Predicting pharmacoresistance in pediatric epilepsyElaine C.Wirrell

Divisions of Epilepsy and Child andAdolescent Neurology, Department of Neurology,

MayoClinic, Rochester, Minnesota, U.S.A.

SUMMARY

Approximately 20% of children with epilepsy will

be pharmacoresistant. The impact of intractable

epilepsy extends far beyond just the seizures to

result in intellectual disability, psychiatric comor-

bidity, physical injury, sudden unexpected death in

epilepsy (SUDEP), and poor quality of life. Various

predictors of pharmacoresistance have been iden-

tified; however, accurate prediction is still chal-

lenging. Population-based epidemiologic studies

show that the majority of children who develop

pharmacoresistance do so relatively early in the

course of their epilepsy. However, approximately

one third of children who initially appear pharma-

coresistant in the first few years after epilepsy

onset will ultimately achieve seizure freedom

without surgery. The most significant predictor

that early pharmacoresistance will not remit is the

presence of a neuroimaging abnormality. Such

children should be strongly considered for surgical

evaluation.

KEY WORDS: Pharmacoresistance, Intractable,

Pediatric, Epilepsy.

Epilepsy is one of the most common neurologic dis-orders in children, with an approximate incidence of 45per 100,000 per year (Camfield et al., 1996; Wirrellet al., 2011). Although population-based studies haveshown a reasonably favorable long-term outcome, withnearly two thirds achieving seizure freedom and nearlyhalf being able to discontinue antiepileptic medication(Brorson & Wranne, 1987; Camfield & Camfield, 2003;Sillanpaa & Schmidt, 2006), approximately 20% ofchildren show pharmacoresistance to trials of multipleantiepileptic drugs (AEDs) and are deemed “medicallyintractable.” Uncontrolled seizures and exposure to highdoses of multiple, ineffective medications result in con-siderable comorbidity, including intellectual disability;learning and attention problems; physical injury; suddenunexplained death in epilepsy (SUDEP); psychiatricproblems such as depression, anxiety disorders, failureto achieve or loss of independence; and poor quality oflife.

First-line therapy for pediatric epilepsy consists ofAEDs. However, the probability of seizure controldiminishes with increasing numbers of ineffective drugstried. In a prospective study of children with new-onset

epilepsy, the first AED failed for lack of efficacy in25% (Carpay et al., 1998). Fifty-one percent of thesechildren had a good response to the second agent. How-ever, the chance of achieving a remission of >1 yearwith subsequent regimens was only 29% after twoAEDs had failed and 10% after three AEDs had failed.The prognosis appears more guarded for nonidiopathicfocal epilepsy (Elkis et al., 1993; Aso & Watanabe,2000).

For children with pharmacoresistent epilepsy, othertherapeutic options exist, and at times can be very effec-tive. In select cases, with an identified, surgically reme-diable focus, targeted resection is a viable option, withup to 60–70% achieving seizure freedom. Dietary ther-apy with the ketogenic diet may result in seizure free-dom in 10–15%, and worthwhile seizure reduction inmore than half of cases. Palliative surgeries may alsomarkedly reduce seizure burden. Callosotomy is ofteneffective for children with drop seizures, who are notcandidates for focal resection, and vagus nerve stimula-tion results in meaningful seizure reduction in one thirdto one half of children.

Rapid and complete seizure control is the best mecha-nism to limit associated comorbidities. Although earliersurgery offers the benefit of quicker seizure control, andpossible reduction of associated comorbidities, surgery isnot without risk. Hence, accurate and early prediction ofpharmacoresistance is crucial to make the correct manage-ment choice.

Address correspondence to Elaine C. Wirrell, Child and AdolescentNeurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, U.S.A.E-mail: Wirrell.elaine@mayo.edu

Wiley Periodicals, Inc.© 2013 International League Against Epilepsy

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EPIDEMIOLOGYANDCLINICALASPECTSOFPHARMACORESISTANCE

What Factors Are Predictiveof Pharmacoresistancein Pediatric Epilepsy?

Electroclinical syndrome can be defined in approxi-mately one third of children with new-onset epilepsy, andis one of the most robust predictors of outcome(Table 1). Most syndromes have a clearly defined naturalhistory, and identification provides important informationon likelihood of seizure control and chance of long-termremission. Furthermore, some syndromes have uniqueresponse to specific AEDs, with some drugs resulting inmarked seizure reduction and others in significant exac-erbation. Identification of a structural etiology on neuro-imaging is also predictive of higher likelihood ofpharmacoresistance; however, the specific pathologyappears important. Studies have shown high rates ofpharmacoresistance with cortical dysplasia, mesial tem-poral sclerosis, and dual pathology, but lower rates withencephalomalacia (Semah et al., 1998; Dhamija et al.,2011). Other reported adverse predictors of outcome areshown in Table 2 and include underlying neurologicdeficit (Holowach et al., 1972; Annegers et al., 1979;Shorvon & Reynolds, 1982; Elwes et al., 1984; Brorson& Wranne, 1987; Hauser et al., 1996; Cockerell et al.,1997), partial onset seizures or multiple seizure types (El-wes et al., 1984; Brorson & Wranne, 1987; CollaborativeGroup, 1992; Cockerell et al., 1997; Arts et al., 1999),high initial seizure frequency (Elwes et al., 1984; Colla-borative Group, 1992; Cockerell et al., 1997; Arts et al.,1999; Berg et al., 2001b; Brodie & Kwan, 2002; Cam-field & Camfield, 2003; Mohanraj & Brodie, 2006) neo-natal seizures (Berg et al., 2001b; Camfield & Camfield,2003), early age at onset, or onset after 12 years (Casettaet al., 1999; Berg et al., 2001b; Camfield & Camfield,2003), and failure to respond to the first AED (Sillanpaa,1993; Camfield & Camfield, 1996; Kwan & Brodie,2000). Predictors that are inconsistently associated withpoorer outcome are epileptiform discharge or focal slow-ing on electroencephalography (EEG) (Shafer et al.,1988; Berg et al., 2001b; Camfield & Camfield, 2003;Spooner et al., 2006), status epilepticus (Sillanpaa, 1993;Casetta et al., 1999; Berg et al., 2001a; Callaghan et al.,2007), or history of febrile seizures (Dlugos, 2001; Hitiriset al., 2007).

Several models have been proposed to predict outcomes,based on combinations of the above factors. Based on acombined model utilizing data from both the Nova Scotiaand Dutch studies on epilepsy, Geelhoed et al. (2005)found that accurate prediction of remission could be madein 70% of cases, with the two most significant factors beingepilepsy type and age at first seizures. In another modelidentifying pharmacoresistance in children presentingbefore 3 years of age, probability of pharmacoresistanceranged from 0.01 to 0.97 based on the presence of absence

of four factors—age at onset <12 months, developmentaldelay at diagnosis, neuroimaging abnormality, and focalslowing on initial EEG (Wirrell et al., 2012).

When Does PharmacoresistanceOccur?

Several population-based studies of children with new-onset epilepsy have suggested that pharmacoresistance

Table 1. Electroclinical syndromes and

natural history

Syndrome

Chance of

long-term

seizure

control

Likelihood

of remission

Neonatal onset

Benign familial neonatal epilepsy Very high Very high

Early myoclonic encephalopathy Very low Very low

Ohtahara’s syndrome Very low Very low

Infancy

Epilepsy of infancy with migrating

focal seizures

Very low Very low

West syndrome Lowa Low

Myoclonic epilepsy in infancy Moderate

to high

High

Benign infantile epilepsy Very high Very high

Dravet syndrome Very low Very low

Childhood

Genetic epilepsy with febrile

seizures plus

High Often

Panayiotopoulos syndrome High Very high

Myoclonic atonic epilepsy of

Doose

Moderateb High

Benign epilepsy with

centrotemporal spikes

Very high Very high

Autosomal dominant frontal lobe

epilepsy

Very high Unknown

Epilepsy with myoclonic absences Low Low

Lennox-Gastaut syndrome Very low Very low

Continuous spike-wave in slow

sleep

Moderatec Moderate to high

Landau-Kleffner syndrome High High

Childhood absence epilepsy Moderate

to high

Moderate to high

Adolescence-adult

Juvenile absence epilepsy Moderate

to high

Low

Juvenile myoclonic epilepsy Moderate

to high

Low

Epilepsy with generalized tonic

clonic seizures alone

Moderate

to high

Low

Progressive myoclonic epilepsies Very low Very low

Autosomal dominant epilepsy with

auditory features

High Unknown

aAlthough spasms may respond to therapy, many children have recurrentseizures of other types.

bSeizures are often pharmacoresistent for a period after onset, butusually ultimately are controlled.

cSeizures often refractory during period of active continuous spike andwave in sleep but frequently remit with increasing age.

Epilepsia, 54(Suppl. S2):19–22, 2013doi: 10.1111/epi.12179

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E. C.Wirrell

usually is seen early in the course of epilepsy. In the Con-necticut study of epilepsy, nearly three fourths of the 23%of children who were medically intractable at final follow-up developed pharmacoresistance in the first 3 years oftheir epilepsy (Berg et al., 2006). Although those with“catastrophic” epilepsy developed pharmacoresistanceearly, those with focal epilepsy were more likely to have“delayed” intractability, defined as pharmacoresistancedeveloping after the first 3 years. In the Dutch study ofepilepsy, of the 8.4% of children who were pharmacore-sistent at final follow-up, more than half had met thesecriteria in the first 5 years of follow-up (Geerts et al.,2012). Finally, in the Olmsted County, MN, study ofepilepsy, two thirds of children who were pharmacoresis-tent at final follow-up had met these criteria within2 years of their diagnosis (Wirrell EC, unpublished data).

However, data obtained from surgical centers suggest asomewhat different picture. In a study of 333 adults andchildren presenting to seven surgical centers with pharma-coresistent epilepsy, Berg et al. (2003) found that themean latency from epilepsy onset until failure of the sec-ond AED was 9.1 years, and that more than one fourthhad experienced a prior remission lasting longer than1 year. Furthermore, younger age at onset was associatedwith both longer latency to failure of second medicationand higher incidence of prior remission.

Do Children with EarlyPharmacoresistance Ever

Experience Seizure Controlwithout Surgery?

Children with pharmacoresistent epilepsy are at risk formultiple comorbidities and are often exposed to numerousineffective AEDs at high therapeutic doses. Although epi-lepsy surgery may be considered, there is often reluctanceto proceed with such an invasive therapy in the hopes thatepilepsy may ultimately remit. Only a small number ofstudies have reported outcome in medically intractableepilepsy. Although Callaghan et al. (2007) found that only

11% continuing medical treatment achieved a 6-monthterminal remission and remained seizure free at follow-up, Huttenlocher & Hapke (1990) reported a somewhatbrighter picture, particularly if cognition was normal. Sei-zure control was achieved in 4% of children with intracta-ble epilepsy who had normal cognitive function per year,but in only 1.5% of those with low IQ. There are variedresults in the literature regarding how often new AEDsresult in seizure control. In adults, Kwan and Brodie(2000) noted only 4% achieved seizure control withanother AED after two failed for lack of efficacy. How-ever, Luciano and Shorvon (2007) reported that 16% ofnew drug additions resulted in seizure freedom for� 12 months and 28% of their population with chronicepilepsy achieved a 12-month remission with changes inmedication.

In the Dutch study of epilepsy, 59% of children whoappeared medically intractable during the first 5 yearsafter epilepsy onset either continued to be intractable atfinal follow-up or had undergone epilepsy surgery (Geertset al., 2012). Compared to those who were no longerintractable at final follow-up, those with persisting intrac-tability had a slightly longer time to intractability(2.0 years compared to 1.2 years, p < 0.05). In the Olm-sted County, MN, study of epilepsy, nearly 20% of chil-dren met criteria for pharmacoresistance within the first2 years of their epilepsy, meaning they had failed toachieve seizure control with two or more AEDs and hadcontinued seizures more frequently than every 6 months.Of these, 36% achieved seizure freedom with medicaltherapy alone, and another 9% became seizure-free aftersuccessful epilepsy surgery (Wirrell et al., 2013). Themost significant predictor against achieving seizure free-dom without surgery was neuroimaging abnormality—only 8.6% of children with an abnormal magneticresonance imaging (MRI) with early pharmacoresistanceachieved seizure control without surgery. Therefore, inchildren with early pharmacoresistance and an abnormalneuroimaging study, early surgical intervention should bestrongly considered to limit comorbidities. Conversely,a more cautious approach is suggested for children withnormal imaging, as many remit with time.

ConclusionsPharmacoresistent epilepsy in children results in

significant intellectual, behavioral, and psychiatric co-morbidities, which may be more problematic to the childthan the actual seizures. Accurate prediction of pharmaco-resistance remains challenging. In contrast to studies fromsurgical centers, population-based studies suggest thatmost children who develop pharmacoresistance do so rela-tively early in their epilepsy course. Although one third ofchildren with early pharmacoresistance ultimately achieveseizure control, the prognosis is much grimmer for those

Table 2. Predictors of pharmacoresistent

epilepsy

Consistent Inconsistent

Syndrome: symptomatic generalized >nonidiopathic focal > idiopathic

High initial seizure frequency

Neonatal seizure

Age at onset >12 years

Intellectual disability

Abnormal exam

Abnormal imaging

Failure of first AED or failure to

respond in first year

Febrile seizures

Status epilepticus

EEG discharges or focal

slowing

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Predicting Pharmacoresistance in Pediatric Epilepsy

with abnormal neuroimaging. Such children should beevaluated for early surgical intervention, as further trialsof medical therapy are likely to be futile.

DisclosureDr. Wirrell has no conflicts of interest to disclose The author confirms

that she has read the Journal’s position on issues involved in ethical publi-cation and affirms that this report is consistent with those guidelines.

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