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Department of Pediatric Neurology, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, GermanyCenter for Chronically Sick Children, Augustenburger Platz 1, Berlin, GermanyCharité – Universitätsmedizin Berlin, Institute of Cell- and Neurobiology, Charitéplatz 1, Berlin 10117, Germany
Department of Pediatric Neurology, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, GermanyCenter for Chronically Sick Children, Augustenburger Platz 1, Berlin, Germany
Department of Pediatric Neurology, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, GermanyCenter for Chronically Sick Children, Augustenburger Platz 1, Berlin, GermanyCharité – Universitätsmedizin Berlin, Institute of Cell- and Neurobiology, Charitéplatz 1, Berlin 10117, Germany
Excellent seizure control after epilepsy surgery in the first six months of life.
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89% of all patients show a reduction of seizures or are seizure free after surgery.
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A large proportion of infants can reduce or discontinue anti-seizure medication.
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Cognitive gain is almost exclusively seen in seizure-free infants after surgery.
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Moderate complication rate with same hydrocephalus rate as in older patients.
Abstract
Introduction
Nearly one-third of all infants with epilepsy develop drug-resistant epilepsy. Although epilepsy surgery is a well-established therapy across all age groups, there might be a reluctance to operate on infants in the first six months of life due to unique surgical and anesthesiologic difficulties.
Methods
We performed a meta-analysis and systematic review to assess the outcome and complication rate of epilepsy surgery in infants operated on ≤ six months of life.
Results
158 infants underwent epilepsy surgery, most frequently a hemispherotomy rather than focal surgery. Overall seizure freedom after surgery was 65.6% [CI: 0.5785; 0.7261], with higher seizure-free rates following hemispherotomy (71%) than after focal surgery (58%). Complications occurred in 27.7% [0.1794; 0.4004] of patients. Most prevalently, a hydrocephalus developed in 20 out of 136 cases (14.71%). Anti-seizure medication (ASM) was discontinued in 21.5% [0.1431; 0.3100] and reduced in 85.9% [0.515; 0.9721] of 93 patients postoperatively. 84.6% of infants displayed cognitive impairment (development quotient (DQ) <85) preoperatively. After surgery, there was a trend toward a cognitive gain. However, cognitive gain was seen almost exclusively in seizure-free patients.
Discussion
Excellent seizure control can be achieved with epilepsy surgery in the first six months of life, a large proportion of patients are able to reduce or discontinue ASM. Data regarding cognitive outcome are promising, but also show that the primary goal should be to achieve seizure freedom. Given the more difficult surgical conditions, epilepsy surgery in the first six months of life should only be performed in specialized epilepsy centers.
]. These patients are referred to as “drug resistant”. Drug resistant epilepsy (DRE) in children is not clearly defined. In early infancy the definition is even more complicated and differs in many aspects from DRE in children and adolescents. Seizures in the neonatal period and first month of life are most frequently caused by acute brain injury, i.e., hypoxic-ischemic encephalopathy or intraventricular hemorrhage [
]. Catastrophic epilepsy in the sensitive developmental period of infancy, often associated with polypharmacy, can result in neurological deterioration and severely impaired quality of life [
]. Given the consequences of early-onset DRE, it seems reasonable to offer early epilepsy surgery to infants with DRE. Especially since shorter epilepsy duration is associated with better cognitive and developmental gains [
]. However, there might be a great reluctance to operate on these patients. This can be traced back to the fear of anesthesiologic complications due to low weight and blood volume, the more fragile brain tissue and smaller situs at this age, the difficulty to identify lesion boundaries at a time of incomplete myelination. Additionally, the type of lesion found may be associated with often-necessary larger surgical interventions [
]. Because of this, there is a lack of data on epilepsy surgery safety, outcome, and functional development postoperatively.
This systematic review and meta-analysis aims to provide an overview of outcome and safety dealing with epilepsy surgery in infants operated in the first six months of life.
2. Methods
2.1 Search strategy and study selection
This systematic review was performed in accordance with the PRISMA guidelines for systematic review. The final search string we used on PubMed/Medline is attached (Supplemental 1). We selected relevant studies published after 1999 and before August 31, 2021, in English or German. The year 2000 was chosen as a cutoff, due to advances in surgical techniques and imaging over the last years. The reference list of all included reports was searched manually to identify additional studies. Studies had to report age at surgery, surgical technique, seizure freedom after surgery, and a minimum of three patients. Other aspects such as complications, ASM, reoperation, and cognitive development, if available, were collected. Patients who underwent a callosotomy were excluded, given its mostly palliative approach. Each study was independently reviewed by the first author (KLM). Initially, title and abstract were screened for eligibly. Secondly, full texts of potential studies were assessed.
2.2 Data extraction
A standardized excel data sheet was used by the first author (KLM) to extract the data with the senior author (AMK) consulted in any instances in which clarification was needed. After data extraction, the data was discussed and crosschecked by the senior author. Successful seizure freedom was classified as Engel Class I (“free of disabling seizures”), the equivalent ILAE Class 1, or a description of seizure outcome equivalent to these classifications, based on the last reported follow-up visit [
]. Successful surgery in terms of significant seizure reduction was classified as ILAE Class 2-4 or Engel Class 2-3, whereas unsuccessful surgery was defined as ILAE Class 5-6/Engel 4 or equivalent description. In case of reoperations, the last available seizure outcome data was included in analysis. Complications were defined as an undesired, unexpected event after surgery. We included complications related to surgery such as hydrocephalus, infarction, postoperative hemorrhage, or cerebrospinal fluid (CSF) leak. Also, data on the intra- and postoperative transfusion of red blood cells were collected. Anesthesiologic complications such as intubation problems were not included. The overall rate of complications was analyzed only for studies reporting on complications per patient (n/N). However, every single reported complication was listed to provide an overview of the most frequent complications.
Due to varying surgical techniques regarding hemispheric disconnection in some studies (anatomical or functional technique), we classified all hemispheric surgeries, i.e., anatomical hemispherectomy or functional hemispherotomy, as hemispherotomy. For statistical analysis lobectomies and lesionectomies were classified as focal.
2.3 Statistical analysis
Statistical analysis was performed using the “metafor” and “meta” package with RStudio [
]. To calculate the overall pooled outcome and confidence intervals (CI) we used a random effect model incorporating any heterogeneity between studies. Due to the small sample size of the subgroups, only a pooled result was calculated for the overall result. For subgroup analysis, a weighted average was calculated, which was also calculated for follow up length. I2 was used to assess heterogeneity between studies, where 25%, 50%, and 75% were considered to represent low, medium, and high heterogeneity, retrospectively [
]. Using funnel plots we assessed visually publication bias Furthermore, Egger´s test was conducted to check for potential publication bias if applicable (Supplemental 2). To compare pre- and postoperative DQ values the Wilcoxon test was applied. For comparison between independent samples, the Mann-Whitney-Test was used. P-values < 0.05 were used to declare statistical significance. Pooled results are presented as outcome% [95% confidence interval (CI)].
3. Results
3.1 Search results
The PubMed search - using the search string given in Supplemental 1 - identified 1912 studies, of which 1239 were excluded after reading the abstract (Fig. 1). Of the remaining 214 studies the full text was assessed for the inclusion criteria mentioned above. Only 14 were included [
Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlations with the surgical technique. A report on 15 cases.
]. All studies were retrospective. For those studies that included infants and older patients, information was extracted only for infants operated on before the age of seven months.
The total sample included 158 infants reported in 16 studies (Table 1). Studies reported a median of 4 patients (interquartile range 5.5). The classification of the underlying cause of epilepsy was heterogeneous. Most common causes were hemimegencephaly (HME) and cortical dysplasia (CD) (Table 1). The most performed surgical technique was a hemispherotomy in a total of 98 infants (62%). As focal surgery, lobectomies (n = 26) and focal resections (n = 23) were performed with almost equal frequency.
Table 1Reports and patients included in the study. Abbreviations: CD, cortical dysplasia; HME, hemimegaloencephaly; FCD, focal cortical dysplasia; SWS, Sturge Weber syndrome; TSC, tuberous sclerosis; MCD, multilobar cortical dysplasia; MalDev, malformation of cortical development; HS, Hemispherotomy; L, lobectomy; FR, focal resection; NA, not available.
Outcome was reported for 157 of 158 patients. In one patient, no postoperative outcome is reported because of immediate postoperative death. Overall seizure freedom after surgery was 65.6% [CI 57.85; 72.61] (I2 = 0.0% [0.0%; 60.2%]) (Fig. 2A, B). Seizure freedom in studies ranged from 33% to 100%. Following hemispherotomies, the seizure-free rate was 71% compared to only 58% for focal surgery (Fig. 2C, D). Seizure freedom was achieved in a total of 103 patients (65.6%). In addition, a significant seizure reduction was achieved in 37 patients (23.6%). This means that in 89.2% a satisfactory surgical result was achieved. Only 17 infants (10.8%) did not show a successful outcome. Roth et al. described eight patients with ILAE V outcome without further information (6% focal surgery, 14% hemispheric surgery) [
]. In nine studies, a follow-up with a mean observation period of 3.6 years was reported. Data on reoperations was available for 121 patients and performed in 34 patients (28.1% [20.82; 36.75]; I2 = 0.0% [0.0%; 62.4%]). Regarding reoperations, detailed information was available for 18 patients. Most frequently, a functional hemispherotomy was extended to an anatomical hemispherectomy (n = 5, 27.8%). In four cases each, a focal resection was extended to a hemispherotomy (22.2%) or an extended focal resection (22.2%). A hemispherotomy was planned in two stages in four patients and thus was not completed until reoperation. In one patient, a repeat lobectomy was performed on the same surgical site after hemispherotomy (5.6%).
Fig. 2Outcome after epilepsy surgery in infants < seven months-of-age. (A) Forest Plot showing pooled outcome of 65.6% [0.5757; 0.7261] in a total of 157 patients after epilepsy surgery in the first six months of life using a GLMM and a random effects model. Events relate to seizure free patients (n), Total relates to patients overall (n). Abbreviations: GLMM, generalized linear mixed model; CI, confidence interval. (B) Bar chart showing overall outcome after epilepsy surgery (dotted line = pooled outcome). The numbers above the bars indicate the number of infants reported in the individual study. (C) Bar chart showing outcome after hemispherotomy in infants with 71% (dotted line; weighted average) of all operated infants being seizure free and outcome for each study. The numbers above the bars indicate the number of infants reported in the individual study. (D) 58% of infants (dotted line; weighted average) who underwent focal surgery achieved seizure freedom. Bar charts indicate seizure freedom in individual studies. The numbers above the bars indicate the number of infants reported in the individual study.
ASM could be discontinued in 21.5% [14.31; 31.00] (I2 = 0.0% [0.0%; 79.2%]) and reduced in further 85.9% [51.50; 97.21] (I2 = 28.9% [0.0%; 72.3%]) of 93 patients in the postoperative course (Fig. 3A, B).
Fig. 3ASM prescription after surgery. (A) In more than a fifth of all patients (22%) it was possible to taper off all antiseizure medication (ASM). (B) Forest plot showing that in 85.9% of all patients it was possible to reduce ASM postoperatively. Events relate to patients without/reduced ASM (n), Total relates to patients overall (n). Abbreviations: GLMM, generalized linear mixed model; CI, confidence interval; ASM, antiseizure medication.
Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlations with the surgical technique. A report on 15 cases.
]. The most prevalent complication was the development of a hydrocephalus which occurred in 20 out 136 cases (14.7%) (Table 2). Ten studies calculated the complications per patient in their cohort resulting in an overall complication rate 27.7% [17.94; 40.04] (I2 = .0% [0.0%; 60.2%]) (Fig. 4A). Complications ranged from none to as high as 75% mentioned in individual studies. Roth et al. does not give a complication rate (total complications: n = 47) but describes the need for further red blood concentrates (RBC) in sixteen patients (25%) as the most common postoperative complication followed by 13 patients who developed a hydrocephalus (20%) [
Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlations with the surgical technique. A report on 15 cases.
]. In total 72 complications in 136 patients were described. Other common complications were infection (n = 6), aseptic meningitis (n = 4) and infarction (n = 2). One death occurred in two studies each [
]. Kumar et al. reported on the death of an infant with HME who underwent hemispherotomy without complications at the age of two months. Three months after surgery, care was withdrawn due to persistent seizures from the contralateral side. Prayson et al. reported the death of a six-month-old infant who underwent frontal lobectomy in the postoperative period. No further information is given. Data on intraoperative RBCs was available in five studies (96 patients) [
]. Almost all patients (97.8% [0.9164; 0.9945]; I2 = 0.0% [0.0%; 79.2%]) required intraoperative RBCs (Fig. 4B).
Table 2Overview of complications following epilepsy surgery in young infants. The most frequent complication was the development of hydrocephalus in 20 out of 136 cases (14.7%), followed by additional red blood concentrates, wound complications and infection.
Fig. 4Complication rate. (A) Forest plot showing that in 26.8% of 72 patients had reported complications. (B) Almost all patients required intraoperative red blood concentrates. Events relate patients with complications/RBC (n), Total relates to patients overall (n). Abbreviations: RBC, red blood concentrates; GLMM, generalized linear mixed model; CI, confidence interval.
To assess cognitive postoperative development, we extracted available pre- and postoperative standardized testing from all studies. In a total of four studies, it was possible to perform pre- and postoperative testing in 26 patients [
]. With an average preoperative development quotient (DQ) of 43.58 ± 32.23 a wide range of 0–113 existed. The median is 34 with an interquartile range of 23–63. Defining 85 as a cut off, only four infants (15.4%) had a DQ of more than 85 and, thus, showed an average cognitive development. Postoperatively, the average developmental quotient was 49.35 ± 30.98 (Wilcoxon test, z = -.915, p = .36) (Fig. 5D). Assuming five points as a significant change threshold in the pre-post comparison, twelve patients showed an increase and ten losses. Accordingly, four infants stagnated. Infants who gained cognitively increased by a mean of 26.57 ± 19.94 DQ points, whereas infants lost a mean of -18.5 (±19.16) points. Cognitive improvement was seen almost exclusively in seizure-free patients (+13.82 ± 25.59 DQ points), while non-seizure free patients on average lost DQ points postoperatively (-9.44 ± 32.92 DQ points) (Mann-Whitney-Test, p = .058. (Fig. 5B). Age at postoperative testing was not available in any of these studies. However, a follow-up duration of 65.5 ± 46.07 months (median: 49) was reported in 20 patients.
Fig. 5Cognitive development before and after epilepsy surgery. (A) Graph depicting individual cognitive development before and after epilepsy surgery, with an average increase of 5.77 ± 29.89 development quotient (DQ) points (Wilcoxon test, z = -.915, p = .36). (B) Boxplot showing the difference of delta after surgery of DQ for seizure free and non-seizure free patients. Cognitive gain was almost exclusively seen in seizure free patients. The blue area represents nonsignificant changes individual defined as a change of <5 DQ points.
We report the outcome of 158 infants with DRE who underwent epilepsy surgery in the first six months of life for catastrophic drug resistant lesional epilepsy. The results support epilepsy surgery as an effective treatment approach in young infants with lesional DRE. Seizure freedom and discontinuation or reduction of ASM are favorable for the developmental outcome after surgery.
Like older pediatric patients, a large proportion of young infants underwent hemispherotomy [
]. Seizure outcome of young infants in our review with an overall seizure-freedom of 65.6% is comparable to that achieved in children, who undergo epilepsy surgery at a later state, as determined in Widjaja et al. with 64.8% [
]. The average rate of seizure-free surgery is about 13% higher than that of focal surgery as determined in this review. One possible cause could be, that due to the problems in imaging at this age, the borders of the lesions are difficult to determine clearly. However, it should be noted that due to often small patient numbers in individual studies, these values are only a weighted average, and no pooled value could be determined. The data shows that it is possible to achieve good seizure control with established surgical techniques in very young infants.
Although the seizure frequency is higher for hemispheric surgery, a wide variety of surgical techniques are grouped together under this term, such as anatomic hemispherectomy or functional hemispherotomy with different surgical techniques. Whether the outcome or the complication rate differs between these surgical methods cannot be determined from the available data.
A large proportion of patients (69.3%) were able to reduce the prescribed amount of ASM. In more than a fifth of patients a discontinuation of ASM was possible. ASM, particularly polypharmacy, has a significant impact on cognitive development [
]. The possible reduction of ASM, or even their discontinuation, through postoperative seizure freedom enables infants to develop without the harmful influence of seizures and multiple ASM. Generally, the timing for AED withdrawal is debatable with little evidence about an optimum timing [
]. The rapid tapering of ASM allows, in particular, to identify patients in whom the complete epileptogenic lesion may not have been removed/deafferented and who therefore may need continuous treatment and/or a second epilepsy surgery [
Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study.
]. This is particularly relevant in the cohort of patients of very young infants since cranial imaging may reach its limits to clearly identify lesions in this developmental period [
]. However, it should be noted that in most patients in this age group, large unilateral structural lesions are causative for their epilepsy.
Neurosurgery in infants represents age specific risks. A higher risk for intraoperative hypoglycemia, hypothermia, and critical events are observed and require close expertise monitoring [
]. In our review, it became obvious that almost all patients received intraoperative red blood cell concentrates. In this age group, the individual blood volume can be estimated relatively well by weight and corresponds to approximately 80 ml/kg [
]. Specifically, patients with HME, one of the most common causes of detrimental infant-onset DRE, is described to result in highest risk of intraoperative blood loss [
]. This may be linked to distorted anatomy and relatively small ventricles as anatomical guiding structures. In contrast, infants with large hypoxic-ischemic lesions are associated with large ventricles and are thus less prone to such complications. In addition to intraoperative blood loss, the individual hemoglobin level decreases to about 9 g/dl in the first 3 months of life [
], which increases the risk for relevant intraoperative hemodynamic instable episodes. If blood loss is not managed preventively and might lead to hemostatic derangements or may even be associated with intraoperative arterial vascular injury it is described as cause of death during epilepsy surgery in infants [
]. At present, data on intraoperative complications in infants in relation to intraoperative bleeding remain to be not available on a solid basis and will need further investigation in future perspective.
The reported postoperative complication rate was as high as 27.6%. The most prevalent complication was the development of a hydrocephalus in 14.7% of all patients. Iwasaki et al. observed a complication rate of 33% (19/57 patients) in patients operated before the age of three years, while Dunkley et al. reported a complication rate of 12% in the same age group [
]. This suggests that the rate of complications in infancy may be increased but is comparable to patients operated in the first three years of life. However, the complication rates differ greatly between studies with a wide range of definitions of the term complication. In addition, the complication rates can only be transferred to other cohorts to a limited extent due to the individual composition of patients, cause of epilepsy, applied surgical methods and expertise of the epilepsy center team. Consistent standards are indispensable to compare surgical techniques. The likelihood of developing a hydrocephalus after hemispherotomy is determined to be as high as 23% in the pediatric age group [
]. Due to the high number of operated infants with HME and low body weight, this could result in an increased risk for infants. With 14.7% of all patients operated on as very young infants, the incidence of a postoperative hydrocephalus as calculated in this review is not increased.
Death related directly to epilepsy surgery is uncommon [
]. The mortality rate of 1.3% (2/158) observed in this study in young infants is comparable to that reported for older patients. The latter has been estimated to range from 0.1% to 0.5% with the highest mortality rate for extratemporal focal resection (1.2%) and hemispherotomy (2.2%) [
]. It is important to note that no death occurred perioperatively but rather occurred in the postoperative course. It is not yet clear whether infants require or benefit from special surgical techniques. It must also be critically noted that with a median of four patients per study reporting on complications, patient data on complications are very limited.
Data on postoperative cognitive development was available for only 16.4% (n = 26) of all operated patients. Infants with DRE generally represent a difficult cohort in which standardized/normed testing is usually difficult. In addition, there is a high variability due to different test procedures, norm data, examiners, and a general variability in age. Loddenkemper et al. reported on 24 children operated on in the first three years of life, of which six where operated on in the first six months of life [
]. Here he described an increase of DQ points in 71% in all children postoperatively. Particularly infants operated in the first 12 months of life were more likely to show an increase of their DQ postoperatively. Furthermore, all infants operated in the first six months of life show cognitive improvement. Battaglia et al. reported on 45 children operated before the age of seven years [
]. Here, he describes for most patients an unchanged neurocognitive level. Similarly, to Loddenkemper et al. Honda et al. describes that shorter seizure duration as well as seizure freedom correlate with better postoperative development in patients with HME and epileptic encephalopathy [
]. 46.2% showed a significant increase in DQ points and 38.5% losses. A gain of DQ points was associated with seizure freedom after surgery, which also is described in older patients [
]. However, in older patients most patients show stagnation and only 19% improvement, as calculated in a review conducted by van Schooneveld and Braun [
]. This leads to two rationales: (i) a greater proportion of infants show postoperative cognitive development compared to older patients; early intervention thus allows a strong chance of cognitive improvement in almost half of all patients, especially since early surgery likely correlates with better cognitive development (ii) since a positive effect of epilepsy surgery on cognitive development is seen almost exclusively in seizure-free patients, the surgical objective should necessarily be seizure freedom. Epilepsy surgery should be seen as a great opportunity for this patient group of infant-onset DRE and should motivate pediatricians to obtain an epilepsy surgery evaluation at a center specialized in infants rapidly. In the best case, these patients can develop postoperatively without the negative influence of seizures and ASM. However, there is a high need for prospective studies to assess the exact development and to identify patients who may not benefit from early epilepsy surgery. After all, these potential benefits must always be weighed against the surgical risks.
5. Conclusion
In this review, we demonstrated that excellent seizure control can be achieved through epilepsy surgery in the first six months of life in infants with catastrophic epilepsy. In these patients the high seizure burden was weighed against the risk of early surgical intervention. For this reason, our review cannot be applied to all infants, especially not to those with low seizure frequency. In these patients, other therapeutic options may need to be considered first. The chances for these patients to achieve seizure freedom and to develop with less ASM are enormous. The data on postoperative development are sparse but show the potential and chances for these patients. They emphasize that the primary goal should be to achieve seizure freedom and that complications in the postoperative course need to be closely monitored. Consequently, this group of patients needs to be managed and operated on in epilepsy centers specialized on infants with DRE. An interdisciplinary team of neuropaediatricians, neurosurgeons, neuroradiologists, therapist and social workers is needed. Experienced anesthesiologists are needed for neurosurgical procedures in infancy to manage the more difficult surgical conditions. Furthermore, to get more information on the decisive question of postoperative cognitive gain, a detailed pre- and postsurgical neuropsychological assessment is warranted to assess the functional development and possible deficits at an early stage.
Nevertheless, with only 158 young infants receiving epilepsy surgery published in the last 21 years, there is a lack of concise data for this special age group. For this reason, prospective studies adding as many centers as possible and consistent standards are necessary to evaluate these patients and to improve epilepsy surgery for these patients.
CRediT authorship contribution statement
Konstantin L. Makridis: Conceptualization, Funding acquisition, Formal analysis, Writing – original draft, Writing – review & editing. Deniz A. Atalay: Writing – original draft, Writing – review & editing. Ulrich-Wilhelm Thomale: Writing – original draft, Writing – review & editing. Anna Tietze: Writing – original draft, Writing – review & editing. Christian E. Elger: Writing – original draft, Writing – review & editing. Angela M. Kaindl: Conceptualization, Funding acquisition, Formal analysis, Writing – original draft, Writing – review & editing.
Declaration of Competing Interest
Nothing to report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlations with the surgical technique. A report on 15 cases.
Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study.
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