Predicting antiepileptic drug response in children with epilepsy

CME

877

CME Review

www.expert-reviews.com ISSN 1473-7175© 2011 Expert Reviews Ltd10.1586/ERN.11.11

THEMED ARTICLE y Epilepsy

Matti Sillanpää1 and Dieter Schmidt†2

1Departments of Public Health and Child Neurology, University of Turku, Turku, Finland 2Epilepsy Research Group, Goethestr. 5, D-14163 Berlin, Germany †Author for correspondence:Tel.: +49 308 017 679 [email protected]

In clinical practice, after diagnosis and when treatment has begun, it is important to predict as soon as possible which children will become seizure-free and which are likely to develop medically intractable seizures. This article summarizes factors predicting seizure remission in childhood-onset epilepsy treated with antiepileptic drugs (AEDs). Sustained seizure remission can be expected in over 90% of idiopathic epilepsies of childhood and in neurologically normal children with epilepsy having infrequent seizures showing early remission after starting treatment with AEDs. Even in the presence of symptomatic etiology of epilepsy – focal seizures and syndromes; high seizure frequency prior to or during treatment; seizure clustering; and poor or delayed response to first adequate drug therapy – up to 60% of children with treated epilepsy are able to enter long-term remission. However, remission can be expected in only 30% or less of those with catastrophic epilepsies of childhood.

KEywoRDs: drug-resistant epilepsy • epilepsy • future epilepsy management • prediction • remission • seizure freedom

Predicting antiepileptic drug response in children with epilepsyExpert Rev. Neurother. 11(6), 877–886 (2011)

Learning objectivesUpon completion of this activity, participants should be able to:• Describe factors predating epilepsy that predict seizure remission in patients with childhood-onset epilepsy treated with AEDs• Describe seizure-related factors that predict seizure remission in patients with childhood-onset epilepsy treated with AEDs• Describe treatment-related and other factors that predict seizure remission in patients with childhood-onset epilepsy treated with AEDs

Medscape: Continuing Medical Education OnlineThis activity has been planned and implemented in accordance with the Essential Areas and poli-cies of the Accreditation Council for Continuing Medical Education through the joint sponsorship

of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://www.medscape.org/journal/expertneurothera (4) view/print certificate.Release date: June 8, 2011; Expiration date: June 8, 2012

Financial & competing interests disclosureEditorElisa Manzotti, Editorial Director, Future Science Group, London, UK Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.CME AuthorLaurie Barclay, MD, Freelance writer and reviewer, Medscape, LLCDisclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.AuthorsMatti Sillanpää, Departments of Public Health and Child Neurology, University of Turku, Turku, Finland Disclosure: Matti Sillanpää has disclosed no relevant financial relationships.Dieter Schmidt, Epilepsy Research Group, Berlin, GermanyDisclosure: Dieter Schmidt has disclosed no relevant financial relationships.

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Expert Rev. Neurother. 11(6), (2011)878

Review Sillanpää & Schmidt

The ultimate goal of epilepsy treatment is seizure freedom with-out any disturbing side effects. Although seizure freedom is seen more often in childhood-onset epilepsy than in epilepsy starting in adults, not all children become seizure-free. In clinical prac-tice, it is of importance to promptly predict, following diagnosis and starting treatment, which children will become seizure-free and which are likely to develop medically intractable seizures. Predicting which child has a good chance of becoming seizure-free is reassuring for the patient and parents or caregivers. Early prediction of poor seizure outcome allows physicians to adequately inform the parents or caregivers and is useful in helping plan allocation of resources for medical support including surgery, if needed. This article focuses on antiepileptic drug (AED) response in terms of seizure outcome reported in recent population-based studies of patients with childhood-onset epilepsy. This review includes neither a discussion of adverse outcomes of AED treat-ment, nor seizure outcome after AED withdrawal or seizure out-come in adult-onset epilepsy, unless the latter is mentioned for comparison with childhood-onset epilepsy. A number of reviews have covered the less than recent literature on predicting seizure outcome in childhood-onset epilepsy [1–7].

MethodsThis article reviews AED response in terms of seizure outcome reported in population-based studies of patients with childhood-onset epilepsy published between 1990 and 2009, unless other-wise indicated. We have included population-based studies from Western countries based on two criteria, unless otherwise noted. The first criteria is follow-up of 10 years or more and the sec-ond is publications that include exact risk estimation data for individual factors.

The following definitions have been used for description of seizure outcome. Seizure remission is defined as the proportion of patients entering at least 5-year seizure freedom on or off medica-tion or terminal remission of 5 years or more seizure freedom at the end of follow-up [4,8], unless otherwise indicated. Poor seizure outcome (synonym: persistent seizures, difficult-to-treat, intrac-table, refractory or drug-resistant epilepsy) is defined either as failure to enter remission, as noted above, or as defined in the individual study. A task force of the International League Against Epilepsy (ILAE) recently defined drug-resistant epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [9].

Seizure outcome Most long-term seizure outcome studies examine the proportion of patients ever entering at least 5-year remission on or off medica-tion or terminal remission of 5 years (5YTR) or more at the end of follow-up [4,8]. A number of factors may influence the seizure outcome of children with epilepsy (Figure 1) [10,11].

Long-term population-based outcome studies in childhood-onset epilepsy commonly report approximately 70% of the patients to be in 5-year remission [12]. In a Japanese study of childhood-onset epilepsy [12], 63% were in remission after the mean follow-up

of 19 years. Patients with epilepsy tend to achieve seizure freedom over the course of time and the remission rate is subsequently dependent on the duration of follow-up. After the first 5-year remission, the 5YTR was maintained with incident epilepsy in 57, 58 and 68% of the patients at 10, 20 and 30 years from the diag-nosis, respectively [4,5]. The outcome in childhood-onset epilepsy is similar to that reported in the well-known Rochester study, which included adults and children. Annegers et al. reported the percent-age of patients that demonstrate 5 consecutive seizure-free years within 10 years after diagnosis to be 65% and within 20 years to be 76% [13]. From the viewpoint of achieving remission, favorable predictors were idiopathic/cryptogenic versus symptomatic etiol-ogy (74 vs 46%); generalized tonic–clonic seizures versus focal sei-zures (85 vs 65%); and age of less than 10 years versus 10–19 years versus more than 19 years (85 vs 68 vs 63%, respectively).

Predicting long-term outcomeTable 1 summarizes predictors of epilepsy outcome reported in studies using multivariable ana lysis. Early liability to seizures may be manifested as neonatal seizures that are, with the exception of rare genetic epilepsies, caused by underlying structural abnor-malities. Structural brain pathology may appear as neurodeficits (cerebral palsy or mental retardation/learning disability [LD]) or MRI lesions and can predispose patients to early onset of epi-lepsy. A high frequency of seizures before and during the early stage of treatment and seizure clustering during treatment predict difficult-to-treat or even intractable epilepsy [14–17].

Gender & age In a long-term incident cohort of childhood-onset epilepsy, in the group who had weekly seizures during the first year of treat-ment (which indicated a poorer seizure outcome), two-thirds were males (66 vs 34%) [18]. In a study from The Netherlands that did not examine seizure frequency during the first year of treatment, no significant difference was found between boys and girls with regard to the following variables at study onset: sex, age, seizure type, type of epilepsy, etiology, pre-existing neurological signs, postictal signs, family history, standard EEG at intake and tem-poral seizure pattern [19]. However, when the abovementioned variables were combined at study onset and at 6 months, boys had a 1.64-fold higher risk for not achieving 1-year terminal remission within 5-year follow-up [19]. Whether early childhood age at onset is a predictor of seizure outcome is controversial [20].

EtiologyIn a long-term cohort of childhood-onset epilepsy, patients with symptomatic etiology failed to enter 5YTR significantly more often than the idiopathic/cryptogenic group [8,15]. However, even the remote symptomatic group achieved cumulative 5-year remis-sion at 9–10 years follow-up of more than 60%. An underly-ing congenital cause or early childhood brain damage causing neurodeficits is a strong predictor for a poor long-term seizure outcome [21]. Finally, there is compelling evidence from a com-munity-based cohort of 77 children with new-onset temporal lobe epilepsy, who were followed prospectively with formal review

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www.expert-reviews.com 879

ReviewPredicting antiepileptic drug response in children with epilepsy

at 7 and 14 years following seizure onset, that lesions on MRI, but not initial seizure frequency or early seizure remissions, were predictive of seizure outcome [22].

Neuropsychological comorbidityChildren with epilepsy and neurodeficits bear a less favorable outlook for long-term remission [21]. In a long-term followed population-based study of 242 patients with childhood-onset epilepsy [23], risk factors for any LD (whether associated with mental retardation or not) in multivariate ana lysis included occur-rence of cerebral palsy, onset of epilepsy before the age of 6 years, and poor early effect of therapy. Among mentally normal or near normal (IQ>70) individuals, the only significant predictor for LD was a symptomatic etiology. Subjects with no LD had a 4.3-fold increased chance of 5-year remission compared with those with LD. Furthermore, the risk for relapse after a 5-year remission (with or without medication) was 3.2-fold in patients with LD compared with those who had no LD [23].

An overall incidence of psychiatric disorders of 14% was found in a long-term follow-up study of patients with childhood-onset epilepsy. Psychotic disorders were identified in 3% [24]. The most common psychoses were manic–depressive psychosis and paranoid schizophrenia. In a Canadian population-based study of intellectu-ally normal children with epilepsy, 22% were assessed to need men-tal health consultation for behavioral disturbances. Two significant predictors for poor seizure outcome were found: LD and greater than 21 seizures prior to treatment [18]. Psychiatric comorbidity was not found to be a predictor of poor seizure outcome [18].

Post-traumatic brain injuryBrain injury may be a cause or consequence of epilepsy. In a retrospective population study of children up to 18 years of age, following a post-traumatic brain injury, the risk for future epilepsy was increased in line with the severity of the trauma [25], but even mild trauma increased the risk in children and young adults [26].

Status epilepticusDuring 5-year follow-up, children with epilepsy, but without a history of status epilepticus achieved a >1-year remission (1YR) nonsignificantly less often than those without status epilepticus before intake or during follow-up [27]. However, in a long-term follow-up of childhood-onset epilepsy, status epilepticus was a predictor for not achieving remission [28]. The reasons for the discrepancy between the two studies are not clear, but there were some considerable methodological differences between the stud-ies. In the Dutch study, one status epilepticus was enough to fulfill the definition of epilepsy [27], while the long-term study, followed the ILAE definition of epilepsy [28]. The follow-up period was also different between the studies at 5 years [27] compared with at least 30 years [28].

Seizure type & epilepsy syndromeIn a Finnish population-based long-term incident study of child-hood-onset epilepsy [8], a remission of at least 5 years was achieved by 29 out of 45 (64%) people with generalized epilepsy. In the

generalized epilepsy group, remission was found in 27 out of 31 (87%) patients with idiopathic epilepsy, 14 out of 15 (93%) indi-viduals with generalized tonic–clonic seizures only (for a definition, see [7]), and in 13 out of 14 (93%) patients with other generalized epilepsies. In those with localization-related epilepsy, 57 out of 86 (66%) patients were in 5-year remission. Within the localiza-tion-related epilepsies, remission was found in 13 out of 14 (93%) patients with rolandic epilepsy, in 39 out of 65 (60%) with focal symptomatic epilepsy and in 23 out of 43 (53%) with temporal lobe epilepsy. Among patients with other localization-related epilepsy, 21 out of 29 (72%) became seizure free [8].

For a comparison, a mixed study including children and adults, demonstrated that, at 10 years of follow-up, there was a 5-year remission in 68–75% of cases with idiopathic generalized tonic–clonic seizures [13]. In childhood absence epilepsy, applying strict diagnostic criteria [29], 95% entered remission [30], while in juve-nile absence epilepsy only 44% (8 out of 17) of seizures were con-trolled after the mean 6-year duration of follow-up [31]. Of patients with juvenile myoclonic epilepsy, 44–74% become seizure free on drug treatment [32–34].

Catastrophic epilepsies of childhoodPatients with West syndrome or Lennox–Gastaut syndrome (LGS) are most unlikely to become seizure free. In 20–30 years of follow-up, a 5-year remission can be expected in approximately a third of surviving patients [35,36]. The etiology of the syndrome is a strong predictor for cognitive outcome. Mental retardation occurs in 30–50% with cryptogenic etiology and in 80–95% with symptomatic etiology [37]. LGS is often (in 13–65% of cases), and in cases of symptomatic etiology in particular, a continuation of West syndrome [36,38,39]. However, as shown in a community-based study, prenatal or perinatal abnormalities are not necessar-ily in correlation with the severity of epilepsy [40]. At follow-up of at least 10 years, 5–13% of individuals were in remission and 8% were not mentally retarded. Patients with cryptogenic LGS had a better cognitive outcome compared with patients who had symptomatic LGS [38], but another study reported no difference between the groups [39].

Delayed treatmentresponse

High seizure frequency,seizure clustering

Psychiatric comorbidities

AED: choice,dose, tolerance

Seizure type,epilepsy syndromeGenetic

factors

Seizure outcome

Etiology

Figure 1. Potential predictive factors involved in seizure outcome of children with epilepsy.AED: Antiepileptic drug.

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Table 1. Reported factors predicting drug response in multivariate ana lyses of individual population-based studies in Western countries that reported a follow-up of 10 years or more.

Variable Number in remission Risk estimation (95%CI)

p-value Study authors (total number of cases; average follow-up in years)

Ref.

Predictors of seizure remission on or off AEDs

Pre-seizure factors

Remote symptomatic etiology 37/83 (45%) vs 46/83 (55%) RR: 0.8 (0.6–1.1) ns overall cohort Sillanpää et al. (1998) (n = 176; 31 years)

[2]

35/74 (47%) vs 39/74 (53%) RR: 0.9 (0.7–1.2) ns overall incident cohort†

Sillanpää et al. (1998) (n = 176; 31 years)

[2]

Normal vs abnormal intelligence 100/130 (77%) vs 24/64(38%)

RR: 2.1 (1.5–2.9) p < 0.001 Brorson and Wranne (1987) (n = 194; 12 years)

[3]

Normal vs abnormal neurological examination

108/151 (72%) vs 16/43(35%)


[3]

Seizure frequency 2 per 6 months vs >2 per 6 months

85/109 (78%) vs 39/46(46%)


[3]

One seizure type vs several seizure types

89/123 (72%) vs 35/71(49%)

RR: 1.5 (1.1–1.9) p = 0.001 Brorson and Wranne (1987) (n = 194; 12 years)

[3]

Localization-related idiopathic vs others

13/14 (93%) vs 84/130 (65%)

RR: 1.4 (1.2–1.7) p = 0.0361 Sillanpää and Schmidt (2006) (n = 144; 37 years)

[8]

Localization-related symptomatic vs others

39/65 (0%) vs 58/79 (73%) RR: 0.8 (0.6–1.0) p = 0.00875 Sillanpää and Schmidt (2006) (n = 144; 37 years)

[8]

Temporal lobe vs others 23/43 (53%) vs 74/101(73%)


[8]

Generalized vs others 29/45 (64%) vs 68/99 (69%)

RR: 0.9 (0.7–1.2) p = 0.6148 Sillanpää and Schmidt (2006) (n = 144; 37yrs)

[8]

Generalized idiopathic vs others 27/31 (87%) vs 70/113 (62%)


[8]

Generalized cryptogenic/symptomatic vs others

2/14 (14%) vs 95/130 (73%) RR: 0.2 (0.1–0.7) p < 0.0001 Sillanpää and Schmidt (2006) (n = 144; 37 years)

[8]

Seizure-related factors

Complex partial seizures 35/74 (47%) vs 39/74 (53%) RR: 0.3 (0.2–0.5) p < 0.001 overall cohort


[2]

Complex partial seizures 15/43 (35%) vs 39/74 (53%) RR: 03 (0.1–0.6) p 0.001 overall incident cohort†


[2]

Atonic seizures 3/14 (21%) vs 11/14 (79%) RR: 0.2 (0.1–0.7) p < 0.002 overall cohort


[2]

Atonic seizures 35/74 (47%) vs 39/74 (53%) RR: 0.3 (0.2–0.5) p < 0.001 overall incident cohort†


[2]

Treatment-related factors

Early response to therapy 80/102 (78%) vs 40/102(39%)

RR: 3.7 (2.0–6.7) p < 0.001 overall cohort


[2]

Early response to therapy 50/73 (68%) vs 23/73(32%) RR: 2.2 (1.2–4.0) p < 0.001 incident cohort


[2]

†Remission off medication. Predictors of entering 5-year remission and predictors of not entering remission, each as defined by the study authors, are given separately.5YTR: 5-year terminal remission; AED: Antiepileptic drug; HR: Hazard ratio; ns: Not significant; OR: Odds ratio; RR: Rate ratio.

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Seizure frequency & seizure clusteringProspective studies of outcome in populations of children and adults with newly treated epilepsy have consistently shown that the single most important factor associated with the chance of remis-sion of seizures is the frequency of seizures in the early phase of epilepsy, with an association between increased number of seizures in this period and poorer outcome [8,41]. Two factors, present early in the course of treatment, were found to be associated with poor seizure outcome. Having weekly seizures during the first year of treatment carried a eightfold increased risk (hazard ratio [HR]: 8.2 [95% CI: 1.6–43.0]; p = 0.0125) of developing drug-resistant epi-lepsy and a twofold increased risk of never entering terminal 1YR (HR: 2.7 [95% CI: 1.5–5.0]; p = 0.0010). Having weekly seizures

prior to treatment only slightly increased the risk of never entering terminal 1YR (HR: 1.7 [95% CI: 1.04–2.9]; p = 0.0350) [15]. To provide evidence as to whether seizure clustering is associated with drug resistance, a prospective, long-term population-based study was performed. In total, 120 of the 150 patients with childhood-onset epilepsy who had been followed since the onset of the disor-der (for an average of 37.0 years, standard deviation: 7.1, median: 40.0; range: 11–42; incident, i.e., followed-up since the first sei-zure) [8]. At the end of follow-up, 26 out of 120 patients (22%) had recorded clusters of seizures. A total of 14 out of 26 patients had a cluster before drug therapy (10 out of 14 as first seizures) and 12 out of 26 during drug treatment. Seizure cluster occurring during drug therapy was significantly negatively associated with

Table 1. Reported factors predicting drug response in multivariate ana lyses of individual population-based studies in Western countries that reported a follow-up of 10 years or more.

Variable Number in remission Risk estimation (95%CI)

p-value Study authors (total number of cases; average follow-up in years)

Ref.

Predictors of seizure remission on or off AEDs


Entering 1 year remission withinfirst 5 years of treatment

93/97 (96%) vs 27/47 (57%) RR: 4.7 (1.9–11.4) p < 0.001 Sillanpää and Schmidt (2006) (n = 144; 37 years)

[8]

Likelihood for 5YTR off AEDs 45/120(45%) vs 1/8(8%) OR: 9.0 (1.1–71.9) p = 0.0383 Sillanpää and Schmidt (2009)

[44]

Predictors of not entering seizure remission

Pre-seizure factors

Symptomatic etiology 37/83 (33%) vs 75/93 (81%) RR: 0.6 (0.4–0.7) p < 0.001 Sillanpää et al. (1998) (n = 176; 31 years)

[2]

Normal vs abnormal intelligence 23/74(31%) vs 39/74(53%) RR: 0.6 (0.4–0.9) p < 0.05 Brorson and Wranne (1987) (n = 194; 12 years)

[3]

Seizure-related factors

Weekly vs less than weekly seizures prior to treatment

23/37 (62%) vs 55/65 (85%) HR: 1.7 (1.04–2.9) p = 0.00350 for never entering 1-year remission

Sillanpää and Schmidt (2009) (n = 102; 37 years)

[15]

Frequent seizures (undefined) 46/85 (54%) vs 24/109 (22%)


[3]

Several types of seizures 36/71(51%) vs 34/123 (28%)

RR: 1.8 (1.3–2.6) p = 0.001 Brorson and Wranne, (1987) (n = 194; 12 years)

[3]

Seizure-cluster vs no seizure cluster prior to drug treatment

5/12(42%) vs 12/94 (13%) RR: 3.3 (1.4–7.7) p = 0.012 Sillanpää and Schmidt (2008) (120; 37 years)

[14]


Weekly vs less than weekly seizures during first year of treatment

2/8 (25%) vs 18/19 (95%) HR: 8.2 (1.6–43.0)

p = 0.0125 for drug-resistant epilepsy


[15]

Weekly vs less than weekly seizures during first year of treatment

During first year of treatment 19/38 (50%) vs 59/64 (92%)

HR: 2.7 (1.5–5.0) p = 0.001 never entering terminal 1-year remission


[15]

†Remission off medication. Predictors of entering 5-year remission and predictors of not entering remission, each as defined by the study authors, are given separately.5YTR: 5-year terminal remission; AED: Antiepileptic drug; HR: Hazard ratio; ns: Not significant; OR: Odds ratio; RR: Rate ratio.

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both 5YTR (p = 0.0039) and with 5-year remission (p = 0.0230). By contrast, patients with seizure clustering prior to treatment versus no clustering showed no difference in seizure outcome [14]. Despite symptomatic etiology, as indicated by lesional MRI, being shown in a hospital-based study to be a risk factor even for children with low seizure frequency [22], a population-based study has dem-onstrated that those with symptomatic etiology plus early weekly seizures have a poorer seizure outcome compared with those with symptomatic etiology and less frequent seizures [15]. Finally, it is important in that regard to note that despite having either a weekly seizure frequency or symptomatic epilepsy, 76–81% of children will have entered 1YR at 10 years follow-up. In addi-tion, the proportion of children entering 1YR in both groups will increase with further long-term follow-up. Despite having either a weekly seizure frequency or symptomatic epilepsy, 63–66% of children will have entered 1-year terminal remission at 40 years of follow-up. Even in the presence of a combination of frequent seizures in the first year of treatment and symptomatic etiology, 19 out of 24 (79%) children will enter one or more periods of 1YR, and 1-year terminal remission will be achieved in nine out of 24 (37%) in the course of their disorder. However, none of these 24 children can expect to remain seizure-free from the start of treatment to the end of follow-up. It is reassuring that virtually all (51 out of 52 [98%]) children with low seizure frequency and nonsymptomatic etiology will enter 1YR during the 40 years of follow-up, and almost all (49 out of 52 [94%]) will enter 1-year terminal remission. In addition, as we have shown earlier, nearly one in five children whose epilepsy is initially well controlled will later develop drug resistance [8].

Prior AED treatmentObserving treatment outcome with AEDs provides insights into risk factors for seizure outcome. Failure of the first-ever AED treatment in newly diagnosed epilepsy is a risk factor for poor seizure outcome. Logistic regression indicated that the best model to predict refractory temporal lobe epilepsy contained only the variable ‘failure of first AED trial’, with a positive predictive value of 0.89 (95% CI: 0.76–0.96) and negative predictive value of 0.95 (95% CI: 0.87–0.99) to predict refractory temporal lobe epilepsy at 2 years [41]. This hospital-based, retrospective study of children shows that failure of first AED trial accurately predicts refrac-tory temporal lobe epilepsy at 2 years after onset. If confirmed in a prospective setting and with longer follow-up, this finding should support earlier consideration of surgical options [41]. More recently, the same group developed a model to predict the out-come of treatment with carbamazepine in children with newly diagnosed focal epilepsy of presumed temporal lobe origin, using data available at the time of diagnosis [42]. A total of 149 patients completed an adequate first AED trial. Carbamazepine was the initial drug used in 129 (87%) patients. A total of 41 of these 129 patients (32%) had persistent seizures. Significant predic-tors of initial carbamazepine failure were as follows: early risk factor for epilepsy (risk ratio: 3.1 [95% CI: 1.6–4.0]) and tem-poral lobe abnormality on MRI scan (risk ratio: 3.1 [95% CI: 1.7–4.2]). The outcome of the initial carbamazepine trial was

correctly classified in up to 78% of patients. Accurate predic-tion of initial carbamazepine failure was as high as the predictive value of 0.67 (95% CI: 0.53–0.79). Accurate prediction of initial carbamazepine success was as high as the predictive value of 0.87 (95% CI: 0.77–0.94). In this hospital-based study, standard clini-95% CI: 0.77–0.94). In this hospital-based study, standard clini-0.77–0.94). In this hospital-based study, standard clini-cal data were less than adequate for predicting response to the initial trial of carbamazepine, with prediction of carbamazepine failure being particularly difficult [43]. This study suggests that better markers of AED response and nonresponse are required to guide optimal therapy in patients with epilepsy. In a Dutch population-based study of childhood-onset epilepsy, a remission of at least 1 year at 5 years follow-up was attained by 46% of patients on the first AED, by 19% on the second AED, and by 9% on all additional AED regimens [19]. Almost 60% of the children treated with a second or additional AED regimen had a remission of at least 1 year, showing that after failure of the first AED, treatment can still be successful [19]. In a prospec-tive population-based study of childhood-onset epilepsy, delayed time to first remission identified poor long-term drug response of childhood-onset epilepsy [44]. The authors assessed time to first 1YR as a determinant of entering future 5YTR in a population-based cohort of 144 children prospectively followed up since their first unprovoked seizure before the age of 16 years up to the mean age of 48 years. The proportion of patients entering 5YTR was highly dependent on the length of time to first 1YR after start-ing adequate treatment. For 144 patients, the overall 5YTR rate decreased from 32% for those in remission at year 1 to 24% at year 2, to 5% after 3 and 4 years, to 2% after 5 years or longer. Patients who entered 1YR within the first 5 years of treatment had an 11-fold improved chance of entering 5YTR (odds ratio = 11.4; 95% CI: 2.9–45.3; p = 0.0005) and a ninefold chance for uninter-rupted 5YTR off medications (odds ratio: 9.0; 95% CI: 1.17–1.9; p = 0.0383) compared with those who did not enter 1YR within the first 5 years of treatment. Three additional independent prog-nostic factors for predicting 5YTR were confirmed: etiology, sei-zure frequency prior to treatment and seizure frequency during treatment. The study authors concluded that delayed efficacy after starting drug treatment gradually diminishes chances for long-term seizure remission, whether on medication or not. Not entering remission within 5 years of starting treatment predicts failure to achieve long-term seizure freedom in the future for the vast majority of patients [44].

Methodological concernsThe variability and the range of factors predicting seizure out-come of treatment can be explained at least in part by a number of pitfalls in the design of the published reports. Most of the studies dealing with factors predicting long-term seizure out-come are observational, retrospective, short-lasting, clinic-based and carried out in small samples of patients. Lack of specificity and sensitivity of observed risk factors is of concern [45]. Lack of predefined definitions of seizure-free periods, short duration of follow-up, small sample size and selection bias all contribute to a biased assessment of the treatment outcome and to a biased identification of the risk factors. Furthermore, predicting long

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terminal remission has been shown to be more successful than predicting continuing seizures [19]. In the absence of a random- In the absence of a random-In the absence of a random-ized control group without treatment, one cannot assess whether the observed outcome reflects changes in the natural history of epilepsy. In addition, risk factors for seizure outcome should be predefined and, if possible, assessed without knowledge of the patient’s status (whether treated or untreated).

Expert commentary Based on the available evidence, which includes studies with a small sample size, our review indicates that the long-term seizure outcome of a child with epilepsy can be predicted in many cases at the very first visit and in all cases during the first years of treatment. Although remote symptomatic etiology of the epilepsy as shown by MRI or neurocognitive deficits are risk factors for drug-resistant epilepsy, up to 60% of new-onset patients will enter remission with early treatment. Children with idiopathic epilepsy and those without MRI or neurocognitive deficits and no history of status epilepticus usually have treatable epilepsy resulting in early and long-lasting remission. The take-home messages from this article are first, that the outcome of childhood-onset epilepsy can be predicted early in most cases; second, that commonly accessible diagnostic features, such as remote symptomatic etiol-ogy, abnormal intelligence and having one of the symptomatic generalized epilepsy syndromes, generally allow the prediction of a poorer prognosis for childhood-onset epilepsy; third, the fact outlined previously that a small majority of cases do enter remission despite the presence of these poor prognostic factors shows that our current ability to predict seizure outcome is lim-ited. The obvious conclusion, which raises concern, is that we are missing important factors that determine or at least allow us to predict seizure outcome in childhood-onset epilepsy. The clinical features that were examined for their prognostic validity in the past are useful, as outlined in this review, but help us to recog-nize that they are just the ‘tip of the iceberg’. Equally important

and perhaps even more important features that determine the natural history of the child’s epilepsy remain elusive to clinical examination at present. Candidate factors to better predict the prognosis of childhood-onset epilepsy are neurobiological factors that determine the individual’s epileptogenesis prior to the first seizure and, perhaps, even during the early years of epilepsy.

Animal models of epilepsy and human tissue studies suggest that epileptogenesis involves a cascade of molecular, cellular and neuronal network alterations [46]. Within minutes to days fol-lowing the initial insult, there are acute early changes in neu-ronal networks, which include rapid alterations to ion channel kinetics as a result of membrane depolarization, post-translational modifications to existing functional proteins and activation of immediate early genes. Subacute changes occur from hours to weeks and include transcriptional events, neuronal death and activation of inflammatory cascades. The chronic changes that follow over weeks to months include anatomical changes, such as neurogenesis, mossy fiber sprouting, network reorganization and gliosis. These epileptogenic processes are developmentally regulated and might contribute to differences in epileptogenesis between adult and developing brains and, perhaps, between drug-responsive and drug-resistant cases of epilepsy. An understanding of these factors could yield potential biomarkers for the preven-tion of epileptogenesis and, more importantly for the topic of this article, also provide biomarkers for identifying patients at risk of developing drug-resistant epilepsy.

Five-year view Although knowledge regarding the predictive factors for seizure outcome of children with epilepsy is informative, the challenge for the next 5 years is to translate this knowledge into clinical benefit. To achieve higher rates of seizure freedom, this may mean being able to eliminate symptomatic causes of epilepsy such as prenatal or postnatal brain damage through injury and status epilepti-cus. Better perinatal care may decidedly improve the occurrence

Key issues

• Based on the available evidence, which includes studies with a small sample size, our article indicates that long-term seizure outcome of a child with epilepsy can be predicted in many cases at the very first visit and in all cases during the first years of treatment.

• Although remote symptomatic etiology of the epilepsy as shown by MRI or neurocognitive deficits are risk factors for drug-resistant epilepsy, up to 60% of new-onset patients will enter remission with early treatment.

• Children with idiopathic epilepsy and those without MRI or neurocognitive deficits and no history of status epilepticus usually have well-treatable epilepsy, resulting in early and long-lasting remission.

• A small majority of cases do enter remission despite the presence of these poor prognostic factors. This shows that our current ability to predict seizure outcome is limited.

• The obvious conclusion, which raises concern, is that we are missing important factors that determine or at least allow us to predict seizure outcome in childhood-onset epilepsy.

• Candidate factors to better predict the prognosis of childhood-onset epilepsy are neurobiological factors, including molecular, cellular and neuronal network alterations, that determine the individual’s epileptogenesis – that is, the process of developing epilepsy – prior to the first seizure and, perhaps, even during the early years of epilepsy.

• The chronic changes that follow in the weeks to months after a first seizure include anatomical changes, such as neurogenesis, mossy fiber sprouting, network reorganization and gliosis. These epileptogenic processes are developmentally regulated and might contribute to differences in epileptogenesis between adult and developing brains, and, perhaps, between drug-responsive and drug-resistant cases of epilepsy.

• An understanding of these factors could yield potential biomarkers for identifying patients at risk of developing drug-resistant epilepsy.

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ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Sillanpää & Schmidt

rate of epilepsy in childhood. Another area for improvement of seizure outcome in children is to tackle the elusive causes of mental retardation. More aggressive treatment early in the course of epilepsy through modern drugs may avoid children entering into the dark universe of drug-resistant epilepsy with high mor-bidity. One further challenge is to identify factors that predict

epileptogenesis – that is, the underlying disease process that enter-tains the occurrence of seizures as symptoms. The quest for finding a cure for epilepsy includes a search for predictive factors that drive the development from injury of the brain in the widest sense to the development of the first seizure and, furthermore, what propels the disease to become intractable to drugs.

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Predicting antiepileptic drug response in children with epilepsy

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Predicting antiepileptic drug response in children with epilepsy

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Sillanpää & Schmidt

1. You are asked to see a 3-year-old boy with seizures. Based on the above review by Drs. Sillanpää and Schmidt, which of the following statements about factors predating epilepsy that predict seizure remission is most likely correct?

£ A Intelligence is not a factor predicting remission

£ B Boys have a better prognosis for remission than girls

£ C Neurologic examination is not a factor predicting remission

£ D Remote symptomatic etiology based on MRI or neurocognitive deficits may increase risk of not achieving remission

3. Based on the above review, which of the following statements about treatment-related and other factors that predict seizure remission in patients with childhood-onset epilepsy treated with AEDs is most likely correct?

£ A Early response to therapy is not a predictor of remission

£ B Entering 1-year remission, on or off AEDs, within the first 5 years of treatment is not a predictor of maintaining remission

£ C Children with poor prognostic factors inevitably require surgery

£ D Neurobiologic factors, including molecular, cellular and neuronal network changes that determine epileptogenesis, may help predict prognosis of childhood-onset epilepsy

2. Based on the above review, which of the following seizure-related factors in the patient described in question 1 is most likely to predict seizure remission in response to antiepileptic drug (AED) treatment?

£ A Generalized idiopathic seizures

£ B 4 seizures in a 6-month period

£ C Temporal lobe seizures

£ D Atonic seizuresExp

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Predicting antiepileptic drug response in children with epilepsy