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Journal of the Formosan Medical Association (2015) xx, 1e8
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
REVIEW ARTICLE
Comorbidity of childhood epilepsy Shu-Hao Wei a, Wang-Tso Lee b,c,* a
Department of Pediatrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan c College of Medicine, National Taiwan University, Taipei, Taiwan b
Received 13 September 2012; received in revised form 2 July 2015; accepted 2 July 2015
KEYWORDS children; comorbidity; epilepsy
Abstract Epilepsy in children is occasionally associated with variable comorbidities although the frequency of such comorbidity is often difficult to determine. They can be divided into three categories: neurological, psychological, and physical comorbidities. The goal of the present review is to discuss the reported comorbidities of epilepsy in children. The possible mechanisms and associated risk factorsdincluding the effect of seizure frequency and seizure control, types of epilepsy, age of seizure onset, duration of illness, and the possible detrimental effect of antiepileptic drugsdwill be described. Copyright ª 2015, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
Introduction Epilepsy is the most common childhood neurologic disorder, affecting 0.5e1.0% of children younger than 16 years.1 Population-based studies show that 70e76% of children with epilepsy have some types of disability or handicap affecting their daily life and choices for the future.2,3 Epilepsy in children is associated with variable comorbidities although the frequency of such comorbidities is often difficult to determine. This article reviews the current knowledge of comorbidities in children with epilepsy, and
Conflicts of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. Department of Pediatrics, National Taiwan University Hospital, Number 8, Chung-Shan South Road, Taipei 100, Taiwan. E-mail address:
[email protected] (W.-T. Lee).
divides them into three categories: neurological, psychological, and physical comorbidities (Table 1). The possible mechanisms and associated risk factors, including seizure frequency and seizure control, types of epilepsy, age of onset, duration of illness, and antiepileptic drugs (AEDs), will be discussed.
Neurological comorbidities Many factors may contribute to the development of neurological morbidities in children with epilepsy,4 such as the detrimental effects of chronic seizures on brain development, the medications used to treat seizures, and possibly an independent effect of the physiological disturbances that predispose the brain to seizures. Neurological comorbidities in children with epilepsy are variable, including cognitive impairment, language impairment, migraine, and sleep problems. We will discuss these issues in the following sections.
http://dx.doi.org/10.1016/j.jfma.2015.07.015 0929-6646/Copyright ª 2015, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
Please cite this article in press as: Wei S-H, Lee W-T, Comorbidity of childhood epilepsy, Journal of the Formosan Medical Association (2015), http://dx.doi.org/10.1016/j.jfma.2015.07.015
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S.-H. Wei, W.-T. Lee Table 1
Comorbidities of epilepsy in children.
Neurological comorbidities
Psychological comorbidities
Physical comorbidities
Cognitive impairment Language impairment Migraine & headache Sleep problems
Autism spectrum disorders Attention deficit/hyperactivity disorder Mood disorders (anxiety and depression) Psychosocial & familial problems Rare: psychosis, oppositional defiant or conduct disorders, & tic disorders
Bone loss Immunological disturbances Retardation of body height growth Hypothyroidism Polycystic ovary syndrome Body weight changes Dyslipidemia Carnitine deficiency
Cognitive impairment The association between mental retardation and epilepsy has been well described in the literature.5 Children with epilepsy had high rates of grade retention and placement in special education compared with sibling controls.6 Several population-based prevalence studies of children with epilepsy reported that intellectual disability (full-scale intelligence quotient < 70) was the most common comorbidity (30e40%).7 However, the long-term risk of learning problems exists even in those with normal IQs and wellcontrolled seizures.6 Moreover, in a follow-up study the cognitive deficits associated with childhood-onset epilepsy, despite the duration of epilepsy, may remain consistent to 60 years of age.8 The various epilepsy syndromes of childhood differ greatly in terms of cognitive outcome. Children with infantile spasms and Dravet syndrome (severe myoclonic epilepsy in infancy) usually have long-term cognitive and behavioral problems.9 LennoxeGastaut syndrome is also associated with a poor prognosis in children.10 Although “benign epilepsy” is supposed to have better prognosis in children, absence epilepsy has been reported to have an increased risk for neurocognitive impairment.11 Some studies in the past also showed that children with symptomatic generalized epilepsy had a lower full-scale intelligence quotient than those with idiopathic generalized epilepsy and focal epilepsy,12 and temporal lobe epilepsy specifically had much worse memory function than frontal lobe epilepsy and childhood absence epilepsy.13 Many factors of childhood epilepsy may contribute to the development of cognitive impairment in children. Children with epilepsy and abnormal electroencephalograms scored lower than those with normal electroencephalograms on reading and spelling measures, even with comparable IQs.6 Young age at onset, symptomatic cause, epileptic encephalopathy, and continued treatment of AEDs were also reported to be independently associated with cognitive outcome.14,15 Older AEDs (prior to1990), such as phenobarbital, can produce greater cognitive impairment. However, carbamazepine, phenytoin, and valproic acid (VPA) are comparable in their cognitive effect.16 Among the new AEDs, topiramate is reported to be significantly associated with memory and cognitive problems,17 and the frequency of side effects in cognition is dose-related.18 Oxcarbazepine,19 lamotrigine,20 and levetiracetam21 are found to have no or few adverse effects on cognition. Careful
selection of AEDs, avoiding polytherapy, slow titration, and using the lowest effective AED dose are reported to decrease the cognitive side effects of AEDs in children with epilepsy.16
Language impairment The language impairment in children with epilepsy may arise from a number of factors, including underlying neuropathology, the impact of seizures on the developing brain, the development of cognition, and the severity of epilepsy in children.22 The occurrence of speech disorders may be as high as 27.5% in children with epilepsy.5 Compared with their siblings, children with epilepsy may also have significantly lower language scores in word knowledge, category fluency, and response to commands of increasing length and complexity,23 especially in those with an earlier age of onset. Some epileptic syndromes have been well documented in association with language impairment. The LandaueKleffner syndrome (LKS) and the epilepsy with continuous spike waves during slow-wave sleep (CSWS) share several common features: both are age-related, first appear in childhood, and are characterized by mild epilepsy associated with severe neuropsychological dysfunction. Language disorders in LKS mainly involve comprehension with preservation of nonverbal intellectual functions.24 Children with LKS have a variable prognosis. Some regain speech and others have permanent speech impairment.9 By contrast, language disorders associated with CSWS are predominant in the areas of lexical and grammatical judgment, whereas comprehension is spared. Patients in remission and those in an active phase of CSWS have the same language impairment profiles.25 Children with benign epilepsy with centrotemporal spikes, which is now recognized as lying on a spectrum with the LKS, may also have the comorbidity of mild language impairment, mainly with oromotor performance and auditory discrimination, including poor tongue movements and articulation, and worse performance on dichotic listening.26
Migraine The links between epilepsy and migraine have long been known but have been incompletely understood. Both are believed to result from brain hyperexcitability, and the therapeutic agents effective for each disorder may
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Comorbidity of children with epilepsy
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overlap.27 Migraine and epilepsy are highly comorbid and individuals with each disorder are more than twice as likely to have the other.28 Stevenson29 reported a higher prevalence of migraine in children with epilepsy (14.7%) than in the general population (2.7e11%). Children with epilepsy had a 4.5-fold increased risk of developing migraine headache than tension-type headache.30 The headaches usually start in the same year or after the diagnosis of epilepsy and occur mostly in children older than 10 years with idiopathic epilepsy.31 Specifically, a strong association of epilepsy with rolandic paroxysms and migraine in children has been reported.32 A controlled study revealed that migraine was more prevalent in children with benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy.33
which is estimated to be w20e25% of the whole spectrum.43 However, the prevalence of ASD in children with epilepsy is rarely reported, and varies depending on age, types of epilepsy, and method of evaluation. In a questionnaire-based study, as high as 32% of children fit the criteria of autism screening questionnaires for having ASD.44 Most of them had not been previously diagnosed. The children identified as being at risk of having ASD have right temporal lobe lesions,45 worse behavior, daytime sleepiness, and a younger mean age of seizure onset, at w2 years of age.44 The high correlation between ASD, neurologic dysfunction, and epilepsy suggests an underlying encephalopathy presenting with a combination of neurologic abnormalities, including clinical epileptiform activity.46
Sleep problems
ADHD
It has been reported that children with epilepsy have significantly more sleep problems,34 including parasomnias, parent/child interaction during the night, sleep fragmentation, daytime drowsiness, and bedtime difficulties.35 Children with seizures also have more sleep problems than seizure-free children.35 Evidence suggests that both the occurrence of seizures and AEDs are associated with significant sleep disruption. Persistent daytime drowsiness in children with epilepsy is not always due to the side effects of AEDs and may arise from sleep fragmentation.36 Children with epilepsy have longer stage 1 sleep percentage and latency to rapid eye movement (REM) sleep compared with controls.37,38 It is also found that REM latency, length of apnea, and periodic leg movement in children with epilepsy correlated with depression, inattentiveness and hyperactivity, and/or oppositional behavior.37 It is reported that continuous positive airway pressure treatment of obstructive sleep apnea, which is a specific type of sleep disorder, and more comorbid in children (20%) than in adults (10%) with epilepsy, improves seizure control, cognitive performance, and quality of life.38 Moreover, a particular pattern of association has been found between nocturnal frontal lobe epilepsy and non-REM arousal parasomnias, the latter being found in the personal or family history of up to one-third of children with nocturnal frontal lobe epilepsy.38
The prevalence of ADHD is estimated to be between 12% and 39% in children with epilepsy, and is much higher than 3e7% in the general population of children.47 ADHD is significantly more prevalent in children with new-onset epilepsy compared to healthy controls (31% vs. 6%, respectively), and the predominant ADHD type is the inattentive type.48 A population-based study using data from the Taiwan National Health Insurance Research Database revealed a 2.54-fold increased risk of subsequent ADHD in children with epilepsy compared to normal controls, and the age-specific risks increased with age, at 2.26-, 3.53-, and 5.30-fold for patients aged 0e6 years, 6e12 years, and 12e18 years, respectively.49 Symptoms of ADHD are more common in some specific types of epilepsies, such as frontal lobe epilepsy, childhood absence epilepsy, and rolandic epilepsy, and may antedate seizure onset in a significant proportion of cases.50,51 In a study of Taiwanese children with epilepsy, a history of developmental delay predicted ADHD-related symptoms and an earlier onset of epilepsy predicted inattention and hyperactivity/impulsivity.52
Psychiatric comorbidities Psychiatric comorbidities are common in children with epilepsy, and constitute a significant burden to the children and their families. Some studies have shown that a psychiatric disorder can emerge in children early in the course of their illness39 or even prior to the onset of seizures.40 The most common psychiatric disorders among children who have epilepsy include attention deficit/hyperactivity disorder (ADHD), and depressive and anxiety disorders. Although infrequent, psychosis, oppositional defiant, and tic disorders may occur in children who have epilepsy.41,42
Autism spectrum disorders It is well documented that children with autism spectrum disorder (ASD) have an increased prevalence of seizures,
Mood disorders Mood disorders had been reported in 12e26% of children with epilepsy.53 Emotional disorders can be found in 16.7% of children with complicated epilepsy and in 16% of those with uncomplicated epilepsy compared with 4.2% in the general population.54 Ott et al55 reported mood disorders in 12% and 13% of children with complex partial seizures and childhood absence epilepsy, respectively. In general, children with epilepsy display more internalizing problems (withdrawal, somatic complaints, anxiety, and depression symptoms) than they do externalizing problems such as acting out and conduct problems.23,55 The higher ratings on the somatization and emotional withdrawal were found among children with poor seizure control.56 In addition to ADHD, the most common psychiatric disorders among children with epilepsy are depressive and anxiety disorders.41 Seizure frequency,57 AED polytherapy,57,58 types of AEDs,59,60 and duration of illness57,58 are all related to the development of these comorbidities. The depression, which is more comorbid in those
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4 treated with phenobarbital,59 or phenytoin,60 resolves in the children whose medication is discontinued but persists in those maintained on this medication. The brain regions commonly involved in various types of epilepsies, such as the hippocampus and amygdala in temporal lobe epilepsy and subcortical nuclei in idiopathic generalized epilepsies, are important components of current models of depression.60,61 One study also found a sex effect with more depression in adolescent girls with epilepsy,62 and another study noted an age effect with higher depression rates in adolescents.57 In contrast to depression with a trend in older children with epilepsy, anxiety is more comorbid in younger children (< 12 years old) with epilepsy.53,57 Certain psychiatric disorders, including primary mood disorders, increase the risk for suicide in adults with epilepsy.63 Only a few studies, however, examined suicidality in children with epilepsy.55,59 Ott et al55 reported suicidal ideation in 17% and 18% and suicidal intent in 8% and 11% of complex partial seizure and childhood absence epilepsy, respectively, but these rates were not significantly higher than those in normal children (9% ideation, 1% intent). Brent et al59 found suicidal ideation in 40% of children with epilepsy treated with phenobarbital, compared with only 4% of children with epilepsy treated with carbamazepine. Among the new AEDs, topiramate and lamotrigine already list suicidality on their package inserts but lack the evidence of clinical trials in pediatric patients.64
Other neuropsychiatric problems To compare with healthy children, oppositional defiant (13% vs. 2%) and tic disorders (9.4% vs. 2%) are more common but considerably less prevalent.41 A significantly increased rate of tic disorders is evident among children with localization-related epilepsy, and a significantly increased rate of conduct disorders in children with primary generalized epilepsy.41 The incidence of psychosis appears to be rare in children who have epilepsy. Ictal and postictal psychosis can occur but are rare.42 A postictal psychotic episode may occur after a prolonged seizure or a cluster of seizures. The psychotic episode can last several days and typically resolves spontaneously. If psychotic symptoms occur during seizures, they typically are stereotyped, and children may be unable to recall the content of the hallucination. This pattern is in contrast to children who have psychosis, who generally are able to describe the hallucination, which can vary from episode to episode. Changes in AEDs always should be considered when evaluating psychosis in children who have epilepsy. AED-induced psychotic reactions have been reported with the following medications: phenytoin, topiramate, lamotrigine, ethosuximide, vigabatrin, zonisamide, and felbamate.42
Psychosocial and familial problems Epilepsy is a chronic disorder, affecting children and their families across the environments in which children function, specifically home and school,65 and increasing adjustment reactions, and familial and social stress.66 They are also at increased risk for poor health-related quality of
S.-H. Wei, W.-T. Lee life even in the absence of active seizures.67 Depression or psychological distress is the strongest predictors of their quality of life.68 Also, family factors, especially those related to the quality of parentechild relationship, appear to be strong predictors of the quality of life among these children and their family.69 Moreover, a study of psychological health about the family members of patients revealed an increased risk of psychiatric problems among the mothers of the chronically epileptic children, but not fathers and siblings.39
Physical comorbidities Children with epilepsy may experience physical comorbid conditions caused by the disease itself or adverse effects of treatment. Most well-known adverse effects of AED treatment, including allergic reaction, cytopenia, electrolyte imbalance, and renal or hepatic impairment, are notable and probably reversible after ceasing AED use. However, some physical comorbidities related to AEDs, including disturbances of hormonal balance, may potentially have a long-term impact on the medical health and quality of life of the children with epilepsy. Table 2 summarizes the reported physical comorbidities caused by specific AEDs in children with epilepsy.
Bone loss Recent studies revealed that abnormal bone mineral density (BMD) was found in 58.3% of patients with epilepsy, with osteopenia and osteoporosis in 75% and 25%, respectively.70 Patients with symptomatic epilepsy, severe mental retardation, lack of autonomous gait, and less physical activity significantly correlated with abnormal BMD,70 and boys with more chronic epilepsy ( 6 years) had the lowest BMD.71 AEDs and the duration of treatmentdrather than the number of drugsdseem to play a significant role in abnormal BMD. Topiramate as adjunctive therapy and, to a
Table 2 Relationship between physical comorbidities and medical treatment of antiepileptic drugs (AEDs) in children with epilepsy. Comorbidities Bone loss Immunological disturbances Hypothyroidism Polycystic ovary syndrome Weight gain Weight loss Dyslipidemia Carnitine deficiency
Type of AEDs a
Refs
TPM, VPA, LMT, PB CBZ, VPA
70
CBZ, VPA VPA
81,82
VPA,a GBP, PGB, VGB TPM, FBM, ZNS CBZ, PB VPA,a OXC. CBZ, PHT, PB
87,89,90
75e77
85
89 94e96 98e100
CBZ Z carbamazepine; FBM Z felbamate; GBP Z gabapentin; LMT Z lamotrigine; OXC Z oxcarbazepine; PB Z phenobarbital; PGB Z pregabalin; PHT Z phenytoin; TPM Z topiramate; VGB Z vigabatrin; VPA Z valproic acid; ZNS Z zonisamide. a More significant than the other drugs.
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Comorbidity of children with epilepsy lesser extent, VPA, phenobarbital, and lamotrigine also correlated with lower BMD.70 Although > 50% of children and adolescents with epilepsy have low serum vitamin D levels, this finding does not correlate with BMD.72
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Polycystic ovary syndrome and sexual maturation
Immunological disturbances have been found in children with epilepsy prior to and after AED treatment. Immune mechanisms may be involved in the pathogenesis of some epilepsy syndromes in children, including West syndrome, LennoxeGastaut syndrome, and LKS, which may benefit from treatment with intravenous immunoglobulin (Ig).73 A Dutch study also found that serum levels of IgA, IgG1, IgG2, and IgG4 in children with newly diagnosed epilepsy were increased prior to the treatment, and that these disturbances were independent from etiology and the types of epilepsy syndromes.74 It indicates that epileptic seizures may affect the immune system indirectly. Treatment with AEDs, including phenytoin,75,76 carbamazepine,76,77 and VPA,77 had also been shown to change the humoral and cellular immunity.
The polycystic ovary syndrome (PCOS) is an important physical concern in female adolescents with epilepsy.83 In PCOS, anovulatory cycles are associated with more frequent seizures and migraine attacks.83 An association between PCOS and AED treatment has not always been demonstrated.84 The view that AEDs, in particular VPA, play a role in the development of PCOS is based on experience from several other series, clinical improvement after switching from VPA to lamotrigine, and recent animal data.85 The mechanism by which VPA may precipitate PCOS has not been entirely elucidated, and VPA-mediated changes in androgen metabolism may play a key role.79,86 Although AEDs are presumed to be associated with PCOS, current evidence shows that AEDs do not seem to have any adverse effects on pubertal development79 and sexual maturation87 in girls with epilepsy. Epilepsy itself may also be related to PCOS via epileptiform discharges disrupting normal hypothalamic function.88 Female teens with epilepsy usually have a high prevalence of PCOS, independent of the types of AEDs or the characteristics of the epilepsy.79
Body height and growth hormone deficiency
Body weight changes
Retardation of body height growth in children with epilepsy has been described in many studies.78 Children with epilepsy have reduced mean height percentile compared with controls, which was negatively correlated with the types of epilepsy, the duration of epilepsy, and the degree of seizure control.78,79 Although basal growth hormone levels showed no significant change, post provocation growth hormone and insulin growth factor-1 levels were significantly lower in patients with epilepsy.78 By contrast, the effect of AEDs on body height or growth hormone of children with epilepsy is controversial. A reduction in growth hormone response was found in both treated and untreated children with epilepsy, whereas treatment with phenytoin and VPA resulted in a significant increase and decrease, respectively, in growth hormone release after different stimulatory tests.80 However, other studies showed that VPA, carbamazepine, or oxcarbazepine had no significant difference in affecting linear growth or growth hormone of these children.78
Many AEDs are associated with substantial weight changes. Felbamate, topiramate, and zonisamide may cause weight loss, whereas VPA, gabapentin, pregabalin, and vigabatrind and, possibly, carbamazepinedare related to weight gain.89 VPA is the most recognized one causing weight gain,87,90 and the relationship seems to be sex-specific in adolescents.90 Studies have reported the association of obesity and hyperinsulinemia with VPA-related PCOS and hyperandrogenism in puberty and postpuberty girls with epilepsy.86 In prepubertal children with epilepsy, the VPA-related weight gain may be associated with the increase in serum ghrelin, a major hormone regulating the energy balance of the body, in the early treatment period,91 but there is no more significance of excessive weight gain in the long-term follow-up of VPA use.92 Nevertheless, a recent study showed that obesity is also a common comorbidity in children with newly diagnosed epilepsy prior to treatment, and correlates with increasing age, idiopathic etiology, and absence of concomitant medication.93
Hypothyroidism
Dyslipidemia
Long-term AED therapy has been reported to cause subclinical hypothyroidism in children with epilepsy.81,82 EirisPunal et al81 found that subclinical hypothyroidism was more common in children receiving VPA (26%) and carbamazepine (8.2%) treatment compared to normal controls (3.6%). Hypothyroidism was also reported to be more evident if carbamazepine was given with VPA. However, thyroid-stimulating hormone and thyrotropin-releasing hormone levels were not affected, suggesting that AEDs did not affect hypothalamic function in these children.82
Previously published studies on the effect of AEDs on serum lipid profiles have mostly comprised adults or adults and children together.94 Studies in children alone were limited, and most showed the changes to be transient and reversible.95 Recently, it was reported that total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels were all increased in children on long-term therapy with carbamazepine or phenobarbital, whereas long-term VPA therapy decreased values of these lipid profiles.96
Immunological disturbances
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Carnitine deficiency Carnitine deficiency causes clinical signs and symptoms such as gastrointestinal dysmotility, manifesting by vomiting, delayed gastric emptying, and constipation, and other symptoms such as muscle weakness, hypotonia, cardiomyopathy, and even encephalopathy.97 Hypocarnitinemia have been reported in pediatric patients receiving AEDs, especially during long-term or high-dose therapy, including oxcarbazepine. carbamazepine, phenytoin, phenobarbital, and particularly VPA.98e100 Some epileptic children taking VPA may have depleted carnitine stores, especially in their muscles, despite having normal serum carnitine levels.99
Perspective strategies and recommendations Comorbid conditions are variable and common in children with epilepsy, and often more disabling than the seizures themselves. Management strategies focus not only on controlling seizures, but also on early diagnosis and therapy of comorbid conditions. Therefore, identification of such difficulties should be an integral part of management in childhood epilepsy. Most important of all, it is recommended that clinicians screen and assess the possible neurological and psychological comorbidities both in children with newly diagnosed epilepsy and those with regular follow-up after treatment. Some of these difficulties may occur as early as in newly diagnosed epilepsy prior to treatment and in children with controlled epilepsy. Many factors may contribute to the development of physical morbidities in children with epilepsy, such as the detrimental effects of chronic seizures and AEDs. When a physical comorbidity is suspected to result from a specific medication (Table 2), alternatives should be considered. Because of a significant impact of childhood epilepsy on children and their families, further work should also focus on the educational strategies of psychosocial support to decrease the adjustment problems, and familial and social stress.
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