Epilepsy surgery in patients with autism

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OBJECTIVE

The purpose of this study was to report outcomes of epilepsy surgery in 56 consecutive patients with autism spectrum disorder.

METHODS

Medical records of 56 consecutive patients with autism who underwent epilepsy surgery were reviewed with regard to clinical characteristics, surgical management, postoperative seizure control, and behavioral changes.

RESULTS

Of the 56 patients with autism, 39 were male, 45 were severely autistic, 27 had a history of clinically significant levels of aggression and other disruptive behaviors, and 30 were considered nonverbal at baseline. Etiology of the epilepsy was known in 32 cases, and included structural lesions, medical history, and developmental and genetic factors. Twenty-nine patients underwent resective treatments (in 8 cases combined with palliative procedures), 24 patients had only palliative treatments, and 3 patients had only subdural electroencephalography. Eighteen of the 56 patients had more than one operation. The mean age at surgery was 11 ± 6.5 years (range 1.5–35 years). At a mean follow-up of 47 ± 30 months (range 2–117 months), seizure outcomes included 20 Engel Class I, 12 Engel Class II, 18 Engel Class III, and 3 Engel Class IV cases. The age and follow-up times are stated as the mean ± SD. Three patients were able to discontinue all antiepileptic drugs (AEDs). Aggression and other aberrant behaviors observed in the clinical setting improved in 24 patients. According to caregivers, most patients also experienced some degree of improvement in daily social and cognitive function. Three patients had no functional or behavioral changes associated with seizure reduction, and 2 patients experienced worsening of seizures and behavioral symptoms.

CONCLUSIONS

Epilepsy surgery in patients with autism is feasible, with no indication that the comorbidity of autism should preclude a good outcome. Resective and palliative treatments brought seizure freedom or seizure reduction to the majority of patients, although one-third of the patients in this study required more than one procedure to achieve worthwhile improvement in the long term, and few patients were able to discontinue all AEDs. The number of palliative procedures performed, the need for multiple interventions, and continued use of AEDs highlight the complex etiology of epilepsy in patients with autism spectrum disorder. These considerations underscore the need for continued analysis, review, and reporting of surgical outcomes in patients with autism, which may aid in better identification and management of surgical candidates. The reduction in aberrant behaviors observed in this series suggests that some behaviors previously attributed to autism may be associated with intractable epilepsy, and further highlights the need for systematic evaluation of the relationship between the symptoms of autism and refractory seizures.

ABBREVIATIONSAED = antiepileptic drug; ASD = autism spectrum disorder; DSM-5 = Diagnostic and Statistical Manual, 5th Edition; EEG = electroencephalographic; MRE = medically refractory epilepsy; MTS = mesial temporal sclerosis; PDD-NOS = pervasive developmental disorder, not otherwise specified; RNS = responsive neurostimulation; TS = tuberous sclerosis; VNS = vagus nerve stimulator.

Abstract

OBJECTIVE

The purpose of this study was to report outcomes of epilepsy surgery in 56 consecutive patients with autism spectrum disorder.

METHODS

Medical records of 56 consecutive patients with autism who underwent epilepsy surgery were reviewed with regard to clinical characteristics, surgical management, postoperative seizure control, and behavioral changes.

RESULTS

Of the 56 patients with autism, 39 were male, 45 were severely autistic, 27 had a history of clinically significant levels of aggression and other disruptive behaviors, and 30 were considered nonverbal at baseline. Etiology of the epilepsy was known in 32 cases, and included structural lesions, medical history, and developmental and genetic factors. Twenty-nine patients underwent resective treatments (in 8 cases combined with palliative procedures), 24 patients had only palliative treatments, and 3 patients had only subdural electroencephalography. Eighteen of the 56 patients had more than one operation. The mean age at surgery was 11 ± 6.5 years (range 1.5–35 years). At a mean follow-up of 47 ± 30 months (range 2–117 months), seizure outcomes included 20 Engel Class I, 12 Engel Class II, 18 Engel Class III, and 3 Engel Class IV cases. The age and follow-up times are stated as the mean ± SD. Three patients were able to discontinue all antiepileptic drugs (AEDs). Aggression and other aberrant behaviors observed in the clinical setting improved in 24 patients. According to caregivers, most patients also experienced some degree of improvement in daily social and cognitive function. Three patients had no functional or behavioral changes associated with seizure reduction, and 2 patients experienced worsening of seizures and behavioral symptoms.

CONCLUSIONS

Epilepsy surgery in patients with autism is feasible, with no indication that the comorbidity of autism should preclude a good outcome. Resective and palliative treatments brought seizure freedom or seizure reduction to the majority of patients, although one-third of the patients in this study required more than one procedure to achieve worthwhile improvement in the long term, and few patients were able to discontinue all AEDs. The number of palliative procedures performed, the need for multiple interventions, and continued use of AEDs highlight the complex etiology of epilepsy in patients with autism spectrum disorder. These considerations underscore the need for continued analysis, review, and reporting of surgical outcomes in patients with autism, which may aid in better identification and management of surgical candidates. The reduction in aberrant behaviors observed in this series suggests that some behaviors previously attributed to autism may be associated with intractable epilepsy, and further highlights the need for systematic evaluation of the relationship between the symptoms of autism and refractory seizures.

Epilepsy is a common neurological comorbidity in children with autism. An estimated 5%–40% of autistic children experience epileptic seizures, and the association tends to be stronger in more severely affected patients.9,25 The burden of medically refractory epilepsy (MRE) has been well established in the pediatric population, and when combined with autism, the cost to the child, caregivers, and society is inevitably higher.3 Epilepsy surgery, although still an underutilized treatment in the armamentarium against medically refractory seizures in children39 and adults,6,13,22 is effective in controlling seizures and bringing about tangible gains in health-related quality of life and development in lesional as well as nonlesional epilepsy from both temporal and extratemporal sources. However, the few reports on outcomes of epilepsy surgery in children with autism show mixed results, and some suggest concerns over the implications of the presence of autism for a worthwhile surgical outcome.10,30,40 We describe our experience at a comprehensive epilepsy center with a large population of children with autism, where a highly tailored, multimodality surgical approach was used to mitigate the seizure burden associated with these comorbidities.

Methods

Study Design

Approval for retrospective review of existing medical records with waiver of patient consent was obtained prior to collection and analysis of deidentified data. Pertinent medical records were reviewed for patients with autism who underwent surgical treatment for MRE between January 2005 and May 2014, including physician referrals, neuroimaging, genetic testing, neuropsychological records, surgical notes, pathology findings, and neurology and neurosurgery follow-up notes.

Patients with the following diagnoses: autism; Asperger syndrome; Rett syndrome with autistic features; and pervasive developmental disorder, not otherwise specified (PDD-NOS) were included, regardless of etiology. These patients are collectively referred to throughout this report as those with autism spectrum disorder (ASD), based on recent changes in the Diagnostic and Statistical Manual, 5th Edition (DSM-5) guidelines for autism diagnosis.1,2

Study Participants

Fifty-six consecutive surgical patients with ASD were identified (Table 1): 49 patients with autism, 2 boys with Asperger syndrome, 2 girls with Rett syndrome, and 3 children with PDD-NOS. There were no patients with childhood disintegrative disorder (known as CDD).1 Comorbid genetic disorders included tuberous sclerosis ([TS], 3 patients), Sturge-Weber syndrome (1 patient), Angelman syndrome (1 patient), Costello syndrome (1 patient), Cornelia de Lange syndrome (1 patient), and Down syndrome (1 patient). Additionally, 3 patients had point mutations in genes with a known link to epilepsy (SCN1A, PCDH19, and PRICKLE1, all revealed after surgery), and 3 more had at least 1 family member with a history of seizures. Ten patients had some form of migrational abnormality or abnormal cortical organization, 2 patients had brain lesions related to prior medical procedures, 9 had mesial temporal sclerosis (MTS), 3 had epilepsy associated with tumor, and 4 had a presumed vascular etiology for their epilepsy (3 childhood stroke patients were previously published).19 To our knowledge, 24 of the 56 patients had no comorbidities, structural abnormalities, or genetic mutations associated with an increased risk of autism and epilepsy (Table 2).

TABLE 1.

Summary of clinical characteristics of surgical candidates and surgical procedures performed in patients with ASD and epilepsy

Patient CharacteristicsValue
Demographics
  Mean age at surgery (yrs)11 ± 6.5, range 1.5–35
  Mean age at 1st surgery (yrs)10 ± 6, range 1.5–28
  Sex39 M, 17 F
Epilepsy
  Mean duration (yrs)9 ± 5, range 1–28
  Mean age at onset (yrs)1.5 ± 3, range 0–12
  Etiology32 structural &/or genetic, 24 idiopathic
Autism
  Severity45 severe, 8 moderate, 3 mild
  Speech30 nonverbal, 26 verbal
Surgical treatments
  Resective
    Focal &/or lobar7 temporal, 5 frontal, 1 HH
    Multilobar4 hemispherotomy, 12 subhemispheric
    Side*17 lt, 11 rt
  Palliative
    CC26
    VNS14
  Invasive monitoring
    Staged resections25
    Diagnostic only4 bilat strips, 3 grids & strips

CC = corpus callosotomy; HH = hypothalamic hamartoma.

Epilepsy duration before initial surgery is given. All procedures performed at our center, including invasive monitoring, were considered when calculating age at surgery. Severity of ASD was graded according to the DSM-5, as described in Methods.

No side was assigned to the resection of the HH; therefore the sides only total 28.

TABLE 2.

Detailed clinical characteristics of individual surgical candidates, surgical treatments, and outcomes of epilepsy surgery in patients with ASD

Case NoSexAge at Op (yrs)Severity of ASDRelated DiagnosesRadiology FindingsPathology FindingsSurgical Procedure(s)Seizure Outcome (FU, mos)
1M123 nonverbalHemimegalencephalyNear complete lt hemispheric dysplasiaNeuronal loss &/or gliosisLt hemispherotomyID (59)
2M8, 121NormalNormalCC, staged lt TLIIC (45)
3M63 nonverbalLt temporal cortical dysplasiaCortical dysplasiaStaged lt TLIA (39)
4F183 nonverbalNormalNACCIIIA (36)
5M173 nonverbalNormalNAVNSIIB (45)
6M83Lt parietofrontal polymicrogyriaNACCIIIA (18)
7M12, 143 nonverbalNormalNAVNS, CCIVC (102)
8F73 nonverbalFHxNormalNACCIIIA (11)
9M151ALLRt Fr posttraumatic gliosisNACCIB (73)
10M1.51FHxLt temporoparietal cortical dysplasiaCortical dysplasiaStaged lt TL + PLIA (79)
11M102NormalNormalStaged lt TLIA (77)
12M23, 283 nonverbalNormalNAVNS, CCIC (85)
13F11, 123SCN1ALt MTSNormalStaged lt TL, VNSIIIA (102)
14M28, 353 nonverbalLt Fr leukoencephalomalaciaPolymicrogyria, gliosis, white matter heterotopiaVNS, staged lt FLIIIA (10)
15F33 nonverbalNormalNACCIIIA (15)
16F62NormalNACCIIA (27)
17M83Sturge-WeberSturge-Weber, rt hemispheric atrophy, rt posterior focal lesionSturge-Weber, MTSRt hemispherotomyIA (15)
18M12, 143 nonverbalRt occipitotemporal cortical dysplasiaCortical dysplasiaCC, staged rt TL + Fr + Oc resectionIIIA (38)
19F2.53 nonverbalNormalNAVNSIIA (35)
20M103 nonverbalNormalNACCIIIA (14)
21M123MCA CVARt frontoparietal opercular lesionMTSStaged rt hemispherotomyIA (52)
22M13, 173 nonverbalNormalNormalCC, staged lt TL + Fr disconnectIIIA (35)
23F3.53PCDH19NormalNormalStaged lt cingulate resectionIIIA (35)
24F17, 19, 203NormalNormalVNS, CC, staged rt FLIIC (80)
25M8, 103NormalNACC, VNSIB (100)
26M112AVMRt temporal porencephalic cyst, rt occipital atrophyIschemic damage w/encephalomalciaStaged rt TL + partial FL + partial OLIA (40)
27M82NormalNAVNS, CCIA (37)
28M53HHHHResection of HHIA (42)
29F193 nonverbalIschemic eventLt temporoparietal infarct, bilat encephalomalaciaMTSStaged lt TL + OF resectionIIA (53)
30F173 nonverbalRett syndromeNormalNACCIVB (22)
31F93 nonverbalNormalNACCIIIA (75)
32M43Rt parahippocampal massGliomaStaged rt TLIA (62)
33M82Lt Fr cortical dysplasiaMild cortical dysplasiaStaged lt Fr resectionIA (91)
34M153 nonverbalNormalNABilat strips, CCIIA (30)
35F8, 103Down syndromeNormalNACC, VNSIIIA (50)
36F43 nonverbalNormalNACCIA (2)
37M43NormalNACCIVC (47)
38M163 nonverbalCornelia de Lange syndromeBilat MTSMTSBilat strips, staged lt TL + OF resectionIA (47)
39M193 nonverbalNormalElements resembling balloon cells, no true cortical dysplasiaStaged lt TL + Fr disconnectIIIA (21)
40F83 nonverbalPRICKLE1Lt MTSMTSStaged lt TL + OF resectionIIIA (37)
41M7, 103 nonverbalNormalNAVNS, CCIID (105)
42M163 nonverbalFHxNormalNormalStaged lt TL + Fr disconnectIIIA (14)
43F73Rett syndromeRt MTSMTS, orbitofrontal cortical dysplasiaStaged rt TL + OF resectionIIA (26)
44M8, 143 nonverbalCostello syndromeNormalNAVNS, CCIIIA (29)
45M72Rt Fr cystic encephalomalacia, lt cerebellar arachnoid cystMTSStaged rt TLID (13)
46M4, 5, 73 nonverbalNormalNormal(Lt partial TL), CC, staged lt TL + Oc-P disconnect + partial FLIIIA (76)
47M8, 10, 11, 123 nonverbalTSMultiple tubersNA(VNS, staged rt TL), bilat strips, CCIIA (100)
48M5, 73 nonverbalTSMultiple tubers, rt temporal lobe expansionCortical tuberVNS, staged rt TLIIA (51)
49M193NormalNACCIIIA (21)
50M22 nonverbalNormalNormalStaged rt TL + Fr disconnectIA (15)
51F73Angelman syndromeNormalNAVNSIIB (117)
52M173Hemophilia, CVAExtensive rt hemispheric encephalomalaciaMTSRt hemispherotomyIA (10)
53M23 nonverbalTSMultiple tubersCortical tuberBilat strips, staged lt FLIA (8)
54F33 nonverbalLt mesial temporal atrophyNAImplant; no resectionIIA (17)
55M92Lt temporooccipital encephalomalaciaNAImplant; no resectionIA (75)
56M63Rt Fr polypachygyriaNAImplant; no resectionIIA (68)

ALL = acute lymphoblastic leukemia; AVM = arteriovenous malformation; CVA = cerebrovascular accident; FHx = family history of seizures; FL = frontal lobectomy; Fr = frontal; FU = follow-up; MCA = middle cerebral artery; NA = not applicable; Oc = occipital; OF = orbitofrontal; OL = occipital lobectomy; P = parietal; PL = parietal lobectomy; TL = temporal lobectomy.

Seizure outcomes were measured using the Engel classification. Severity of autism was graded as follows: 1 = mild, 2 = moderate, and 3 = severe, as described in Methods. In the “Surgical Procedures” column, a plus sign indicates procedures done during the same operation, and commas separate subsequent surgeries; procedures done at another center are in parentheses. Outcome and follow-up of the most recent surgery is given.

The following DSM-5 criteria were used to classify autism severity: 1 = mild—individual resists changes in routine, requires mild support due to difficulty with effective communication and reciprocal social interactions; 2 = moderate—obvious social impairment requiring substantial support in daily functioning, reduced expressive and receptive communication, and elevated levels of distress when interrupted or redirected; and 3 = severe—very limited speech and facial or other nonverbal expressions, very limited receptive communication, marked distress when disrupted or redirected from fixation, unable to establish relationships beyond those with caregivers, and unable to function without very substantial support.2 Individuals 2 years of age or older who use fewer than 5 words purposefully and meaningfully each day were considered nonverbal.43

Assessment of Outcomes

Seizure outcomes were evaluated using the Engel classification system12 (Fig. 1, Table 2). Additionally, current antiepileptic drugs (AEDs) were compared with preoperative prescriptions. Functional outcomes were assessed based on available neuropsychological records as well as caregivers' accounts and direct evaluation during follow-up visits.

FIG. 1.
FIG. 1.

Bar graph showing seizure outcomes of epilepsy surgery in patients with ASD. Palliative procedures performed prior to definitive resective treatments are not shown. In the only case in which a palliative procedure was performed subsequent to resection, outcomes of both surgeries are shown (VNS and temporal lobectomy). The mean follow up was 47 ± 30 months (range 2–117 months); see text and Table 2 for individual follow-up times. CC = corpus callosotomy.

Disruptive behaviors observed in the clinical setting, such as unprovoked aggression, intentional breaking of hospital property, oppositional and combative behavior during clinical procedures, and attempts to manipulate caregivers by threatening self-injury or violence, were considered aberrant behaviors. Absence of these disruptive behaviors during follow-up visits was considered marked improvement. Nonviolent autistic mannerisms (e.g., rocking, arm waving, odd repetitive sounds) were not included in the aberrant category.

Parental reports of changes noted since surgery in the child's overall health, behavior, and cognitive ability were collected from neuropsychological records and follow-up notes. Annual assessments for patients residing in group homes were reviewed along with parental reports. Functional categories listed in Table 3 were based on the most frequently noted changes. When sufficient details were available, patient status in specific areas was interpreted as better, same, or worse than before surgery. The 2-tailed Fisher's exact test was performed to assess statistical significance of changes after surgery; p < 0.05 was considered significant. Any documented comments regarding parents' satisfaction with surgery and experience of the overall process were also collected, especially when “most difficult part,” “main benefit [other than seizure control],” and “overall positive/negative outcome” were explicitly stated (Table 4). The chi-square test was used to assess the association of clinical features and Engel outcome.

TABLE 3.

Parent-assessed functional outcomes of epilepsy surgery

OutcomeParents' Reports of Changes After Opp Value
BetterNo ChangeWorse
Functional area
  Areas related to autism diagnosis
    Speech & language development22251<0.01
    Nonverbal communication skills21270<0.001
    Relating to others28161<0.001
    Adaptation to change15273>0.05
  Cognitive function
    Attention span24194<0.05
    Memory & learning28182<0.001
    Following directions29171<0.001
    Academic progress24121<0.01
  Aberrant behaviors
    Overall severity of all symptoms*25156<0.05
    Impulsivity19216>0.05
    Aggression18218>0.05
    Self-injury8324>0.05
Overall severity of behavioral symptoms by seizure outcome*
    Engel I961>0.05
    Engel II713>0.05
    Engel III970>0.05
    Engel IV012>0.05

Outcomes were not assessed for patients for whom recent follow-up was not available; see Methods for details of data collection and analysis.

The same overall findings are first presented in aggregate and then grouped by seizure outcome.

TABLE 4.

Long-term benefits outweigh the stress of surgery

Parents' Perspective: Most Common Parental Comments on OutcomeNo. of Cases
Most important benefit
  Increased awareness &/or cognitive improvement13
  Patient's happiness & improved quality of life10
  Reduced AED side effects7
Most difficult part
  Parents' anxiety over outcome, stress during surgery12
  Recovery11
  Decision9
Overall outcome
  Positive43
  No improvement2
  Equivocal4

Benefits and difficulties most frequently mentioned by parents of patients with recent follow-up are listed (see Methods). High parental satisfaction with outcome was noted, with improvements in mood and cognition perceived as the most important benefits of improved seizure control. Comments on difficulties were typically associated with the short-term stress of surgery.

Maximum follow-up was available for 52 of the 56 patients (1 patient died after an accident unrelated to epilepsy 3 years after surgery—follow-up as of time of death is given; and 3 patients were lost to follow-up—their outcome is given as of the last visit). For patients who had multiple interventions, follow-up times for individual procedures are calculated through the subsequent surgery. The age and follow-up times are reported as the mean ± SD.

Results

Surgical Procedures and Seizure Control

In our population of patients with epilepsy and autism, a total of 69 surgeries were performed at our center, including 25 staged resections and/or disconnections with invasive monitoring, 3 single-stage hemispherotomies, 1 lesionectomy, 26 corpus callosotomies, and 14 vagus nerve stimulator (VNS) placements. In addition, 4 patients had bilateral strip electrodes implanted in a separate procedure, and 3 more patients underwent invasive monitoring with grid and strip electrodes without a secondary resection. One-third of the patients (18 of 56) had more than one operation, and 2 underwent prior epilepsy surgery before referral to our center. Seizure outcomes are summarized in Fig. 1 and detailed in Table 2. Resective outcomes are discussed below with regard to lesional or nonlesional etiology, extent of resection, and whether the temporal lobe was involved, followed by a discussion of palliative procedures.

Resections in Patients With Structural Lesions

Of the 29 patients who underwent focal or multifocal resections and/or disconnections, in 20 patients their epilepsy was associated with abnormal radiological findings. Three hemispherotomies were performed in patients with extensive hemispheric lesions and baseline hemiparesis, and all 3 resulted in seizure freedom (follow-up 59, 15, and 10 months). Another hemispherotomy was performed in a boy with a small parietal lesion associated with a vascular insult (Case 21), in whom invasive monitoring confirmed diffuse seizure onsets involving the entire hemisphere (Engel IA, follow-up 52 months).

Six patients had MRI evidence supporting a temporal seizure focus (either MTS, cortical dysplasia limited to the temporal region, a temporal epileptogenic tuber, or abnormality in the parahippocampal gyrus). One additional patient (Case 38) had bitemporal MTS, but one-sided seizure onsets were demonstrated with bilateral subdural strip electrodes. Four staged temporal lobectomies were performed in these 7 patients, and 3 staged multilobar resections involved the temporal lobe. Three of these patients remain seizure free since surgery (follow-up 62, 47, and 39 months), and 2 more are mostly seizure free (follow-up 51 and 26 months). The patient in Case 40 (MTS, focal electroencephalographic [EEG] findings) enjoyed 2 years of seizure freedom, after which a reduction in medication dose was followed by new-onset generalized seizures with a bilateral Lennox-Gastaut–like EEG pattern never observed prior to surgery. She was recently diagnosed with a mutation in the PRICKLE1 gene. The patient in Case 13 (MTS, focal EEG findings) experienced only 6 months of seizure freedom after temporal lobectomy, and subsequently an SCN1A mutation was diagnosed.

Four more multilobar resections were performed in cases in which MRI abnormalities involved, but were not limited to, the temporal lobe. Two boys in this group achieved a long-term Engel IA outcome (follow-up 79 and 40 months); 1 girl with vascular etiology achieved an Engel Class II outcome (follow-up 53 months) with new-onset generalized seizures following a period of 2.5 years of seizure freedom; and 1 boy (Case 18) achieved an Engel Class III outcome (follow-up 38 months), despite surgical removal or disconnection of epileptogenic areas of cortical dysplasia.

The only extratemporal lesional cases were 3 staged frontal lobectomies, 1 of them associated with TS (2 Engel IA, follow-up 91 and 8 months; 1 Engel IIIA, follow-up 10 months). One additional patient with extratemporal lesions underwent a temporal lobectomy, based on subdural recordings pointing to temporal seizure onsets (Engel ID, 13-month follow-up). In the final patient in this group, single-stage removal of a hypothalamic hamartoma resulted in seizure freedom (42-month follow-up).

Additionally, 3 patients with abnormal MRI findings whose ictal onsets could not be definitively localized with scalp EEG recordings (Cases 54–56) underwent implantation of subdural electrodes without subsequent resection, because no seizures or only atypical seizures occurred during monitoring. All 3 patients are currently responding well to pharmacotherapy, in 1 case supplemented by experimental use of cannabidiol.

Resections in Patients With Nonlesional Epilepsy

Nine of the 29 patients in our series who underwent resective procedures were considered nonlesional cases after dedicated epilepsy protocol MRI was performed. Four focal or lobar and 5 multilobar resections and/or disconnections were performed, all aided by invasive monitoring. The 3 lobectomies resulted in Engel IA (follow-up 77 months) and IIC outcomes (follow-up 80 and 45 months), and resection of the cingulate gyrus resulted in an Engel IIIA outcome (follow-up 35 months). All 5 nonlesional multilobar resections involved the temporal lobe. One resulted in seizure freedom (follow-up 15 months) and 4 resulted in seizure reduction (Engel IIIA, follow-up 76, 35, 21, and 14 months). Neuropathological examination revealed abnormalities resembling balloon cells in the amygdala of the patient in Case 39, but not true cortical dysplasia. Normal tissue structure and cellular morphology were found in the other 4 patients with nonlesional epilepsy who had an Engel IIIA outcome. The patient in Case 23 was later diagnosed with a PCDH19 mutation, following the gene's discovery.

Complete Corpus Callosotomy

Twelve patients had corpus callosotomy as their only treatment, and 5 more had only callosotomy following prior implantation of a VNS. Six of these 17 patients became seizure free or almost seizure free after callosotomy (mean follow-up 55 months, range 2–105 months); 8 patients experienced recurrence of seizures at reduced frequency and/or severity (mean follow-up 27 months, range 11–75 months); 1 had no worthwhile seizure reduction (follow-up 22 months); and 2 reported seizure worsening (follow-up 47 and 102 months). In addition, subsequent laterality was observed in 4 of these 17 patients, 1 of whom (Case 8) has already been deemed a candidate for resection. Similarly, 5 of the resective procedures included in this report followed an earlier corpus callosotomy, which had led to localization of seizure foci. Two more callosotomies were performed after unsuccessful attempts to lateralize seizure onsets with bilateral strip electrodes, in 1 case related to multiple tubers, and resulted in good lasting seizure control (Engel IIA, 100- and 35-month follow-up). Two additional callosotomy cases in which seizures persisted and did not demonstrate focality were followed by implantation of a VNS (see below).

Placement of a VNS

Fourteen patients had a VNS placed at our center, and in 11 of those the VNS was the initial epilepsy surgery. In 3 of the 11 cases, the VNS provided a significant benefit when combined with medical therapy (Engel II, follow-up 117, 45, and 35 months), and 8 of the patients proceeded with other surgical options. A VNS was also implanted as a further palliative measure in 2 patients with nonlesional epilepsy in whom, despite a reduction in drop attacks, seizures remained generalized or had bilateral onsets after corpus callosotomy (Engel IB, follow-up 100 months; Engel IIIA, follow-up 50 months). In 1 case, a VNS device was used as a supplementary palliative treatment following a temporal lobe resection in the patient with the SCN1A mutation (Engel IIIA, 102-month follow-up).

Use of AEDs

Three of the 29 patients who underwent resection achieved long-term seizure freedom without the use of any AED (follow-up 91, 79, and 62 months), and 2 more remained seizure free with continuation of monotherapy (follow-up 77 and 42 months). Eight patients discontinued 1 or 2 AEDs after surgery, and 14 of the 29 patients remained on polytherapy. Two patients who underwent resection were lost to follow-up and their current AED dose was not available. In the patients who underwent palliative treatments, there was no benefit with regard to AEDs.

Autism Severity and Surgical Outcome

Patients with less severe autism, specifically those with autism severity scores of 1 or 2 (10 patients total) all achieved seizure outcomes of Engel I or II, whereas all 21 patients with Engel outcome III or IV were among the 43 patients with severe ASD (severity score of 3). This trend approached but did not reach significance (p = 0.080).

Functional and Behavioral Outcomes

Aberrant Behaviors Observed in the Clinical Setting

In a direct examination by a clinician, improvements in aberrant behaviors were noted in 24 of the 27 patients who, prior to surgery, presented with significant levels of aggression and other disruptive behaviors, including 20 cases of marked behavioral improvement in patients with severe ASD, and 7 cases of such improvement in patients who did not become seizure-free. Seventeen of the patients who experienced marked improvement had resective treatment (1 removal of a hypothalamic hamartoma, 3 temporal lobectomies, 4 frontal resections, and 9 multilobar operations [including 2 hemispherotomies]), and 7 had undergone corpus callosotomy. Two callosotomy patients who initially improved later experienced behavioral regression brought on by recurrence of seizures.

Long-Term Functional and Behavioral Outcomes

Progress was noted over time in the majority of patients who experienced seizure reduction following surgery (Table 3). According to caregivers' reports, a significant number of patients experienced gains in cognitive function (e.g., increased awareness, ability to pay attention and retain new information), which the parents partially attributed to a reduction in AED side effects. Many patients also made progress in the development of language and other communication skills (e.g., eye contact, using gestures to communicate, more appropriate response to caregivers' mood and facial expressions); social behavior (e.g., more engagement with caregivers, ability to play cooperatively with a sibling, initiative to hold hands with children at school); and ability to cope with changes in personal routines and/or fixations and the environment. Among other postoperative trends noted were improvements in overall well-being (e.g., sleep quality, digestive health, physical activity throughout the day) and reduction in concerns over patients' safety and in the amount of daily care required. Notably, the fewest negative changes were observed in socialization, expressive language, and nonverbal communication, areas particularly problematic in ASD.

The severity of all behavioral symptoms observed by caregivers on a daily basis improved in 25 of the 46 patients evaluated, whereas 21 reported no change or worsening of behavior (Table 3). Also, some parents who noted overall improvement reported negative symptoms as well (e.g., hyperactivity, inability to control provoked aggression, and other impulsive behaviors). There was no significant association with Engel outcome, with approximately half of the parents of patients with Engel I outcomes (9 of 16) reporting behavioral improvement, and half of the parents of patients with Engel outcomes II–IV reporting behavioral improvement (16 of 30), with variability in individual outcomes. In some cases, a moderate reduction in seizures was associated with marked improvements in behavior, obvious to all observers (e.g., Case 39). In other cases some behavioral symptoms persisted in patients who became seizure free and made excellent developmental progress (e.g., Case 11), as well as cases in which aberrant behaviors ceased after corpus callosotomy, but returned 1 year later following recurrence of seizures (e.g., Case 49).

Additionally, parents of 3 surgical patients with severe ASD reported no noticeable change in behavior or overall functional status resulting from seizure reduction (Case 5: Engel IIB, 45-month follow-up; Case 13: Engel IIIA, 102-month follow-up; Case 22: Engel IIIA, 35-month follow-up). The 2 worst functional-behavioral outcomes in our series, with no reported long-term improvement in any area compared with baseline—and worsening of some symptoms—were associated with Engel IV outcomes (Case 7, 102-month follow-up, and Case 37, 47-month follow-up).

Overall Satisfaction With Outcome

Forty-three of the 49 families with recent follow-up (88%) considered the outcome of surgical treatment positive, with improvements in quality of life and cognitive ability most frequently cited as the main benefits of improved seizure control (Table 4), although 1 family in this group also stated that they had hoped for a better outcome with regard to the child's physical development, and 2 families were disappointed that their children remained nonverbal. Parents of 3 children who experienced seizure reduction but did not become seizure free attributed better postsurgical seizure control to continued adjustments in medical therapy.

Surgery-Related Complications

Four of the 56 patients in our report experienced complications related to surgical treatment. Three of these were associated with subdural electrodes and 1 with a lesionectomy without invasive monitoring. The complications included 2 cases of hydrocephalus (1 required placement of a ventriculoperitoneal shunt, and 1 resolved after placement of an external ventricular drain), and 2 cases of infection necessitating treatment with intravenous antibiotics (purulence, or stain or culture positive for Staphylococcus aureus noted at the time of electrode removal). Other than 3 cases of expected peripheral visual field loss after occipital resections, no permanent surgery-related physical or neurological deficits were observed. There were no complications related to the callosotomy and VNS procedures. All surgical treatments were successfully performed according to clinical plan, including invasive monitoring, and the complications were deemed unrelated to the presence of autistic symptoms or behaviors. This success was credited partially to enhanced inpatient care protocols focused on minimizing stress to the child and expanding direct family involvement, including intensive involvement with child-life specialists and music therapists, anesthesia protocols involving family members and familiar companions, multidisciplinary family meetings, and familiarity with the epilepsy monitoring unit environment and staff (our unpublished data).

Discussion

Our results support the feasibility of epilepsy surgery in children with ASD, highlight the potential for improved seizure control and associated cognitive-behavioral gains, and attest to the safety of surgical intervention in this population.21,37,38 Contrary to the prevalent concern that epilepsy surgery in patients with ASD may have limited utility,10,11,14,40,45 we found that even for severely affected individuals, surgery often had tangible benefits, reducing the burden of seizures and aberrant behaviors on the families and facilities that provide lifelong care to these patients, many of whom require special medical attention and very substantial support due to the presence of developmental delay and other comorbidities.

Historical Perspective

Although autism was historically thought to be a general contraindication to epilepsy surgery, the initial case reports of surgical intervention related positive outcomes. Gillberg et al. reported on 2 boys with severe autism and epilepsy associated with TS pathology, both of whom became seizure free after resection of epileptogenic foci.20 One of these patients experienced a drastic behavioral improvement and ultimately loss of autism diagnosis. In another early report of 2 surgical cases involving the temporal lobe, long-term seizure freedom was achieved by both patients, and “autistic features demonstrated a clear response to surgical treatment.”33 Later reports, however, each including 2–5 patients with autism and intractable seizures, described mixed surgical results ranging from seizure freedom to seizure worsening, with no consistent effect on the severity of behavioral symptoms.8,9,17,29,31,32,45 Furthermore, McLellan et al. found that among 23 patients with autism who underwent temporal lobectomy, 10 became seizure free (with 2 cases of loss of autism diagnosis), but in their series children without psychiatric comorbidities or with psychiatric disorders other than autism had better overall seizure control postoperatively.30

Larger studies of surgical outcomes in patients with ASD are not found in the literature, with the exception of 2 nonconsecutive series of patients who underwent VNS placement, the majority of whom experienced seizure reduction in the 1st year after surgery, according to data voluntarily submitted to the manufacturer by the treating physicians.27,35 However, this trend was not confirmed in 8 consecutive independently reported patients with autism in whom implantation of a VNS had no appreciable benefit.10 With the exception of autistic patients with epileptogenic tubers,8,40,47 the outcomes of epilepsy surgery in children with intractable seizures and autistic symptoms are not well established in the literature.

Presurgical Counseling

In evaluating an autistic patient for epilepsy surgery, we used an approach similar to that taken with other pediatric patients with medically refractory seizures in the risk-benefit analysis, and multiple adjustments in pharmacotherapy were undertaken prior to considering surgery. Most of the patients in our series were severely autistic, some also had other chronic comorbidities, and the 7 patients in our group who underwent surgery when they were older than 17 years required a pediatric setting in which practitioners had expertise in managing patients with severe developmental delay and experience in performing presurgical evaluation and invasive monitoring in patients with a history of uncooperative behavior. However, unlike the parents of children with MRE and global developmental delay, who are typically focused on preventing the detrimental effect of uncontrolled seizures and high doses of AEDs on the developing brain, in our experience, the parents of children with the comorbidity of autism seek additional answers as to the relative implications of ASD and seizures for the child's development and functional-behavioral status, and the outcomes of epilepsy surgery in autistic patients.

The literature cites poor long-term outcomes in children with autism and uncontrolled seizures who did not undergo surgery,7,9,24 but offers little insight into factors predictive of surgical outcome in this diverse population. Because autism is presumed to arise from a combination of environmental and genetic factors, the unknown implications of these presumed risk factors on seizure outcomes were part of the presurgical discussion with families and caregivers, and genetic counseling was offered. Availability of genetic testing was often limited prior to surgery, either due to historical reasons or the high cost associated with comprehensive autism and epilepsy panels, which insurance providers did not consider justifiable, given the general lack of evidence linking specific genetic findings to surgical prognosis. All of our patients with either Engel III or Engel IV outcome had severe ASD, and although it is important to set realistic expectations and keep in mind that such cases may be challenging and that many of the severely affected patients have limited potential for full resolution of all developmental symptoms, surgery is always considered in patients with pharmacoresistant seizures who are potential surgical candidates at our epilepsy center, regardless of the presence of ASD.

Resections and Seizure Outcomes

As with the general population of pediatric patients with epilepsy who undergo surgery, the best seizure freedom rates in our series were observed in hemispherotomy cases,5,41 followed by focal and multifocal resections15,16,44 (Fig. 1), but in our experience, localizable but nonlesional epilepsy cases were the most challenging. Recent meta-analyses of outcomes of resections in pediatric epilepsy patients found long-term seizure freedom rates of 60%–81% associated with MRI abnormalities, and 49%–51% in patients with normal MRI findings.15,16 Thirteen of the 20 patients in our series with MRI abnormalities became seizure free after resection (10 of 14, or 71% of patients with > 24-month follow-up), compared with 2 of the 9 patients (1 of 7, or 14% of patients with > 24-month follow-up) with normal MRI findings who achieved an Engel I outcome.

Similar to the general population, for the patients in our series who experienced seizure recurrence after surgery, the cause of relapse was often presumed to be genetic, especially in cases in which the resected tissue appeared morphologically normal on pathological assessment, such as in the patient in Case 23, who was later revealed to have a PCDH19 mutation. Similarly, in 2 patients with abnormal MRI and concordant EEG findings (Case 40, focal temporal lobe epilepsy with MTS; and Case 19, vascular etiology), both of them experienced new-onset generalized seizures after > 2 years of seizure freedom. Genetic testing was repeated after surgery, and in the patient in Case 40 a novel mutation in the PRICKLE1 gene was diagnosed. Our results are also consistent with recent reports of poor outcomes of surgery in patients with SCN1A mutations.4,42 On the other hand, the patient in Case 10, with a family history of epilepsy associated with developmental delay (who could not be positively diagnosed using the genetic testing available at the time) became seizure free and made excellent developmental progress after a resection.

Although many of the patients in our series were able to reduce the number of medications following surgery, only 3 of the 22 patients who underwent resection with a > 2-year follow-up were able to discontinue all AEDs (Cases 10, 32, and 33). This was partially due to occurrence of breakthrough seizures, the presence of EEG abnormalities despite seizure freedom, and general parental reluctance to discontinue medications, leading to a conservative pace in weaning patients off AEDs.

One of the 3 patients who did not have a resection following invasive monitoring has not had a seizure in the 6 years since implantation of intracranial electrodes, and the other 2 patients have had a drastic improvement in their epilepsy. Similar cases of seizure remission after invasive monitoring have been previously reported in a minority of patients with both lesional and nonlesional etiology,26,38 and this may be at least in part due to mechanical modulation caused by surgical intervention, leading to the disruption of epileptogenic networks.

Outcomes of Palliative Procedures

Notably, more than half of patients in our series (32 of 56) had one or more palliative procedures. The relatively high number of callosotomies performed (26 in 56 patients) reflects a high incidence of generalized epilepsy and atonic seizures in our group. At our center, corpus callosotomy remains the recommended treatment for atonic seizures with or without a Lennox-Gastaut pattern. Our results support existing data showing that callosotomy can be performed safely with minimal risk of a new deficit.36 The procedure brought seizure relief to 21 of 26 patients; either directly, by ameliorating atonic and/or tonic seizures, and/or generalized seizures with apneic-cyanotic spells, or indirectly, by enabling lateralization and resective treatment.34 Our experience in some patients with nonlesional epilepsy that lateralized after callosotomy, but whose seizures recurred after resective procedures from another location, has prompted a shift toward the possible application of responsive neurostimulation (RNS) in similar future cases.

Five patients in our series had a VNS device implanted prior to callosotomy, and 3 of the patients who ultimately underwent resective procedures also initially opted for VNS implantation before considering other surgical modalities that were better indicated. Such decision making reflects a natural and inherent bias favoring a reversible extracranial procedure over an irreversible resective or disconnective intracranial operation, and in our experience is not unique to the autistic population. Currently, 5 of the 14 patients who underwent VNS placement are experiencing some relief from seizures due to VNS combined with pharmacotherapy, and are not seeking other treatment options.

Future Directions: Neuromodulation in Lieu of Ablation

Our patients who underwent resection had less favorable outcomes in cases in which apparent focal or region-alized epilepsy led to lobectomies and/or disconnections, compared with complete remission of seizures in the hemispherotomy group. Where MRI findings were nonlesional, only 2 of 9 patients achieved an Engel I outcome, compared with 2 patients with Engel II and 5 with Engel III seizure control. In the 5 cases in our series in which complete callosotomy was associated with the opportunity for a more focal or lateralized attempt at seizure control via staged resection and/or disconnection, our results were not curative, with Engel II and III outcomes. These findings have resulted in a change in approach that we have taken toward patients with autism and nonlesional focal or regional epilepsy, who are not candidates for hemispherotomy. We are concerned about more global hemispheric or even bihemispheric epileptogenic potential in these patients, that with time can result in early and late failures. Thus, we have begun to recommend a modulatory rather than ablative approach in similar patients, with preliminarily beneficial results (our unpublished data). Until a better understanding of the mechanisms of seizure propagation has been established through genetic and epileptic network analyses, the RNS procedure using strip electrodes in the region of putative seizure onsets, combined with anterior thalamic nucleus electrodes, has been proposed as a palliative measure. Given the ability to perform long-term electrocorticographic analyses with an RNS device, we feel that we will have better diagnostic and potentially therapeutic advantages to guide long-term management.

Outcomes of Surgery With Regard to Symptoms Associated With ASD

Rare cases of the loss of autism diagnosis have been previously described in some autistic patients undergoing surgery for intractable seizures.20,30 While not observed in our series, improvements in aberrant behaviors such as violence and defiant behavior were among the benefits of surgery, suggesting that at least some of the behavioral issues prior to surgery were related to poorly controlled seizures. Although many of the gains reported here may be intangible when measured by standard methods, the trend toward overall cognitive-behavioral improvement observed in this series is in stark contrast to the cognitive decline and overall poor outcomes reported in children with ASD and refractory seizures.7,9,18,23,24 According to caregivers' reports, the reduction in aberrant behaviors was particularly beneficial to family life, where unprovoked aggression and other disruptive behaviors can be more of a concern than the social delay, restricted interests, or repetitive behaviors of autism.28

Study Limitations

Our study is hampered by a number of limitations. The behavioral changes reported here were assessed using both neuropsychological records and nonstandard methods. We chose this “direct caregiver perspective” to assess behavioral outcome as a meaningful and sensitive measure of the patients' functional status, since the changes were noted by those providing daily care and support to the patients, and we did not believe that a more globally applicable grading scale was available in the population we were studying, without prospective planning. The study is limited by retrospective design, and no control group is available for comparison of outcomes because clinically indicated surgical treatments were provided to all patients. Although uncontrolled seizures in autism correlate with poor long-term outcomes, spontaneous remission of epilepsy has also been reported,9 and the possibility cannot be definitively excluded. Our numbers do not allow for statistical analysis within each clinical category, but instead build on data from other studies with similar designs4,30,32,40,42,45,46 to provide a more complete picture of the range of underlying pathologies and outcomes of epilepsy surgery in this genetically and etiologically diverse population who all share the diagnoses of epilepsy and ASD.

The association between autism and epilepsy continues to be the subject of intense scientific inquiry, with a rapidly evolving understanding at genetic, synaptic, and molecular levels. Surgical and behavioral failures in our population highlight the limited understanding of this association and the imperfect ability to identify the optimal surgical candidate. However, we know that favorable surgical outcomes are possible in autistic patients, and the autistic population cannot be excluded when medical intractability dictates the need for intervention in epilepsy that is believed to be surgically remediable.

Conclusions

Patients with autism and pharmacoresistant epilepsy can achieve worthwhile seizure reduction and should not be denied surgery. However, much remains unknown about the etiology of autism, so genetic counseling should be provided regardless of MRI findings, conservative adjustments in pharmacotherapy are recommended, and novel surgical methods for the understanding of epileptogenic networks and their modulation such as RNS should be considered. Continued review of epilepsy surgery outcomes in autism is needed as new genetic and other risk factors emerge and may affect prognosis.

Acknowledgments

We thank Dr. Robert R. Goodman for his input during early stages of the study. The support for this study was provided entirely by the Department of Neurosurgery, Mount Sinai Health System, New York, NY.

References

  • 1

    American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV ed 4Washington, DCAmerican Psychiatric Association1994

  • 2

    American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-5 ed 5Washington, DCAmerican Psychiatric Association2013

  • 3

    Austin JKCaplan R: Behavioral and psychiatric comorbidities in pediatric epilepsy: toward an integrative model. Epilepsia 48:163916512007

  • 4

    Barba CParrini ECoras RGaluppi ACraiu DKluger G: Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia 55:100910192014

  • 5

    Basheer SNConnolly MBLautzenhiser ASherman EMHendson GSteinbok P: Hemispheric surgery in children with refractory epilepsy: seizure outcome, complications, and adaptive function. Epilepsia 48:1331402007

  • 6

    Berg ATLangfitt JShinnar SVickrey BGSperling MRWalczak T: How long does it take for partial epilepsy to become intractable?. Neurology 60:1861902003

  • 7

    Bjørnaes HStabell KHenriksen OLøyning Y: The effects of refractory epilepsy on intellectual functioning in children and adults. A longitudinal study. Seizure 10:2502592001

  • 8

    Connolly MBHendson GSteinbok P: Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects. Childs Nerv Syst 22:8969082006

  • 9

    Danielsson SGillberg ICBillstedt EGillberg COlsson I: Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia 46:9189232005

  • 10

    Danielsson SViggedal GGillberg COlsson I: Lack of effects of vagus nerve stimulation on drug-resistant epilepsy in eight pediatric patients with autism spectrum disorders: a prospective 2-year follow-up study. Epilepsy Behav 12:2983042008

  • 11

    Danielsson SViggedal GSteffenburg SRydenhag BGillberg COlsson I: Psychopathology, psychosocial functioning, and IQ before and after epilepsy surgery in children with drug-resistant epilepsy. Epilepsy Behav 14:3303372009

  • 12

    Engel J Jr: Surgical Treatment of the Epilepsies ed 2New YorkRaven Press1993

  • 13

    Engel J Jr: Why is there still doubt to cut it out?. Epilepsy Curr 13:1982042013

  • 14

    Engelhart MCvan Schooneveld MMJennekens-Schinkel Avan Nieuwenhuizen O: ‘With the benefit of hindsight’: would you opt again for epilepsy surgery performed in childhood?. Eur J Paediatr Neurol 17:4624702013

  • 15

    Englot DJBreshears JDSun PPChang EFAuguste KI: Seizure outcomes after resective surgery for extra-temporal lobe epilepsy in pediatric patients. J Neurosurg Pediatr 12:1261332013

  • 16

    Englot DJRolston JDWang DDSun PPChang EFAuguste KI: Seizure outcomes after temporal lobectomy in pediatric patients. J Neurosurg Pediatr 12:1341412013

  • 17

    Fohlen MBulteau CJalin CJambaque IDelalande O: Behavioural epileptic seizures: a clinical and intracranial EEG study in 8 children with frontal lobe epilepsy. Neuropediatrics 35:3363452004

  • 18

    Gabis LPomeroy JAndriola MR: Autism and epilepsy: cause, consequence, comorbidity, or coincidence?. Epilepsy Behav 7:6526562005

  • 19

    Ghatan SMcGoldrick PPalmese CLa Vega-Talbott MKang HKokoszka MA: Surgical management of medically refractory epilepsy due to early childhood stroke. J Neurosurg Pediatr 14:58672014

  • 20

    Gillberg CUvebrant PCarlsson GHedstrom ASilfvenius H: Autism and epilepsy (and tuberous sclerosis?) in two pre-adolescent boys: neuropsychiatric aspects before and after epilepsy surgery. J Intellect Disabil Res 40:75811996

  • 21

    Hader WJTellez-Zenteno JMetcalfe AHernandez-Ronquillo LWiebe SKwon CS: Complications of epilepsy surgery: a systematic review of focal surgical resections and invasive EEG monitoring. Epilepsia 54:8408472013

  • 22

    Haneef ZStern JDewar SEngel J Jr: Referral pattern for epilepsy surgery after evidence-based recommendations: a retrospective study. Neurology 75:6997042010

  • 23

    Hartley SLBarker ETSeltzer MMFloyd FGreenberg JOrsmond G: The relative risk and timing of divorce in families of children with an autism spectrum disorder. J Fam Psychol 24:4494572010

  • 24

    Hrdlicka MKomarek VPropper LKulisek RZumrova AFaladova L: Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry 13:2092132004

  • 25

    Jeste SSTuchman R: Autism spectrum disorder and epilepsy: two sides of the same coin?. J Child Neurol 30:196319712015

  • 26

    Katariwala NMBakay RAPennell PBOlson LDHenry TREpstein CM: Remission of intractable partial epilepsy following implantation of intracranial electrodes. Neurology 57:150515072001

  • 27

    Levy MLLevy KMHoff DAmar APPark MSConklin JM: Vagus nerve stimulation therapy in patients with autism spectrum disorder and intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry. J Neurosurg Pediatr 5:5956022010

  • 28

    Lord CRutter MDiLavore PCRisi S: Autism Diagnostic Observation Schedule (ADOS) Manual. Torrance, CAWestern Psychological Services2000

  • 29

    Major PThiele EA: Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex. Epilepsy Behav 13:3573602008

  • 30

    McLellan ADavies SHeyman IHarding BHarkness WTaylor D: Psychopathology in children with epilepsy before and after temporal lobe resection. Dev Med Child Neurol 47:6666722005

  • 31

    Murphy JVWheless JWSchmoll CM: Left vagal nerve stimulation in six patients with hypothalamic hamartomas. Pediatr Neurol 23:1671682000

  • 32

    Nass RGross AWisoff JDevinsky O: Outcome of multiple subpial transections for autistic epileptiform regression. Pediatr Neurol 21:4644701999

  • 33

    Neville BGHarkness WFCross JHCass HCBurch VCLees JA: Surgical treatment of severe autistic regression in childhood epilepsy. Pediatr Neurol 16:1371401997

  • 34

    Ono TBaba HToda KOno K: Callosotomy and subsequent surgery for children with refractory epilepsy. Epilepsy Res 93:1851912011

  • 35

    Park YD: The effects of vagus nerve stimulation therapy on patients with intractable seizures and either Landau-Kleffner syndrome or autism. Epilepsy Behav 4:2862902003

  • 36

    Passamonti CZamponi NFoschi NTrignani RLuzi MCesaroni E: Long-term seizure and behavioral outcomes after corpus callosotomy. Epilepsy Behav 41:23292014

  • 37

    Roth JCarlson CDevinsky OHarter DHMacallister WSWeiner HL: Safety of staged epilepsy surgery in children. Neurosurgery 74:1541622014

  • 38

    Roth JOlasunkanmi AMa TSCarlson CDevinsky OHarter DH: Epilepsy control following intracranial monitoring without resection in young children. Epilepsia 53:3343412012

  • 39

    Sánchez Fernández IAn SLoddenkemper T: Pediatric refractory epilepsy: A decision analysis comparing medical versus surgical treatment. Epilepsia 56:2632722015

  • 40

    Sansa GCarlson CDoyle WWeiner HLBluvstein JBarr W: Medically refractory epilepsy in autism. Epilepsia 52:107110752011

  • 41

    Schramm JKuczaty SSassen RElger CEvon Lehe M: Pediatric functional hemispherectomy: outcome in 92 patients. Acta Neurochir (Wien) 154:201720282012

  • 42

    Skjei KLChurch EWHarding BNSanti MHolland-Bouley KDClancy RR: Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy. J Neurosurg Pediatr 16:6686742015

  • 43

    Sparrow SSCicchetti DVBalla DA: Vineland Adaptive Behavior Scales ed 2.Circle Pines, MNAGS Publishing2005

  • 44

    Spencer SHuh L: Outcomes of epilepsy surgery in adults and children. Lancet Neurol 7:5255372008

  • 45

    Szabó CAWyllie EDolske MStanford LDKotagal PComair YG: Epilepsy surgery in children with pervasive developmental disorder. Pediatr Neurol 20:3493531999

  • 46

    Wang DDBlümcke ICoras RZhou WJLu DHGui QP: Sturge-Weber syndrome is associated with cortical dysplasia ILAE Type IIIc and excessive hypertrophic pyramidal neurons in brain resections for intractable epilepsy. Brain Pathol 25:2482552015

  • 47

    Weiner HLFerraris NLaJoie JMiles DDevinsky O: Epilepsy surgery for children with tuberous sclerosis complex. J Child Neurol 19:6876892004

Disclosures

Dr. Wolf is on the Speaker's Bureau for Eisai, Novartis, Lund-beck, Supernus, and UCB. Ms. McGoldrick is on the Speaker's Bureau for Lundbeck and Supernus.

Author Contributions

Conception and design: Ghatan, Kokoszka, Palmese. Acquisition of data: Ghatan, Kokoszka, McGoldrick, La Vega-Talbott, Raynes, Palmese, Wolf. Analysis and interpretation of data: Ghatan, Kokoszka, Harden. Drafting the article: Ghatan, Kokoszka, Harden. Critically revising the article: Ghatan, McGoldrick, La Vega-Talbott, Raynes, Palmese, Wolf, Harden. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ghatan. Statistical analysis: Kokoszka, Harden. Administrative/technical/material support: Ghatan. Study supervision: Ghatan.

Supplemental Information

Previous Presentations

Portions of this manuscript were presented in poster form at the 66th Annual Meeting of the American Epilepsy Society (AES), held in San Diego, California, in 2012; and at the 69th AES Meeting held in Philadelphia, Pennsylvania, in 2015.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

INCLUDE WHEN CITING Published online November 25, 2016; DOI: 10.3171/2016.7.PEDS1651.

Correspondence Saadi Ghatan, Department of Neurosurgery, Mount Sinai West, 1000 Tenth Ave., Ste. 5G-80, New York, NY 10019. email: sghatan@chpnet.org.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Bar graph showing seizure outcomes of epilepsy surgery in patients with ASD. Palliative procedures performed prior to definitive resective treatments are not shown. In the only case in which a palliative procedure was performed subsequent to resection, outcomes of both surgeries are shown (VNS and temporal lobectomy). The mean follow up was 47 ± 30 months (range 2–117 months); see text and Table 2 for individual follow-up times. CC = corpus callosotomy.

References

1

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV ed 4Washington, DCAmerican Psychiatric Association1994

2

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-5 ed 5Washington, DCAmerican Psychiatric Association2013

3

Austin JKCaplan R: Behavioral and psychiatric comorbidities in pediatric epilepsy: toward an integrative model. Epilepsia 48:163916512007

4

Barba CParrini ECoras RGaluppi ACraiu DKluger G: Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia 55:100910192014

5

Basheer SNConnolly MBLautzenhiser ASherman EMHendson GSteinbok P: Hemispheric surgery in children with refractory epilepsy: seizure outcome, complications, and adaptive function. Epilepsia 48:1331402007

6

Berg ATLangfitt JShinnar SVickrey BGSperling MRWalczak T: How long does it take for partial epilepsy to become intractable?. Neurology 60:1861902003

7

Bjørnaes HStabell KHenriksen OLøyning Y: The effects of refractory epilepsy on intellectual functioning in children and adults. A longitudinal study. Seizure 10:2502592001

8

Connolly MBHendson GSteinbok P: Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects. Childs Nerv Syst 22:8969082006

9

Danielsson SGillberg ICBillstedt EGillberg COlsson I: Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia 46:9189232005

10

Danielsson SViggedal GGillberg COlsson I: Lack of effects of vagus nerve stimulation on drug-resistant epilepsy in eight pediatric patients with autism spectrum disorders: a prospective 2-year follow-up study. Epilepsy Behav 12:2983042008

11

Danielsson SViggedal GSteffenburg SRydenhag BGillberg COlsson I: Psychopathology, psychosocial functioning, and IQ before and after epilepsy surgery in children with drug-resistant epilepsy. Epilepsy Behav 14:3303372009

12

Engel J Jr: Surgical Treatment of the Epilepsies ed 2New YorkRaven Press1993

13

Engel J Jr: Why is there still doubt to cut it out?. Epilepsy Curr 13:1982042013

14

Engelhart MCvan Schooneveld MMJennekens-Schinkel Avan Nieuwenhuizen O: ‘With the benefit of hindsight’: would you opt again for epilepsy surgery performed in childhood?. Eur J Paediatr Neurol 17:4624702013

15

Englot DJBreshears JDSun PPChang EFAuguste KI: Seizure outcomes after resective surgery for extra-temporal lobe epilepsy in pediatric patients. J Neurosurg Pediatr 12:1261332013

16

Englot DJRolston JDWang DDSun PPChang EFAuguste KI: Seizure outcomes after temporal lobectomy in pediatric patients. J Neurosurg Pediatr 12:1341412013

17

Fohlen MBulteau CJalin CJambaque IDelalande O: Behavioural epileptic seizures: a clinical and intracranial EEG study in 8 children with frontal lobe epilepsy. Neuropediatrics 35:3363452004

18

Gabis LPomeroy JAndriola MR: Autism and epilepsy: cause, consequence, comorbidity, or coincidence?. Epilepsy Behav 7:6526562005

19

Ghatan SMcGoldrick PPalmese CLa Vega-Talbott MKang HKokoszka MA: Surgical management of medically refractory epilepsy due to early childhood stroke. J Neurosurg Pediatr 14:58672014

20

Gillberg CUvebrant PCarlsson GHedstrom ASilfvenius H: Autism and epilepsy (and tuberous sclerosis?) in two pre-adolescent boys: neuropsychiatric aspects before and after epilepsy surgery. J Intellect Disabil Res 40:75811996

21

Hader WJTellez-Zenteno JMetcalfe AHernandez-Ronquillo LWiebe SKwon CS: Complications of epilepsy surgery: a systematic review of focal surgical resections and invasive EEG monitoring. Epilepsia 54:8408472013

22

Haneef ZStern JDewar SEngel J Jr: Referral pattern for epilepsy surgery after evidence-based recommendations: a retrospective study. Neurology 75:6997042010

23

Hartley SLBarker ETSeltzer MMFloyd FGreenberg JOrsmond G: The relative risk and timing of divorce in families of children with an autism spectrum disorder. J Fam Psychol 24:4494572010

24

Hrdlicka MKomarek VPropper LKulisek RZumrova AFaladova L: Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry 13:2092132004

25

Jeste SSTuchman R: Autism spectrum disorder and epilepsy: two sides of the same coin?. J Child Neurol 30:196319712015

26

Katariwala NMBakay RAPennell PBOlson LDHenry TREpstein CM: Remission of intractable partial epilepsy following implantation of intracranial electrodes. Neurology 57:150515072001

27

Levy MLLevy KMHoff DAmar APPark MSConklin JM: Vagus nerve stimulation therapy in patients with autism spectrum disorder and intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry. J Neurosurg Pediatr 5:5956022010

28

Lord CRutter MDiLavore PCRisi S: Autism Diagnostic Observation Schedule (ADOS) Manual. Torrance, CAWestern Psychological Services2000

29

Major PThiele EA: Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex. Epilepsy Behav 13:3573602008

30

McLellan ADavies SHeyman IHarding BHarkness WTaylor D: Psychopathology in children with epilepsy before and after temporal lobe resection. Dev Med Child Neurol 47:6666722005

31

Murphy JVWheless JWSchmoll CM: Left vagal nerve stimulation in six patients with hypothalamic hamartomas. Pediatr Neurol 23:1671682000

32

Nass RGross AWisoff JDevinsky O: Outcome of multiple subpial transections for autistic epileptiform regression. Pediatr Neurol 21:4644701999

33

Neville BGHarkness WFCross JHCass HCBurch VCLees JA: Surgical treatment of severe autistic regression in childhood epilepsy. Pediatr Neurol 16:1371401997

34

Ono TBaba HToda KOno K: Callosotomy and subsequent surgery for children with refractory epilepsy. Epilepsy Res 93:1851912011

35

Park YD: The effects of vagus nerve stimulation therapy on patients with intractable seizures and either Landau-Kleffner syndrome or autism. Epilepsy Behav 4:2862902003

36

Passamonti CZamponi NFoschi NTrignani RLuzi MCesaroni E: Long-term seizure and behavioral outcomes after corpus callosotomy. Epilepsy Behav 41:23292014

37

Roth JCarlson CDevinsky OHarter DHMacallister WSWeiner HL: Safety of staged epilepsy surgery in children. Neurosurgery 74:1541622014

38

Roth JOlasunkanmi AMa TSCarlson CDevinsky OHarter DH: Epilepsy control following intracranial monitoring without resection in young children. Epilepsia 53:3343412012

39

Sánchez Fernández IAn SLoddenkemper T: Pediatric refractory epilepsy: A decision analysis comparing medical versus surgical treatment. Epilepsia 56:2632722015

40

Sansa GCarlson CDoyle WWeiner HLBluvstein JBarr W: Medically refractory epilepsy in autism. Epilepsia 52:107110752011

41

Schramm JKuczaty SSassen RElger CEvon Lehe M: Pediatric functional hemispherectomy: outcome in 92 patients. Acta Neurochir (Wien) 154:201720282012

42

Skjei KLChurch EWHarding BNSanti MHolland-Bouley KDClancy RR: Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy. J Neurosurg Pediatr 16:6686742015

43

Sparrow SSCicchetti DVBalla DA: Vineland Adaptive Behavior Scales ed 2.Circle Pines, MNAGS Publishing2005

44

Spencer SHuh L: Outcomes of epilepsy surgery in adults and children. Lancet Neurol 7:5255372008

45

Szabó CAWyllie EDolske MStanford LDKotagal PComair YG: Epilepsy surgery in children with pervasive developmental disorder. Pediatr Neurol 20:3493531999

46

Wang DDBlümcke ICoras RZhou WJLu DHGui QP: Sturge-Weber syndrome is associated with cortical dysplasia ILAE Type IIIc and excessive hypertrophic pyramidal neurons in brain resections for intractable epilepsy. Brain Pathol 25:2482552015

47

Weiner HLFerraris NLaJoie JMiles DDevinsky O: Epilepsy surgery for children with tuberous sclerosis complex. J Child Neurol 19:6876892004

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