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Cognitive outcome of pediatric epilepsy surgery across ages and different types of surgeries: A monocentric 1-year follow-up study in 306 patients of school age

Open ArchivePublished:July 26, 2019DOI:https://doi.org/10.1016/j.seizure.2019.07.021

      Highlights

      • Neuropsychological outcomes across different surgeries in a large cohort of children are reported.
      • Before surgery, 85% of the patients were neuropsychologically impaired.
      • Seizure control was excellent with 81% being seizure free one year after surgery.
      • Recovery is evident in many children and across most neuropsychological domains.
      • Cognitive change depends on age, damage, seizure control, and drug load.

      Abstract

      Objective

      The neuropsychological outcome of pediatric epilepsy surgery has been reported before, but only few studies compared different major types of surgery in differentially located epilepsies.

      Methods

      Neuropsychological performance of 306 children and adolescents (ages 6–17 years) were assessed before and one year after epilepsy surgery. Individual impairments, changes into and out of impairment, as well as intraindividually meaningful positive or negative changes were examined. Regression analyses addressed the effects of site, side, pathology, type of surgery, seizure outcome, and drug change on the cognitive and behavioral domains.

      Results

      Preoperatively 85% of the patients had cognitive impairments in at least one domain, 71% had behavioral problems. Postoperatively the number of impaired patients dropped considerably: 21–50% of the patients changed from impaired to unimpaired, individually significant gains were registered in 16–42%. Seizure freedom was achieved in 81% of all patients. The number of antiepileptic drugs decreased significantly. Seizure freedom, a younger age at evaluation, a later age at onset, a lower antiepileptic drug load, and less baseline damage predict better cognitive and behavioral outcomes. Gender, pathology, localization, and lateralization had little or no impact.

      Conclusion

      Differentially located and lateralized epilepsies hardly differed in cognition and behavior indicating nonspecific developmental rather than domain specific impairments. Childhood epilepsy surgery is very successful and the functional improvements one year after surgery confirm the general relevance of baseline damage, mental reserve capacities, functional plasticity, the preservation of functional tissues and the functional release due to seizure freedom and drug load reduction.

      Keywords

      1. Introduction

      Pediatric patients with epilepsy for whom epilepsy surgery is a treatment option very often profit from this intervention in terms of becoming seizure free. However, while seizure freedom can be achieved in many patients, the eventual neuropsychological costs of successful and even more important of non-successful surgery represent a relevant issue under discussion. Neuropsychological impairments are almost present when epilepsy starts already, they can increase with ongoing epilepsy, and surgery may add to this [
      • Hermann B.
      • Seidenberg M.
      • Bell B.
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      • Magnotta V.
      The neurodevelopmental impact of childhood-onset temporal lobe epilepsy on brain structure and function.
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      • Schulze-Bonhage A.
      • Bast T.
      Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence.
      ,
      • Farwell J.R.
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      Neuropsychological abilities of children with epilepsy.
      ,
      • Freitag H.
      • Tuxhorn I.
      Cognitive function in preschool children after epilepsy surgery: rationale for early intervention.
      ]. The existence of the weakening of cognitive functions in epilepsy patients is emphasized by a study comparing the IQ and other cognitive tasks of TLE-patients with their healthy siblings. It was revealed that more than 50% of these patients showed worse performances (difference of more than one standard deviation) than their siblings [
      • Helmstaedter C.
      Effects of chronic temporal lobe epilepsy on memory functions.
      ]. Postoperative impairments in addition to baseline deficits are likely in the time shortly after surgery and this needs to be considered in clinical decision making and patient counseling [
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative neuropsychological profiles in children and adolescents with temporal lobe epilepsy.
      ,
      • Gleissner U.
      • Sassen R.
      • Schramm J.
      • Elger C.E.
      • Helmstaedter C.
      Greater functional recovery after temporal lobe epilepsy surgery in children.
      ].
      Today, when epilepsy surgery can be considered a well-established treatment for epilepsy, the cognitive outcomes of epilepsy surgery and their determinants are largely known [
      • Helmstaedter C.
      • Witt J.A.
      How neuropsychology can improve the care of individual patients with epilepsy. Looking back and into the future.
      ]. The relevant predictors are baseline performance reflecting pathology and reserve capacities, the involvement of functional tissues in surgery (i.e. the extent of surgery), seizure control, and change of antiepileptic drug treatment (tapering, withdrawal) [
      • Hermann B.
      • Seidenberg M.
      • Bell B.
      • Rutecki P.
      • Sheth R.
      • Ruggles K.
      • Wendt G.
      • O’Leary D.
      • Magnotta V.
      The neurodevelopmental impact of childhood-onset temporal lobe epilepsy on brain structure and function.
      ,
      • Loddenkemper T.
      • Holland K.D.
      • Stanford L.D.
      • Kotagal P.
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      • Wyllie E.
      Developmental outcome after epilepsy surgery in infancy.
      ,
      • Ramantani G.
      • Kadish N.E.
      • Brandt A.
      • Strobl K.
      • Stathi A.
      • Wiegand G.
      • Schubert‐Bast S.
      • Mayer H.
      • Wagner K.
      • Korinthenberg R.
      Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence.
      ,
      • Shurtleff H.A.
      • Barry D.
      • Firman T.
      • Warner M.H.
      • Aguilar-Estrada R.L.
      • Saneto R.P.
      • Kuratani J.D.
      • Ellenbogen R.G.
      • Novotny E.J.
      • Ojemann J.G.
      Impact of epilepsy surgery on development of preschool children: identification of a cohort likely to benefit from early intervention.
      ,
      • Puka K.
      • Rubinger L.
      • Chan C.
      • Smith M.L.
      • Widjaja E.
      Predictors of intellectual functioning after epilepsy surgery in childhood: the role of socioeconomic status.
      ,
      • Skirrow C.
      • Cross J.H.
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      • Vargha-Khadem F.
      • Baldeweg T.
      Long-term intellectual outcome after temporal lobe surgery in childhood.
      ,
      • Puka K.
      • Tavares T.P.
      • Smith M.L.
      Development of intelligence 4 to 11 years after paediatric epilepsy surgery.
      ,
      • Helmstaedter C.
      • Petzold I.
      • Bien C.G.
      The cognitive consequence of resecting nonlesional tissues in epilepsy surgery- results from MRI- and histopathology-negative patients with temporal lobe epilepsy.
      ,
      • Boshuisen K.
      • van Schooneveld M.M.
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      • Cross J.H.
      • Harrison S.
      • Polster T.
      • Daehn M.
      • Djimjadi S.
      • Yalnizoglu D.
      • Turanli P.G.
      • Sassen R.
      • Hoppe C.
      • Kuczaty S.
      • Barba C.
      • Kahane P.
      • Schubert-Bast S.
      • Reuner G.
      • Bast T.
      • Strobl K.
      • Mayer H.
      • de Saint-Martin A.
      • Seegmuller C.
      • Laurent A.
      • Arzimanoglou A.
      • Braun K.P.
      IQ improves after antiepileptic drug withdrawal following pediatric epilepsy surgery.
      ,
      • Helmstaedter C.
      • Elger C.E.
      • Witt J.A.
      The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery.
      ]. The predictors in children and adults are generally the same, but the conditions of these groups differ in regard to the neuro(psycho)developmental context. The normal and sometimes pathological ageing process needs to be considered in epilepsy and epilepsy surgery in adults, while in children epilepsy and its treatment interact with the maturation and development of the brain [
      • Helmstaedter C.
      Effects of chronic temporal lobe epilepsy on memory function.
      ].
      Since the infantile brain has a greater ability to reorganize specific neurological functions after brain destructions like it is caused by surgeries, children have a lower risk of cognitive interferences after surgery [
      • Cross J.H.
      • Jayakar P.
      • Nordli D.
      • Delalande O.
      • Duchowny M.
      • Wieser H.G.
      • Guerrini R.
      • Mathern G.W.
      Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the subcommission for pediatric epilepsy surgery.
      ,
      • Johnston M.V.
      Brain plasticity in paediatric neurology.
      ,
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative neuropsychological profiles in children and adolescents with temporal lobe epilepsy.
      ,
      • Gleissner U.
      • Sassen R.
      • Schramm J.
      • Elger C.E.
      • Helmstaedter C.
      Greater functional recovery after temporal lobe epilepsy surgery in children.
      ]. Age at epilepsy onset and age at surgery are therefore factors of major importance as most preceding studies point out that children have a greater chance for a better postoperative outcome than adults [
      • Cross J.H.
      • Jayakar P.
      • Nordli D.
      • Delalande O.
      • Duchowny M.
      • Wieser H.G.
      • Guerrini R.
      • Mathern G.W.
      Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the subcommission for pediatric epilepsy surgery.
      ,
      • Johnston M.V.
      Brain plasticity in paediatric neurology.
      ,
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative neuropsychological profiles in children and adolescents with temporal lobe epilepsy.
      ,
      • Gleissner U.
      • Sassen R.
      • Schramm J.
      • Elger C.E.
      • Helmstaedter C.
      Greater functional recovery after temporal lobe epilepsy surgery in children.
      ]. Nevertheless it is worth mentioning that the age of the child is also important – but the current results of the studies dealing with this topic are diverse [
      • Flint A.E.
      • Waterman M.
      • Bowmer G.
      • Vadlamani G.
      • Chumas P.
      • Morrall M.
      Neuropsychological outcomes following paediatric temporal lobe surgery for epilepsies: evidence from a systematic review.
      ]. Some studies point out that an older age at seizure onset as well as an older age at surgery lead to a better cognitive outcome [
      • Ramantani G.
      • Kadish N.E.
      • Brandt A.
      • Strobl K.
      • Stathi A.
      • Wiegand G.
      • Schubert‐Bast S.
      • Mayer H.
      • Wagner K.
      • Korinthenberg R.
      Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence.
      ,
      • Shurtleff H.A.
      • Barry D.
      • Firman T.
      • Warner M.H.
      • Aguilar-Estrada R.L.
      • Saneto R.P.
      • Kuratani J.D.
      • Ellenbogen R.G.
      • Novotny E.J.
      • Ojemann J.G.
      Impact of epilepsy surgery on development of preschool children: identification of a cohort likely to benefit from early intervention.
      ,
      • Puka K.
      • Rubinger L.
      • Chan C.
      • Smith M.L.
      • Widjaja E.
      Predictors of intellectual functioning after epilepsy surgery in childhood: the role of socioeconomic status.
      ,
      • Vasconcellos E.
      • Wyllie E.
      • Sullivan S.
      • Stanford L.
      • Bulacio J.
      • Kotagal P.
      • et al.
      Mental retardation in pediatric candidates for epilepsy surgery: the role of early seizure onset.
      ,
      • Van Schooneveld M.M.
      • Braun K.P.
      Cognitive outcome after epilepsy surgery in children.
      ], others associate an older age at onset and an older chronological age with more cognitive deteriorations [
      • Loddenkemper T.
      • Holland K.D.
      • Stanford L.D.
      • Kotagal P.
      • Bingaman W.
      • Wyllie E.
      Developmental outcome after epilepsy surgery in infancy.
      ,
      • Hermann B.P.
      • Seidenberg M.
      • Haltiner A.
      • Wyler A.R.
      Relationship of age at onset, chronologic age, and adequacy of preoperative performance to verbal memory change after anterior temporal lobectomy.
      ]. A shorter duration of epilepsy though is correlated with reduced risks for cognitive deficits [
      • Farwell J.R.
      • Dodrill C.B.
      • Batzel L.W.
      Neuropsychological abilities of children with epilepsy.
      ,
      • Shurtleff H.A.
      • Barry D.
      • Firman T.
      • Warner M.H.
      • Aguilar-Estrada R.L.
      • Saneto R.P.
      • Kuratani J.D.
      • Ellenbogen R.G.
      • Novotny E.J.
      • Ojemann J.G.
      Impact of epilepsy surgery on development of preschool children: identification of a cohort likely to benefit from early intervention.
      ,
      • Hermann B.P.
      • Seidenberg M.
      • Haltiner A.
      • Wyler A.R.
      Relationship of age at onset, chronologic age, and adequacy of preoperative performance to verbal memory change after anterior temporal lobectomy.
      ,
      • Bjornaes H.
      • Stabell K.E.
      • Heminghyt E.
      • Roste G.K.
      • Bakke S.J.
      Resective surgery for intractable focal epilepsy in patients with low IQ: predictors for seizure control and outcome with respect to seizures and neuropsychological and psychosocial functioning.
      ].
      The global picture of the neuropsychological outcome of epilepsy surgery and its determinants, however, has to be inferred from studies addressing very individual questions, different types of epilepsies (e.g. temporal, extra-temporal etc.), different types of surgery (e.g. selective, lobes, hemispheric, left/right) [
      • Lassonde M.
      • Sauerwein H.C.
      • Jambaque I.
      • Smith M.L.
      • Helmstaedter C.
      Neuropsychology of childhood epilepsy: pre- and postsurgical assessment.
      ] using different assessment tools as outcome measures [
      • Vogt V.L.
      • Aikia M.
      • Del Barrio A.
      • Boon P.
      • Borbely C.
      • Bran E.
      • Braun K.
      • Carette E.
      • Clark M.
      • Cross J.H.
      • Dimova P.
      • Fabo D.
      • Foroglou N.
      • Francione S.
      • Gersamia A.
      • Gil-Nagel A.
      • Guekht A.
      • Harrison S.
      • Hecimovic H.
      • Heminghyt E.
      • Hirsch E.
      • Javurkova A.
      • Kalviainen R.
      • Kavan N.
      • Kelemen A.
      • Kimiskidis V.K.
      • Kirschner M.
      • Kleitz C.
      • Kobulashvili T.
      • Kosmidis M.H.
      • Kurtish S.Y.
      • Lesourd M.
      • Ljunggren S.
      • Lossius M.I.
      • Malmgren K.
      • Mameniskiene R.
      • Martin-Sanfilippo P.
      • Marusic P.
      • Miatton M.
      • Ozkara C.
      • Pelle F.
      • Rubboli G.
      • Rudebeck S.
      • Ryvlin P.
      • van Schooneveld M.
      • Schmid E.
      • Schmidt P.M.
      • Seeck M.
      • Steinhoff B.J.
      • Shavel-Jessop S.
      • Tarta-Arsene O.
      • Trinka E.
      • Viggedal G.
      • Wendling A.S.
      • Witt J.A.
      • Helmstaedter C.
      • consortium, E.P
      Current standards of neuropsychological assessment in epilepsy surgery centers across Europe.
      ].
      On this background, we evaluated the impact of the above-mentioned potential predictive variables on the one year follow-up cognitive changes after epilepsy surgery in a cohort of children who underwent epilepsy surgery in the epilepsy center of Bonn. The neuropsychological outcomes of subgroups of children and adolescents operated in this center have been published before, but a synopsis of the outcomes in one analysis is missing [
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative neuropsychological profiles in children and adolescents with temporal lobe epilepsy.
      ,
      • Gleissner U.
      • Sassen R.
      • Lendt M.
      • Clusmann H.
      • Elger C.E.
      • Helmstaedter C.
      Pre- and postoperative verbal memory in pediatric patients with temporal lobe epilepsy.
      ,
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative neuropsychological profiles in children and adolescents with temporal lobe epilepsy.
      ,
      • Lendt M.
      • Gleissner U.
      • Helmstaedter C.
      • Sassen R.
      • Clusmann H.
      • Elger C.E.
      Neuropsychological outcome in children after frontal lobe epilepsy surgery.
      ,
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative socioeconomic development of 151 patients with focal epilepsies.
      ,
      • Lendt M.
      • Helmstaedter C.
      • Kuczaty S.
      • Schramm J.
      • Elger C.E.
      Behavioural disorders in children with epilepsy: early improvement after surgery.
      ,
      • Althausen A.
      • Gleissner U.
      • Hoppe C.
      • Sassen R.
      • Buddewig S.
      • von Lehe M.
      • Schramm J.
      • Elger C.E.
      • Helmstaedter C.
      Long-term outcome of hemispheric surgery at different ages in 61 epilepsy patients.
      ,
      • Ormond D.R.
      • Clusmann H.
      • Sassen R.
      • Hoppe C.
      • Helmstaedter C.
      • Schramm J.
      • et al.
      Pediatric temporal lobe epilepsy surgery in Bonn and review of the literature.
      ,
      • Gleissner U.
      • Kuczaty S.
      • Clusmann H.
      • Elger C.E.
      • Helmstaedter C.
      Neuropsychological results in pediatric patients with epilepsy surgery in the parietal cortex.
      ]
      Hence, the principal idea of the present retrospective work was to provide a global picture of neuropsychological performance after epilepsy surgery and its determinants in addition to the mosaic of results addressing individual clinical factors and cognitive/behavioral domains in separate publications in the past. The factors that impact the cognitive outcome after epilepsy surgery are not fully independent of each other and it needs to be shown which aspects dominate when they are considered competitively in one multivariate analysis.

      2. Methods

      2.1 Patients

      We included 306 children aged between 6 and 17 years at the time of the presurgical evaluation in this analysis. These 306 children represent all children operated in the epilepsy center in Bonn between 1988 and 2015 who underwent formal neuropsychological evaluation before and one year after surgery. It needs to be noted that this represents some bias since children and adolescents who were impaired to a degree which did not allow standardized formal assessment were not considered. Children operated at a younger age (<6 yrs.) were not considered for the following analysis.

      2.2 Neuropsychological evaluation

      Whenever possible, patients underwent neuropsychological examination preoperatively and about 12 months after surgery. For the purpose of the present study, we focused on presurgical and 1-year postoperative IQ, attention, verbal and visual memory, language, visuospatial abilities, and behavior according to our previous reports on pediatric TLE patients [
      • Ormond D.R.
      • Clusmann H.
      • Sassen R.
      • Hoppe C.
      • Helmstaedter C.
      • Schramm J.
      • et al.
      Pediatric temporal lobe epilepsy surgery in Bonn and review of the literature.
      ,
      • Clusmann H.
      • Kral T.
      • Gleissner U.
      • Sassen R.
      • Urbach H.
      • Blumcke I.
      • Bogucki J.
      • Schramm J.
      Analysis of different types of resection for pediatric patients with temporal lobe epilepsy.
      ]. The neuropsychological assessment battery is presented in Table 1. It corresponds largely to what is being recommended by the German work group for neuropsychology in epilepsy and is largely in line with standards across the EU [
      • Vogt V.L.
      • Aikia M.
      • Del Barrio A.
      • Boon P.
      • Borbely C.
      • Bran E.
      • Braun K.
      • Carette E.
      • Clark M.
      • Cross J.H.
      • Dimova P.
      • Fabo D.
      • Foroglou N.
      • Francione S.
      • Gersamia A.
      • Gil-Nagel A.
      • Guekht A.
      • Harrison S.
      • Hecimovic H.
      • Heminghyt E.
      • Hirsch E.
      • Javurkova A.
      • Kalviainen R.
      • Kavan N.
      • Kelemen A.
      • Kimiskidis V.K.
      • Kirschner M.
      • Kleitz C.
      • Kobulashvili T.
      • Kosmidis M.H.
      • Kurtish S.Y.
      • Lesourd M.
      • Ljunggren S.
      • Lossius M.I.
      • Malmgren K.
      • Mameniskiene R.
      • Martin-Sanfilippo P.
      • Marusic P.
      • Miatton M.
      • Ozkara C.
      • Pelle F.
      • Rubboli G.
      • Rudebeck S.
      • Ryvlin P.
      • van Schooneveld M.
      • Schmid E.
      • Schmidt P.M.
      • Seeck M.
      • Steinhoff B.J.
      • Shavel-Jessop S.
      • Tarta-Arsene O.
      • Trinka E.
      • Viggedal G.
      • Wendling A.S.
      • Witt J.A.
      • Helmstaedter C.
      • consortium, E.P
      Current standards of neuropsychological assessment in epilepsy surgery centers across Europe.
      ]. The best available age norms were applied.
      Table 1Neuropsychological assessment [
      • Althausen A.
      • Gleissner U.
      • Hoppe C.
      • Sassen R.
      • Buddewig S.
      • von Lehe M.
      • Schramm J.
      • Elger C.E.
      • Helmstaedter C.
      Long-term outcome of hemispheric surgery at different ages in 61 epilepsy patients.
      ,
      • Gleissner U.
      • Kuczaty S.
      • Clusmann H.
      • Elger C.E.
      • Helmstaedter C.
      Neuropsychological results in pediatric patients with epilepsy surgery in the parietal cortex.
      ].
      Functional domainStandardized tests
      IQHAWIK/HAWIE Vocabulary (Tewes et al., 1984, 1991, 1999), K-ABC (Kaufman & Kaufman, 1991),
      Verbal MemoryHAWIK-R/HAWIK-III Digit span (Tewes et al., 1984, 1999); VLMT (Helmstaedter et al., 2001)
      Figural MemoryCorsi block test (Milner, 1975); DCS-R (Helmstaedter et al., 1991); Benton test-AFC (Benton, 1981)
      LanguagePhonematic fluency (Horn, 1983; Regard et al., 1982; Halperin et al., 1989; Gaddes & Crocektt, 1975; Ruff et al., 1996); Semantic fluency (Spreen & Strauss, 1998; Strauss et al., 2006); Token test (Orgass, 1982; Huber et al. 1983); Naming (Huber et al., 1983); Boston Naming Test (Spreen & Strauss, 1998; Strauss et al., 2006); HAWIK/HAWIE Vocabulary (Tewes et al., 1984, 1991, 1999)
      AttentionD2 test (Brickenkamp, 1978); c.I. Test (Lehrl & Fischer, 1984); HAWIK Digit Symbol Coding (Tewes et al., 1984, 1999); Reaction times (Spreen and Strauss, 1998; Strauss et al. 2006); Trail Making Test A/B (Reitan 1955; Spreen and Strauss, 1998; Strauss et al. 2006)
      Motor functionsLuria Sequences (Luria 1970), Finger Tapping (Finlayson & Reitan 1976)
      Visuospatial & constructional abilitiesHAWIK Block Design test (Tewes et al., 1984, 1991, 1999); K-ABC Triangles (Kaufman & Kaufman, 1991); Mental rotation (Horn, 1983); Mazes (Tewes et al. 1984, 1999; Chapuis 1959)
      BehaviorCBCL (Achenbach 1998), KINDL (Bullinger 1994), KOPKIJ (Gleissner et al. 2006, Helmstaedter et al. 2017)
      AFC, alternative forced choice; c.I.T., cerebrale Insuffizienzen-Test (i.e. test of cerebral insufficiency); CBCL, Child behavior check list; DCS-R, Diagnostikum für Cerebralschäden revised (design list learning test); HAWIK, Hamburg-Wechsler-Intelligenz-Test für Kinder (German adaptation of Wechsler Intelligence Scale for Children); K-ABC, Kaufmann Assessment Battery for Children; KINDL, Health Related Quality of Life in children and adolescents; KOPKIJ, Cognitive Problems in Children and Adolescents Questionnaire; (VLMT, Verbaler Lern- und Merkfähigkeitstest (word list learning test, German version of Rey's Auditory and Verbal Learning Test).
      As different tests had to be chosen for children of different ages and since the test selection was slightly modified over time we here report higher-order expert ratings with the following scoring system which had been used in previous studies already [
      • Ormond D.R.
      • Clusmann H.
      • Sassen R.
      • Hoppe C.
      • Helmstaedter C.
      • Schramm J.
      • et al.
      Pediatric temporal lobe epilepsy surgery in Bonn and review of the literature.
      ,
      • Clusmann H.
      • Kral T.
      • Gleissner U.
      • Sassen R.
      • Urbach H.
      • Blumcke I.
      • Bogucki J.
      • Schramm J.
      Analysis of different types of resection for pediatric patients with temporal lobe epilepsy.
      ,
      • Clusmann H.
      • Schramm J.
      • Kral T.
      • Helmstaedter C.
      • Ostertun B.
      • Fimmers R.
      • Haun D.
      • Elger C.E.
      Prognostic factors and outcome after different types of resection for temporal lobe epilepsy.
      ,
      • Grote A.
      • Witt J.A.
      • Surges R.
      • von Lehe M.
      • Pieper M.
      • Elger C.E.
      • Helmstaedter C.
      • Ormond D.R.
      • Schramm J.
      • Delev D.
      A second chance--reoperation in patients with failed surgery for intractable epilepsy: long-term outcome, neuropsychology and complications.
      ]: 0 = strongly impaired (i.e. at least two of the test scores for the respective function were smaller than mean – 2 SD); 1 = impaired (i.e., at least two respective test scores were smaller than mean – 1 SD); 2 = borderline (i.e. one test score smaller than mean – 1SD or at least two test scores roughly equaling mean – 1 SD; 3 = average (i.e. a maximum of one test score roughly equals mean – 1 SD while all other scores were average at least); 4 = above average (i.e. at least two test scores were larger than mean + 1 SD]). For additional analyses we dichotomized performance in each function as impaired versus unimpaired (whereby cases categorized as "borderline" were included in the "impaired" category).
      As for performance changes from before to after surgery, we report the number of patients which positively or negatively exceeded the expected change with repeated testing in healthy subjects. Accordingly, a change by one category over time represents a statistically reliable change (p < 0.1) [
      • Clusmann H.
      • Schramm J.
      • Kral T.
      • Helmstaedter C.
      • Ostertun B.
      • Fimmers R.
      • Haun D.
      • Elger C.E.
      Prognostic factors and outcome after different types of resection for temporal lobe epilepsy.
      ]. We report the patients who individually improved or deteriorated in a given domain in absolute numbers and in addition corrected by the number of patients who, because of a bottom or ceiling effect, could not deteriorate or improve.
      Apart from the number of patients who changed in relation to reliability of change intervals, we report the percentage of impaired patients who became unimpaired (i.e. normalization) and the percentage of unimpaired patients who became impaired (i.e. loss of functional integrity). These percentages are reported in relation to the subsamples of impaired or unimpaired patients at baseline, respectively, and therefore might serve as realistic estimates for neuropsychological risks and chances of epilepsy surgery in pediatric patients.
      Detailed data on pre- and postoperative seizure frequencies per month were not available. Therefore the seizure outcome was kept simple by differentiating only between completely seizure free (Engel class I) and non-seizure free patients.

      2.3 Statistical analyses

      Effects of site and side of pathology/surgery, type of surgery (selective and tailored resections vs. lobectomies), seizure outcome (seizure free vs. not seizure free) and drug change (change in the number of antiepileptic drugs) on a given neuropsychological domain were evaluated in separate regression analyses using pairwise exclusion of patients with missing data and backward stepwise removal of factors not being significant. Additional statistical procedures were paired sample t-tests and chi2 cross-tabulation. The p-value considered significant was set to 0.05 (two-sided). Post hoc statistical comparisons were not corrected for multiple testing according to the retrospective and explorative nature of this study.
      All statistics were calculated by use of IBM SPSS 25.

      3. Results

      3.1 Clinical outcome

      The demographic and clinical data of this group are listed in Table 2. The male to female ratio was close to one, the average age at surgery was 11.4 years. The mean age at the onset of epilepsy was 5.8 years and the mean duration of epilepsy at the time of surgery was 5.5 years.
      Table 2Demographic and clinical data.
      Demographic and clinical data
      N306
      Sex: male/female147 (48%)/ 159 (52%)
      Age (yrs.)11.4 ± 3.9
      Age at epilepsy onset (yrs.)5.8 ± 4.1
      Duration of epilepsy (yrs.)5.5 ± 4.1
      Lateralization: left/right165 (54%)/141 (46%)
      Localization:
      temporal154 (50%)
      frontal70 (23%)
      posterior51 (17%)
      hemispheric31 (10%)
      Pathology:
      No finding7 (2%)
      Tumor105 (35%)
      Developmental50 (17%)
      AHS20 (7%)
      Vascular10 (3%)
      Inflammatory7 (2%)
      Other100 (34%)
      No. antiepileptic drugs: pre-/ postop.1.84 ± 0.8 / 1.43 ± 0.7
      Monotherapy: pre-/ postop.33%/57% (5% off drug)
      Surgery: lesionectomy169 (55%)
      Seizure free (12 months follow up)248 (81%)
      Fig. 1 depicts the frequencies of the patients according the site of surgery, i.e. the localization and lateralization of the suggested epileptogenic region and/or MRI lesion pathology and the percentage of patients who became seizure free in the respective group (% in brackets). With 154 patients (50%), the largest group underwent temporal lobe surgery, followed by 70 patients with frontal (23%), 51 with posterior (17%), and 31 patients with hemispheric surgery (10%). The rate of seizure free outcomes differed across the resection sites, with the best outcome after hemispherectomy (94%), followed by posterior, frontal, and temporal lobe surgeries (78%). The group difference showed only a nonsignificant trend (chi2 = 6.5, df = 1, p = 0.09). The same was true for larger resections, which showed a trend towards being more often successful (84%) than selective surgeries (78%) (chi2 = 2.1, df = 1, p = 0.14). Overall seizure freedom (Engel Class I) was achieved in 81% of all evaluated patients.
      Fig. 1
      Fig. 1The figure displays the number of patients who underwent left vs. right frontal, temporal, posterior, hemispheric surgery with the percent seizure free patients reported in brackets.
      The number of antiepileptic drugs decreased significantly from 1.8 at baseline to 1.4 at the 1-year follow-up (paired sample test, t = 7.2, p < 0.001). At baseline, only 34% of the patients were on monotherapy and this number increased significantly to 57% on monotherapy after surgery and another 5% of the patients being off drug (chi2 = 24.9, df = 2, p < 0.001). It is to be mentioned that the systematic withdrawal of antiepileptic drugs after successful surgery is started only one year after surgery at this center.

      3.2 Neuropsychological outcome

      Regarding the neuropsychological results, the number of patients who entered the analyses for the different domains varied because of missing values at the pre- or postoperative assessment. In order to report consistent results, only patients with pre- and postoperative data were considered. (Tables 3, 4)
      Table 3Group level neuropsychological performance changes from preoperative (T1) to postoperative assessment (T2).
      Pre-and postoperative cognition and behavior / group level
      DomainNmeanSDtz
      Motor functionT11762,2500,97101−4.617
      = p < 0.001.
      −4.380
      = p < 0.001.
      T21762,5795,82423
      AttentionT12192,18261,11843−3.134
      = p < 0.01.
      −3.016
      = p < 0.01.
      T22192,40181,09343
      Verbal memoryT12531,69571,31168−0.729−0.729
      T22531,75491,31958
      Figural memoryT12292,28381,13661−1.750−1.286
      T22292,41051,11492
      LanguageT12391,92051,19081−2.969
      = p < 0.01.
      −2.986
      = p < 0.01.
      T22392,12131,14767
      VisuoconstructionT12302,4043,94706−4.139
      = p < 0.001.
      −3.821
      = p < 0.001.
      T22302,6435,92695
      IntelligenceT11481,83781,36054−0.195−0.437
      T21481,85141,38193
      BehaviorT11611,6460,89729−2.557
      = p < 0.05.
      −2.287
      = p < 0.05.
      T21611,8447,95236
      * = p < 0.05.
      ** = p < 0.01.
      *** = p < 0.001.
      Table 4Individual level pre- (T1) and postoperative (T2) neuropsychological impairments and performance changes from T1 to T2.
      Pre-and postoperative cognition and behavior / individual level
      NImpaired at T1Impaired at T2Individually significant losses and gains from T1 to T2 (absolute)Individually significant losses and gains from T1 to T2 (corrected)Losses of functional integrity vs. functional normalization
      Motor fuction17656%36%18% ↓ 42% ↑19% ↓ 45% ↑19%↓ 50%↑
      Attention21948%35%16% ↓ 30% ↑18% ↓ 32% ↑15%↓ 44%↑
      Verbal memory25367%66%29% ↓ 34% ↑39% ↓ 37% ↑39%↓ 20%↑
      Figural memory17252%46%25% ↓ 34% ↑27% ↓ 39% ↑25%↓ 35%↑
      Language23959%52%16% ↓ 31% ↑18% ↓ 33% ↑25%↓ 29%↑
      Visuoconstruction23043%31%13% ↓ 34% ↑14% ↓ 36% ↑14%↓ 46%↑
      Intelligence (IQ)14856%51%14% ↓ 16% ↑21% ↓ 21% ↑15%↓ 21%↑
      Behavior16171%61%11% ↓ 24% ↑11% ↓ 24% ↑30%↓ 26%↑
      N = Number of patients with pre- and postop. testing; % patients impaired at baseline T1 and one year follow-up T2; % patients with intraindividually significant gains (↑) or losses (↓), once “absolute” and again “corrected” by those who could not win or lose; % of unimpaired patients who became impaired (loss of functional integrity ↓) versus % of impaired patients who became unimpaired (normalization ↑).
      Comparing pre- and postoperative ratings on a group level with statistics for dependent measures, all functions with the exception of verbal memory, figural memory, and IQ significantly improved (t-tests for paired samples and Wilcoxon test, t for significant tests ranging from 2.5 for behavior to 4.6 for motor functions, with p ranging from <0.01 to  < 0.001; (see Table 3)
      At the preoperative baseline, behavior as assessed by parent questionnaires was most frequently affected (71% impaired, 29% unimpaired). Objective neuropsychological impairments (yes/no) in the different cognition domains were seen in 43%–67% of the patients. The verbal memory domain was most frequently affected (67%), followed by impairments in language, IQ, figural memory, motor functions (>50%), attention and visuo-spatial functions (>40%) (see the number of impaired patients at T1 column 3/Table 4). Focusing on the impairments in the four domains for which most frequent assessments were available, i.e. attention, verbal/figural memory and language, 15% were unimpaired at baseline (T1), and 85% showed impairment in at least one of these domains, 44% showed impairment in at least three domains. Postoperatively behavioral problems were still prominent with 61% impaired, followed by verbal memory (66%), language (52%), and figural memory (46%) (see the number of impaired patients at T2 column 4/Table 4). Overall, 20% were unimpaired in the four domains attention, verbal/figural memory and language, 80% showed at least one domain impaired, and 35% at least three domains.
      According to individual level analyses, and compared to T1, the number of impaired patients generally dropped. This was particularly the case in the domains of motor functions and attention, and less in the domains of verbal memory, language, IQ, (see the number of impaired patients at T1 and T2 in columns 3 and 4/Table 4).
      When looking at the number of patients who experienced intra-individual gains or losses in the different domains, improvements rather than declines in a ratio of about 2:1 were observed in motor functions, attention, language, and visuo-construction, whereas verbal and figural memory, IQ, and behavior showed minor gains compared to losses (see column 5/Table 4).
      When controlling for bottom and ceiling effects, i.e. by excluding those who could not lose or win, the number of patients with intra-individually significant performance changes increased (column 6/Table 4). Motor functions, attention, language, and visuo-construction were still the domains with major gains and comparably less declines. For these domains, the numbers changed only slightly when compared to column 5 which reports the non-corrected data. In contrast, the numbers changed significantly for verbal memory and IQ. When patients were excluded who could not deteriorate because they performed very poor at baseline already (bottom effect), 39% instead of 29% lost in verbal memory and 21% instead of 14% lost in regard to IQ. These corrected percentages represent more realistic risk estimates for the relevant population.
      The last column in Table 4 additionally reports the percentage of patients who changed from presurgical impairment range into postoperative normal range and vice versa. This analysis does not consider the degree of change and whether this change was intra-individually relevant, but simply whether a patient changed into the impairment or unimpairment range. The percent of impaired patients who became unimpaired dominated for motor functions, attention, visuo-constructional functions (44–50%) and as a trend also for IQ (21%). In memory functions and language, however, the percentage of unimpaired patients who experienced a loss of functional integrity was greater than the percentage of patients who were impaired and gained functional normalization.
      The relevant determinants of the presurgical and postsurgical performance were calculated by multiple regression analyses, the results of which are displayed in Table 5, Table 6. Significant predictors (at least p < 0.05) and the direction of the relation are indicated by the solid arrows pointing up or downwards. Arrows in brackets indicate non-significant trends with p < 0.1.
      Table 5Predicting baseline performance (T1): Regression models.
      Predicting baseline performance: regression analyses (backward / pairwise exclusion)
      r-

      square
      Sex

      fem.
      Age

      older
      Onset

      earlier
      FrontalPosteriorHemis-

      pheric
      Develop.

      lesion
      AED

      more
      Motor fct.0.04 **
      Attention0.16 ***
      Verb. mem0.10 ***(↓)
      Fig. mem0.07 ***
      Language0.13 ***
      Visuoconstr.0.16 ***(↓)
      IQ0.23 ***(↑)
      Behavior0.03 *
      * p < 0.05; ** p < 0.01; *** p < 0.001; ↓↑ = significant contributions, (↑)(↓) non-significant trends (p < .10).
      Table 6Predicting postsurgical outcome at the 12-month follow-up (T2): regression models.
      Predicting outcome: regression analyses (backward / pairwise exclusion)
      r-

      square
      Base-

      line
      Sex

      fem.
      Age

      younger
      Onset

      later
      Seizure

      free
      AED

      reduced
      AED

      less
      Side

      right
      Select.

      surgery
      Motor fct.0.22**
      Attention0.33***
      Verb. mem0.33***(↑)
      Fig. mem0.34***(↑)
      Language0.47***(↑)
      Visuoconstr.0.58***(↑)
      IQ0.76***(↑)(↑)
      Behavior0.29*(↑)
      * p < 0.05; ** p < 0.01; *** p < 0.001; ↓↑ = significant contributions, (↑)(↓) non-significant trends (p < .10).
      According to the results, worse cognition in the different domains at baseline (T1) is observed with older age (motor functions are the exception), younger age at epilepsy onset, in patients with hemispheric lesions, and those with more antiepileptic drugs (Table 5). Apart from hemispheric lesions, the site and side of the lesions/epilepsies had a comparably negligible or no impact on the performance pattern. Behavior was predicted only by age at surgery. All regressions apart from those for motor functions (p < 0.01) and behavior (p < 0.05) were highly significant (p < 0.001). The r-square values, however, indicate that the overall variance explained by the prediction models was low (highest for IQ with 23% of the variance explained). Factors which were tested with the regression model were those displayed in the table plus “side”, “hippocampal sclerosis”, “tumor”, and “duration of epilepsy”.
      Performance at the one year follow-up evaluation (T2) was particularly predicted by baseline performance (T1), i.e. those who were better at baseline, were better at the follow-up (Table 6). In addition, age at surgery and age at epilepsy onset were relevant, i.e. the earlier the surgery and the later the onset the better the outcome. Different from objectively assessed functions, behavior was rated as worsened with a later onset. Furthermore seizure control, less antiepileptic drugs, reduction of drugs, and in part a more selective/tailored surgery were favorable. In this analysis the explained variance was much better, ranging from 22 to 76%. Factors like gender, side of surgery or pathology which were considered as additional potential predictors but played a minor or no role in the prediction models.
      As mentioned above, baseline performance is one of the strongest predictors of postoperative performance. The analysis above, however, does not consider change scores. Therefore it needs to be added that baseline performance reflects both reserve capacity and functionality of the affected structures. Choosing verbal memory as the example, this is expressed by the fact that better baseline positively correlates with better postoperative performance (N = 253 r=0.516 p < 0.001) and at the same time negatively with greater losses (N = 253 r=-0.487 p < 0.001).

      4. Discussion

      The present study evaluated the cognitive and behavioral outcomes of epilepsy surgery in a large monocentric series of children and adolescents with therapy refractory structural epilepsies aged between 6 and 17. The analysis considered the neuropsychological status before surgery and one year after surgery on the group level and on an individual basis (losses/gains, loss of functional integrity/normalization). Different from previous neuropsychological outcome studies on pediatric epilepsy surgery, patients with different types of epilepsies, pathologies and types of surgeries were considered in one analysis in the present study.
      A total of 306 patients could be extracted from the Bonn database and evaluated retrospectively. With half of the patients temporal lobe epilepsy and surgery was most common followed by frontal, posterior and hemispheric epilepsies. The left/right lateralization of lesions/epilepsies and consequently surgery was quite balanced. The same is true for the gender distribution.
      Although this manuscript is about neuropsychology, seizure outcome after epilepsy surgery is surely of major importance for the operated children.
      Seizure control was good to excellent with 81% of all operated children being completely seizure free one year after surgery. The outcomes particularly of temporal lobe and as a trend also of frontal lobe surgery were not as good as those after posterior surgery or functional hemispherectomy. However, seizure control was achieved for the vast majority of the patients.
      In previous studies concerning different specific resection sites or types of surgery the results were quite different as regards seizure freedom. The findings (concerning hemispherectomies, posterior, temporal or frontal lobe resections) reached from 52% up to 90% of postsurgical seizure freedom not showing that a specific type of operation leads in general to a better seizure outcome [
      • Gleissner U.
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      ]. However it has to be considered that these numbers are just the seizure freedom rates (Engel Outcome I), not taking into account reductions in seizure frequency. Namely all studies were able to show an improvement of the seizure condition in regard to frequency and/or intensity in the majority of the patients.
      Apart from seizure control epilepsy surgery aims at the preservation of neurological and cognitive functions. In pediatric patients the use of time windows with still high functional cerebral plasticity allowing to functionally catch up or recover are of high relevance. These time windows tend to close with puberty and adolescents.
      Fully in line with the literature the present data show that neuropsychological impairments are very common already before epilepsy surgery [
      • Hermann B.
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      • Freitag H.
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      Cognitive function in preschool children after epilepsy surgery: rationale for early intervention.
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      • Helmstaedter C.
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      The cognitive consequence of resecting nonlesional tissues in epilepsy surgery- results from MRI- and histopathology-negative patients with temporal lobe epilepsy.
      ,
      • Althausen A.
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      • Hoppe C.
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      • von Lehe M.
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      • Elger C.E.
      • Helmstaedter C.
      Long-term outcome of hemispheric surgery at different ages in 61 epilepsy patients.
      ,
      • Verdinelli C.
      • Olsson I.
      • Edelvik A.
      • Hallböök T.
      • Rydenhag B.
      • Malmgren K.
      A long-term patient perspective after hemispherotomy–a population based study.
      ]. Eighty five percent of the patients were impaired in at least one cognitive domain, taking into consideration only the partial functions of attention, language and memory. Behavioral problems were indicated in 71% at baseline. Regression analyses revealed that an older age at the time of the evaluation, an earlier age at the onset of, a greater antiepileptic drug load and the extent of the cerebral damage (hemispheric lesions) predict worse presurgical performance. The literature to these correlations is mixed, some studies support these results while others do not [
      • Shurtleff H.A.
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      Impact of epilepsy surgery on development of preschool children: identification of a cohort likely to benefit from early intervention.
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      • Puka K.
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      Predictors of intellectual functioning after epilepsy surgery in childhood: the role of socioeconomic status.
      ,
      • Flint A.E.
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      Neuropsychological outcomes following paediatric temporal lobe surgery for epilepsies: evidence from a systematic review.
      ,
      • Vasconcellos E.
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      Mental retardation in pediatric candidates for epilepsy surgery: the role of early seizure onset.
      ,
      • Hermann B.P.
      • Seidenberg M.
      • Haltiner A.
      • Wyler A.R.
      Relationship of age at onset, chronologic age, and adequacy of preoperative performance to verbal memory change after anterior temporal lobectomy.
      ]. The prediction pattern of baseline performance in Table 5 seems quite non-specific and not to be suited to go deeper into interpretations of individual relations between predictor variables and individual domains. Gender, the localization, and interestingly also the lateralization of the lesion/epilepsy appeared less or not relevant – not matching with results from some other studies [
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative neuropsychological profiles in children and adolescents with temporal lobe epilepsy.
      ,
      • Flint A.E.
      • Waterman M.
      • Bowmer G.
      • Vadlamani G.
      • Chumas P.
      • Morrall M.
      Neuropsychological outcomes following paediatric temporal lobe surgery for epilepsies: evidence from a systematic review.
      ,
      • Gleissner U.
      • Sassen R.
      • Lendt M.
      • Clusmann H.
      • Elger C.E.
      • Helmstaedter C.
      Pre- and postoperative verbal memory in pediatric patients with temporal lobe epilepsy.
      ,
      • Clusmann H.
      • Kral T.
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      • Sassen R.
      • Urbach H.
      • Blumcke I.
      • Bogucki J.
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      Analysis of different types of resection for pediatric patients with temporal lobe epilepsy.
      ].
      The finding largely points into the direction that the epilepsies hit the maturing and not yet fully organized and specialized brain resulting in quite nonspecific impairments and developmental hindrance as indicated also by low intelligence. Of note is the relation of worse performances with an older age. However it is difficult to determine whether this is due to the duration of epilepsy, or what is known under the term growing into impairment in childhood developmental neuropsychology, i.e. that lesion related impairments become increasingly evident when the brain matures. Since age at onset and age but not duration entered the regression models one may favor the second explanation.
      After surgery children recovered significantly in motor functions, attention, visualspatial/visuoconstructional functions, and language. Verbal memory, figural memory, and IQ, however, showed no significant improvement on a group level.
      The results are confirmed on an individual level. Overall the absolute numbers of patients being impaired in the different cognitive domains had dropped at the one year follow-up, 21–50% of the children who were impaired at baseline experienced functional recovery. Individually significant gains in performance were seen in between 16% and 42%. In the domains of motor functions, attention, language, visuospatial and visuo-constructive functions as well as in behavior, about twice as much patients experienced gains than losses. As already mentioned IQ, figural memory, and especially verbal memory were exceptions from the trend towards postoperative improvement. The data in Table 4, however, show that the finding of no change on group level results from the balance of gains and losses. However, a number of 29–39% patients with a significant deterioration in verbal memory performance for example is nevertheless highly relevant for the individual patient, as are 34–37% with significant gains in this performance.
      The regression analyses revealed that a better baseline performance is the most important determinant of the postoperative outcome in all domains, indicating safety and an overall cognitive stability after pediatric epilepsy surgery. However, as demonstrated with the example of verbal memory, those who are better at baseline, are also at greater risk to lose. Thus baseline performance reflects both mental reserve capacity and vulnerability [
      • Helmstaedter C.
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      Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy.
      ]. To some degree this issue was also considered here by the analyses looking at individual changes and controlling for bottom and ceiling effects.
      In addition to baseline performance, a younger age, a later onset of epilepsy, seizure control, less antiepileptic drugs, respectively the reduction of antiepileptic drugs were predictive for better outcomes. In part also tailored/selective surgery appeared favorable. The side of surgery interestingly had close to no predictive value in this pediatric cohort. The findings across differentially located left and right surgeries show that not only the presurgical impairments but also the postoperative changes are non-specific rather than specific [
      • Lendt M.
      • Helmstaedter C.
      • Elger C.E.
      Pre- and postoperative neuropsychological profiles in children and adolescents with temporal lobe epilepsy.
      ]. Accordingly it is difficult to predict individual decline or improvement in a particular domain including behavior. Memory functions demonstrate the largest postoperative dynamics in the positive and negative direction. The fact that most surgeries included temporal lobe structures and the fact that in children many functions (attention, language, visuo-construction, IQ) converge on memory may explain this finding.
      The results demonstrate that the presurgical damage, the mental reserve capacities, functional plasticity [
      • Gleissner U.
      • Sassen R.
      • Schramm J.
      • Elger C.E.
      • Helmstaedter C.
      Greater functional recovery after temporal lobe epilepsy surgery in children.
      ], preservation of functional tissues [
      • Helmstaedter C.
      • Petzold I.
      • Bien C.G.
      The cognitive consequence of resecting nonlesional tissues in epilepsy surgery- results from MRI- and histopathology-negative patients with temporal lobe epilepsy.
      ], and release effects due to seizure control and reduction of the antiepileptic drug load [
      • Skirrow C.
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      Long-term intellectual outcome after temporal lobe surgery in childhood.
      ,
      • Boshuisen K.
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      • Arzimanoglou A.
      • Braun K.P.
      IQ improves after antiepileptic drug withdrawal following pediatric epilepsy surgery.
      ,
      • Helmstaedter C.
      • Elger C.E.
      • Witt J.A.
      The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery.
      ] are decisive for the question of whether recovery from preoperative damage and the surgical sequels can be expected. The suggestion that reduction of antiepileptic medication is important is underlined by the fact that attention and motor skills are particular areas that improved. In this regard our recent publication linking antiepileptic drug treatment with attention/executive functions and IQ in children and adolescents may be of importance [
      • Helmstaedter C.
      • Witt J.A.
      • Hoppe C.
      Evaluating the mediating role of executive functions for antiepileptic drugs’ effects on IQ in children and adolescents with epilepsy.
      ].
      In conclusion we can state that, on the basis of this retrospective single center observation, epilepsy surgery can control seizures in the majority of patients, that most children have deficits in IQ and one or more cognitive domains already before surgery, and that in most domains including behavior postoperative improvements are more likely than deteriorations. The memory domains appear at particular risk for additional impairments but improvements are as likely as deteriorations. Overall baseline performance/damage, sparing functional tissues, seizure control, and tempering of drug treatment appear essential for better cognitive behavioral outcomes and this applies to all types of patients and surgeries dealt with in this study.
      Shortcomings of the present study are the retrospective design, the monocentric view, and varying numbers of patients for different cognitive domains due to missing values. The authors are well aware that non-randomized studies like the present bear a high risk of bias [
      • Flint A.E.
      • Waterman M.G.
      • Siddell P.
      • Houston A.L.
      • Vadlamani G.
      • Chumas P.
      • et al.
      Assessing evidence quality in research reporting neurocognitive outcomes following paediatric temporal lobe surgery for epilepsy.
      ]. Nevertheless the retrospective analysis of such a large cohort provides a first and comprehensive overview of the cognitive surgical outcomes and its determinants in pediatric patients with differentially located and lateralized epilepsies. The determinants of cognitive surgical outcome very much parallel those obtained in adults [
      • Helmstaedter C.
      • Witt J.A.
      How neuropsychology can improve the care of individual patients with epilepsy. Looking back and into the future.
      ]. The long-term (>5 years) follow-up of such a mixed cohort would be very much appreciated as particularly in younger patients positive and negative changes may become more evident during the further development. In addition, the seizure freedom rates and medication are likely to change over longer periods of time. Longer term follow-up evaluations could in particular also reveal the relevance of different cognitive domains and their development in regard to everyday function and behavior and in regard to school career. Finally it should be noted that the rating system chosen here and in previous studies may qualify to be used to collect data across different centers using different outcome measurements. Respective suggestions have been made as part of the work for the EU-funded E-Pilepsy and EpiCare networks of European reference centers for epilepsy surgery and rare epilepsies. (https://www.epilepsyallianceeurope.org/programmes/e-pilepsy/ https://epi-care.eu/)

      Declaration of Competing Interest

      None of the authors has any disclosure in regard to this publication.

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