada-wide prospective cohort study of children (aged 4-12 years) with newly diagnosed epilepsy. Parents reported on their children's HRQOL at diagnosis, and at 0.5-, 1-, 2-, 8-, and 10-year follow-ups using the Quality of Life in Childhood Epilepsy Questionnaire-55. Trajectories of HRQOL were identified using latent class growth models. Characteristics of children, parents, and families at the time of diagnosis that were associated with each trajectory were identified using multinomial logistic regression. RESULTS: A total of 367 children were included. Four unique HRQOL trajectories were identified; 11% of the cohort was characterized by low and stable scores, 18% by intermediate and stable scores, 35% by intermediate scores that increased then plateaued, and 43% by high scores that increased then plateaued. Absence of comorbidities, less severe epilepsy, and better family environment (greater satisfaction with family relationships and fewer family demands) at the time of diagnosis were associated with better long-term HRQOL trajectories. Although the analyses used estimates for missing values and accounted for any nonrandom attrition, the proportion of children with poorer HRQOL trajectories may be underestimated. SIGNIFICANCE: Children with new onset epilepsy are heterogenous and follow unique HRQOL trajectories over the long term. Overall, HRQOL improves for the majority in the first 2 years after diagnosis, with these improvements sustained over the long term.

Childhood epilepsy with a small number of seizures may be left untreated: an international prospective study.

It is unknown whether treatment with antiepileptic drugs in children with epilepsy with a presumed good prognosis is always necessary. We aimed to study the course of newly diagnosed epilepsy in children with a presumed good prognosis who are managed without AED treatment. A total of 151 children (one month to 12 years of age) with two to five lifetime unprovoked seizures (excluding febrile convulsions), were followed for three years. Treatment was initially withheld. Children with symptomatic epilepsy, or absence or myoclonic epilepsy, were excluded. AED treatment was started after >10 lifetime seizures or an episode of status epilepticus during follow-up, or if the parents or treating physician deemed it otherwise necessary. During follow-up, 113 children continued to meet our criteria for refraining from treatment with antiepileptic drugs, yet 30 started treatment at the request of the parents. Thirty-eight children at some time met the criteria to start treatment, but the parents of 16 declined treatment. In all, 99 (66%) children maintained the no-treatment regime. Ninety-eight children (65% of 151) reached terminal remission for at least one year, including 83 who did not receive antiepileptic drug treatment (84% of the untreated 99). Mean terminal remission was significantly longer in the group with a total of <10 seizures compared to those with >10 seizures. Treatment did not increase the length of terminal remission. Adverse events, including traumatic injury, occurred equally in the treated and untreated children. Measures of quality of life suggested a better outcome in those without treatment. Children with newly diagnosed epilepsy with a presumed good prognosis may not need immediate AED treatment. Postponing treatment does not alter the chance of remission or the risk of accidents and adverse events and appears to be associated with a good quality of life.

Regression in children with epilepsy.

Regression in children with epilepsy may involve loss of cognitive abilities, failure to progress or a slowing of developmental trajectory. A few seizures do not lead to regression. Large numbers of seizures may be associated with regression but the cause is an important cofounder. Individual spike discharges on EEG are associated with transient cognitive impairment and continuous spike discharges with regression. Regression may be global in continuous spike wave in slow sleep (CSWS) or specific (auditory agnosia) in Landau Kleffner syndrome. Regression is mild and transient in Rolandic Epilepsy or profound and permanent in West Syndrome. Epilepsy syndromes grouped under "epileptic encephalopathies" may lead to regression, although proof of this concept is not strong for many syndromes. The absence of cognitive assessment before epilepsy onset, the contribution of the cause and complications of treatment make for difficult methodological problems. The large majority of children with epilepsy do not have regression. There is need for more longitudinal studies of children with epileptic encephalopathies and other epilepsies associated with regression.

Cognitive Disabilities and Long-term Outcomes in Children with Epilepsy: A Tangled Tail.

Cognitive problems ranging from mild specific learning problems to profound intellectual disability (ID) are very common in children with epilepsy. For most affected patients there is good evidence that the cognitive problems are present at the onset of seizures and do not deteriorate over time. There is no evidence that a few seizures lead to cognitive deterioration. An exception may occur in children with epileptic encephalopathies, although this contention is not always easy to prove. ID is a strong predictor of intractable epilepsy, and the greater the degree of the ID the greater the risk of medication resistant epilepsy. It is not known if specific learning disorders are associated with more severe epilepsy. Rolandic epilepsy is unusual because possibly one-third of patients have transient cognitive and behavioral difficulties during the active phase but later have normal adult social outcome. More longitudinal studies with baseline and repeated cognitive assessments are needed to fully understand the relationship of cognitive problems to childhood onset epilepsy.

Epilepsy as a Network Disorder (1): What can we learn from other network disorders such as autistic spectrum disorder and mood disorders?

Epilepsy is a neurologic condition which often occurs with other neurologic and psychiatric disorders. The relation between epilepsy and these conditions is complex. Some population-based studies have identified a bidirectional relation, whereby not only patients with epilepsy are at increased risk of suffering from some of these neurologic and psychiatric disorders (migraine, stroke, dementia, autism, depression, anxiety disorders, Attention deficit hyperactivity disorder (ADHD), and psychosis), but also patients with these conditions are at increased risk of suffering from epilepsy. The existence of common pathogenic mechanisms has been postulated as a potential explanation of this phenomenon. To reassess the relationships between neurological and psychiatric conditions in general, and specifically autism, depression, Alzheimer's disease, schizophrenia, and epilepsy, a recent meeting brought together basic researchers and clinician scientists entitled "Epilepsy as a Network Disorder." This was the fourth in a series of conferences, the "Fourth International Halifax Conference and Retreat". This manuscript summarizes the proceedings on potential relations between Epilepsy on the one hand and autism and depression on the other. A companion manuscript provides a summary of the proceedings about the relation between epilepsy and Alzheimer's disease and schizophrenia, closed by the role of translational research in clarifying these relationships. The review of the topics in these two manuscripts will provide a better understanding of the mechanisms operant in some of the common neurologic and psychiatric comorbidities of epilepsy.

Intractable seizures after a lengthy remission in childhood-onset epilepsy.

OBJECTIVES: To establish the risk of subsequent intractable epilepsy after ≥2, ≥5, and ≥10 years of remission in childhood-onset epilepsy. METHODS: From the Nova Scotia childhood-onset epilepsy population-based cohort patients with all types of epilepsy were selected with ≥20 years follow-up from seizure onset (incidence cases). Children with childhood absence epilepsy were excluded. The rate of subsequent intractable epilepsy was then studied for patients with ≥5 years remission on or off AED treatment and compared with the rate for those with ≥2 and ≥10 years of remission. RESULTS: Three hundred eighty-eight eligible patients had ≥20 years follow-up (average 27.7 ± (standard deviation) 4 years) until they were an average of 34 ± 6.5 years of age. Overall, 297 (77%) had a period of ≥5 years of seizure freedom (average 21.2 ± 8 years), with 90% of these remissions continuing to the end of follow-up. Seizures recurred in 31 (10%) and were intractable in 7 (2%). For the 332 with a remission of ≥2 years seizure-free, 6.9% subsequently developed intractable epilepsy (p = 0.001). For the 260 with ≥10 years remission, 0.78% subsequently developed intractable epilepsy (p = 0.25 compared with ≥5 years remission). SIGNIFICANCE: Even after ≥5 or ≥10 years of seizure freedom, childhood-onset epilepsy may reappear and be intractable. The risk is fortunately small, but for most patients it is not possible to guarantee a permanent remission.

Understanding Death in Children With Epilepsy.

Death in children with epilepsy is profoundly disturbing, with lasting effects on the family, community, and health care providers. The overall risk of death for children with epilepsy is about ten times that of the general population. However, the risk of premature death for children without associated neurological comorbidities is similar to that of the general population, and most deaths are related to the cause of the epilepsy or associated neurological disability, not seizures. The most common cause of seizure-related death in children with epilepsy is sudden unexpected death in epilepsy (SUDEP). SUDEP is relatively uncommon in childhood, but the risk increases if epilepsy persists into adulthood. Although the direct cause of SUDEP remains unknown, most often death follows a generalized convulsive seizure and the risk of SUDEP is strongly related to drug-resistant epilepsy and frequent generalized tonic-clonic seizures. The most effective SUDEP prevention strategy is to reduce the frequency of seizures, although a number of seizure detection devices are under development and in the future may prove to be useful for seizure detection for those at particularly high risk. There are distinct benefits for health care professionals to discuss mortality with the family soon after the diagnosis of epilepsy. An individual approach is appropriate. When a child with epilepsy dies, particularly if the death was unexpected, family grief may be profound. Physicians and other health care professionals have a critical role in supporting families that lose a child to epilepsy. This review will provide health care providers with information needed to discuss the risk of death in children with epilepsy and support families following a loss.

Treatment issues for children with epilepsy transitioning to adult care.

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.

The transition from pediatric to adult care for youth with epilepsy: Basic biological, sociological, and psychological issues.

Transition from pediatric to adult health care for adolescents with epilepsy is challenging for the patient, family, and health care workers. This paper is the first of three that summarize the main findings from the 2nd Symposium on Transition in Epilepsies, held in Paris from June 14-25, 2016. In this paper we describe five basic themes that have an important effect on transition. First, there are important brain changes in adolescence that leave an imbalance between risk taking and pleasure seeking behaviors and frontal executive function compared with adults. Second, puberty is a major change during the transition age. The three most important but separate neuroendocrine axes involved in puberty are gonadarche (activation of the gonads), adrenarche (activation of adrenal androgen production), and activation of the growth hormone-insulin like growth factor. Third, sexual debut occurs during the transition years, and at an earlier age in adolescents with epilepsy than controls. Adult sexual performance is often unsatisfactory. Although AED-induced alterations in sexual hormones and temporal lobe epilepsy may play a role in hyposexuality, depression, anxiety, and other social factors appear most important. Fourth, psychological development is very important with an evolution from an early stage (ages 10-13years) with concrete thinking, to a middle stage (ages 14-17) with analytic and more abstract introspective thinking, and then to a late stage (ages 18-21) with at least the beginnings of adult reasoning. Epilepsy may derail this relatively orderly progression. Adolescents with autistic spectrum disorder may present with severe behavior problems that are sometimes related to undiagnosed epilepsy. Fifth, bone health in adolescence is critical to establish adequate mineralization for all of adult life. While AED interference with Vitamin D metabolism is important, there is evidence that the effects of AEDs on bone are more complex and involve changes in remodeling. Hence, some non-inducing AEDs may have a significant effect on bone health. All five of these themes lead to recommendations for how to approach adolescents and young adults during transition and some specific interventions to achieve maximum long-term adult independence and quality of life.

Poor versus rich children with epilepsy have the same clinical course and remission rates but a less favorable social outcome: A population-based study with 25 years of follow-up.

OBJECTIVE: To explore the influence of several estimates of family socioeconomic status on the long-term clinical course and social outcomes of children with epilepsy. METHODS: The Nova Scotia childhood epilepsy cohort is population based and includes all children in this Canadian province who developed epilepsy between 1977 and 1985. Eligible patients had ≥10 years of follow-up. Children with childhood absence epilepsy were excluded. Total family income at seizure onset was assessed at seizure onset and classified as "poor" (first quintile), "adequate" (second to third quintiles), and "well-off" (fourth to fifth quintiles). We also assessed parental education and home ownership. Social outcome was assessed in those with normal intelligence who were ≥18 years of age at the end of follow-up using a semistructured interview that explored eight adverse effects. RESULTS: Of 584 patients, 421 (72%) were included. Average follow-up was 26 ± 5.6 years. Overall 137 families (33%) had "poor" income, 159 (38%) had "adequate income," and 125 (30%) were "well-off." Terminal remission of epilepsy occurred in 65% of the poor, 61% of the adequate, and 61% of the well-off (p = ns). Intractable epilepsy, status epilepticus, number of antiepileptic drugs (AEDs) used, and the number of generalized tonic-clonic or focal with secondary generalization seizures through the clinical course was the same in all groups. Home ownership did not predict remission. Neither paternal nor maternal education was associated with remission. Poor children had significantly more adverse social outcomes including failure to graduate from high school, unemployment, personal poverty, inadvertent pregnancy, and psychiatric diagnoses. SIGNIFICANCE: In Nova Scotia with universal health care, coming from a poor or more affluent family does not seem to affect the clinical course or long-term seizure outcome of childhood epilepsy. Unfortunately children from poor families are less likely to have a good social outcome.

Helping Families Cope with the Severe Stress of Dravet Syndrome.

A child with Dravet syndrome shakes family life to the core. Dravet syndrome usually has three phases: (1) up to 1-1½ years: with episodes of febrile status epilepticus but normal development; (2) age 1½ to ~6-10 years: with frequent seizures of varying types, developmental stagnation, behavioural and sleep problems; (3) after ~10 years: improvement in seizures, deteriorating gait, intellectual disability but some developmental gains. Complete seizure control is rare-simply prescribing medication is inadequate to help families. Based on structured interviews with 24 families and confirmed by more informal discussions with other families, we suggest strategies for coping with this catastrophe. A child with Dravet syndrome usually means that one parent cannot work-financial pressures should be anticipated. In Stage 1, the approach to status should include a written protocol. An indwelling catheter for rapid venous access may be helpful. In Stage 2, assistance finding qualified babysitters is required, and the extended family needs encouragement to help. Appropriate equipment, rescue medication and protocols should travel with the child. Siblings may benefit from a system of one parent "on call." An internet support group provides an invaluable lifeline. In Stage 3, family isolation may be extreme-respite care and personal time for parents are important. Death from status, accidents and SUDEP (sudden unexplained death in epilepsy) occurs in 15%. Fear of SUDEP needs to be addressed. Moving from paediatric to adult care is frightening; an epilepsy transition clinic is useful. Attention to these realities may improve the quality of life for both child and family.

What do epileptologists recommend about discontinuing antiepileptic drugs for a second time in children?

OBJECTIVE: There is a broad consensus that antiepileptic drugs (AEDs) may be withdrawn after two years of seizure freedom for most children with epilepsy. If seizures recur and are, again, completely controlled with AEDs, little is known about discontinuing a second time. We surveyed American and Canadian pediatric epileptologists to understand their current practice. METHODS: In 2014, a survey was sent via e-mail to 193 pediatric epileptologists to learn about AED discontinuation practices in children. The survey asked direct questions about practice and posed five "real-life" cases where the decision to discontinue might be difficult. Participants were identified through membership lists of several US and Canadian epilepsy organizations. RESULTS: There were 94 (49%) completed surveys. Sixty-three participants had ≥ 10 years in practice ("more experienced": mean 23 ± 9 years), and 31 had < 10 years ("less experienced": mean 6 ± 2 ). Overall, 62% recommended AED discontinuation for the first time after 2-3 years of seizure freedom, and 61% recommended discontinuation for the second time after 2-3 years. Fifty-six percent of "more experienced" clinicians required a longer seizure-free period prior to a second discontinuation (p < 0.001) compared with 26% of "less experienced" clinicians (p = ns). Overall, most participants suggested an AED taper duration of 2-6 months for the first and second attempts, 52% and 68%, respectively. Both groups wean AEDs more slowly during the second attempt (p < 0.001). There was only 40-60% agreement among participants to discontinue AEDs in four of the cases. CONCLUSION: Nearly half (46%) of pediatric epileptologists require a longer seizure-free period the second time they attempt to discontinue AEDs compared with the first attempt and wean down AEDs somewhat more slowly. Although a variety of factors influence decision-making, there was a high level of disagreement to discontinue AEDs a second time in "real-life" cases.

Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+).

To review the literature about febrile seizures and GEFS plus with special emphasis on management and outcome. Selected literature review. Febrile seizures are the most common convulsive event in humans, occurring in 2-6% of the population. The aetiology is complex with strong evidence for a heterogeneous genetic predisposition interacting with fever of any cause, with certain viral infections having a greater effect. A large amount of literature has established that febrile seizures have no long-term consequences on cognition or behaviour. Unfortunately, about 40% of children with a first febrile seizure will have a recurrence. The strongest predictor of recurrence is age <14-16 months at the time of the first febrile seizure. Epilepsy follows febrile seizures in ∼3% cases, with the concepts of simple and complex febrile seizures providing relatively weak prediction. Very prolonged febrile seizures may lead to mesial temporal sclerosis and temporal lobe epilepsy although the degree of risk remains uncertain. Investigations beyond establishing the cause of the provoking fever are nearly always unnecessary. Treatment is mainly reassurance and there is some evidence that parents eventually "come to grips" with the fear that their children are dying during a febrile seizure. Antipyretic medications are remarkably ineffective to prevent recurrences. Daily and intermittent prophylactic medications are ineffective or have unacceptable side effects or risks. "Rescue" benzodiazepines may prevent prolonged recurrences for selected patients with a first prolonged febrile seizure although this has not been proven. Genetic epilepsy with febrile seizures plus (GEFS+) is a complex autosomal dominant disorder usually caused by mutations in SCN1A (a voltage-gated sodium channel). One third of patients have febrile seizures only; two thirds have a variety of epilepsy syndromes, both focal and generalized. Febrile seizures may distress parents but rarely have any long-term consequences. Reassurance is the only treatment for the vast majority. Identifying patients with GEFS plus may lead to further investigations and counselling.

Injuries from seizures are a serious, persistent problem in childhood onset epilepsy: a population-based study.

PURPOSE: Document the frequency, types and risk factors for injuries caused by seizures for people with childhood onset epilepsy. METHOD: We contacted patients with all types of epilepsy except childhood absence from the Nova Scotia Childhood Epilepsy population-based cohort. Seizure onset was between 1977 and 1985. Patients and parents were asked about serious injuries resulting from a seizure, defined as severe enough for an urgent physician or dentist visit. RESULTS: Of 595 eligible patients, we contacted 472 (79%). During an average follow up of 23.9 ± 8 years, 52 (11%) experienced ≥1 serious injury for a total of 81 injuries. Of all injuries, 24 (30%) were lacerations requiring sutures, 15 (19%) fractures, 11 (14%) broken teeth, 8 (10%) concussions, 4 (5%) burns, and 20 (25%) other. "Other" included 1 fatal drowning, 2 near-drownings, 3 shoulder dislocations and 1 severe eye injury. Four injuries occurred with the first seizure; all others after a long gap from seizure onset (range 1.5-30 years). Injuries occurred in all epilepsy syndromes, most commonly with symptomatic generalized epilepsy (17% vs. 11% p = 0.03) and intractable epilepsy (28% vs. 8% p<0.0001). Most injuries occurred during normal daily activities and were judged not to be easily preventable. CONCLUSIONS: During ∼24 years of follow up 1 out of 10 patients with childhood onset epilepsy had a serious injury as the result of a seizure. Most injuries occurred years after the initial diagnosis and were more common when seizures were more frequent. The only practical solution to injury prevention is better seizure control.

Incidence, prevalence and aetiology of seizures and epilepsy in children.

AIM: To (1) summarize published, peer-reviewed literature about the incidence and prevalence of epilepsy in children from developed and developing countries around the world, and (2) discuss problems in defining aetiologies of epilepsy in children, and distinguish between seizures and epilepsy. METHODS: Review of selected literature with particular attention to systematic reviews. RESULTS: The incidence of epilepsy in children ranges from 41-187/100,000. Higher incidence is reported from underdeveloped countries, particularly from rural areas. The incidence is consistently reported to be highest in the first year of life and declines to adult levels by the end of the first decade. The prevalence of epilepsy in children is consistently higher than the incidence and ranges from 3.2-5.5/1,000 in developed countries and 3.6-44/1,000 in underdeveloped countries. Prevalence also seems highest in rural areas. The incidence and prevalence of specific seizure types and epilepsy syndromes is less well documented. In population-based studies, there is a slight, but consistent, predominance of focal seizures compared with generalized seizures. Only about one third of children with epilepsy can be assigned to a specific epilepsy syndrome, as defined by the most recently proposed system for organization of epilepsy syndromes. CONCLUSIONS: The incidence and prevalence of epilepsy in children appears to be lower in developed countries and highest in rural areas of underdeveloped countries. The reasons for these trends are not well established. Although focal seizures predominate, the incidence and prevalence of specific epilepsy syndromes is not well documented.