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Keywords:

  • Pharmacoresistance;
  • Intractable;
  • Pediatric;
  • Epilepsy

Summary

  1. Top of page
  2. Summary
  3. What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?
  4. When Does Pharmacoresistance Occur?
  5. Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?
  6. Conclusions
  7. Disclosure
  8. References

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 comorbidity, physical injury, sudden unexpected death in epilepsy (SUDEP), and poor quality of life. Various predictors of pharmacoresistance have been identified; however, accurate prediction is still challenging. 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 pharmacoresistant 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.

Epilepsy is one of the most common neurologic disorders in children, with an approximate incidence of 45 per 100,000 per year (Camfield et al., 1996; Wirrell et al., 2011). Although population-based studies have shown a reasonably favorable long-term outcome, with nearly two thirds achieving seizure freedom and nearly half being able to discontinue antiepileptic medication (Brorson & Wranne, 1987; Camfield & Camfield, 2003; Sillanpaa & Schmidt, 2006), approximately 20% of children show pharmacoresistance to trials of multiple antiepileptic drugs (AEDs) and are deemed “medically intractable.” Uncontrolled seizures and exposure to high doses of multiple, ineffective medications result in considerable comorbidity, including intellectual disability; learning and attention problems; physical injury; sudden unexplained death in epilepsy (SUDEP); psychiatric problems such as depression, anxiety disorders, failure to achieve or loss of independence; and poor quality of life.

First-line therapy for pediatric epilepsy consists of AEDs. However, the probability of seizure control diminishes with increasing numbers of ineffective drugs tried. In a prospective study of children with new-onset epilepsy, the first AED failed for lack of efficacy in 25% (Carpay et al., 1998). Fifty-one percent of these children had a good response to the second agent. However, the chance of achieving a remission of >1 year with subsequent regimens was only 29% after two AEDs had failed and 10% after three AEDs had failed. The prognosis appears more guarded for nonidiopathic focal epilepsy (Elkis et al., 1993; Aso & Watanabe, 2000).

For children with pharmacoresistent epilepsy, other therapeutic options exist, and at times can be very effective. In select cases, with an identified, surgically remediable focus, targeted resection is a viable option, with up to 60–70% achieving seizure freedom. Dietary therapy with the ketogenic diet may result in seizure freedom in 10–15%, and worthwhile seizure reduction in more than half of cases. Palliative surgeries may also markedly reduce seizure burden. Callosotomy is often effective for children with drop seizures, who are not candidates for focal resection, and vagus nerve stimulation results in meaningful seizure reduction in one third to one half of children.

Rapid and complete seizure control is the best mechanism to limit associated comorbidities. Although earlier surgery offers the benefit of quicker seizure control, and possible reduction of associated comorbidities, surgery is not without risk. Hence, accurate and early prediction of pharmacoresistance is crucial to make the correct management choice.

What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?

  1. Top of page
  2. Summary
  3. What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?
  4. When Does Pharmacoresistance Occur?
  5. Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?
  6. Conclusions
  7. Disclosure
  8. References

Electroclinical syndrome can be defined in approximately one third of children with new-onset epilepsy, and is one of the most robust predictors of outcome (Table 1). Most syndromes have a clearly defined natural history, and identification provides important information on likelihood of seizure control and chance of long-term remission. Furthermore, some syndromes have unique response to specific AEDs, with some drugs resulting in marked seizure reduction and others in significant exacerbation. Identification of a structural etiology on neuroimaging is also predictive of higher likelihood of pharmacoresistance; however, the specific pathology appears important. Studies have shown high rates of pharmacoresistance with cortical dysplasia, mesial temporal sclerosis, and dual pathology, but lower rates with encephalomalacia (Semah et al., 1998; Dhamija et al., 2011). Other reported adverse predictors of outcome are shown in Table 2 and include underlying neurologic deficit (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 (Elwes et al., 1984; Brorson & Wranne, 1987; Collaborative Group, 1992; Cockerell et al., 1997; Arts et al., 1999), high initial seizure frequency (Elwes et al., 1984; Collaborative Group, 1992; Cockerell et al., 1997; Arts et al., 1999; Berg et al., 2001b; Brodie & Kwan, 2002; Camfield & Camfield, 2003; Mohanraj & Brodie, 2006) neonatal seizures (Berg et al., 2001b; Camfield & Camfield, 2003), early age at onset, or onset after 12 years (Casetta et 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 with poorer outcome are epileptiform discharge or focal slowing 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; Hitiris et al., 2007).

Table 1. Electroclinical syndromes and natural history
SyndromeChance of long-term seizure controlLikelihood of remission
  1. a

    Although spasms may respond to therapy, many children have recurrent seizures of other types.

  2. b

    Seizures are often pharmacoresistent for a period after onset, but usually ultimately are controlled.

  3. c

    Seizures often refractory during period of active continuous spike and wave in sleep but frequently remit with increasing age.

Neonatal onset  
Benign familial neonatal epilepsyVery highVery high
Early myoclonic encephalopathyVery lowVery low
Ohtahara's syndromeVery lowVery low
Infancy  
Epilepsy of infancy with migrating focal seizuresVery lowVery low
West syndromeLowaLow
Myoclonic epilepsy in infancyModerate to highHigh
Benign infantile epilepsyVery highVery high
Dravet syndromeVery lowVery low
Childhood  
Genetic epilepsy with febrile seizures plusHighOften
Panayiotopoulos syndromeHighVery high
Myoclonic atonic epilepsy of DooseModeratebHigh
Benign epilepsy with centrotemporal spikesVery highVery high
Autosomal dominant frontal lobe epilepsyVery highUnknown
Epilepsy with myoclonic absencesLowLow
Lennox-Gastaut syndromeVery lowVery low
Continuous spike-wave in slow sleepModeratecModerate to high
Landau-Kleffner syndromeHighHigh
Childhood absence epilepsyModerate to highModerate to high
Adolescence-adult  
Juvenile absence epilepsyModerate to highLow
Juvenile myoclonic epilepsyModerate to highLow
Epilepsy with generalized tonic clonic seizures aloneModerate to highLow
Progressive myoclonic epilepsiesVery lowVery low
Autosomal dominant epilepsy with auditory featuresHighUnknown
Table 2. Predictors of pharmacoresistent epilepsy
ConsistentInconsistent

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

Several models have been proposed to predict outcomes, based on combinations of the above factors. Based on a combined model utilizing data from both the Nova Scotia and Dutch studies on epilepsy, Geelhoed et al. (2005) found that accurate prediction of remission could be made in 70% of cases, with the two most significant factors being epilepsy type and age at first seizures. In another model identifying pharmacoresistance in children presenting before 3 years of age, probability of pharmacoresistance ranged from 0.01 to 0.97 based on the presence of absence of four factors—age at onset <12 months, developmental delay at diagnosis, neuroimaging abnormality, and focal slowing on initial EEG (Wirrell et al., 2012).

When Does Pharmacoresistance Occur?

  1. Top of page
  2. Summary
  3. What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?
  4. When Does Pharmacoresistance Occur?
  5. Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?
  6. Conclusions
  7. Disclosure
  8. References

Several population-based studies of children with new-onset epilepsy have suggested that pharmacoresistance usually is seen early in the course of epilepsy. In the Connecticut 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 of their epilepsy (Berg et al., 2006). Although those with “catastrophic” epilepsy developed pharmacoresistance early, those with focal epilepsy were more likely to have “delayed” intractability, defined as pharmacoresistance developing after the first 3 years. In the Dutch study of epilepsy, of the 8.4% of children who were pharmacoresistent at final follow-up, more than half had met these criteria in the first 5 years of follow-up (Geerts et al., 2012). Finally, in the Olmsted County, MN, study of epilepsy, two thirds of children who were pharmacoresistent at final follow-up had met these criteria within 2 years of their diagnosis (Wirrell EC, unpublished data).

However, data obtained from surgical centers suggest a somewhat different picture. In a study of 333 adults and children presenting to seven surgical centers with pharmacoresistent epilepsy, Berg et al. (2003) found that the mean latency from epilepsy onset until failure of the second AED was 9.1 years, and that more than one fourth had experienced a prior remission lasting longer than 1 year. Furthermore, younger age at onset was associated with both longer latency to failure of second medication and higher incidence of prior remission.

Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?

  1. Top of page
  2. Summary
  3. What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?
  4. When Does Pharmacoresistance Occur?
  5. Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?
  6. Conclusions
  7. Disclosure
  8. References

Children with pharmacoresistent epilepsy are at risk for multiple comorbidities and are often exposed to numerous ineffective AEDs at high therapeutic doses. Although epilepsy surgery may be considered, there is often reluctance to proceed with such an invasive therapy in the hopes that epilepsy may ultimately remit. Only a small number of studies have reported outcome in medically intractable epilepsy. Although Callaghan et al. (2007) found that only 11% continuing medical treatment achieved a 6-month terminal remission and remained seizure free at follow-up, Huttenlocher & Hapke (1990) reported a somewhat brighter picture, particularly if cognition was normal. Seizure control was achieved in 4% of children with intractable epilepsy who had normal cognitive function per year, but in only 1.5% of those with low IQ. There are varied results in the literature regarding how often new AEDs result in seizure control. In adults, Kwan and Brodie (2000) noted only 4% achieved seizure control with another AED after two failed for lack of efficacy. However, Luciano and Shorvon (2007) reported that 16% of new drug additions resulted in seizure freedom for ≥12 months and 28% of their population with chronic epilepsy achieved a 12-month remission with changes in medication.

In the Dutch study of epilepsy, 59% of children who appeared medically intractable during the first 5 years after epilepsy onset either continued to be intractable at final follow-up or had undergone epilepsy surgery (Geerts et al., 2012). Compared to those who were no longer intractable at final follow-up, those with persisting intractability had a slightly longer time to intractability (2.0 years compared to 1.2 years, p < 0.05). In the Olmsted County, MN, study of epilepsy, nearly 20% of children met criteria for pharmacoresistance within the first 2 years of their epilepsy, meaning they had failed to achieve seizure control with two or more AEDs and had continued seizures more frequently than every 6 months. Of these, 36% achieved seizure freedom with medical therapy alone, and another 9% became seizure-free after successful epilepsy surgery (Wirrell et al., 2013). The most significant predictor against achieving seizure freedom without surgery was neuroimaging abnormality—only 8.6% of children with an abnormal magnetic resonance imaging (MRI) with early pharmacoresistance achieved seizure control without surgery. Therefore, in children with early pharmacoresistance and an abnormal neuroimaging study, early surgical intervention should be strongly considered to limit comorbidities. Conversely, a more cautious approach is suggested for children with normal imaging, as many remit with time.

Conclusions

  1. Top of page
  2. Summary
  3. What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?
  4. When Does Pharmacoresistance Occur?
  5. Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?
  6. Conclusions
  7. Disclosure
  8. References

Pharmacoresistent epilepsy in children results in significant intellectual, behavioral, and psychiatric co-morbidities, which may be more problematic to the child than the actual seizures. Accurate prediction of pharmacoresistance remains challenging. In contrast to studies from surgical centers, population-based studies suggest that most children who develop pharmacoresistance do so relatively early in their epilepsy course. Although one third of children with early pharmacoresistance ultimately achieve seizure control, the prognosis is much grimmer for those with abnormal neuroimaging. Such children should be evaluated for early surgical intervention, as further trials of medical therapy are likely to be futile.

Disclosure

  1. Top of page
  2. Summary
  3. What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?
  4. When Does Pharmacoresistance Occur?
  5. Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?
  6. Conclusions
  7. Disclosure
  8. References

Dr. Wirrell has no conflicts of interest to disclose The author confirms that she has read the Journal's position on issues involved in ethical publication and affirms that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. What Factors Are Predictive of Pharmacoresistance in Pediatric Epilepsy?
  4. When Does Pharmacoresistance Occur?
  5. Do Children with Early Pharmacoresistance Ever Experience Seizure Control without Surgery?
  6. Conclusions
  7. Disclosure
  8. References