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Outcome of corpus callosotomy in adults
Epilepsy & Behavior 28 (2013) 181–184
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Outcome of corpus callosotomy in adults Michael S. Park a,⁎, Emily Nakagawa b, Mike R. Schoenberg c, Selim R. Benbadis b, Fernando L. Vale a a b c
Department of Neurosurgery & Brain Repair, University of South Florida, Tampa, FL, USA Department of Neurology, University of South Florida, Tampa, FL, USA Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA
a r t i c l e
i n f o
Article history: Received 2 April 2013 Revised 22 April 2013 Accepted 25 April 2013 Available online 7 June 2013 Keywords: All epilepsy/seizures Epilepsy surgery Generalized seizures Vagus nerve stimulation
a b s t r a c t We present, to our knowledge, the first published series of corpus callosotomy (CC) in adults with medically intractable symptomatic generalized epilepsy (SGE). Fifteen adults were followed for the outcome measures of seizure and antiepileptic drug (AED) burden and quality of life (QoL). Five (33%) patients reported >60%, one (7%) reported between 30 and 60%, and nine (60%) reported b 30% reduction in the total number of seizures after CC. Seven (47%) patients reported >60%, three (20%) experienced between 30 and 60%, and five (33%) reported b 30% atonic seizure reduction. Twelve patients had no change in AED burden. Nine (60%) patients had no change in QoL, while six (40%) reported some improvement. Corpus callosotomy should be considered as a safe option for adults with medically intractable SGE with demonstrated reduction in the frequency of atonic seizures, and some patients experience a meaningful improvement in quality of life. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Symptomatic generalized epilepsies (SGEs) are a group of epilepsy syndromes characterized by multiple generalized seizure types and evidence of diffuse brain damage. The prototype is the Lennox– Gastaut syndrome, and the most recent classification proposal divides the etiologies as structural, metabolic (equivalent to “symptomatic”), or unknown (equivalent to “cryptogenic”). The greatest challenge in the management of patients with SGE is adequate seizure control [1]. The first-line treatment for SGE is antiepileptic medication; however, SGEs are often refractory to medications, and patients frequently proceed to nonpharmacological treatments such as vagus nerve stimulation (VNS) and ketogenic diet [2]. Vagus nerve stimulation has been found to reduce the number of monthly seizures by 50% [3,4]. Despite these interventions, approximately 60% of adult patients with SGE remain dependent with an impaired quality of life (QoL). Corpus callosotomy (CC) limits the spread of seizure discharges rather than removing the epileptic focus [5,6]. As most generalized seizures persist after callosotomy, there are other interhemispheric connections that are likely responsible for the generalization of seizures [6]. Anterior CC spares the splenium in order to preserve perceptual information and avoid the disconnection syndrome associated with total callosotomy [7].
⁎ Corresponding author at: Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, 2 Tampa General Circle, 7th Floor, Tampa, FL 33606, USA. Fax: +1 813 259 0944. E-mail address: [email protected] (M.S. Park). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.04.015
In children with SGE of the Lennox–Gastaut type with drop attacks, CC is an accepted surgical treatment [6]. Corpus callosotomy is effective in reducing atonic, tonic, and generalized tonic–clonic seizures [8,9]. However, these studies often evaluate a combination of children and adults with SGE. To our knowledge, there are no published series of corpus callosotomy in adult patients with SGE. As such, the role of corpus callosotomy in adults with SGE has not been fully characterized. The goal of our study was to evaluate the effectiveness and quality of life after corpus callosotomy in adult patients with SGE. 2. Methods A data registry was established in 1998 for all patients referred to our comprehensive epilepsy center for surgical evaluation. Patients and/or their caregivers participating in this data registry have completed the informed consent process. This study has been approved by the institutional review board and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Fifteen patients aged 18 or older with drug-resistant epilepsy underwent anterior two-thirds corpus callosotomy without resection of the anterior commissure based on seizure type(s), semiology, and results of phase I monitoring (surface EEG) and neuroimaging (MRI with SPECT in some cases) as well as neuropsychological study [10]. Outcomes were measured in several ways. Modified Engel classification scale (I: seizure-free; II: improved (i.e., greater than 90%); III: better, but less than 90% reduction; IV: no worthwhile improvement) was used to determine and stratify surgical outcomes [11]. Questionnaires were also used at scheduled follow-up visits. Pre- and postoperative management of antiepileptic drugs was deferred to the patient's
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treating neurologist. Outcomes measured included seizure burden, AED burden, and quality of life (QoL). Seizure burden (% seizure reduction) was subjectively quantified as b30% reduction, 30–60% reduction, and >60% reduction. Presurgical antiepileptic drug burden was compared to the number of drugs the patient required at the most recent follow-up. Finally, QoL was investigated via ordinal analysis where the patient or caregiver categorized his/her QoL as “much worse”, “worse”, “no change”, “better”, or “much better” as compared to presurgery. Outcome measures were analyzed individually as well as in combination via nonparametric analysis (Mann–Whitney U) [10]. Neuropsychological evaluations were obtained pre- and postoperatively for patients who did not present with severe intellectual disabilities, mental retardation, or lack of sufficient receptive/expressive speech. Mini-Mental Status Examination (MMSE) scores were obtained pre- and postoperatively for those subjects not undergoing neuropsychological evaluation. As part of a presurgical work-up, preoperative comprehensive neuropsychological studies were completed for 3 (20%) of the patients who met the inclusion/exclusion criteria for undergoing neuropsychological study. Postoperative studies were completed 24 and 35 months after corpus callosotomy. Neuropsychological tests were administered according to each test's respective manuals and assessed neuropsychological functions in six different neuropsychological domains: general cognitive/IQ [12,13], attention [13–15], memory [16–18], language [19–21], and visuoconstructional [16,17] and executive [14,22,23] functions, generating 25 different test scores. In addition, fine manual dexterity [24], quality of life in epilepsy [25], and screening measures for anxiety [26] and depressive [27] symptoms were administered. 3. Results We identified 15 adult patients who underwent anterior twothirds CC since the inception of the epilepsy registry between 1999 and 2012. Demographic data are displayed in Table 1. There were 6 men and 9 women. Ages at CC ranged from 19 years to 33 years (mean: 25 years), and ages at seizure onset ranged from 4 months to 23 years (mean: 8 years). Fourteen (93%) patients had received VNS before CC, while the remaining patient ultimately underwent VNS placement after callosotomy. Follow-up duration ranged from 7 months to 122 months (mean: 31 months). The number of AEDs
Table 1 Patient population characteristics. Number of patients Age at corpus callosotomy (years) Mean Median Range Age of seizure onset (years) Mean Median Range Duration of follow-up (months) Mean Median Range Gender (%) Male Female Number with preoperative VNS (%) Number of AEDs tried preoperatively Three Four Five Six Seven Eight Nine Ten
15 25 27 19–33 8 6 4 months–23 years
Table 2 Pre- and postoperative AED requirements. Patient
Preop
Postop
Change
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
3 3 1 3 4 3 3 4 4 4 4 7 4 4 5
3 3 1 2 2 5 3 4 4 4 4 7 4 4 5
0 0 0 −1 −2 2 0 0 0 0 0 0 0 0 0
tried prior to CC ranged from 3 to 10 (mean: 5.4). One patient underwent VNS initially followed by CC for persistent status epilepticus without significant improvement; he ultimately expired secondary to multiorgan system failure. Of the remaining 14, six had documented diagnoses of Lennox–Gastaut syndrome, while the others also experienced multiple generalized seizure types, all with drop attacks. Most exhibited mental retardation and early age of onset (i.e., by age 8). There was one procedure complicated by postoperative wound infection requiring reoperation for removal of the craniotomy flap. No patients experienced symptoms suggestive of disconnection syndrome. One patient underwent reoperation for completion of CC after anterior two-thirds CC for persistent atonic seizures; this patient did not experience any change with regard to outcomes of total or atonic seizure burden, AED burden, or QoL following either procedure. Table 2 shows outcome data with respect to AED use. The numbers of AEDs at the time of surgical intervention ranged between one and seven (mean: 3.73). There was no change in the range of the numbers of AEDs used postoperatively, with a minimal change in the mean (3.66). Table 2 demonstrates that only three patients had any alteration in their AED regimen after their surgery, with two patients (patients numbered 4 and 5) reducing the number of AEDs and one patient requiring two additional AEDs since the procedure. Review of Engel outcome data shows one patient with a completely seizure-free outcome and one with no improvement; the remainder showed various degrees of improvement in the reduction of seizures. Class III outcomes were the most prevalent in this cohort with 8 of 15 patients experiencing less than 90% seizure reduction. Fig. 1 shows self-reported overall seizure burden data. Five (33%) of the patients reported greater than 60% reduction in the total number of seizures, which include all of the patients with Engel I and II outcomes. One patient (7%) experienced a modest, i.e., 30 to 60%, overall seizure reduction, and the remainder (60%) experienced less than 30% reduction in the total number of seizures. With regard to
31 15 7–122 6 (40%) 9 (60%) 14 (93%) 2 5 2 2 2 0 1 1
Fig. 1. Overall seizure burden. Percentage of patients reporting reduction in total number of seizures.
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4. Discussion The overall goals of corpus callosotomy are to limit the spread of seizure discharges and to improve patient (and caregiver) quality of life. It is well known that drop attacks (atonic seizures) are the most common indication for and respond very well to corpus callosotomy [6,28–30]. Unfortunately, CC is not often used as a treatment option for both adults and children with SGE with drop attacks. By the time they present for callosotomy, they are often adults with severe intractable epilepsy who may have benefited from the procedure at an earlier age.
Fig. 2. Atonic seizure burden. Percentage of patients reporting reduction in atonic seizures.
specifically atonic seizure burden, seven (47%) patients reported greater than 60% seizure reduction, including five with complete elimination (i.e., 100% reduction) of atonic seizures. Three (20%) patients experienced between 30 and 60% atonic seizure reduction, and 5 (33%) patients reported less than 30% atonic seizure reduction (Fig. 2). Quality-of-life analysis demonstrated that nine (60%) patients had no change in self-reported quality of life. No patients reported either “worse” or “much worse” quality of life following corpus callosotomy, while six (40%) patients and/or their caregivers reported an improvement in QoL (i.e., “better” or “much better”, three patients each; Fig. 3). Mann–Whitney U analysis did not suggest any individual significant correlation when comparing QoL to AED or seizure burden. Twelve patients were developmentally delayed or mentally retarded, precluding neuropsychological testing. These patients completed pre- and postoperative MMSE testing; their scores ranged from zero to twelve, with a mean of 3.67 and a median of 2.5. There was no change in their MMSE scores postoperatively. Three patients completed a preoperative neuropsychological evaluation; two of these patients demonstrated a full-scale IQ of 68, while the third had a FSIQ of 47, consistent with severe global impairment. While limited to 13% of the sample because of the majority of patients exhibiting gross cognitive/intellectual and language deficits, the available data for individuals undergoing anterior corpus callosotomy are generally good. Patients' perceptions of cognitive changes were minimal, and objective assessment found that, compared to presurgical neuropsychological studies, 6 of 25 test scores improved one standard deviation or, if available, published reliable change, while only 3/25 declined. Scores that exhibited improvement were in attention [TMT, part A], verbal and visual memory, confrontation naming [BNT], and fine manual dexterity with the nondominant (left) hand. There was no change in general cognitive/IQ.
Fig. 3. Quality of life. Percentage of patients reporting change in quality of life.
4.1. How effective was the surgery at reducing seizure frequency? There are few studies that have evaluated corpus callosotomy in adults [31,32]; these studies investigated the role of CC in idiopathic generalized epilepsy (IGE). Most studies of callosotomy for SGE are limited to children or a combination of children and adults with intractable epilepsy [9,28,30,33–35]. The overall common conclusion from these studies is that CC can help reduce the frequency of drop attacks and also, in some cases, result in complete resolution. Our patient population consisted of patients whose SGE was refractory to medication and VNS therapy, and our results are similar to prior CC studies. Out of the 15 adult patients, 14 patients experienced a reduction in atonic seizures (Fig. 2) with half of our patients reporting a greater than 60% reduction of atonic seizures and 5 patients having complete resolution of atonic seizures. Rathore's pediatric study of 17 children with severe mental retardation reported a greater number of patients (2/3) with resolution or greater than 90% reduction of atonic seizures. Comparisons of pediatric CC studies have found overall that children younger than 16 years old with anterior callosotomy have a greater decrease of atonic seizures compared to other generalized seizure types [6]. It was found that in our adult study, atonic seizures had the greatest reduction compared to other generalized types of seizures. Corpus callosotomy can also help reduce seizures other than atonic seizures. The studies by Cukiert et al., Maehara and Shimizu, and Oguni et al. have the largest numbers of adult and pediatric patients and indicate a reduction of generalized seizures of greater than 50% in more than half of their study populations [28,33,35]. The adult IGE studies report significant reduction of generalized tonic–clonic (GTC) and absence seizures. Jenssen et al.'s series of nine patients revealed more than 80% reduction in GTC seizures in 4 patients and more than 50% GTC seizure reduction in the 8 surviving patients. Five of the patients had absence seizures, two had complete resolution, and one had more than 80% reduction [31]. Cuckiert et al.'s series of extended CC reported at least 75% reduction in GTC seizures and at least 90% reduction in absence seizures (3 with complete resolution) for all eleven patients [32]. Our results demonstrated that the majority of our patients (60%) had seizure reduction but indicated a less than 30% seizure reduction (Fig. 1). When comparing our results to the results of Maehara and Shimizu (ages at surgery: 4–41 years old, median age: 18 years) and Cukiert et al. (ages at surgery: 2–28 years old, mean age: 11.2 years), it appears that, with our adult patients, there was a smaller percentage of overall seizure reduction. In our series, the ages of patients at callosotomy ranged from 19 to 33 (mean: 25, median: 27) (Table 1), and our results suggest that although corpus callosotomy can reduce seizure frequency in adult patients, that reduction may not be as great as for pediatric patients. Children with favorable outcomes from other studies also had a shorter mean duration of their epilepsy prior to the callosotomy [29]. This may indicate that corpus callosotomy should be considered earlier in younger patients with intractable seizures, although an earlier study did not find any correlation between age at CC or duration of epilepsy prior to CC with outcome [35].
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4.2. How was the quality of life after the surgery?
References
In our study, no patients observed worsening of quality of life following callosotomy, and nearly half reported at least some degree of improvement (Fig. 3). Except for one postoperative infection, there were no significant complications, including that of disconnection syndrome. A nonsignificant trend was noted in our series in which patients with higher preoperative functioning (as assessed by neuropsychological testing) tended to derive greater satisfaction from the procedure and improved quality of life (2 of 3 patients, 66% v. 4 of 12, 33%, p = 0.20). Conversely, poorly functioning patients did not appear to derive any significant overall benefit. This is not inconsistent with Oguni et al.'s findings, which did not find any correlation between preoperative functioning or intelligence and outcome from CC [35]. Several studies suggest that patient and caregiver satisfaction vis-á-vis quality of life is higher for children when compared to adult patients [5,6,29,33]. Families of children from these prior studies noted improvements in behavior, attentiveness, and daily function [29,33]. Carmant et al. evaluated the quality-of-life scores of 28 patients with corpus callosotomy from age 2 to 26 years old where quality-of-life improvements were noted more by family in patients with reduction of atonic seizures [5]. A similar trend was found in our patients. Adults with complete resolution or greater than 90% reduction of their atonic seizures reported the greatest quality-of-life improvements. Interestingly, the adult IGE studies reported no change in QoL despite the excellent reduction in seizure burden. Both series reported no change or improvement in neuropsychological functioning [31,32]. Their populations differed from ours in several respects. The clinical entity under investigation (i.e., IGE as opposed to SGE) is fundamentally different as atonic seizures are not a feature of IGE. Furthermore, most patients with IGE have normal intelligence; most of our patients with SGE were precluded from undergoing neuropsychological evaluation secondary to severe developmental delay and/or mental retardation. Additionally, both groups proceeded with callosotomy before VNS. It is our practice to perform VNS before CC in both IGE and SGE [2], although the patients in our study gained little benefit from VNS and, therefore, proceeded to anterior CC.
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New York: Oxford University Press; 1998. [22] Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis G. Wisconsin Card Sorting Test (WCST) manual, revised and expanded. Odessa, FL: Psychological Assessment Resources; 1993. [23] Ruff R. Ruff Figural Fluency Test. Odessa, FL: Psychological Assessment Resources; 1998. [24] Matthews CG, Klove K. Instruction manual for the Adult Neuropsychology Test Battery. Madison, WI: University of Wisconsin Medical School; 1964. [25] Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA. State–Trait Anxiety Inventory (STAI). Menlo Park, CA: Mind Garden Inc.; 1970. [26] Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory — 2nd edition (BDI-II). San Antonio, TX: The Psychological Corp.; 1996. [27] Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann BP. Development and cross-cultural translation of a 31-item quality of life questionnaire (QOLIE-31). Epilepsia 1998;39:81–8. [28] Cukiert A, Burattini JA, Mariani PP, Câmara RB, Seda L, Baldauf CM, et al. Extended, one-stage callosal section for treatment of refractory secondarily generalized epilepsy in patients with Lennox–Gastaut and Lennox-like syndromes. Epilepsia 2006;47(2):371–4. [29] Rathore C, Abraham M, Rao RM, George A, Sarma PS, Radhakrishnan K. Outcome after corpus callosotomy in children with injurious drop attacks and severe mental retardation. Brain Dev 2007;29:577–85. [30] Feichtinger M, Schröttner O, Eder H, Holthausen H, Pieper T, Unger F, et al. Efficacy and safety of radiosurgical callosotomy: a retrospective analysis. Epilepsia 2006;47(7):1184–91. [31] Jenssen S, Sperling MR, Tracy JI, Nei M, Joyce L, David G, et al. Corpus callosotomy in refractory idiopathic generalized epilepsy. Seizure 2006;15:621–9. [32] Cuckiert A, Burattini JA, Mariani PP, Cuckiert CM, Argentoni-Baldochi M, Baise-Zung C, et al. Outcome after extended callosal section in patients with primary idiopathic generalized epilepsy. Epilepsia 2009;50:1377–80. [33] Maehara T, Shimizu H. Surgical outcome of corpus callosotomy in patients with drop attacks. Epilepsia 2001;42(1):67–71. [34] Hanson RR, Risinger M, Maxwell R. The ictal EEG as a predictive factor for outcome following corpus callosum section in adults. Epilepsy Res 2002;49: 89–97. [35] Oguni H, Olivier A, Andermann F, Comair J. Anterior callosotomy in the treatment of medically intractable epilepsies: a study of 43 patients with a mean follow-up of 39 months. Ann Neurol 1991;30:357–64.
4.3. How was neuropsychological function affected? While neuropsychological studies could not be completed for the majority of the subjects, outcome data suggest little subjective perception of cognitive change. One patient exhibited no meaningful change across time, while another patient exhibited a slight decrease in verbal memory and subtle ideomotor dyspraxia with her nondominant hand. Our data suggest that earlier callosotomy, particularly in higherfunctioning patients, may provide greater benefit to patients with symptomatic generalized epilepsy. While limited to a single institution, we present, to our knowledge, the first series of adults with SGE undergoing callosotomy. Additional studies may provide further evidence supporting the trends identified herein. 5. Conclusion Our study showed that corpus callosotomy is effective and safe in adult patients with symptomatic generalized epilepsies of the Lennox–Gastaut type. Its efficacy is best observed with regard to self-reported quality of life and for atonic seizure control. Based on the pediatric literature, there may be additional patients that may benefit from corpus callosotomy, and it should be considered as part of the treatment armamentarium for patients with intractable epilepsy, particularly atonic seizures. For adults with atonic seizures, corpus callosotomy should still be considered to potentially reduce the frequency of atonic seizures and thus improve their quality of life.
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Outcome of corpus callosotomy in adults Michael S. Park a,⁎, Emily Nakagawa b, Mike R. Schoenberg c, Selim R. Benbadis b, Fernando L. Vale a a b c
Department of Neurosurgery & Brain Repair, University of South Florida, Tampa, FL, USA Department of Neurology, University of South Florida, Tampa, FL, USA Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA
a r t i c l e
i n f o
Article history: Received 2 April 2013 Revised 22 April 2013 Accepted 25 April 2013 Available online 7 June 2013 Keywords: All epilepsy/seizures Epilepsy surgery Generalized seizures Vagus nerve stimulation
a b s t r a c t We present, to our knowledge, the first published series of corpus callosotomy (CC) in adults with medically intractable symptomatic generalized epilepsy (SGE). Fifteen adults were followed for the outcome measures of seizure and antiepileptic drug (AED) burden and quality of life (QoL). Five (33%) patients reported >60%, one (7%) reported between 30 and 60%, and nine (60%) reported b 30% reduction in the total number of seizures after CC. Seven (47%) patients reported >60%, three (20%) experienced between 30 and 60%, and five (33%) reported b 30% atonic seizure reduction. Twelve patients had no change in AED burden. Nine (60%) patients had no change in QoL, while six (40%) reported some improvement. Corpus callosotomy should be considered as a safe option for adults with medically intractable SGE with demonstrated reduction in the frequency of atonic seizures, and some patients experience a meaningful improvement in quality of life. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Symptomatic generalized epilepsies (SGEs) are a group of epilepsy syndromes characterized by multiple generalized seizure types and evidence of diffuse brain damage. The prototype is the Lennox– Gastaut syndrome, and the most recent classification proposal divides the etiologies as structural, metabolic (equivalent to “symptomatic”), or unknown (equivalent to “cryptogenic”). The greatest challenge in the management of patients with SGE is adequate seizure control [1]. The first-line treatment for SGE is antiepileptic medication; however, SGEs are often refractory to medications, and patients frequently proceed to nonpharmacological treatments such as vagus nerve stimulation (VNS) and ketogenic diet [2]. Vagus nerve stimulation has been found to reduce the number of monthly seizures by 50% [3,4]. Despite these interventions, approximately 60% of adult patients with SGE remain dependent with an impaired quality of life (QoL). Corpus callosotomy (CC) limits the spread of seizure discharges rather than removing the epileptic focus [5,6]. As most generalized seizures persist after callosotomy, there are other interhemispheric connections that are likely responsible for the generalization of seizures [6]. Anterior CC spares the splenium in order to preserve perceptual information and avoid the disconnection syndrome associated with total callosotomy [7].
⁎ Corresponding author at: Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, 2 Tampa General Circle, 7th Floor, Tampa, FL 33606, USA. Fax: +1 813 259 0944. E-mail address: [email protected] (M.S. Park). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.04.015
In children with SGE of the Lennox–Gastaut type with drop attacks, CC is an accepted surgical treatment [6]. Corpus callosotomy is effective in reducing atonic, tonic, and generalized tonic–clonic seizures [8,9]. However, these studies often evaluate a combination of children and adults with SGE. To our knowledge, there are no published series of corpus callosotomy in adult patients with SGE. As such, the role of corpus callosotomy in adults with SGE has not been fully characterized. The goal of our study was to evaluate the effectiveness and quality of life after corpus callosotomy in adult patients with SGE. 2. Methods A data registry was established in 1998 for all patients referred to our comprehensive epilepsy center for surgical evaluation. Patients and/or their caregivers participating in this data registry have completed the informed consent process. This study has been approved by the institutional review board and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Fifteen patients aged 18 or older with drug-resistant epilepsy underwent anterior two-thirds corpus callosotomy without resection of the anterior commissure based on seizure type(s), semiology, and results of phase I monitoring (surface EEG) and neuroimaging (MRI with SPECT in some cases) as well as neuropsychological study [10]. Outcomes were measured in several ways. Modified Engel classification scale (I: seizure-free; II: improved (i.e., greater than 90%); III: better, but less than 90% reduction; IV: no worthwhile improvement) was used to determine and stratify surgical outcomes [11]. Questionnaires were also used at scheduled follow-up visits. Pre- and postoperative management of antiepileptic drugs was deferred to the patient's
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treating neurologist. Outcomes measured included seizure burden, AED burden, and quality of life (QoL). Seizure burden (% seizure reduction) was subjectively quantified as b30% reduction, 30–60% reduction, and >60% reduction. Presurgical antiepileptic drug burden was compared to the number of drugs the patient required at the most recent follow-up. Finally, QoL was investigated via ordinal analysis where the patient or caregiver categorized his/her QoL as “much worse”, “worse”, “no change”, “better”, or “much better” as compared to presurgery. Outcome measures were analyzed individually as well as in combination via nonparametric analysis (Mann–Whitney U) [10]. Neuropsychological evaluations were obtained pre- and postoperatively for patients who did not present with severe intellectual disabilities, mental retardation, or lack of sufficient receptive/expressive speech. Mini-Mental Status Examination (MMSE) scores were obtained pre- and postoperatively for those subjects not undergoing neuropsychological evaluation. As part of a presurgical work-up, preoperative comprehensive neuropsychological studies were completed for 3 (20%) of the patients who met the inclusion/exclusion criteria for undergoing neuropsychological study. Postoperative studies were completed 24 and 35 months after corpus callosotomy. Neuropsychological tests were administered according to each test's respective manuals and assessed neuropsychological functions in six different neuropsychological domains: general cognitive/IQ [12,13], attention [13–15], memory [16–18], language [19–21], and visuoconstructional [16,17] and executive [14,22,23] functions, generating 25 different test scores. In addition, fine manual dexterity [24], quality of life in epilepsy [25], and screening measures for anxiety [26] and depressive [27] symptoms were administered. 3. Results We identified 15 adult patients who underwent anterior twothirds CC since the inception of the epilepsy registry between 1999 and 2012. Demographic data are displayed in Table 1. There were 6 men and 9 women. Ages at CC ranged from 19 years to 33 years (mean: 25 years), and ages at seizure onset ranged from 4 months to 23 years (mean: 8 years). Fourteen (93%) patients had received VNS before CC, while the remaining patient ultimately underwent VNS placement after callosotomy. Follow-up duration ranged from 7 months to 122 months (mean: 31 months). The number of AEDs
Table 1 Patient population characteristics. Number of patients Age at corpus callosotomy (years) Mean Median Range Age of seizure onset (years) Mean Median Range Duration of follow-up (months) Mean Median Range Gender (%) Male Female Number with preoperative VNS (%) Number of AEDs tried preoperatively Three Four Five Six Seven Eight Nine Ten
15 25 27 19–33 8 6 4 months–23 years
Table 2 Pre- and postoperative AED requirements. Patient
Preop
Postop
Change
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
3 3 1 3 4 3 3 4 4 4 4 7 4 4 5
3 3 1 2 2 5 3 4 4 4 4 7 4 4 5
0 0 0 −1 −2 2 0 0 0 0 0 0 0 0 0
tried prior to CC ranged from 3 to 10 (mean: 5.4). One patient underwent VNS initially followed by CC for persistent status epilepticus without significant improvement; he ultimately expired secondary to multiorgan system failure. Of the remaining 14, six had documented diagnoses of Lennox–Gastaut syndrome, while the others also experienced multiple generalized seizure types, all with drop attacks. Most exhibited mental retardation and early age of onset (i.e., by age 8). There was one procedure complicated by postoperative wound infection requiring reoperation for removal of the craniotomy flap. No patients experienced symptoms suggestive of disconnection syndrome. One patient underwent reoperation for completion of CC after anterior two-thirds CC for persistent atonic seizures; this patient did not experience any change with regard to outcomes of total or atonic seizure burden, AED burden, or QoL following either procedure. Table 2 shows outcome data with respect to AED use. The numbers of AEDs at the time of surgical intervention ranged between one and seven (mean: 3.73). There was no change in the range of the numbers of AEDs used postoperatively, with a minimal change in the mean (3.66). Table 2 demonstrates that only three patients had any alteration in their AED regimen after their surgery, with two patients (patients numbered 4 and 5) reducing the number of AEDs and one patient requiring two additional AEDs since the procedure. Review of Engel outcome data shows one patient with a completely seizure-free outcome and one with no improvement; the remainder showed various degrees of improvement in the reduction of seizures. Class III outcomes were the most prevalent in this cohort with 8 of 15 patients experiencing less than 90% seizure reduction. Fig. 1 shows self-reported overall seizure burden data. Five (33%) of the patients reported greater than 60% reduction in the total number of seizures, which include all of the patients with Engel I and II outcomes. One patient (7%) experienced a modest, i.e., 30 to 60%, overall seizure reduction, and the remainder (60%) experienced less than 30% reduction in the total number of seizures. With regard to
31 15 7–122 6 (40%) 9 (60%) 14 (93%) 2 5 2 2 2 0 1 1
Fig. 1. Overall seizure burden. Percentage of patients reporting reduction in total number of seizures.
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4. Discussion The overall goals of corpus callosotomy are to limit the spread of seizure discharges and to improve patient (and caregiver) quality of life. It is well known that drop attacks (atonic seizures) are the most common indication for and respond very well to corpus callosotomy [6,28–30]. Unfortunately, CC is not often used as a treatment option for both adults and children with SGE with drop attacks. By the time they present for callosotomy, they are often adults with severe intractable epilepsy who may have benefited from the procedure at an earlier age.
Fig. 2. Atonic seizure burden. Percentage of patients reporting reduction in atonic seizures.
specifically atonic seizure burden, seven (47%) patients reported greater than 60% seizure reduction, including five with complete elimination (i.e., 100% reduction) of atonic seizures. Three (20%) patients experienced between 30 and 60% atonic seizure reduction, and 5 (33%) patients reported less than 30% atonic seizure reduction (Fig. 2). Quality-of-life analysis demonstrated that nine (60%) patients had no change in self-reported quality of life. No patients reported either “worse” or “much worse” quality of life following corpus callosotomy, while six (40%) patients and/or their caregivers reported an improvement in QoL (i.e., “better” or “much better”, three patients each; Fig. 3). Mann–Whitney U analysis did not suggest any individual significant correlation when comparing QoL to AED or seizure burden. Twelve patients were developmentally delayed or mentally retarded, precluding neuropsychological testing. These patients completed pre- and postoperative MMSE testing; their scores ranged from zero to twelve, with a mean of 3.67 and a median of 2.5. There was no change in their MMSE scores postoperatively. Three patients completed a preoperative neuropsychological evaluation; two of these patients demonstrated a full-scale IQ of 68, while the third had a FSIQ of 47, consistent with severe global impairment. While limited to 13% of the sample because of the majority of patients exhibiting gross cognitive/intellectual and language deficits, the available data for individuals undergoing anterior corpus callosotomy are generally good. Patients' perceptions of cognitive changes were minimal, and objective assessment found that, compared to presurgical neuropsychological studies, 6 of 25 test scores improved one standard deviation or, if available, published reliable change, while only 3/25 declined. Scores that exhibited improvement were in attention [TMT, part A], verbal and visual memory, confrontation naming [BNT], and fine manual dexterity with the nondominant (left) hand. There was no change in general cognitive/IQ.
Fig. 3. Quality of life. Percentage of patients reporting change in quality of life.
4.1. How effective was the surgery at reducing seizure frequency? There are few studies that have evaluated corpus callosotomy in adults [31,32]; these studies investigated the role of CC in idiopathic generalized epilepsy (IGE). Most studies of callosotomy for SGE are limited to children or a combination of children and adults with intractable epilepsy [9,28,30,33–35]. The overall common conclusion from these studies is that CC can help reduce the frequency of drop attacks and also, in some cases, result in complete resolution. Our patient population consisted of patients whose SGE was refractory to medication and VNS therapy, and our results are similar to prior CC studies. Out of the 15 adult patients, 14 patients experienced a reduction in atonic seizures (Fig. 2) with half of our patients reporting a greater than 60% reduction of atonic seizures and 5 patients having complete resolution of atonic seizures. Rathore's pediatric study of 17 children with severe mental retardation reported a greater number of patients (2/3) with resolution or greater than 90% reduction of atonic seizures. Comparisons of pediatric CC studies have found overall that children younger than 16 years old with anterior callosotomy have a greater decrease of atonic seizures compared to other generalized seizure types [6]. It was found that in our adult study, atonic seizures had the greatest reduction compared to other generalized types of seizures. Corpus callosotomy can also help reduce seizures other than atonic seizures. The studies by Cukiert et al., Maehara and Shimizu, and Oguni et al. have the largest numbers of adult and pediatric patients and indicate a reduction of generalized seizures of greater than 50% in more than half of their study populations [28,33,35]. The adult IGE studies report significant reduction of generalized tonic–clonic (GTC) and absence seizures. Jenssen et al.'s series of nine patients revealed more than 80% reduction in GTC seizures in 4 patients and more than 50% GTC seizure reduction in the 8 surviving patients. Five of the patients had absence seizures, two had complete resolution, and one had more than 80% reduction [31]. Cuckiert et al.'s series of extended CC reported at least 75% reduction in GTC seizures and at least 90% reduction in absence seizures (3 with complete resolution) for all eleven patients [32]. Our results demonstrated that the majority of our patients (60%) had seizure reduction but indicated a less than 30% seizure reduction (Fig. 1). When comparing our results to the results of Maehara and Shimizu (ages at surgery: 4–41 years old, median age: 18 years) and Cukiert et al. (ages at surgery: 2–28 years old, mean age: 11.2 years), it appears that, with our adult patients, there was a smaller percentage of overall seizure reduction. In our series, the ages of patients at callosotomy ranged from 19 to 33 (mean: 25, median: 27) (Table 1), and our results suggest that although corpus callosotomy can reduce seizure frequency in adult patients, that reduction may not be as great as for pediatric patients. Children with favorable outcomes from other studies also had a shorter mean duration of their epilepsy prior to the callosotomy [29]. This may indicate that corpus callosotomy should be considered earlier in younger patients with intractable seizures, although an earlier study did not find any correlation between age at CC or duration of epilepsy prior to CC with outcome [35].
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4.2. How was the quality of life after the surgery?
References
In our study, no patients observed worsening of quality of life following callosotomy, and nearly half reported at least some degree of improvement (Fig. 3). Except for one postoperative infection, there were no significant complications, including that of disconnection syndrome. A nonsignificant trend was noted in our series in which patients with higher preoperative functioning (as assessed by neuropsychological testing) tended to derive greater satisfaction from the procedure and improved quality of life (2 of 3 patients, 66% v. 4 of 12, 33%, p = 0.20). Conversely, poorly functioning patients did not appear to derive any significant overall benefit. This is not inconsistent with Oguni et al.'s findings, which did not find any correlation between preoperative functioning or intelligence and outcome from CC [35]. Several studies suggest that patient and caregiver satisfaction vis-á-vis quality of life is higher for children when compared to adult patients [5,6,29,33]. Families of children from these prior studies noted improvements in behavior, attentiveness, and daily function [29,33]. Carmant et al. evaluated the quality-of-life scores of 28 patients with corpus callosotomy from age 2 to 26 years old where quality-of-life improvements were noted more by family in patients with reduction of atonic seizures [5]. A similar trend was found in our patients. Adults with complete resolution or greater than 90% reduction of their atonic seizures reported the greatest quality-of-life improvements. Interestingly, the adult IGE studies reported no change in QoL despite the excellent reduction in seizure burden. Both series reported no change or improvement in neuropsychological functioning [31,32]. Their populations differed from ours in several respects. The clinical entity under investigation (i.e., IGE as opposed to SGE) is fundamentally different as atonic seizures are not a feature of IGE. Furthermore, most patients with IGE have normal intelligence; most of our patients with SGE were precluded from undergoing neuropsychological evaluation secondary to severe developmental delay and/or mental retardation. Additionally, both groups proceeded with callosotomy before VNS. It is our practice to perform VNS before CC in both IGE and SGE [2], although the patients in our study gained little benefit from VNS and, therefore, proceeded to anterior CC.
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4.3. How was neuropsychological function affected? While neuropsychological studies could not be completed for the majority of the subjects, outcome data suggest little subjective perception of cognitive change. One patient exhibited no meaningful change across time, while another patient exhibited a slight decrease in verbal memory and subtle ideomotor dyspraxia with her nondominant hand. Our data suggest that earlier callosotomy, particularly in higherfunctioning patients, may provide greater benefit to patients with symptomatic generalized epilepsy. While limited to a single institution, we present, to our knowledge, the first series of adults with SGE undergoing callosotomy. Additional studies may provide further evidence supporting the trends identified herein. 5. Conclusion Our study showed that corpus callosotomy is effective and safe in adult patients with symptomatic generalized epilepsies of the Lennox–Gastaut type. Its efficacy is best observed with regard to self-reported quality of life and for atonic seizure control. Based on the pediatric literature, there may be additional patients that may benefit from corpus callosotomy, and it should be considered as part of the treatment armamentarium for patients with intractable epilepsy, particularly atonic seizures. For adults with atonic seizures, corpus callosotomy should still be considered to potentially reduce the frequency of atonic seizures and thus improve their quality of life.