Influence of extent and age at corpus callosotomy on seizure outcomes. A single center experience

Abstract Corpus callosotomy (CC) is a palliative treatment for drop seizures in patients with drug‐resistant nonlocalizable epilepsy. We compared drop seizure outcomes between patients undergoing anterior CC versus complete CC and examined factors impacting outcomes for drop seizures including age at CC and duration of epilepsy. A retrospective review of patients who underwent CC between 2003 and 2022 with a minimum of 6 months postsurgical follow‐up was included. Outcome measure for drop seizures included seizure reduction ≥50% from baseline as well as elimination of drop seizures. Thirty‐eight patients were included. Overall, ≥50% reduction in drop seizures occurred in nearly 70% (23 out of 33) patients with complete elimination in 58% (19 out of 33). Compared with anterior CC (n = 13), patients undergoing complete CC (n = 25) had increased likelihood of ≥50% reduction (p = 0.006) or elimination (p = 0.024) of drop seizures. Regression analysis showed that complete CC was the primary predictor for improved drop seizure outcomes (elimination, p = 0.014 or ≥50% reduction, p = 0.006), while age at CC and duration of epilepsy did not impact the outcomes. Compared to anterior CC, complete CC was significantly more likely to lead to improvement/freedom from drop seizures. Age at CC or duration of epilepsy did not influence drop seizure outcomes.


| INTRODUCTION
2][3] Surgical sectioning of the corpus callosum may commonly include anterior two-thirds (anterior CC) or the entire corpus callosum (complete CC) or rarely the posterior callosum alone (posterior CC).The significance of the extent of CC on seizure outcomes has been debated.A recent meta-analysis and a systematic review suggested that seizure freedom rates were lower with anterior two-thirds CC compared to complete CC. 2,3 However, this inference of the systematic review was based on patients undergoing anterior CC only 4 and a study that failed to demonstrate a difference in seizure outcomes based on extent of disconnection. 5 Thus, clarifying the impact of the extent of callosal disconnection on seizure outcomes could benefit from additional data.
The influence of age at CC on seizure outcomes has not been established.Evaluating the impact of age at CC on seizure outcomes from published data is challenging due to varying outcome definitions in relatively older cohorts undergoing CC (late first decade or second decade). 2 Overall, children were reported to have better seizure outcomes when compared to adults. 2,6,7Recent reports indicate that CC was associated with excellent seizure outcomes (freedom from or >80% reduction of epileptic spasms) in ~50% of patients with West syndrome (mean age at CC was 22.6 months). 8,9This could imply that either age at CC or seizure type (epileptic spasms) could potentially influence seizure outcomes following CC.
We conducted a single-center retrospective study to (a) compare seizure outcomes for drop seizures between anterior two-thirds versus complete CC, (b) evaluate the impact of age at CC surgery on drop seizure outcomes.

| METHODS
The prospectively maintained epilepsy surgery database at Boston Children's Hospital (BCH) was used to identify all patients who underwent CC between 2003 and 2022.Patients who had CC at our center with a minimum of 6 months postoperative follow-up were included.Patients who had other procedures such as Vagus Nerve Stimulator (VNS) implantation were included in the study.Patients who underwent staged CC (ie, anterior two-thirds CC followed by complete CC) were excluded due to the inability to attribute seizure outcomes to a particular procedure when sequential procedures were performed.For example, for patients who may have poor outcomes following sequential 2-stage completion of CC, assigning these results to either surgery would inaccurately represent procedural outcomes.Drop seizures included falls secondary to atonic, tonic or myoclonic seizures.

| Outcome measures
Primary outcome for drop seizures was defined as (a) reduction in drop seizures by ≥50% (provided residual drop seizures in these patients were noninjurious), (b) complete freedom drop seizures.Seizure frequency pre-and post-CC (at last follow-up) were also quantified for other seizure types.
At our center, patients with refractory epilepsy being assessed for a possible CC underwent a presurgical work-up that included brain MRI, electroencephalogram (EEG) recordings (ictal and interictal).Seizure type and frequency were based on clinical documentation obtained from parental recall at clinic visits.Seizure type was confirmed by video-EEG (vEEG) monitoring in most patients pre-CC and in some cases post-CC.Patients with nonlocalizing ictal EEG who were not deemed to have a resectable epileptogenic focus on MRI were offered CC.All decisions were based on the consensus derived at a multidisciplinary epilepsy surgery conference.In general, complete CC was performed in patients with moderate to severe cognitive impairment.Cognitive delay was an important but not the sole determinant of the extent of CC.Decisions regarding the extent of CC were individualized for each patient.Caregiver views regarding the severity of epilepsy, patient's functional status as well as concerns regarding potential complications from complete disconnection were also incorporated before deciding on the extent of CC.Extent of disconnection was guided by intraoperative anatomic landmarks with neuro-navigation, confirmed in most by intraoperative or postoperative brain MRI.
This study was approved by the BCH Institutional Review Board.

| Statistical analysis
Mean and standard deviation were used for continuous variables and counts with percentages were used for categorical variables for summary statistics.The demographic and clinical characteristics as well as the seizure outcomes (drop seizures) associated with the extent of CC were compared.Student's t-test was conducted for continuous variables and Fisher's exact test for categorical variables.We examined the impact of age at CC, duration of epilepsy and other clinical and demographic variable on drop seizure outcomes (≥50% reduction drop seizures and complete freedom drop seizures) using univariate and multivariate logistic regression analysis.Age at surgery and other variables with a p-Value < 0.2 in univariate logistic regression were included in the multivariate logistic regression.Statistical significance was defined as p < 0.05.Data analysis was performed using R version 4.2.0.

| RESULTS
Among the 44 CC patients identified from the surgical database, six were excluded (three due to multistage CC and three due to insufficient follow up at our institution post-CC).A total of 38 patients (71% males) were included, 13 who underwent anterior two-thirds CC and 25 who underwent complete CC.All patients underwent open craniotomy except one patient who had laser interstitial thermal therapy (LITT) callosotomy.Thirteen patients had VNS placement before any CC (anterior or complete) while two had VNS placement after CC.

| Clinical characteristics for the overall group
Mean age at seizure onset was 2.2 ± 2.7 years.The mean duration of epilepsy was 8.7 ± 6.0 years and mean duration of follow up after CC was 45.7 ± 33 months.The mean age at surgery was 11.1 ± 6.3 years.The mean number of antiseizure medications presurgery was 3.2 ± 0.8 and postsurgery was 3.0 ± 0.9.Moderate to severe cognitive impairment was noted in 33 out of 38 patients (87%).Etiology was known in 21 patients (55%).
More than one seizure type was noted in 33 of the 38 patients (87%).Seizure types included varying combinations of tonic (n = 24), atonic (n = 6), generalized tonic clonic (GTC) (n = 10), atypical absence (n = 8), myoclonic (n = 5), focal with impaired awareness (n = 2) and epileptic spasms (n = 2).Multiple daily drop seizures were noted in 33 of the 38 patients.Based on vEEG, drop seizures were due to tonic (n = 22), atonic (n = 6), myoclonic (n = 1) seizures.Drop seizures type was undetermined in four patients as the drop seizures were not captured on video EEG and the drop seizure type (atonic vs tonic) could not be determined based on the caregiver description.

| Other seizures
Among the other seizure types, ≥50% reduction in seizures was noted in five of the eight patient (63%) with atypical absence, 6 of the 10 (60%) with GTC.

| Comparison between anterior two-thirds vs complete CC
Table 1 details the comparison of demographic/clinical characteristics and seizure outcomes between patients following anterior two-thirds vs complete CC.Most of the demographic/clinical variables did not significantly differ between the groups (p > 0.05).Number of seizure types postsurgery differed between the groups (p = 0.012).Complete CC was significantly associated with ≥50% reduction drop seizures when compared to anterior two thirds CC (86.4 vs 36.4%,p = 0.006).Similarly, complete CC was significantly associated with elimination of drop seizures when compared to anterior two-thirds CC (72.7% vs 27.3%, p = 0.024).

| Determinants of drop seizure outcome
Table 2 details logistic regression analysis for seizure outcome ≥50% reduction in drop seizures Multivariate regression analysis showed that complete CC (Odds Ratio (OR) 11.32, confidence interval-CI (2.18, 76.75), p = 0.006) was the only factor that was significantly associated with ≥50% reduction in drop seizures.Age at surgery (OR 1.02, CI-[0.89,1.18], p = 0.752) did not affect the seizure outcomes.Duration of epilepsy, sex, presence of known etiology, abnormal MRI, presurgery variables did not affect the probability of obtaining ≥50% reduction in drop seizures.

Table 3 details logistic regression analysis for complete freedom from drop seizures.
Multivariate regression analysis again showed that complete CC (OR-9.73,CI-[1.81,74.80], p = 0.014) was the only factor that significantly that increased the likelihood of complete freedom from drop seizures.None of the other variables including age at CC or duration of epilepsy affected the odds of elimination of drop seizures (p > 0.05 for all).

| DISCUSSION
In this study, we found that complete CC was significantly more likely to lead to improvement/freedom from drop seizures when compared to anterior two-thirds CC with increased odds of both ≥50% reduction (p = 0.006) as well as freedom from drop seizures (p = 0.014).Our study provides additional support for the higher efficacy of complete CC over anterior two-thirds CC for treatment of   drop seizures. 2,3,6,7,10None of the other factors examined including age at CC and duration of epilepsy correlated with drop seizure outcomes in our cohort.
Studies examining the correlation between seizure outcomes and age at CC have shown mixed results 5,11 largely due to methodological differences in outcome measures (lack of consistent definition of good outcome), patient selection (variable ages at surgery ranging from 3 to 55 years) and types of surgery performed (solely anterior CC).One study noted a trend for better seizure outcomes following CC at younger age 5 while another failed to find an association between age at CC and seizure outcomes. 7Excellent seizure outcomes for epileptic spasms but not for tonic seizures have been reported for patients with WS undergoing CC (mean age of 22.6 months), 8 perhaps suggesting a role for seizure type in determining outcomes.In our cohort, age at CC did not influence outcomes for drop seizures.Reasons for lack of influence of age at CC on seizure outcomes in our cohort are unclear.In general, younger patients tend to undergo complete CC and it is plausible that the better outcomes reported for the younger patients in other studies may reflect the effectiveness of extent of CC rather than age at CC.Our results support this hypothesis as we found that extent of CC (complete CC) was the primary predictor of treatment response after adjusting for other explanatory variables including age at surgery and duration of epilepsy.
Our study did not evaluate developmental outcomes following CC.In resective epilepsy surgery, age at surgery <12 months and shorter preoperative duration of epilepsy lead to improved developmental outcomes. 12imilarly, it has been reported that progressive declines in developmental quotient were prevented in patients with epileptic spasms who underwent early CC and had worthwhile improvement in seizure outcomes. 8Previous studies have also shown that callosotomy at an early age led to an improvement in daily function, family satisfaction T A B L E 3 Univariable and multivariable logistic regression for the probability of complete freedom drop seizure ( a N = 33).
and improved of life. 4,6Hence, despite the lack of correlation of age at surgery or duration of epilepsy on seizure outcomes in our cohort, it is essential to identify candidates for CC early to improve outcomes.A systematic review concluded that when compared with anterior two-thirds CC, complete CC was significantly more likely to result in a reduction in drop seizures 2 based on three studies reporting Engel outcomes.Contrary to the conclusions of the systematic review, a large multicenter pediatric series failed to demonstrate the superiority of complete CC over anterior two-thirds CC for freedom from drop attacks. 13However, data across the literature does suggest lower rates of seizure freedom with anterior two-thirds CC compared to complete CC. 3 Our study corroborates existing literature on the effectiveness of complete CC over anterior two-thirds CC.Despite having a smaller sample size than prior studies, we demonstrated improved seizure outcomes (for drop seizures) with complete CC perhaps related to consistency of patient selection, surgical approach, and confirmation of extent of CC using intraoperative and/or postoperative MRI.
Strengths of the study include a single institutional study with homogenous patient selection, vEEG confirmation of type of drop attacks in majority and a comparatively younger cohort.A small sample size and retrospective study methodology may have potentially limited our ability to detect a clinically meaningful difference for influence of age at CC on seizure outcomes.Other limitations of the study include reliance on caregivers for quantification of seizures, limited number of patients with nondrop seizures, lack of formal neuropsychological testing, and relatively shorter duration of follow-up.

| CONCLUSION
Complete CC was significantly more likely to lead to improvement/freedom from drop seizures.Age at CC or duration of epilepsy did not influence drop seizure outcomes.

3. 3 |
Outcome data3.3.1 | Drop attacksAt the last follow-up, following CC (anterior and complete), nearly 70% patients (23 of the 33 patients) had ≥50% reduction in drop seizures, with complete elimination of drop seizures in 19 of these 23 patients.In the other four patients, residual drop seizures were not associated with injuries and represented a change from the preoperative status.Freedom from drop seizures occurred in 3 of 11 (27%) with anterior two-thirds CC vs 16 of 22 (73%) with complete CC (p = 0.024).
Age at seizure onset (years)

T A B L E 1
Comparison of demographic and clinical characteristics between anterior two-thirds corpus callosotomy CC (n = 13) and complete CC (n = 25).
Univariable and multivariable logistic regression for the probability of >50% reduction drop seizure ( a N = 33).