PEDIATRICS Vol. 119 No. 5 May 2007, pp. 930-935 (doi:10.1542/10.1542/peds.2006-2530)
ARTICLE |
Developmental Outcome After Epilepsy Surgery in Infancy
a Departments of Pediatric Neurology
d Pediatric Neurosurgery, Cleveland Clinic, Cleveland, Ohio
b Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
c Department of Psychiatry, University of Illinois College of Medicine, Chicago, Illinois
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSCASE ILLUSTRATIONSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Our goals were to determine the effect of epilepsy surgery in infants (<3 years of age) on development and describe factors associated with postoperative developmental outcome.
METHODS. We identified 50 infants among 251 consecutive pediatric patients (<18 years old) undergoing epilepsy surgery. Charts were reviewed for clinical data and neurodevelopmental testing with the Bayley Scales of Infant Development. A developmental quotient was calculated to compare scores of children at different ages.
RESULTS. Complete data were available on 24 of 50 infants. Surgeries included 14 hemispherectomies and 10 focal resections. Seventeen patients became seizure free; 5 patients had >90% seizure reduction, 1 had >50% seizure reduction, and 1 had no change. The developmental quotient indicated modest postoperative improvement of mental age. The preoperative and postoperative development quotients correlated well. Younger infants had a higher increase in developmental quotient after surgery. Patients with epileptic spasms were younger and had a lower developmental quotient at presentation, but increase in developmental quotient was higher in this subgroup.
CONCLUSIONS. After surgery, seizure frequency and developmental quotient improved. Developmental status before surgery predicted developmental function after surgery. Patients who were operated on at younger age and with epileptic spasms showed the largest increase in developmental quotient after surgery.
Key Words: epilepsy surgery • infants • development
Abbreviations: AED— antiepileptic drug • MCD—malformation of cortical development • DQ—developmental quotient
Epilepsy surgery is the standard of care for patients with medically intractable focal epilepsy. However, little is known about the impact of epilepsy surgery on development in infants. Decision making about the timing of surgery remains difficult: early surgery may be indicated to prevent recurrent seizures and their devastating effect on development.1 This, however, implies the risk of unnecessary resection and loss of developing brain tissue in cases where potential medical seizure control may be reached as the brain matures.
Relatively few studies and case reports on surgical and developmental outcome after epilepsy surgery are available in children <3 years old.2,3 Two-year postsurgical developmental outcomes were assessed in 24 children with medically intractable infantile spasms who underwent epilepsy surgery. Significant developmental improvement was noted 2 years after surgery. Developmental outcome after surgery was best for patients who received surgery at a younger age and who had the best presurgical developmental scores.2
Our aim was to determine the effect of epilepsy surgery in infants (<3 years of age) on development and to describe factors associated with postoperative developmental outcome. The study reports a 12-year experience with infancy epilepsy surgery at the Cleveland Clinic from 1989 to 2001.
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METHODS |
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TOPABSTRACTMETHODSRESULTSCASE ILLUSTRATIONSDISCUSSIONCONCLUSIONSREFERENCES |
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We identified 50 infants <3 years old among 251 consecutive pediatric patients (<18 years old) undergoing epilepsy surgery at our center between 1989 and 2001. All patients were assessed by a standard protocol including clinical, neuroradiological, neurophysiological, neuropsychiatric, and developmental teams. Each infant was evaluated by using video electroencephalogram monitoring, MRI, and cognitive and developmental assessments. Seizures were classified according to the semiological seizure classification.4 The data were discussed in a multidisciplinary presurgical meeting. Median follow-up duration after surgery was 6 months. Seizure outcome was assessed by using 4 categories of a modified Engel scale: seizure free, >90% seizure reduction, >50% seizure reduction, and no change in seizure frequency.
Charts were reviewed retrospectively for preoperative and postoperative seizure frequency, neuropsychological testing with the Bayley Scales of Infant Development, antiepileptic drugs (AEDs), surgery type, and pathology. The Bayley Scales of Infant Development (1969)5 was used with all patients before 1994, at which time the Bayley Scales of Infant Development, second edition,6 was initiated when it became available at our clinic.
A developmental quotient (DQ; ratio of the Bayley mental age divided by the subject's biological age x 100) was calculated to compare scores of children at different ages. For example, an infant was tested at 12 months’ biological age. Neuropsychological testing revealed a Bayley mental age of 6 months. The DQ was 6/12 x 100 = 50. Fisher's exact test, Mann-Whitney U Wilcoxon test, and Spearman's correlation coefficient were used for statistics. SPSS 10.0 (SPSS Inc, Chicago, IL) was used to calculate statistics.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSCASE ILLUSTRATIONSDISCUSSIONCONCLUSIONSREFERENCES |
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Twenty-four patients (18 boys) with complete data and formal neurodevelopmental evaluation were identified among 50 consecutive patients <3 years of age at surgery. Twenty-six patients were excluded because of incomplete neuropsychological data or different preoperative and postoperative neuropsychological tests. Median age at preoperative assessment was 12 months (range: 3.3–33.1 months), median age at surgery was 14 months (range: 3–34 months), and postoperative evaluation was at 24 months (range: 10–53 months), a median of 6 months (range: 4–42 months) after surgery. Median duration between preoperative testing and surgery was 45.5 days (minimum: 1 day; maximum: 408 days) and 195.5 days (minimum: 128 days; maximum: 1259 days) between surgery and postoperative assessment.
Surgeries (13 right, 11 left) included 14 hemispherectomies and 10 focal resections (3 frontal, 3 frontoparietal, 2 parietal, 1 parieto-occipital, and 1 occipital). Pathology consisted of malformation of cortical development (19 patients, 7 with hemimegalencephaly), malformation of cortical development combined with ganglioglioma (2 patients), Sturge-Weber syndrome (2 patients), and tuberous sclerosis (1 patient).
Patients presented with a median of 2 different semiological seizure types (range: 1–4). Seizure semiology included tonic seizures (15), clonic seizures (15), epileptic spasms (11), eye versive seizures (7), hypomotor seizures (5), and myoclonic seizures (3).
Seizure frequency and number of AEDs decreased after surgery. Before surgery, the patients had a median of 15 seizures per day (range: 0.2–120) and were taking a median of 3 AEDs (range: 0–5). After surgery, seizure frequency decreased to a median of 0 (range: 0–15; P < .001), and the number of AEDs was reduced to a median of 1 (range: 1–3; P < .001). Seventeen patients became seizure free; 5 patients had >90% seizure reduction (with 0.03–6.00 seizures per day [median: 0.3]), 1 had >50% seizure reduction, and 1 had no change.
Median developmental mental age according to the Bayley scale was 3 months (mean: 5.83) before surgery and 9 months (mean: 11.94) after surgery. The DQ was below average (<100) before and after surgery in all infants. There was a modest postoperative improvement of mental age. It increased from a preoperative median of 37 (range: 0–92) to 49 (range: 2–92) after surgery (P < .01). The DQ improved in 17 patients and decreased in 7 patients compared with preoperative assessment (Fig 1). All 7 infants with no measurable mental development (mental age <1 month on the Bayley scale) before surgery made progress after surgery.
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The development of all infants in the study was below that of the average infant (DQ = 100). Only 2 patients were developmentally within the reference range (DQ > 80) before and 3 were within the reference range after surgery. Before surgery, developmental delay (DQ < 70) was present in 22 of 24 children (Table 1). After surgery the number of delayed infants decreased to 18. However, this change was not statistically significant (P = .125, McNemar test). An increase in the number of patients with borderline functioning (DQ = 70–80) accounted for this improvement (0 patients before and 4 after surgery). Profound developmental delay (DQ < 50) was seen in 13 (54%) of 24 infants postoperatively.
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Whereas a higher DQ before surgery was correlated with a higher DQ after surgery (correlation coefficient: 0.67; P < .001), infants with a preoperative DQ >50 were more likely to experience a reduction in DQ (6 of 8) than those with a DQ <50 (1 of 16; P = .01). Although the DQ declined in 7 infants, none of these infants experienced a loss of skills after surgery.
Younger age at the time of surgery was correlated with improvement in the DQ (correlation coefficient: 0.72; P < .001). However, surgery did not affect developmental outcome in infants >12 months of age at time of surgery. The DQ increased after surgery in 10 of the 11 children who had surgery younger than 12 months of age (Fig 2). However, it increased in only 6 of 13 who were older than 12 months of age at the time of surgery (P < .05).
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Analysis of seizure semiology revealed that patients with epileptic spasms presented for preoperative assessment and for surgery at a younger age than patients without epileptic spasms. Median age at presentation in patients with epileptic spasms was 4.2 months and in patients without epileptic spasms was 6.1 months (P < .01). Median age at surgery in patients with epileptic spasms was 6.1 months and in patients without epileptic spasms was 19.9 months (P < .01). Preoperative DQ in infants with epileptic spasms was lower (median: 23) than in infants without epileptic spasms (median: 54; P < .01). Change in DQ and improvement was more prominent in the subgroup of infants with epileptic spasms (Fig 3; P < .01). When analyzed separately, only the group of infants with epileptic spasms had a significant improvement in DQ after surgery. There was no difference in the time interval from presurgical assessment to surgery among patients with or without epileptic spasms. Other semiological features were not related to developmental outcome.
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Other factors that were not associated with development before or after surgery included preoperative and postoperative seizure frequency, postoperative seizure freedom, and change in number of AEDs, side of surgery, type of resection, or pathology.
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CASE ILLUSTRATIONS |
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TOPABSTRACTMETHODSRESULTSCASE ILLUSTRATIONSDISCUSSIONCONCLUSIONSREFERENCES |
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Two cases may illustrate the wide spectrum of development in our patient series.
Case 1 (Patient 4)
This patient had seizures since the age of 1 month presenting with right-eye deviation and bilateral eye blinking occurring up to 40 times per day despite treatment with phenobarbital, phenytoin, carbamazepine, and clonazepam. Baseline evaluation at 3.1 months’ biological age revealed a mental Bayley Scales developmental age of 1 month (DQ = 1/3.1 x 100 = 32%). Based on video electroencephalogram, MRI, and fluorodeoxyglucose positron emission tomographic scan data, the patient underwent right parietal resection. Pathology revealed malformation of cortical development. The patient became seizure free and was only maintained on phenobarbital after 6 months. Neuropsychological reassessment at 9.83 months after surgery revealed a developmental age of 9 months (DQ = 92%) The patient caught up, and development at repeat assessment was comparable to a normal infant.
Case 2 (Patient 8)
Left-arm clonic seizures started at the age of 4 months old. The patient continued to have 5 seizures per day despite phenobarbital and carbamazepine. Examination revealed left hemiparesis, left hemianopia, and a port wine stain over the right hemicranium. Baseline neuropsychological assessment at 19.27 months’ biological age revealed a Bayley Scale mental age equivalent of 11 months (DQ = 57%). Based on video electroencephalogram, MRI, and FDG-positron emission tomography data, the patient underwent right functional hemispherectomy and became seizure free. Carbamazepine was discontinued. The patient underwent repeat neuropsychological assessment at 27.03 months’ biological age, revealing a Bayley Scales mental age equivalent of 14 months (DQ = 52%). Development progressed by 3 months between the first and the second assessment, but not at a normal rate.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSCASE ILLUSTRATIONSDISCUSSIONCONCLUSIONSREFERENCES |
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We present the first study with formal preoperative and postoperative neuropsychological testing limited to infants <36 months of age at the time of epilepsy surgery. All infants (79% with malformation of cortical development) had below average development (DQ < 100) before and after surgery. After surgery, 71% of infants were seizure free, and 92% of patients had at least 90% seizure reduction on reduced AEDs. The median DQ improved after surgery for the group, individual DQs improved for 71% of infants, and postoperative DQ declined in only 7 children. Mental age increased after surgery in every case. Developmental status before surgery predicted developmental function after surgery. Assessment of DQ change in relation to age at surgery will require a refined study design. In our series, patients operated on at a younger age and with epileptic spasms showed the largest increase in DQ after surgery.
Seizure frequency and number of AEDs after surgery decreased significantly in all infants. Seventeen of 24 infants became seizure free. This result confirms a study by Chugani et al.7 that reported seizure freedom or at least 90% seizure frequency reduction in 18 of 23 patients who had focal cortical resections or hemispherectomy between the ages of 5 months to 3.7 years. Our study also reflects previous results from our center that reported 9 of 12 infants with only rare or no epileptic seizures after epilepsy surgery between the ages of 3 and 29 months of age.8 In addition, the results from our study (71% seizure freedom) also match the seizure freedom rates of extratemporal resections in older children9–11 and 67% with seizure freedom or auras in a survey of 2464 patients (adults and children) operated on at 38 different epilepsy centers between 1995 and 1999.12
Discontinuation of AEDs after epilepsy surgery has been described in adults13 and in children,14 but no studies with focus on children <3 years of age are available. We were able to show that, for the first time, epilepsy surgery in infancy reduces AED treatment. Because seizure frequency reduction and AED reduction both occurred after epilepsy surgery, we are not able to determine whether developmental improvement was related to decreased seizure frequency or AED reduction. It is likely that frequent seizures, as well as the sedating effect of the AEDs, both impair cognitive development.
Previous case reports on developmental outcome after epilepsy surgery suggested that early epilepsy surgery in infants with catastrophic epilepsy may allow the resumption of developmental progression during critical stages of brain development and maturation.7,8 Mental development tends to progress in the majority of infants after epilepsy surgery, in particular in those with initially no measurable development. In addition, a statistically significant increase occurs in developmental levels at an average age of 21 months after surgery compared with presurgical results.2 These authors also compared the developmental outcome of their study with all other previously reported infants receiving medical treatment for infantile spasms and found that the developmental outcome in their surgical group was equal and sometimes superior to children treated with either corticotropin or valproic acid.2 Although overall development remains severely impaired, in our series only a short period of follow-up could be included. Some patients may continue to lose ground and develop at a slower pace, whereas others may actually continue to cross percentiles and continue to catch up. Many infants develop at a faster rate or pick up development but remain abnormal. Meaningful changes may be seen in all infants that develop at a faster rate than their preoperative baseline.
Preoperative and postoperative neurodevelopmental testing in infants < 3 years of age undergoing epilepsy surgery is an important tool to predict postsurgical mental outcome and helps to determine the ideal time for resective epilepsy surgery based on presurgical developmental baseline. Developmental outcome was best in children who received epilepsy surgery at a younger age and who had the best baseline assessments before epilepsy surgery.2 One hypothesis that explains the better presurgical test results in children who undergo surgery when they are <1 year of age is that there is less time for seizures to influence development. Early treatment and seizure control seem to be key to improved developmental outcome. This has also been confirmed by a recent study on long-term cognitive outcomes of a cohort of children with infantile spasms of unknown etiology that were treated with high-dose corticotropin.15 Twenty-two infants were treated within 1 month of onset of infantile spasms and 15 after 1 to 6 months. All 22 infants of the early treatment group, but only 40% in the late treatment group, had normal cognitive outcome. In addition, infants with only minimal mental retardation at presentation were more likely to have a normal cognitive outcome between the ages of 6 to 21 years of age.15
Seizure semiology may correlate with outcome after epilepsy surgery. Recent work on the developmental outcomes after epilepsy surgery that also included older children at the time of surgery suggested that postoperative DQ calculated based on the Vineland Adaptive Behavior Scale was better in patients with epilepsy of shorter duration and earlier surgical intervention.16 In this series, infants were classified based on medically refractory spasms, successfully treated spasms, and no epileptic spasms. Interestingly, age at surgery was older with fewer documented spasms.16 This correlates with our results that showed more spasms in the patients that underwent early operative intervention. Epileptic spasms present earlier and, therefore, may just be an indicator for severe developmental delay at the time of presentation and early recognition and treatment of epilepsy. It remains unclear whether epileptic spasms are a separate risk factor or whether the analysis of patients with spasms may be confounded by the early time of presentation and surgery.
Pathologic findings in our group may have influenced our data. The most prominent pathologic diagnosis in our group consisted of malformation of cortical development, which was shown to predispose for less improvement in language and intelligence scores on follow-up after hemispherectomy in a series of older children (age at hemispherectomy ranged from 4 months to 20 years).17 Two patients with Sturge-Weber syndrome did not improve developmentally after epilepsy surgery despite seizure freedom in our series. A previous case series describes the IQ after hemispherectomy in a case series of patients with Sturge-Weber syndrome on development.18 Five of 6 patients had a favorable outcome with intelligence quotients >80%, with follow-up ranging from 1 to 13 years. The sixth patient was the only patient in this series who did not undergo hemispherectomy during the first year of life, and this patient was the only one that had no improvement in his IQ.18 These results correspond to our experience that children undergoing epilepsy surgery during the first year of life may have a better developmental outcome (Fig 2).
A limitation of our series is the lack of an appropriate control group. To compare presurgical and postsurgical development in our series, we had to use the hypothetical construct of the DQ to compare presurgical and postsurgical development. The retrospective study approach led to variable intervals between preoperative and postoperative testing, selection bias because of data acquisition at a tertiary epilepsy center with referral bias and ascertainment bias, as well as limitations of the applied test scales. In addition, neuropsychological data were incomplete in half of the initially included 50 cases. Although our patients were highly selected, it seems unlikely that they were selected to have favorable outcome, because infants were only selected for surgical intervention after they had failed several antiepileptic medications.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSCASE ILLUSTRATIONSDISCUSSIONCONCLUSIONSREFERENCES |
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We present the first study, to our knowledge, with formal preoperative and postoperative neurodevelopmental testing limited to infants <36 months old at the time of epilepsy surgery. The median DQ improved after surgery for the group overall, and individual DQs improved for 71% of infants. Developmental status before surgery predicted developmental function after surgery. Assessment of DQ change in relation to age at surgery and seizure semiology will require a refined prospective study design comparing surgical and medical treatment of seizures in infants.
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FOOTNOTES |
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Accepted Jan 11, 2007.
Address correspondence to Tobias Loddenkemper, MD, Department of Pediatric Neurology, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195-5245. E-mail: loddent{at}ccf.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
Drs Loddenkemper and Holland contributed equally to this work.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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