Abstract
Introduction:
To determine if early epilepsy surgery mitigates detrimental effects from refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex (TSC) who underwent surgery before 2 years of age.
Methods:
Prospective multicenter observational study of 160 children with TSC. Surgical outcomes class was determined for the specific seizure type targeted by the surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II), Mullen Scales of Early Learning (MSEL), and Preschool Language Scales, Fifth Edition (PLS-5) at 3, 6, 9, 12, 18, 24 and 36 months of age. Surgical cases were compared to children without seizures, with controlled seizures and with medically refractory seizures.
Results:
19 children underwent surgery (median age 17 months, range 3.7–21.3) and mean follow-up was 22.8 months (range 12–48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in 7 (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from the surgically targeted type.
All children with seizures demonstrated decline or attenuated gains in neurodevelopment over time, with the surgical group scoring lowest. Favorable surgical outcome was associated with an increase of MSEL receptive and expressive language subscores compared to the medically refractory seizure group. A non-significant but consistent pattern of improvement with surgery was seen in all tested domains. Conclusions: In this pilot data, surgical intervention was associated with neurodevelopmental gains in some domains. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics.
Keywords: children, epilepsy, tuberous sclerosis complex, epilepsy surgery
Introduction
Tuberous sclerosis complex (TSC) is a neurogenetic disorder with an estimated prevalence of 1 in 6,000. Pathogenic variants in the TSC1 and TSC2 genes are associated with disinhibition of the mechanistic target of the rapamycin (mTOR) and dysgenic lesions in multiple organs throughout the body, including the brain, heart, kidneys, eyes, skin and lungs1. Neurological manifestations are common in children, and epilepsy has an approximately 90% lifetime prevalence2. Sixty percent experience seizure onset in the first year of life during a critical period of neurodevelopment, with refractoriness to medications in up to two-thirds of cases2,3.
The association between epilepsy and neurodevelopmental outcome has been repeatedly established. Consistently poor rates of cognitive outcome are seen with earlier seizure onset, increased seizure severity and presence of infantile spasms2,4–6. Early and aggressive seizure control may mitigate these detrimental effects7. In medically refractory cases, early epilepsy surgery may be considered8 as the degree of post-surgical seizure control correlates with improvements in cognition9–11 and quality of life10. While surgical success rates may be higher in young children12,13, systematic assessment of the impact of surgery on neurodevelopmental outcome in the TSC population is lacking.
We investigated surgical and neurodevelopmental outcomes in children with TSC who underwent early epilepsy surgery. Our hypothesis was that these young children with refractory epilepsy, severe enough to warrant epilepsy surgery, would experience an improvement in neurodevelopmental outcome if the targeted seizure type was eliminated - whether or not total seizure freedom was attained.
Methods
Data Collection
From 160 children enrolled at 5 centers in the TSC Autism Center of Excellence Network (TACERN) prospective multicenter observational study of early predictors of epilepsy and autism spectrum disorder, 19 children underwent epilepsy surgery before age two. As no formal definition of early surgery exists, we opted for an arbitrary cut-off age of 2 years, as it would allow for 12 months of clinical follow-up of surgical outcome, and standardized developmental testing through the multicenter prospective study.
Demographic, clinical and neurodevelopmental data were retrieved from case record forms, supplemented by electronic medical records for procedural details, complications and surgical outcomes. Data collected included gender, genetic variant, age at onset for each seizure type, seizure classification, antiepileptic drugs (AED) at surgery, age at operation, surgical technique, surgical complications, pre and postoperative seizure burden, and medications at postoperative follow up. Refractory epilepsy was defined as having failed two appropriately chosen and adequately dosed AEDs, with seizures for more than six months and at least one seizure recorded within six months prior to last study visit.
Surgical Outcomes
As patients with TSC can have multiple seizure types with a multifocal origin, the objective of surgery is often to eliminate one specific seizure type, which in this work we termed the ‘targeted’ seizure. The targeted seizure often represents the seizure type deemed the most clinically detrimental to the patient, e.g. the most frequent seizure, or seizures associated with status epilepticus, desaturation or falls. The targeted seizure was identified for each patient by local physicians based on clinical data including semiology and electroencephalographic localization during the pre-surgical workup. With the goal of surgery limited to a targeted seizure type, we also introduce an adjustment of the Engel class surgical outcome scale14. Those with Engel class I outcome for the targeted seizure were defined as ‘excellent’, and a larger group defined as ‘favorable’ included these children with Engel class I outcomes but also those with Engel Class II outcomes. These outcomes were defined regardless of the presence of ongoing or newly developed seizure types, where were clinically and electrographically distinct from the targeted seizure.
Additional surgical outcome measures reviewed were the number of AEDs following surgery, presence of additional but distinct seizures, and repeat epilepsy surgery. Determination of outcome was made based on case record forms and monthly seizure logs as part of the study, supplemented by medical record review. We considered complications minor when they were transient, anticipated, or still present at 12 months post-operatively but not judged to impact daily function and quality of life. We considered complications major in case of unanticipated neurological deficit persistent at 12 months or more post-operatively.
Developmental Assessment
Developmental scores were collected prospectively at 3, 6, 9, 12, 18, 24 and 36 months of age for each patient – regardless of the timing of surgery. Administered tests included the Vineland Adaptive Behavior Scales – Second Edition (Vineland-II), Mullen Scales of Early Learning (MSEL), and the Preschool Language Scales - Fifth Edition (PLS-5). See supplemental material for details. Patients were also assessed for symptoms of autism spectrum disorder (ASD) at 24 and 36 months of age using the Autism Diagnostic Observation Schedule - Second Edition (ADOS-2).
Developmental testing within 3 months of the operative date was not considered as part of the analysis to control for potential perioperative influence on test performance. The developmental scores for the surgical group (“refractory epilepsy – surgery”) as a whole as well as only those with favorable surgical outcome (Engel I-II for targeted seizure type) were compared to those of three other groups: (1) patients with TSC and no history of seizures (“no epilepsy”); (2) patients with TSC and medically controlled seizures (“epilepsy controlled – no surgery”); and (3) those with TSC and refractory seizures but no surgery (“refractory epilepsy – no surgery”).
Statistical Methods
Baseline categorical variables for each group were compared using Fisher’s exact test, while Wilcoxon rank-sum scores were employed to evaluate continuous variables. Fisher’s exact test was also used to determine differences in surgical outcome with regard to surgical approach, resection size and autism diagnosis. Mean standard scores across the total study duration were calculated for each group and compared using ANOVA.
To account for repeated observations on subjects over time, linear mixed models were used to estimate the population average of each measure as a function of group and time (Figures 3 and 4). All interactions between group, time, and the square of time were considered, but second order time covariates were removed if not statistically significant in the model. The difference in neurocognitive trajectory as a linear function of time was evaluated between surgical and refractory patients. While such an analysis cannot attribute differences in trajectory to a surgical intervention specifically, this method does provide a succinct summary and statistical assessment of any differences in neurodevelopmental trajectory observed between surgery and refractory patients in the study population.
Figure 3: Mean composite standard scores over time.
(A-C) The mean Vineland-II Adaptive Behavioral Composite standard scores, MSEL Composite standard scores and PLS5 Total Language Composite standard scores (are plotted across visit months for each of the 4 groups: No epilepsy (purple), epilepsy controlled – no surgery (blue), refractory epilepsy – no surgery (red), refractory epilepsy – surgery (green solid line: favorable outcome; green dotted line: all). Colored bands indicate 95% confidence interval.
Figure 4: Mean language MSEL and Vineland-II language subscores over time.
(A-B) The mean Vineland-II raw subscores for receptive language (A) and expressive language (B) are plotted across the visit months for each of the 4 groups: No epilepsy (purple), epilepsy controlled – no surgery (blue), refractory epilepsy – no surgery (red), refractory epilepsy – surgery (green).
(C-D) The mean MSEL raw subscores for receptive language (C) and expressive language (D) are plotted in the same way. Colored bands indicate 95% confidence interval.
Additional analyses were performed using identical methods except for fitting the surgical trajectory as a piecewise function of time before and after surgery (Supplemental Figures 1 and 2). Post-surgical intercept and slope were compared to the pre-surgical and refractory populations. However, since no break point could be similarly established in the refractory population, this analysis can only provide evidence of difference in post-surgical trajectory within the surgical population but cannot attribute such a change to the surgery as opposed to a naturally occurring change in trajectory. SAS 9.4 was used for all statistical analyses, and the Kenward-Roger approximation to denominator degrees of freedom was used for all linear mixed model hypothesis tests of fixed effects. A p-value of 0.05 or less was considered statistically significant.
Data Availability Statement
All data from the TSC Autism Center of Excellence Network (TACERN) prospective multicenter observational study of early predictors of epilepsy and autism spectrum disorder is deposited at the National Database for Autism Research (NDAR) and is available to the public and to researchers. Beyond NDAR, researchers can be granted access to additional clinical and surgical data collected for this manuscript by submitting a data access request to the corresponding author (EB).
Results
Patient characteristics
Table 1 summarizes 19 patients who underwent epilepsy surgery before 2 years of age, and the three groups the epilepsy – surgery group is compared to. From 160 patients enrolled in the TACERN study, 126 were included in these four groups. Eighteen nonsurgical patients were excluded due to incomplete clinical records and 16 more patients did not meet inclusion criteria as they were operated after age 2 years.
Table 1.
Patient characteristics
| No Epilepsy | Epilepsy - Controlled | Refractory Epilepsy - No surgery | Refractory Epilepsy - Surgery | Refractory Epilepsy - Surgery | p-values | |
|---|---|---|---|---|---|---|
| ALL | FAVORABLE | |||||
| N (%) | 32 (25.4) | 42 (33.3) | 33 (26.2) | 19 (15.1) | 12 (9.5) | |
| Gender | 0.1279 | |||||
| M | 19 (59.4) | 20 (47.6) | 18 (54.6) | 5 (26.3) | 4 (33.3) | |
| F | 13 (40.6) | 22 (52.4) | 15 (45.5) | 14 (73.7) | 8 (66.7) | |
| Genetics | 0.0035 | |||||
| TSC1 | 12 (37.5) | 4 (9.5)* | 3 (9.1) | 0 (0.0) | 0 (0.0) | |
| TSC2 | 17 (53.1) | 30 (71.4)* | 20 (60.6) | 17 (89.5) | 11 (91.7) | |
| None/No Data | 3 (9.4) | 9 (21.4)* | 10 (30.3) | 2 (10.5) | 1 (8.3) | |
| Age at any seizure onset in months | 0.0001 | |||||
| Median | - | 6.3 | 4.3 | 2.2 | 2.7 | |
| Mean | _ | 8.1 | 5.5 | 3.4 | 3.5 | |
| Range | - | 1.0–22.8 | 0.0–19.9 | 0.3–10.9 | 0.3–10.9 | |
| Seizure Classification | 0.0020 (focal) |
|||||
| Tonic-clonic | - | 3 (7.1) | 6 (18.2) | 0 (0.0) | 0 (0.0) | |
| Absence | - | 1 (2.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Myoclonic | - | 0 (0.0) | 0 (0.0) | 2 (10.5) | 1 (8.3) | |
| Clonic | - | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Tonic | - | 0 (0.0) | 3 (9.1) | 1 (5.3) | 0 (0.0) | |
| Atonic | - | 0 (0.0) | 1 (3.0) | 1 (5.3) | 1 (8.3) | |
| **Focal | - | 29 (69.0) | 32 (97.0) | 18*** (94.8) | 11*** (91.7) | |
| Unclassified | - | 4 (9.5) | 4 (12.1) | 2 (10.5) | 1 (8.3) | |
| Infantile Spasms | 0.5545 | |||||
| Y | 0 (0.0) | 27 (64.3) | 22 (66.7) | 13 (68.4) | 7 (58.3) | |
| None/No Data | 32 (100) | 15 (35.7) | 11 (33.3) | 6 (31.6) | 5 (41.7) | |
| Autism Diagnosis | 0.0003 | |||||
| Yes | 1 (3.1) | 8 (19.1) | 11 (33.3) | 9 (47.4) | 4 (33.3) | |
| No | 28 (87.5) | 33 (78.6) | 17 (51.5) | 10 (52.6) | 8 (66.7) | |
| No Data | 3 (9.4) | 1 (2.4) | 5 (15.2) | 0 (0.0) | 0 (0.0) |
Total exceeds 100% as 1 patient had both a TSC1 and a TSC2 pathogenic variant
Includes focal without impairment of consciousness, focal with impairment of consciousness and focal evolving to bilateral convulsive
One patient had seizures clinically consistent with infantile spasms with focality on EEG.
P values were calculated using Fisher’s exact test for gender, mutation, presence of spasms and presence of focal seizures. Wilcoxon scores and Kruskal-Wallis Test were employed for age at seizure onset.
Focal seizures with impaired awareness represented the targeted seizure type in 18 cases. The remaining patient had seizures clinically consistent with infantile spasms with but with electrographic focality. Thirteen (68%) had infantile spasms, comparable to the frequency in the epilepsy – controlled (64%) and refractory epilepsy – no surgery (66%) groups. In the surgical group, the onset of infantile spasms occurred prior to the onset of the targeted seizure type in 8 (42%). The median age at onset of any seizure type in the surgical group was 2.2 months, younger than epilepsy – controlled group and the refractory epilepsy – no surgery group (6.3 and 4.3 months, respectively, p < 0.0001). The median age at which the surgically targeted seizure first appeared was 4.7 months.
Surgical outcomes
Table 2 provides clinical details on the surgical group. Single stage open resections guided by intraoperative electrocorticography were most common, followed by procedures with subdural with or without depth electrodes and extraoperative monitoring. Stereo-electroencephalography (sEEG) with extraoperative monitoring and three-staged surgery15 were rare. Surgical approaches included tuberectomy (7, 37%), multiple tuberectomy or tuberectomy with adjacent white matter (8, 42%), and partial lobectomy (4, 21%). Resections involved the frontal lobe most often (9, 47%), followed by parietal (6, 32%), occipital (5, 26%) and temporal (4, 21%) lobes, with resection spanning at least 2 lobes in 5 (26%). Surgical complications occurred in 11 (58%) children. The three patients with major complications all had a dense hemiparesis due to surgery in the proximity of motor pathways, and in these cases the deficit was more severe than the anticipated mild or moderate hemiparesis. Eight minor complications consisted of subgaleal or subdural fluid collections, local edema or hemorrhage which resolved over time. Complications were evenly distributed among surgical outcome groups (Table 2).
Table 2.
Surgery details
| Seizure- Surgery, All | Seizure- Surgery, Excellent Outcome (Engel I)* | Seizure- Surgery, Favorable Outcome (Engel I-II)* | Seizure- Surgery, Poor Outcome (Engel III-IV) | p-values | |
|---|---|---|---|---|---|
| N (%) | 19 (100) | 10 (52.6) | 12 (63.2) | 7 (36.8) | |
| Median age at seizure onset in months (range) | 2.2 (0.3–10.9) | 3.7 (0.3–10.9) | 2.7 (0.3–10.9) | 2.2 (1.5–5.6) | |
| Median age of targeted seizure onset in months (range) | 4.7 (0.3–12.8) | 5.0 (0.3–12.8) | 3.9 (0.3–12.8) | 5.6 (1.5–10.8) | |
| Median age at surgery in months (range) | 16.9 (3.7–21.3) | 17.2 (3.7–21.3) | 15.3 (3.6–21.3) | 17.1 (12.0–19.3) | |
| Median time from any seizure onset to surgery in months (range) | 10.5 (3.4–20.0) | 10.1 (3.5–20.0) | 9.8 (3.4–20.0) | 12.7 (10.2–19.5) | |
| Surgical Approach | 0.5104 | ||||
| Single stage | 9/18**(50.0) | 6/10 (60.0) | 6/11 **(54.5) | 3/7 (42.9) | |
| Subdural electrodes | 7/18 (38.9) | 4/10 (40.0) | 5/11 (45.5) | 2/7 (28.6) | |
| Stereo-EEG | 2/18 (11.1) | 0/10 (0.0) | 0/11 (0.0) | 2/7 (28.6) | |
| 3-staged | 2/18 (11.1) | 1/10 (10.0) | 1/11 (9.1) | 1/7 (14.3) | |
| Resection Type | 0.2862 | ||||
| Tuberectomy | 7 (36.8) | 3 (30.0) | 4 (33.3) | 2 (28.6) | |
| Tuberectomy+ | 8 (42.1) | 4 (40.0) | 4 (33.3) | 4 (57.1) | |
| Partial lobectomy | 4 (21.1) | 3 (30.0) | 3 (25.0) | 1 (14.3) | |
| Complications | 11/18 (57.9) | 6/10 (60) | 7/12 (58.3) | 4/7 (57.1) | |
| Major | 3 (27) | 2 (33) | 2 (29) | 1 (25) | |
| Minor | 8 (73) | 4 (67) | 5 (71) | 3 (75) | |
| 9 (47.4) | 6 (60.0) | 6 (50.0) | 3 (42.9) | ||
| 5 (26.3) | 3 (30.0) | 3 (25.0) | 2 (28.6) | ||
| 9 (47.4) | 4 (40.0) | 4 (33.3) | 5 (71.4) |
Fisher’s exact test was used to assess whether surgical approach and resection size impacted seizure freedom at last study visit. Repeat surgery was not considered as many repeat surgeries occurred beyond study cutoff.
Outcomes are described for targeted seizure type. See methods section for details.
Missing operative data
Includes subdural or subgaleal fluid collection, hemorrhage and edema
Ten patients (53%) had an excellent outcome (Engel I), two more had an Engel II outcome, for a total of 12 (63%) with a favorable surgical outcome for the targeted seizure type. The mean duration of clinical follow-up after surgery was 22.8 months (range 12–48). Forty-seven percent had ongoing or new seizures distinct from the targeted type and 5 (26%) underwent at least one additional epilepsy surgery. Seven (36.8%) were completely seizure-free at last documented contact.
Figure 1 shows that the seizure burden differed between all three groups at the 12 month mark (p < 0.0001), and the refractory epilepsy – surgery group had more seizures than the refractory epilepsy – no surgery group (p=0.046). The surgical intervention resulted in a decline in seizures at the time of the last post-operative visit compared to the last pre-operative visit (p = 0.0313). By the time of the 36 month visit, the refractory epilepsy – no surgery had more seizures that the refractory epilepsy – surgery group (p=0.019). In 7 of 18 patients with available data, there was a postoperative reduction in the number of antiepileptic medications. The odds of surgical success was not associated with seizure duration prior to surgery, surgical approach and resection size in this small sample (Table 2).
Figure 1: Mean number of seizures over time.
Mean total seizure number and 95% confidence intervals plotted over time. Mean is calculated for each group as the average seizure frequency reported at the time of each study visit. The group without seizures is not shown. The surgical group had an average age at surgery of 15 months, after which the seizure frequency declines, indicating a favorable surgical outcome. For details, see text.
Developmental outcomes
Figure 2 illustrates group differences in the mean developmental standard scores for, Vineland-II, MSEL and PLS-5 over the entire study period. The surgical group scored lowest, followed by refractory epilepsy – no surgery group, epilepsy controlled – no surgery group and the no epilepsy group (p <0.0001 for all three scores, Supplemental Table 1).
Figure 2: Distribution of mean developmental standard scores over total study period.
Boxplots of the three mean developmental standard scores for each of the 4 groups are shown, over the course of the study period. The surgical group has the lowest mean scores overall.
Box represents the interquartile range; the horizontal line within box indicates the median, the diamond the mean, horizontal endings the minimum and maximum values within 1.5 times the interquartile range; and individual data points represent outliers.
In Figure 3A–C, the three longitudinal developmental scores are plotted for each of the four groups. The no epilepsy group tracked within the average range while the three groups who developed seizures showed a decrease in standard scores over time. Estimated slopes of the developmental trajectories of Vineland-II, MSEL and PLS-5 Total Language Composite (TLC) standard scores did not differ between the surgical group and the refractory epilepsy – no surgery group.
In Figure 4A–C, subscale plots are shown. The surgical group did demonstrate a slower decline in the trajectories of the MSEL receptive and expressive language subscales (p = 0.0146 and 0.0159, respectively), but not for the same subscales of the Vineland-II.
There was however, a consistent and graphically evident pattern of a relative stabilization with surgery, i.e. a decrease of the slope at which the development declined compared to the normative data in Figures 3 and 4.
A complimentary analysis of this data examines potential changes in the developmental trajectory after surgery (Supplemental Figures 1 and 2). The post-surgical slope and intercept in the refractory epilepsy – surgery group was compared to the pre-surgical data using the mean surgical date as a break point. Comparison to the refractory epilepsy – no surgery group was not possible as there is no such break in that data. Within the surgical group, favorable outcome was again associated with improvements in some language subscales, again best appreciated graphically.
The impact of early epilepsy surgery on non-language domains was variable, and did not show a consistent pattern. Improvements were noted in the MSEL gross motor and visual reception raw scores when compared to the refractory epilepsy – no surgery group (p = 0.0109 and 0.0317, respectively), but not when compared with the pre-operative trajectory. Vineland-II Socialization and Daily Living Skills domains did not show any change with surgery. There was no difference of the rate of autism spectrum disorder between the groups. The extent of the surgical resection did not affect mean developmental scores at 36 months (Supplemental Table 2).
Discussion
The correlation between neurodevelopmental outcomes and seizures in TSC has been repeatedly demonstrated, with a higher seizure burden in early life resulting in greater delays and risk of autism spectrum disorder4,16. Recently, data from 1657 children in the TSC Natural History Database showed compelling evidence that uncontrolled earlyonset seizures were again associated with adverse cognitive development5. In our pilot study, we confirmed the association between ongoing seizure activity and developmental decline, and established preliminary support for mitigation of this trajectory through early epilepsy surgery – albeit only in some domains. As complete freedom from all seizures after surgery was rare in our study cohort, we note that these improvements were seen despite ongoing or new seizures distinct from the surgically targeted seizure type.
Population differences in the four defined groups
Comparable to prior studies, 74.6% of our patients developed epilepsy2,3. 41.3% were identified as refractory—defined by ongoing seizures despite pharmacologic intervention—a lower number than reported in the literature2,8. This may be in part due to exclusion of 16 patients with later (> 24 but < 36 months) surgery who would have been otherwise defined as refractory, and of another 18 patients whose seizure status was ill-defined or inconsistent based on case records.
There were differences in TSC genotype, seizure classification, age at seizure onset and autism diagnosis between the four defined groups. Compared to patients with TSC1 mutations, those with TSC2 mutations had an earlier age at seizure onset and a higher incidence of focal seizures and autism spectrum disorder. The relative frequency of patients with TSC2 mutations was higher in the refractory epilepsy – no surgery and refractory epilepsy – surgery groups than in the epilepsy controlled – no surgery and no epilepsy groups, similar to prior studies4,8.
Neurodevelopmental findings
Mean baseline developmental scores (taken at study enrollment, between 3–6 months of age for most patients) were lowest in those who underwent epilepsy surgery. Thus, there was no inclusion bias of children with a relatively good neurodevelopment in the surgical group. In addition, this implies that children in this group are in greatest need for an intervention to prevent ongoing decline. While the limited study sample size prevented us from accounting for tuber burden, the surgical group had a higher prevalence of TSC2 mutations, earlier onset of seizures and subsequent exposure to medications, and a higher seizure burden, as previously reported6,17.
Over time, the developmental scores of the refractory epilepsy – surgery and refractory epilepsy – no surgery groups diverged more from the no epilepsy group. This finding was previously reported by Capal et al. who detailed the impact of seizures on developmental outcome in the TACERN population4. In this same study population, we now provide preliminary data to support that surgically achieved seizure reduction diminished the widening gap in some domains between those with refractory seizures and those who never developed seizures. Gains in intelligence quotient were recently also described in less than a third of 242 patients with TSC and epilepsy surgery at a mean age of 10.4 years. This limited benefits seen with surgery in this study despite its large size could be attributable to its retrospective nature, the lack of true controls, or to the older age at time of surgery – when the developmental trajectory is less steep than at the younger age in our cohort18.
The developmental benefits of epilepsy surgery in our study were not consistently seen in all domains. Language scores improved the most; receptive processes more so than expressive. A similar finding was reported by Capal et al, with patients exhibiting subsequent gains in MSEL receptive language scores and Vineland-II communication domains after at least 6 months of complete seizure freedom4. We suspect that relative greater improvements in language as compared to other domains may reflect timing of surgery in relation to a typical developmental timeline. Complex processes like language acquisition develop later and are more likely to benefit from a decrease of the epileptic encephalopathy.
Perioperative complications and post-surgical deficits, in particular motor weakness, may have impacted observed post-operative developmental scores despite our exclusion of testing performed within 3 months of surgery. With the use of standard scores in particular, a decline in a single (motor) domain may result in disproportionately low standard or composite score. In addition, individual gains may be masked by comparison to normative data from peers. We addressed this by the use of raw rather than standard scores, and also examined developmental domains separately16, 23.
In our study, we did not find any association between resection size and post-operative neurodevelopment and could not confirm a previously reported association between larger resection size and better surgical outcomes19. A larger sample size would be needed to account for confounders including variations in pre-operative baseline developmental scores, effects of surgical center, age at surgery and location of resection.
Surgical outcomes
We demonstrate that epilepsy surgery can be performed with similar success rates as older children in the literature, with 53% having excellent (Engel I) and 63% having favorable (Engel I-II) outcome for targeted seizure8,9,12,20. Surgical complications occurred in more than half of the patients with early surgery, but the vast majority was minor. Even transient deficits can impact developmental assessment, and longer follow-up is necessary to determine lasting effect.
While pre-surgical and surgical approaches were not standardized across institutions, each institution utilized an internally consistent approach to the localization of epileptogenic zone. All decisions on invasive monitoring vs. a single-staged, open resection arose from consensus opinion of epilepsy conference at each institution. The most frequent approach was a single-staged, open resection (50%), and 60% in this group had an excellent surgical outcome. Although we lacked power to show a lower surgical success rate in patients requiring invasive monitoring, such poorer outcomes could reflect inherently more complex epilepsy rather than technique failures.
The prevailing literature on seizure control and epilepsy surgery in TSC has underscored the need for complete seizure freedom4,12,15. In our surgical group, however, developmental gains in some domains were seen even though 47% had new or persistent seizures (of differing semiology from the surgically-targeted seizure), and a quarter went on to have repeat epilepsy surgery. This suggests that relative seizure control, rather than complete control, during critical stages of neurodevelopment may also provide mitigation of seizure-related developmental injury, but it requires further study.
Others have emphasized the importance of early identification of potential surgical candidates. We could not confirm, however, previous reports of an inverse correlation between the duration of seizures prior to surgery and the likelihood of surgical success4,12, again likely due to our sample size.
Limitations
While we demonstrate benefits of early epilepsy surgery on seizure control and neurodevelopment, the gains are not universal, and some patients may be more amenable to improvement with surgery than others. There is a risk for an inclusion bias as early surgery may be performed in a patient with superficial and readily identifiable epileptogenic lesions. Early selection of all potential surgical candidates using standardized presurgical evaluation methods, standardization of surgical techniques and identification of the most sensitive developmental measures for assessment of outcomes in this population should be investigated before the findings are generalizable. This data provides a rationale for the design of future multi-center prospective investigations into early epilepsy surgery in TSC.
Our findings are based on a small sample size of 19 patients with follow-up of 1 year, and this represents a limited portion of the overall cohort. At risk of underpowering, we deliberately included only patients with adequate post-operative developmental testing and clinical records. For these reasons, an adjustment for multiple comparisons was neither feasible nor desirable as we are more interested in preliminary findings to inform future studies, than in conclusive data.
Our data are limited by the presence of comorbid conditions such as autism and TSCassociated neuropsychiatric disorders (TAND) that impact developmental testing independent of the existence of epilepsy and intellectual disability. Variables such as parental intelligence, socioeconomic status, and use of psychoactive medications17 may create measurable discrepancies in developmental scores. Similarly, known predictors of neurodevelopmental outcome in TSC including genotype, tuber burden21, cyst-like lesions22, white matter microstructural integrity23 may dampen the measurable neurodevelopmental benefit of epilepsy surgery and may be independent predictors of poor response to surgery. This could be in part overcome by a larger sample size, and by comparison of post-operative to pre-operative developmental trajectories, i.e. by patients forming their own controls.
There a several major challenges in the serial application of standardized neurodevelopmental tests in this young TSC population. First, the wide variation in neurological phenotype prevents the universal application of a single set of developmental tests to the whole population (see Supplemental material for details). Second, each test consists of domain-specific sub-scores that are converted to age-standardized t scores. When one area is completed but performance is disproportionately poor, the composite score will be compromised. Third, a seizure in the proximity to testing or testing after recent medication administration may inaccurately capture a patient’s potential. Finally, in routine clinical practice, different developmental assessments are administered to track developmental progress over the course of years. For our study, however, some domains of the tests are not suitable for longitudinal use within several months. For example, the Vineland-II and the PLS-5 allow for caregiver report in infants and toddlers, permitting inflation of abilities. Training effects are perceivable, too.
Post-operative seizure control may decline over time19, and we plan to continue follow-up and examine whether the developmental benefits are upheld longitudinally.
Conclusions
In childhood epileptic encephalopathies, seizures interfere with a critical period of steep developmental progress. In TSC, early epilepsy surgery may mitigate these detrimental effects, and the surgical outcome should include metrics of both epilepsy and neurodevelopment. A suitable method, however, for serial neurodevelopmental testing is needed to study beneficial effects of early epilepsy surgery in TSC. This will require input from pediatric neuropsychologists, neurologists and neurosurgeons with insight into the intricacies of epilepsy surgery of this complex population.
There remain many other unknowns in pediatric epilepsy surgery in TSC, including questions regarding timing, key elements of the surgical workup, non-invasive imaging and neurophysiological markers of the epileptogenic zone, and surgical approach. Only a well-coordinated, prospective multicenter observational study which also includes imaging, neurophysiology and tissue along with standardization of clinical documentation can answer these questions.
Supplementary Material
Highlights:
It is not known whether early epilepsy surgery reduces the negative impact of seizures on neurodevelopment in tuberous sclerosis complex
We prospectively studied 19 children who underwent surgery before 2 years of age, serial neurodevelopmental testing, and one year follow up.
Compared to those with refractory seizures but no intervention, epilepsy surgery was associated with modest improvement in some language domains.
Although not significant, a consistent pattern of improvement with surgery was seen in all tested domains
Acknowledgements
We are sincerely indebted to the generosity of the families and patients in TSC clinics across the United States who contributed their time and effort to this study. We would also like to thank the Tuberous Sclerosis Alliance for their continued support in TSC research.
Funding:
Research reported in this publication was supported by the National Institute of Neurological Disorders And Stroke of the National Institutes of Health (NINDS) and Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) under Award Number U01NS082320. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
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Conflicts of interest
The authors report no conflicts of interest relevant to the manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data from the TSC Autism Center of Excellence Network (TACERN) prospective multicenter observational study of early predictors of epilepsy and autism spectrum disorder is deposited at the National Database for Autism Research (NDAR) and is available to the public and to researchers. Beyond NDAR, researchers can be granted access to additional clinical and surgical data collected for this manuscript by submitting a data access request to the corresponding author (EB).