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Overtreatment in children with epilepsy
Epilepsy Research 52 (2002) 35 /42 www.elsevier.com/locate/epilepsyres
Overtreatment in children with epilepsy Gregory L. Holmes * Department of Neurology, Clinical Neurophysiology Laboratory, Harvard Medical School, Children’s Hospital Boston, Hunnewell 2, 300 Longwood Avenue, Boston, MA 02115, USA Received 10 July 2002; accepted 28 July 2002
Abstract Children with epilepsy are at risk for overtreatment, defined as the use of an excessive number or amount of antiepiletic drugs (AEDs). While the extent of overtreatment of epilepsy in children is not known, there is increasing awareness that overtreatment with AEDs contributes to the morbidity associated with childhood epilepsy. Reasons for overtreatment include using AEDs in a child with seizures who does not require therapy, choosing an inappropriate AED for the seizure type or syndrome; treating non-epileptic behaviors as seizures, use of polytherapy when monotherapy would suffice, and inadequate therapeutic options. Despite the introduction of eight new AEDs in the United States during the last decade, many children continue to be treated with the older generation sedative AEDs. Numerous investigators have now demonstrated that sedative AEDs can be safely removed from the drug regimen of children with epilepsy with resultant improvement in behavior, alertness, and improved seizure control. However, the biggest obstacle to overtreatment is the lack of effective therapies for many of the childhood epileptic syndromes. Until there are more effective therapies developed it is highly likely that children will continue to be over-medicated on ineffective and detrimental AEDs. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Seizures; Antiepileptic drugs; Developmental delay; Seizures
1. Introduction Epilepsy is one of the most common, yet frightening neurological conditions to occur in children. In the United States, there are approximately 125,000 new cases of epilepsy each year; 30% of this group will be less than 18 years old at the time of diagnosis (Hauser, 1995; Hauser and
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Hersdorffer, 1990). Fortunately, most children with epilepsy do well when treated with an antiepileptic drug (AED) (Berg et al., 1995; Camfield et al., 1993; Carpay et al., 1998; De Silva et al., 1996). These children enjoy seizure freedom without experiencing any noticeable side effects. However, a substantial number of children with epilepsy do not respond well to AEDs and continue to have seizures despite appropriate therapy (Amann and Dulac, 2001; Huttenlocher and Hapke, 1990; Ko and Holmes, 1999). This group of children are at risk for excessive or incorrect AED therapy. While this is a small group
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of children, the medical, social, and economic consequences of poorly controlled seizures can be enormous. When seizures continue despite the appropriate use of AEDs there is a risk for overtreatment resulting in either an excessive dosage or number of AEDs (Rochat et al., 2001; Tetto et al., 2002). ‘Overtreatment in this paper will refer to an unnecessary or excessive drug load in the management of epilepsy leading to a suboptimal risk-to-benefit balance. In this paper overtreatment will also be expanded to include using an inappropriate drug for the child’s seizure type or syndrome. The consequences of inappropriate use of AEDs are substantial. In a study 392 children treated with long-term monotherapy with phenobarbital, primidone, phenytoin, carbamazepine, or valproate side effects occurred in 50% of the children (Herranz et al., 1988). Chronic use of multiple AEDs appear to contribute to the cognitive deficits in some patients (Bourgeois et al., 1983; Bourgeois, 1998; Rodin et al., 1986). Sadly, the nature of epilepsy leads to overtreatment. The only way one can safely avoid overtreatment is to treat the child with the lowest therapeutic dosage of a single AED. Epilepsy does not have a surrogate marker that provides guidance as to whether the therapy is appropriate. Whereas monitoring cholesterol and blood pressure can reduce the risk of cardiovascular disease, there is not a surrogate marker that can be monitored instead of seizures in children with epilepsy. Effectiveness of therapy can be determined only by seizure frequency, i.e. if the child continues to have seizures the therapy is not totally effective. The physician can never be certain that the child is on the minimal effective concentration of the drug. While serum AED levels provide some guidance, serum therapeutic levels were devised primarily from adult studies. It remains unclear how useful these levels are in children with epilepsy. In addition to the inherent difficulties in treating epilepsy in children there are other reasons for overtreatment. Topics to be discussed in the review include: (i) using an AED in a child with seizures who does not require therapy; (ii) choosing an inappropriate AED for the seizure type or syn-
drome; (iii) treating non-epileptic behavior in children with epilepsy with AEDs; (iv) use of polytherapy when monotherapy would suffice; and (v) inadequate therapeutic options.
2. Inappropriate initiation of AEDs There is now a general consensus that AED therapy does not need to be started in children with a single seizure (Shinnar et al., 1996; Shinnar and Ballaban-Gil, 1991). In a prospective study, 238 children with a first unprovoked seizure were closely followed for a mean of 30 months by Shinnar et al. (1996) in the Bronx. The vast majority of the children were not treated with AEDs. Subsequent seizures occurred in only 36%. The cumulative risk for recurrence was 60% at 36 months in children with a history of a static neurological insult (termed ‘remote symptomatic’) versus 36% in children with an idiopathic seizure. Risk factors associated with recurrence following a single seizure include etiology, timing of the seizure, initial EEG, and seizure type. In addition to a symptomatic etiology other factors associated with a higher recurrence risk include abnormal EEGs, nocturnal seizures, and partial seizures. While the risk for a second seizure is relatively low, children that have two unprovoked seizures have a risk of recurrence of approximately 70%. Since there is no evidence that AED therapy alters the subsequent course of epilepsy (Shinnar et al., 1990), it seems prudent to wait for the second unprovoked seizure to initiate AED therapy. Despite this data initiation of AEDs following an initial seizure remains common. This is particularly the case when the child presents with status epilepticus as the initial seizure. However, even in this situation the risk for a subsequent seizures is no higher than if the child had a briefer seizure (Shinnar et al., 1990). Even in a child with risk factors for a second unprovoked seizure the rationale for starting AED therapy, with the myriad of possible adverse effects, is unclear. With the availability of abortive therapy, i.e. rectal diazepam, waiting for a second seizure before initiating therapy is reasonable.
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While there is also a consensus that febrile seizures do not require prophylactic therapy (Baumann, 2001; Baumann and Duffner, 2000; Shinnar and Glauser, 2002), physicians continue to administer prophylactic AEDs, typically phenobarbital (MacDonald et al., 1999). In a 12-year follow-up study of children with febrile convulsions in the National General Practice Study of Epilepsy, it was found that 11% of 220 children had received medication, and in one third of these cases, it was for simple febrile convulsions (MacDonald et al., 1999).
3. Choosing an inappropriate AED for the seizure type or syndrome In some patients AEDs can exacerbate, rather than improve seizure control (Bauer, 1996; Genton, 2000; Perucca et al., 1998). For example, treating absence seizures with carbamazepine, vigabatrin, or tiagabine is typically ineffective and can result in an increase in seizure frequency or duration (Parker et al., 1998). Conversely, treating partial seizures with ethosuximide is ineffective in controlling the seizures but may cause side effects. Most, if not all, of the AEDs can result in worsening of seizures. In a retrospective study of 1006 patients with focal epilepsy Elger et al. (1998) examined changes in seizure frequency in 2500 phases of add-on therapy with a single AED. Topiramate and vigabatrin were the most frequent drugs to cause an exacerbation in seizures. Patients at maximal risk for a paradoxical effect of AEDs include children, patients with mental retardation, those receiving polytherapy, patients with a high frequency of seizures before treatment, and those with prominent epileptiform EEG activity. The causes for increased seizures when a new AED is introduced can be be multifactorial. The new AED can alter the pharmacokinetics of the other AEDs resulting in increased or decreased serum levels, increase fatigue, a common provocative factor for seizures, or result in paradoxical aggravation of the seizures. Paradoxical aggravation of seizures is fortunately rare but must be considered in patients who worsen with introduc-
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tion of a new drug. Generalized seizures may be exacerbated and new seizure types may develop with carbamazepine (Callahan and Noetzel, 1992; Dhuna et al., 1991; Snead and Hosey, 1985). Patients with generalized spike-wave on their EEG are at particular risk (Snead and Hosey, 1985). Lamotrigine (Genton, 2000; Guerrini et al., 1998a,b, 1999; Janszky et al., 2000), gabapentin (Wilson et al., 1998), vigabatrin (Appleton, 1995; Marciani et al., 1995) phenytoin (Eldridge et al., 1983), and carbamazepine (Shields and Saslow, 1983) can aggravate or precipitate myoclonic seizures. In severe myoclonic epilepsy of infancy lamotrigine has resulted in exacerbation of seizures (Guerrini et al., 1999). AED-induced encephalopathy has been well described, especially in patients treated with valproate (Bauer, 1996; Chen et al., 2001a; Jones et al., 1990; Kifune et al., 2000; Tartara and Manni, 1985). Rarely patients may deteriorate in learning, memory, and cognitive abilities with initiation of AED therapy. If the introduction of an AED results in an increased frequency of seizures, drug-induced encephalopathy should be considered as a possible cause. At times it may be difficult to distinguish between the natural course of the disorder and adverse effects of the AEDs. It should be remembered that seizure frequency may fluctuate in children even when AEDs remain stable. However, if the physician is not aware that AEDs can occasionally exacerbate seizures there may be a tendency is to increase, not decrease the dosage, resulting in a vicious downhill cycle. While decisions should not be made hastily, it is incumbent upon the physician to consider paradoxical exacerbation when seizure frequency or severity increase, rather than decrease, with introduction of a new AED.
4. Treating non-epileptic behaviors as seizures Children with well documented epilepsy may have non-epileptic behaviors that resemble seizures (Donat and Wright, 1990; Paolicchi, 2002). Distinguishing epileptic from non-epileptic behaviors may require use of simultaneous EEG and
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video monitoring (Carmant et al., 1996; Holmes et al., 1980; Rosenow et al., 1998; Wyllie et al., 1990). Failure to consider non-epileptic behaviors in children with epilepsy can lead to overtreatment.
5. Use of polytherapy when monotherapy would suffice It is becoming increasing evident that the treatment of many patients with epilepsy can be best accomplished with the use of fewer drugs or monotherapy (Brodie et al., 1987; Feely and Callaghan, 1981; Pellock and Hunt, 1996; Poindexter et al., 1993; Schmidt, 1983; Shorvon and Reynolds, 1977; Theodore and Porter, 1983). Monotherapy reduces the likelihood of drug toxicity and interactions, increases compliance, and reduces cost when compared to polytherapy. As pointed out by Pellock and Hunt (1996) converting a patient to monotherapy from polytherapy is more difficult than maintaining the patient of monotherapy. Withdrawal of AEDs may result in withdrawal seizures which prompt the physician to restart the drug that was being removed. Children with mental impairment are at particular risk for overtreatment. (Devinsky, 2002; Pellock and Hunt, 1996). In addition to having severe epilepsy the children cannot describe side effects well. Institutionalized patients are frequently prescribed a sedative barbiturate (phenobarbital or primidone) or benzodiazepine (diazepam, clonazepam, clorazepate dipotassium, or lorazepam) (Alvarez, 1998; Alvarez et al., 1998). It is well recognized that AEDs can result in significant behavioral and cognitive difficulties (Camfield et al., 1979; Cavazzuti and Nalin, 1990; Chen et al., 2001b; Farwell et al., 1990; Hanzel et al., 1992; Mayhew et al., 1992; Theodore and Porter, 1983; Vining et al., 1987; Wilder, 1985). Despite the significant number of side effects associated with phenobarbital, the drug continues to be widely used both within institutions as well as with outpatients (Rochat et al., 2001; Tetto et al., 2002). Numerous reports have demonstrated that reduced AED use can effectively maintain seizure
control with fewer adverse effects (Devinsky, 2002; Fischbacher, 1982; Litzinger et al., 1993; Mattson, 1996; Poindexter et al., 1993; Wilkinson et al., 1982). Fischbacher, (1982), in a study of institutionalized, mentally handicapped patients, found that at least one AED could be removed from the therapeutic regimen without loss of seizure control in 20 of 36 patients. Among these 20 patients, there was significant improvement in ‘well-being’ as reflected by a general scale measuring behavior and affect. Pellock and Hunt (1996) attempted to remove or reduce AEDs in 244 institutionalized patients with mental retardation varying in age from 8 to 66 years. A 19% reduction in polytherapy was accomplished and AEDs were discontinued in 13%, although half of the patients in whom AEDs were removed had recurrences. The percentage of patients receiving monotherapy increased from 36.5 to 58.1% with no observed loss of seizure control. The authors reported an overall increase in alertness in patients with reductions of the barbiturates. Alvarez (1989) discontinued AEDs in patients with developmental disabilities and a diagnosis of epilepsy who were seizure-free for several years. During 8 years of follow-up recurrences were noted in 52% of the patients. Clancy (1987), Ferngren et al. (1991), Sivenius et al. (1990), Poindexter et al. (1993) were all able to reduce sedative AEDs in mentally challenged patients with resulting improvements in alertness and quality of life.
6. Inadequate therapeutic options In general, studies examining response rate to AEDs in children with new onset partial or partial with secondarily epilepsy are similar to those seen in adults (De Silva et al., 1996; Elwes et al., 1984). De Silva et al. (1996) randomized 167 children between the ages of 3 /16 years with two or more generalized tonic /clonic or partial seizures with or without secondary generalization to treatment with phenobarbital, phenytoin, carbamazepine, or valproate. The response was quite good with 73% achieving remission after three years of follow-up. No significant differences were found
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between the three drugs with the exception of phenobarbital which resulted in a high withdrawal rate and was eventually dropped from the study. The response of children with partial and generalized tonic /clonic seizures to AEDs is not particularly surprising since the AEDs were tested for efficacy in these seizure types, albeit in adults. However, children with other seizure types such as absence, tonic, atonic, clonic, and myoclonic rarely present after two seizures and would not qualify for studies such as the one performed by De Silva et al. (1996). With the exception of absences, these seizure types are much more difficult to treat (Holmes, 1988). Many of the epileptic syndromes occurring in children also have no effective therapies. Syndromes such severe myoclonic epilepsy of infancy (Dravet syndrome), infantile spasms, Doose syndrome, Lennox /Gastaut syndrome, and Landau /Kleffner syndrome are notoriously difficult to treat with currently available AEDs. These syndromes may have a different pathophysiological basis than the typically encountered partial seizures seen in the adult population. Because seizures rarely cease with a single drug, polytherapy is employed. There is little evidence that polytherapy improves the likelihood of seizure control; however, as previously discussed, there is considerable evidence that polytherapy can increase the likelihood of side effects. AEDs are not developed to treat pediatric epilepsy syndromes. This relates primarily to the lack of suitable animal models for these syndromes (Stafstrom and Holmes, 2002). There has been little progress in the treatment of infantile spasms since the discovery of the usefulness of ACTH by Sorel and Dusaucy-Bauloye (1958) almost 35 years ago. Since there is not yet an animal model that mimics the behavioral and electroencephalographic features of the syndrome it is difficult to investigate new medications. AEDs have traditionally been screened in acute seizure models in normal adult rats, using electroshock threshold or pentylenetetrazol. While AEDs are now being tested in other models, including kindling and auditory-induced seizures, chronic models of epilepsy are not commonly used in preclinical screening. Since only drugs that work in these acute models in adult rodents reach clinical trials, it is
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not surprising that these drugs do not work in pediatric epilepsy syndromes. Another issue with rodent testing of AEDs is that many side effects that will eventually occur in humans are not identified in rodents. The type and extent of animal testing is limited and is particularly weak in assessing central nervous system adverse effects. Animal testing will not detect drug-induced cognitive and behavioral abnormalities. Furthermore, the metabolism of AEDs may be quite different in rodents and humans, reducing the ability of rodent models to predict adverse effects (Dieckhaus et al., 2000).
7. Future directions There have been incredible advances in understanding the genetic basis of the epilepsy and the role of genetics in determining efficacy and adverse effects of AEDs. There is genetic control of virtually every phase of drug metabolism from absorption through final elimination. Genetic control may be particularly important for AEDs, which have a narrow therapeutic index. In general, individuals with poor metabolizing phenotypes as a result of being homozygous for an allelic variant that is inactive, will accumulate drug. If the drug is active the patient may have excellent efficacy but experience toxicity. Conversely, rapid metabolizers will have excellent tolerability but are at risk for low efficacy. Almost every gene involved in drug metabolism is subject to common genetic polymorphisms that may contribute to individual variability in drug response. The cytochrome P450 enzymes (CYPs) are the most widely studied phase I metabolizing enzymes. Genetic variations in the CYPs are known to influence drug toxicity and efficacy (Aithal et al., 1999; Evans and Relling, 1999; Furuta et al., 1998). Polymorphisms resulting in poor or rapid metazolizers have been studied mostly in CYP2D6 and CYP2C19. In addition to cytochrome P450 enzymes, genetic variations of Phase I reactions, which include human enzymes responsible for modification of functional groups and Phase II reactions, which involve conjugation with endogenous compounds have been found.
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It is anticipated that eventually children will be screened for their ability to metabolize AEDs. Dosing will be dependent upon theses genetic tendencies. Ideally genetic testing will allow us to determine not only the best drug for the condition but the dosage required to control seizure without causing toxicity.
8. Conclusions The causes of overtreatment of children with epilepsy are multifactorial. While overtreatment remains an important problem in children with epilepsy there does appear to be an increasing awareness of the issue by epileptologists. Recent trends towards monotherapy and elimination of sedative AEDs have been helpful. However, until AEDs are developed that are effective in the majority of pediatric epilepsy syndromes it is likely that overtreatment will remain one more obstacle a child with epilepsy suffers.
Acknowledgements Supported by a Mental Retardation Research Center grant from NIH (2P30HD18655) and a grant from the NINDS (NS27984).
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Paolicchi, J.M., 2002. The spectrum of nonepileptic events in children. Epilepsia 43 (Suppl. 3), 60 /64. Parker, A.P., Agathonikou, A., Robinson, R.O., Panayiotopoulos, C.P., 1998. Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Dev. Med. Child Neurol. 40, 517 /519. Pellock, J.M., Hunt, P.A., 1996. A decade of modern epilepsy therapy in institutionalized mentally retarded patients. Epilepsy Res. 25, 263 /268. Perucca, E., Gram, L., Avanzini, G., Dulac, O., 1998. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 39, 5 /17. Poindexter, A.R., Berglund, J.A., Kolstoe, P.D., 1993. Changes in antiepileptic drug prescribing patterns in large institutions: preliminary results of a five-year experience. Am. J. Ment. Retard. 98 Suppl., 34 /40. Rochat, P., Hallas, J., Gaist, D., Friis, M.L., 2001. Antiepileptic drug utilization: a Danish prescription database analysis. Acta Neurol. Scand. 104, 6 /11. Rodin, E.A., Schmaltz, S., Twitty, G., 1986. Intellectual functions of patients with childhood-onset epilepsy. Dev. Med. Child Neurol. 28, 25 /33. Rosenow, F., Wyllie, E., Kotagal, P., Mascha, E., Wolgamuth, B.R., Hamer, H., 1998. Staring spells in children: descriptive features distinguishing epileptic and nonepileptic events. J. Pediatr. 133, 660 /663. Schmidt, D., 1983. Reduction of two-drug therapy in intractable epilepsy. Epilepsia 24, 368 /376. Shields, W.D., Saslow, E., 1983. Myoclonic, atonic, and absence seizures following institution of carbamazepine therapy in children. Neurology 33, 1487 /1489. Shinnar, S., Ballaban-Gil, K., 1991. An approach to the child with a first unprovoked seizure. Pediatr. Ann. 20, 29 /33. Shinnar, S., Berg, A.T., Moshe, S.L., O’Dell, C., Alemany, M., Newstein, D., Kang, H., Goldensohn, E.S., Hauser, W.A., 1996. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up. Pediatrics 98, 216 /225. Shinnar, S., Berg, A.T., Moshe, S.L., Petix, M., Maytal, J., Kang, H., Goldensohn, E.S., Hauser, W.A., 1990. Risk of seizure recurrence following a first unprovoked seizure in childhood: a prospective study. Pediatrics 85, 1076 /1085.
Shinnar, S., Glauser, T.A., 2002. Febrile seizures. J. Child Neurol. 17 (Suppl. 1), S44 /S52. Shorvon, S.D., Reynolds, E.H., 1977. Unnecessary polypharmacy for epilepsy. Br. Med. J. 1, 1635 /1637. Sivenius, J., Savolainen, S., Kaski, M., Riekkinen, P.J., 1990. Therapeutic intervention in mentally retarded adult epileptics. Acta Neurol. Scand. 81, 165 /167. Snead, O.C., Hosey, L.C., 1985. Exacerbation of seizures in children by carbamazepine. N. Engl. J. Med. 313, 916 /921. Sorel, L., Dusaucy-Bauloye, E., 1958. A propos de 21 cas d’hypsarhythmia de Gibbs son traitment spectaculaire par l’ACTH. Acta Neurol. Belg. 58, 130 /141. Stafstrom, C.E., Holmes, G.L., 2002. Infantile spasms: criteria for an animal model. Int. Rev. Neurobiol. 49, 391 /411. Tartara, A., Manni, R., 1985. Sodium valproate ‘encephalopathy’: report of three cases with generalised epilepsy. Ital. J. Neurol. Sci. 6, 93 /95. Tetto, A., Manzoni, P., Millul, A., Beghi, E., Garattini, L., Tartara, A., Avanzini, G., 2002. The costs of epilepsy in Italy. A prospective cost-of-illness study in referral patients with disease of different severity. Epilepsy Res. 48, 207 /216. Theodore, W.H., Porter, R.J., 1983. Removal of sedativehypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann. Neurol. 13, 320 /324. Vining, E.P.G., Mellits, D., Dorsen, M., Cataldo, M.F., Quaskey, S.A., Spielberg, S.Y., Freeman, J., 1987. Psychological and behavioral effects of antiepileptic drugs in children: a double blind comparison between phenobarbital and valproic acid. Pediatrics 80, 165 /174. Wilder, B.J., 1985. Drug therapy for seizures. Clin. Ther. 7, 246 /253. Wilkinson, I.A., Murphy, J.V., Georgeson, R., D’Souza, B.J., 1982. On-site seizure clinic: impact on th welfare of mentally retarded, institutionalized patients. Arch. Neurol. 39, 41 / 43. Wilson, E.A., Sills, G.J., Forrest, G., Brodie, M.J., 1998. High dose gabapentin in refractory partial epilepsy: clinical observations in 50 patients. Epilepsy Res. 29, 161 /166. Wyllie, E., Friedman, D., Rothner, A.D., Luders, H., Dinner, D., Morris, H., III, Cruse, R., Erenberg, G., Kotagal, P., 1990. Psychogenic seizures in children and adolescents: outcome after diagnosis by ictal video and electroencephalographic recording. Pediatrics 85, 480 /484.
Overtreatment in children with epilepsy Gregory L. Holmes * Department of Neurology, Clinical Neurophysiology Laboratory, Harvard Medical School, Children’s Hospital Boston, Hunnewell 2, 300 Longwood Avenue, Boston, MA 02115, USA Received 10 July 2002; accepted 28 July 2002
Abstract Children with epilepsy are at risk for overtreatment, defined as the use of an excessive number or amount of antiepiletic drugs (AEDs). While the extent of overtreatment of epilepsy in children is not known, there is increasing awareness that overtreatment with AEDs contributes to the morbidity associated with childhood epilepsy. Reasons for overtreatment include using AEDs in a child with seizures who does not require therapy, choosing an inappropriate AED for the seizure type or syndrome; treating non-epileptic behaviors as seizures, use of polytherapy when monotherapy would suffice, and inadequate therapeutic options. Despite the introduction of eight new AEDs in the United States during the last decade, many children continue to be treated with the older generation sedative AEDs. Numerous investigators have now demonstrated that sedative AEDs can be safely removed from the drug regimen of children with epilepsy with resultant improvement in behavior, alertness, and improved seizure control. However, the biggest obstacle to overtreatment is the lack of effective therapies for many of the childhood epileptic syndromes. Until there are more effective therapies developed it is highly likely that children will continue to be over-medicated on ineffective and detrimental AEDs. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Seizures; Antiepileptic drugs; Developmental delay; Seizures
1. Introduction Epilepsy is one of the most common, yet frightening neurological conditions to occur in children. In the United States, there are approximately 125,000 new cases of epilepsy each year; 30% of this group will be less than 18 years old at the time of diagnosis (Hauser, 1995; Hauser and
* Tel.: /1-617-355-8461; fax: /1-617-738-1734 E-mail address: [email protected] (G.L. Holmes).
Hersdorffer, 1990). Fortunately, most children with epilepsy do well when treated with an antiepileptic drug (AED) (Berg et al., 1995; Camfield et al., 1993; Carpay et al., 1998; De Silva et al., 1996). These children enjoy seizure freedom without experiencing any noticeable side effects. However, a substantial number of children with epilepsy do not respond well to AEDs and continue to have seizures despite appropriate therapy (Amann and Dulac, 2001; Huttenlocher and Hapke, 1990; Ko and Holmes, 1999). This group of children are at risk for excessive or incorrect AED therapy. While this is a small group
0920-1211/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 2 ) 0 0 1 8 3 - 3
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of children, the medical, social, and economic consequences of poorly controlled seizures can be enormous. When seizures continue despite the appropriate use of AEDs there is a risk for overtreatment resulting in either an excessive dosage or number of AEDs (Rochat et al., 2001; Tetto et al., 2002). ‘Overtreatment in this paper will refer to an unnecessary or excessive drug load in the management of epilepsy leading to a suboptimal risk-to-benefit balance. In this paper overtreatment will also be expanded to include using an inappropriate drug for the child’s seizure type or syndrome. The consequences of inappropriate use of AEDs are substantial. In a study 392 children treated with long-term monotherapy with phenobarbital, primidone, phenytoin, carbamazepine, or valproate side effects occurred in 50% of the children (Herranz et al., 1988). Chronic use of multiple AEDs appear to contribute to the cognitive deficits in some patients (Bourgeois et al., 1983; Bourgeois, 1998; Rodin et al., 1986). Sadly, the nature of epilepsy leads to overtreatment. The only way one can safely avoid overtreatment is to treat the child with the lowest therapeutic dosage of a single AED. Epilepsy does not have a surrogate marker that provides guidance as to whether the therapy is appropriate. Whereas monitoring cholesterol and blood pressure can reduce the risk of cardiovascular disease, there is not a surrogate marker that can be monitored instead of seizures in children with epilepsy. Effectiveness of therapy can be determined only by seizure frequency, i.e. if the child continues to have seizures the therapy is not totally effective. The physician can never be certain that the child is on the minimal effective concentration of the drug. While serum AED levels provide some guidance, serum therapeutic levels were devised primarily from adult studies. It remains unclear how useful these levels are in children with epilepsy. In addition to the inherent difficulties in treating epilepsy in children there are other reasons for overtreatment. Topics to be discussed in the review include: (i) using an AED in a child with seizures who does not require therapy; (ii) choosing an inappropriate AED for the seizure type or syn-
drome; (iii) treating non-epileptic behavior in children with epilepsy with AEDs; (iv) use of polytherapy when monotherapy would suffice; and (v) inadequate therapeutic options.
2. Inappropriate initiation of AEDs There is now a general consensus that AED therapy does not need to be started in children with a single seizure (Shinnar et al., 1996; Shinnar and Ballaban-Gil, 1991). In a prospective study, 238 children with a first unprovoked seizure were closely followed for a mean of 30 months by Shinnar et al. (1996) in the Bronx. The vast majority of the children were not treated with AEDs. Subsequent seizures occurred in only 36%. The cumulative risk for recurrence was 60% at 36 months in children with a history of a static neurological insult (termed ‘remote symptomatic’) versus 36% in children with an idiopathic seizure. Risk factors associated with recurrence following a single seizure include etiology, timing of the seizure, initial EEG, and seizure type. In addition to a symptomatic etiology other factors associated with a higher recurrence risk include abnormal EEGs, nocturnal seizures, and partial seizures. While the risk for a second seizure is relatively low, children that have two unprovoked seizures have a risk of recurrence of approximately 70%. Since there is no evidence that AED therapy alters the subsequent course of epilepsy (Shinnar et al., 1990), it seems prudent to wait for the second unprovoked seizure to initiate AED therapy. Despite this data initiation of AEDs following an initial seizure remains common. This is particularly the case when the child presents with status epilepticus as the initial seizure. However, even in this situation the risk for a subsequent seizures is no higher than if the child had a briefer seizure (Shinnar et al., 1990). Even in a child with risk factors for a second unprovoked seizure the rationale for starting AED therapy, with the myriad of possible adverse effects, is unclear. With the availability of abortive therapy, i.e. rectal diazepam, waiting for a second seizure before initiating therapy is reasonable.
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While there is also a consensus that febrile seizures do not require prophylactic therapy (Baumann, 2001; Baumann and Duffner, 2000; Shinnar and Glauser, 2002), physicians continue to administer prophylactic AEDs, typically phenobarbital (MacDonald et al., 1999). In a 12-year follow-up study of children with febrile convulsions in the National General Practice Study of Epilepsy, it was found that 11% of 220 children had received medication, and in one third of these cases, it was for simple febrile convulsions (MacDonald et al., 1999).
3. Choosing an inappropriate AED for the seizure type or syndrome In some patients AEDs can exacerbate, rather than improve seizure control (Bauer, 1996; Genton, 2000; Perucca et al., 1998). For example, treating absence seizures with carbamazepine, vigabatrin, or tiagabine is typically ineffective and can result in an increase in seizure frequency or duration (Parker et al., 1998). Conversely, treating partial seizures with ethosuximide is ineffective in controlling the seizures but may cause side effects. Most, if not all, of the AEDs can result in worsening of seizures. In a retrospective study of 1006 patients with focal epilepsy Elger et al. (1998) examined changes in seizure frequency in 2500 phases of add-on therapy with a single AED. Topiramate and vigabatrin were the most frequent drugs to cause an exacerbation in seizures. Patients at maximal risk for a paradoxical effect of AEDs include children, patients with mental retardation, those receiving polytherapy, patients with a high frequency of seizures before treatment, and those with prominent epileptiform EEG activity. The causes for increased seizures when a new AED is introduced can be be multifactorial. The new AED can alter the pharmacokinetics of the other AEDs resulting in increased or decreased serum levels, increase fatigue, a common provocative factor for seizures, or result in paradoxical aggravation of the seizures. Paradoxical aggravation of seizures is fortunately rare but must be considered in patients who worsen with introduc-
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tion of a new drug. Generalized seizures may be exacerbated and new seizure types may develop with carbamazepine (Callahan and Noetzel, 1992; Dhuna et al., 1991; Snead and Hosey, 1985). Patients with generalized spike-wave on their EEG are at particular risk (Snead and Hosey, 1985). Lamotrigine (Genton, 2000; Guerrini et al., 1998a,b, 1999; Janszky et al., 2000), gabapentin (Wilson et al., 1998), vigabatrin (Appleton, 1995; Marciani et al., 1995) phenytoin (Eldridge et al., 1983), and carbamazepine (Shields and Saslow, 1983) can aggravate or precipitate myoclonic seizures. In severe myoclonic epilepsy of infancy lamotrigine has resulted in exacerbation of seizures (Guerrini et al., 1999). AED-induced encephalopathy has been well described, especially in patients treated with valproate (Bauer, 1996; Chen et al., 2001a; Jones et al., 1990; Kifune et al., 2000; Tartara and Manni, 1985). Rarely patients may deteriorate in learning, memory, and cognitive abilities with initiation of AED therapy. If the introduction of an AED results in an increased frequency of seizures, drug-induced encephalopathy should be considered as a possible cause. At times it may be difficult to distinguish between the natural course of the disorder and adverse effects of the AEDs. It should be remembered that seizure frequency may fluctuate in children even when AEDs remain stable. However, if the physician is not aware that AEDs can occasionally exacerbate seizures there may be a tendency is to increase, not decrease the dosage, resulting in a vicious downhill cycle. While decisions should not be made hastily, it is incumbent upon the physician to consider paradoxical exacerbation when seizure frequency or severity increase, rather than decrease, with introduction of a new AED.
4. Treating non-epileptic behaviors as seizures Children with well documented epilepsy may have non-epileptic behaviors that resemble seizures (Donat and Wright, 1990; Paolicchi, 2002). Distinguishing epileptic from non-epileptic behaviors may require use of simultaneous EEG and
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video monitoring (Carmant et al., 1996; Holmes et al., 1980; Rosenow et al., 1998; Wyllie et al., 1990). Failure to consider non-epileptic behaviors in children with epilepsy can lead to overtreatment.
5. Use of polytherapy when monotherapy would suffice It is becoming increasing evident that the treatment of many patients with epilepsy can be best accomplished with the use of fewer drugs or monotherapy (Brodie et al., 1987; Feely and Callaghan, 1981; Pellock and Hunt, 1996; Poindexter et al., 1993; Schmidt, 1983; Shorvon and Reynolds, 1977; Theodore and Porter, 1983). Monotherapy reduces the likelihood of drug toxicity and interactions, increases compliance, and reduces cost when compared to polytherapy. As pointed out by Pellock and Hunt (1996) converting a patient to monotherapy from polytherapy is more difficult than maintaining the patient of monotherapy. Withdrawal of AEDs may result in withdrawal seizures which prompt the physician to restart the drug that was being removed. Children with mental impairment are at particular risk for overtreatment. (Devinsky, 2002; Pellock and Hunt, 1996). In addition to having severe epilepsy the children cannot describe side effects well. Institutionalized patients are frequently prescribed a sedative barbiturate (phenobarbital or primidone) or benzodiazepine (diazepam, clonazepam, clorazepate dipotassium, or lorazepam) (Alvarez, 1998; Alvarez et al., 1998). It is well recognized that AEDs can result in significant behavioral and cognitive difficulties (Camfield et al., 1979; Cavazzuti and Nalin, 1990; Chen et al., 2001b; Farwell et al., 1990; Hanzel et al., 1992; Mayhew et al., 1992; Theodore and Porter, 1983; Vining et al., 1987; Wilder, 1985). Despite the significant number of side effects associated with phenobarbital, the drug continues to be widely used both within institutions as well as with outpatients (Rochat et al., 2001; Tetto et al., 2002). Numerous reports have demonstrated that reduced AED use can effectively maintain seizure
control with fewer adverse effects (Devinsky, 2002; Fischbacher, 1982; Litzinger et al., 1993; Mattson, 1996; Poindexter et al., 1993; Wilkinson et al., 1982). Fischbacher, (1982), in a study of institutionalized, mentally handicapped patients, found that at least one AED could be removed from the therapeutic regimen without loss of seizure control in 20 of 36 patients. Among these 20 patients, there was significant improvement in ‘well-being’ as reflected by a general scale measuring behavior and affect. Pellock and Hunt (1996) attempted to remove or reduce AEDs in 244 institutionalized patients with mental retardation varying in age from 8 to 66 years. A 19% reduction in polytherapy was accomplished and AEDs were discontinued in 13%, although half of the patients in whom AEDs were removed had recurrences. The percentage of patients receiving monotherapy increased from 36.5 to 58.1% with no observed loss of seizure control. The authors reported an overall increase in alertness in patients with reductions of the barbiturates. Alvarez (1989) discontinued AEDs in patients with developmental disabilities and a diagnosis of epilepsy who were seizure-free for several years. During 8 years of follow-up recurrences were noted in 52% of the patients. Clancy (1987), Ferngren et al. (1991), Sivenius et al. (1990), Poindexter et al. (1993) were all able to reduce sedative AEDs in mentally challenged patients with resulting improvements in alertness and quality of life.
6. Inadequate therapeutic options In general, studies examining response rate to AEDs in children with new onset partial or partial with secondarily epilepsy are similar to those seen in adults (De Silva et al., 1996; Elwes et al., 1984). De Silva et al. (1996) randomized 167 children between the ages of 3 /16 years with two or more generalized tonic /clonic or partial seizures with or without secondary generalization to treatment with phenobarbital, phenytoin, carbamazepine, or valproate. The response was quite good with 73% achieving remission after three years of follow-up. No significant differences were found
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between the three drugs with the exception of phenobarbital which resulted in a high withdrawal rate and was eventually dropped from the study. The response of children with partial and generalized tonic /clonic seizures to AEDs is not particularly surprising since the AEDs were tested for efficacy in these seizure types, albeit in adults. However, children with other seizure types such as absence, tonic, atonic, clonic, and myoclonic rarely present after two seizures and would not qualify for studies such as the one performed by De Silva et al. (1996). With the exception of absences, these seizure types are much more difficult to treat (Holmes, 1988). Many of the epileptic syndromes occurring in children also have no effective therapies. Syndromes such severe myoclonic epilepsy of infancy (Dravet syndrome), infantile spasms, Doose syndrome, Lennox /Gastaut syndrome, and Landau /Kleffner syndrome are notoriously difficult to treat with currently available AEDs. These syndromes may have a different pathophysiological basis than the typically encountered partial seizures seen in the adult population. Because seizures rarely cease with a single drug, polytherapy is employed. There is little evidence that polytherapy improves the likelihood of seizure control; however, as previously discussed, there is considerable evidence that polytherapy can increase the likelihood of side effects. AEDs are not developed to treat pediatric epilepsy syndromes. This relates primarily to the lack of suitable animal models for these syndromes (Stafstrom and Holmes, 2002). There has been little progress in the treatment of infantile spasms since the discovery of the usefulness of ACTH by Sorel and Dusaucy-Bauloye (1958) almost 35 years ago. Since there is not yet an animal model that mimics the behavioral and electroencephalographic features of the syndrome it is difficult to investigate new medications. AEDs have traditionally been screened in acute seizure models in normal adult rats, using electroshock threshold or pentylenetetrazol. While AEDs are now being tested in other models, including kindling and auditory-induced seizures, chronic models of epilepsy are not commonly used in preclinical screening. Since only drugs that work in these acute models in adult rodents reach clinical trials, it is
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not surprising that these drugs do not work in pediatric epilepsy syndromes. Another issue with rodent testing of AEDs is that many side effects that will eventually occur in humans are not identified in rodents. The type and extent of animal testing is limited and is particularly weak in assessing central nervous system adverse effects. Animal testing will not detect drug-induced cognitive and behavioral abnormalities. Furthermore, the metabolism of AEDs may be quite different in rodents and humans, reducing the ability of rodent models to predict adverse effects (Dieckhaus et al., 2000).
7. Future directions There have been incredible advances in understanding the genetic basis of the epilepsy and the role of genetics in determining efficacy and adverse effects of AEDs. There is genetic control of virtually every phase of drug metabolism from absorption through final elimination. Genetic control may be particularly important for AEDs, which have a narrow therapeutic index. In general, individuals with poor metabolizing phenotypes as a result of being homozygous for an allelic variant that is inactive, will accumulate drug. If the drug is active the patient may have excellent efficacy but experience toxicity. Conversely, rapid metabolizers will have excellent tolerability but are at risk for low efficacy. Almost every gene involved in drug metabolism is subject to common genetic polymorphisms that may contribute to individual variability in drug response. The cytochrome P450 enzymes (CYPs) are the most widely studied phase I metabolizing enzymes. Genetic variations in the CYPs are known to influence drug toxicity and efficacy (Aithal et al., 1999; Evans and Relling, 1999; Furuta et al., 1998). Polymorphisms resulting in poor or rapid metazolizers have been studied mostly in CYP2D6 and CYP2C19. In addition to cytochrome P450 enzymes, genetic variations of Phase I reactions, which include human enzymes responsible for modification of functional groups and Phase II reactions, which involve conjugation with endogenous compounds have been found.
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It is anticipated that eventually children will be screened for their ability to metabolize AEDs. Dosing will be dependent upon theses genetic tendencies. Ideally genetic testing will allow us to determine not only the best drug for the condition but the dosage required to control seizure without causing toxicity.
8. Conclusions The causes of overtreatment of children with epilepsy are multifactorial. While overtreatment remains an important problem in children with epilepsy there does appear to be an increasing awareness of the issue by epileptologists. Recent trends towards monotherapy and elimination of sedative AEDs have been helpful. However, until AEDs are developed that are effective in the majority of pediatric epilepsy syndromes it is likely that overtreatment will remain one more obstacle a child with epilepsy suffers.
Acknowledgements Supported by a Mental Retardation Research Center grant from NIH (2P30HD18655) and a grant from the NINDS (NS27984).
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