The Epilepsy Surgery Experience in Children With Infantile Epileptic Spasms Syndrome at a Tertiary Care Center in Canada

Abstract

Background: Infantile epileptic spasms syndrome is an epileptic encephalopathy, characterized by spasms, hypsarrhythmia, and developmental regression. Appropriately selected patients with infantile epileptic spasms syndrome may be candidates for epilepsy surgery. Methods: This is a single-center retrospective case series of children 0-18 years with a current or previous diagnosis of infantile epileptic spasms syndrome with a lesion on magnetic resonance imaging (MRI) and/or positron emission tomography scan who underwent epilepsy surgery at The Hospital for Sick Children (HSC) in Toronto, Canada. The records of 223 patients seen in the infantile epileptic spasms syndrome clinic were reviewed. Results: Nineteen patients met inclusion criteria. The etiology of infantile epileptic spasms syndrome was encephalomalacia in 6 patients (32%), malformations of cortical development in 12 patients (63%), and atypical hypoglycemic injury in 1 patient (5%). Nine patients (47%) underwent hemispherectomy, and 10 patients (53%) underwent lobectomy/lesionectomy. Three patients (16%) underwent a second epilepsy surgery. Fifteen patients (79%) were considered ILAE seizure outcome class 1 (completely seizure free; no auras) at their most recent follow-up visit. The percentage of patients who were ILAE class 1 at most recent follow-up decreased with increasing duration of epilepsy prior to surgery. Developmental outcome after surgery was improved in 14 of 19 (74%) and stable in 5 of 19 (26%) patients. Conclusions: Our study found excellent seizure freedom rates and improved developmental outcomes following epilepsy surgery in patients with a history of infantile epileptic spasms syndrome with a structural lesion detected on MRI brain. Patients who undergo surgery earlier have improved seizure freedom rates and improved developmental outcomes.

Keywords

epilepsy infantile spasms neurosurgery seizures West syndrome

Infantile epileptic spasms syndrome (IESS) is a rare catastrophic epileptic encephalopathy with an estimated incidence of 3 per 10 000 live births.¹ It is characterized by epileptic spasms, hypsarrhythmia on electroencephalogram (EEG), often with developmental regression or stagnation. Comprehensive diagnostic evaluation including magnetic resonance imaging (MRI), genetic, and metabolic testing can provide an underlying etiology in 60% to 70% of infants with infantile epileptic spasms syndrome.² The current first-line treatment options for infantile epileptic spasms syndrome are hormonal therapy (adrenocorticotrophic hormone [ACTH] or prednisolone) and vigabatrin.³ Treatment efficacy is defined by complete cessation of the spasms and resolution of the hypsarrhythmia on EEG. Thirty to ninety percent of infants with infantile epileptic spasms syndrome will respond to treatment with ACTH or prednisolone, whereas 38% to 42% of infants will respond to vigabatrin, and only 9% of infants treated with conventional antiseizure medications will respond.^4-7 Despite treatment, neurodevelopmental outcomes remain poor. Epilepsy is sustained in 90% of cases, and drug-resistant seizures persist in 14% of cases.⁵ Development is abnormal in 45% to 80% of cases, and the prevalence of autism spectrum disorder ranges from 10% to 35%.⁸

For infants who are refractory to first-line therapies, the ketogenic diet and epilepsy surgery should be considered.⁹ Epilepsy surgery should be considered in children with infantile epileptic spasms syndrome with any of the following: focal seizures before, during, or after infantile epileptic spasms syndrome, a focal lesion on brain imaging, focal EEG features, focal ictal/interictal metabolism changes on positron emission tomography (PET) scan, EMG laterality, or focal neurologic signs. Studies of epilepsy surgery in patients with infantile epileptic spasms syndrome have reported seizure freedom rates of 60% to 80%.^10-14 Previous studies have concluded that the strongest predictors of long-term postoperative developmental outcomes were early epilepsy surgery, preoperative developmental status, and etiology of infantile epileptic spasms syndrome.^14,15 Epilepsy surgery should be considered as early as technically feasible; however, surgery prior to 6 months of age poses unique risks, including high-volume intraoperative blood loss, coagulopathy, permanent postoperative neurologic deficits, and recurrence of seizures requiring repeat surgery.^16,17 Advances in neurosurgical techniques, anaesthesia, critical care, and neuroradiology have made early surgery possible and young age may no longer be a limiting factor; however, the most appropriate time for surgery remains controversial.^17,18

This is a retrospective case series of children with infantile epileptic spasms syndrome who have undergone epilepsy surgery at the Hospital for Sick Children in Toronto, Canada. The primary objective of this study was to review our experience with epilepsy surgery in patients with infantile epileptic spasms syndrome and to evaluate the long-term outcomes based on seizure freedom and development.

Materials and Methods

This was a single-center retrospective study completed at the Hospital for Sick Children, Toronto, Ontario Canada. The Hospital for Sick Children has a dedicated infantile epileptic spasms syndrome clinic, where all infants with a diagnosis of infantile epileptic spasms syndrome are followed over time. All infants who were seen in the infantile epileptic spasms syndrome clinic between 2010 and 2018 were screened for inclusion in the study. The inclusion criteria for the study were as follows: (1) age of children 0-18 years, (2) confirmed current or previous diagnosis of infantile epileptic spasms syndrome (defined by clinical spasms, and evidence of EEG abnormalities consistent with infantile epileptic spasms syndrome including hypsarrhythmia or modified hypsarrhythmia),¹⁹ (3) confirmed lesion on MRI and or PET scan, and (4) having undergone epilepsy surgery. The exclusion criteria were as follows: (1) cases that underwent palliative disconnective surgery (ie, corpus callosotomy); (2) cases with vagal nerve stimulator insertion; and (3) cases that were not considered amenable to surgery because of nonlesional imaging; bilateral lesions on MRI, PET, or magnetoencephalogram (MEG); or bilateral ictal EEG onset.

Patients diagnosed with infantile epileptic spasms syndrome at the Hospital for Sick Children were treated with vigabatrin first-line. If the patient demonstrated clinical cessation of spasms and electrographic disappearance of hypsarrhythmia at a 2-week follow-up point, they were maintained on vigabatrin for 6 months, followed by a 1- to 2-month wean. If patients did not respond to initial vigabatrin monotherapy, hormonal therapy (prednisolone or ACTH) was added either as monotherapy (for patients with no response to vigabatrin) or as combination vigabatrin and hormonal therapy (for patients with a partial response to vigabatrin therapy). ACTH was initially used as first-line hormonal therapy before 2017, after which time it was no longer available in Ontario, Canada. All children underwent presurgical evaluation, including history and physical examination, scalp video EEG, high-resolution 3-tesla (T) MRI brain, and neurodevelopmental assessment. Selected patients underwent PET and/or MEG scans. None of the patients in our study underwent invasive EEG monitoring. All EEGs were read by board-certified neurophysiologists, and MRIs were read by a dedicated neuroradiologist with an expertise in epilepsy. Patients were discussed in a multidisciplinary epilepsy surgery conference to determine surgical candidacy. Resective surgery was performed based on the identified epileptogenic zones. All surgical specimens were sent for surgical pathology testing. Outcome was reported based on the International League Against Epilepsy (ILAE) Seizure Outcome Classification²⁰ based on retrospective review of the clinical notes from the patient's most recent follow-up visit. Development was assessed by one author (JG) based on formal age-appropriate neuropsychological assessments performed as part of the workup for epilepsy surgery by a clinical neuropsychologist when available and by retrospective review of clinical notes. Development prior to surgery was recorded as normal, gross motor delay, fine motor delay, language delay, social/cognitive delay, or global developmental delay (defined as significant delay in at least 2 developmental domains).²¹ Development postsurgery was recorded and was assessed by one author (JG) to be worsened (showing regression, loss of skills, or stagnation), stable (progressing at expected trajectory based on prior deficits), or improved (progressing and some gaining age-appropriate developmental milestones).

Data were collected from the electronic medical records of patients. EEG, MRI, PET, and MEG reports were reviewed. Data were collated using the REDCAP database housed at the Hospital for Sick Children. Descriptive statistics were used to describe the clinical profiles of the study subjects.

Results

Patient Demographics

Nineteen patients met inclusion criteria. Thirteen patients were male (68%) and 6 patients were female (32%). The current age of patients at the time of data collection ranged from 35 to 175 months, with a median age of 82 months. The etiology of infantile epileptic spasms syndrome was congenital brain malformations in 12 patients (63%), encephalomalacia secondary to remote ischemic or hemorrhagic stroke in 6 patients (32%), and atypical hypoglycemic injury in 1 patient (5%). Six patients (32%) had epilepsy prior to the diagnosis of infantile epileptic spasms syndrome. No patients with encephalomalacia had epilepsy prior to the diagnosis of infantile epileptic spasms syndrome. The demographic and clinical characteristics of the patients are in Table 1.

Table 1.

Demographic and Clinical Characteristics of Patients With IS Who Underwent Epilepsy Surgery at the Hospital for Sick Children.

Patient	Current age (mo)	Time since surgery at last follow-up (mo)	Etiology of IS/comorbidities	Seizures prior to the diagnosis of IS (Y/N)	Age at onset of IS (mo)	Lead time between onset of spasms and initiation of treatment (mo)	Presurgical EEG findings	PET/MEG	Age at time of surgery (mo)	Duration of epilepsy before surgery (mo)	Type of surgery	Number of ASMs that were used prior to surgery	Number of ASMs at last follow-up visit	Developmental status after surgery	Seizure outcome (ILAE classification)
1	54	61	Encephalomalacia—rt MCA infarct	N	8	0	Hyps; rt F, rt T, rt P, rt O, rt hemispheric, lt F, lt hemispheric, and multifocal discharges	No	20	12	Rt functional hemispherectomy Complication: pseudomeningocele, infection	3	3	Improved—GDD	1
2	35	22	Other—rt P/O hypoglycemic brain injury	Y	4	0	Modified hyps; rt T, rt P, rt O, and lt O discharges	PET	13	13	Rt functional hemispherectomy	5	2	Improved—GDD	1
3	65	72	CBM—rt P/O FCD	Y	1	0	Rt hemihyps; rt T, rt P, rt O, and lt T discharges	PET	17	17	Rt T/P lesionectomy; being worked up for second surgery	3	3	Improved—ASD	4
4	77	53	CBM—lt F PMG, filaminopathy on pathology of second surgical resection	Y	5	0	Lt hemihyps; lt hemispheric discharges	PET	5; 24	20	Lt F lobectomy, followed by lt hemispherectomy	4	3	Improved—GDD	1
5	58	114	CBM—rt T/O FCD; genetic testing on surgical specimen revealed a likely pathogenic variant in COL4A2	N	11	0	Modified hyps; lt P, lt O	PET and MEG	31	20	Rt T /O lobectomy	2	3	Improved—GDD	1
6	175	122	CBM—rt T/P/O FCD; VUS in LEMCT3 and VUS in RTTN	N	3	0	Rt hemihyps; rt hemispheric discharges	PET and MEG	61	58	Rt T/O lobectomy, extensive cortical resection involving the rt P and F lobes with preservation of the motor and sensory cortices	4	4	Improved—GDD	5
7	70	69	Encephalomalacia—rt MCA infarct	N	4	0	Rt hemihyps; rt hemispheric discharges	No	9	5	Rt functional hemispherectomy Complication: rt PCA stroke, requiring O lobectomy and EVD insertion	5	5	Improved—GM delay	1
8	139	66	CBM—lt O FCD	N	6	0	Modified hyps; lt O discharges	PET and MEG	17	11	Lt O lobectomy Complication: bleeding and venous thrombosis	3	0	Stable—dyslexia; homonymous hemianopia	1
9	78	100	Encephalomalacia—lt MCA infarct	N	6	0	Lt hemihyps; lt hemispheric discharges	No	9	3	Lt functional hemispherectomy	3	3	Improved—GDD	1
10	83	12	CBM—lt T FCD; epidermal nevus syndrome; VUS in CLN1	N	2	4	Hyps; lt T, lt P, lt O	No	17; 71	69	Lobectomy, followed by corpus callosotomy	2	2	Stable—GDD	4
11	83	62	CBM—rt T FCD; pathogenic variant in DEPDC5	N	5	9	Modified hyps; rt F, rt T, lt F, and lt T discharges	PET	21	16	Rt T lobectomy with amygdalectomy with hippocampal sparing; being worked up for second surgery	1	2	Stable—GDD	4
12	118	83	Encephalomalacia—lt MCA infarct; transposition of the great arteries	N	8	0	Lt hemihyps; lt hemispheric discharges	No	18	10	Lt functional hemispherectomy	3	3	Improved—GDD; ADHD	1
13	104	37	Encephalomalacia—lt T haemorrhage	N	6	0	Hyps; lt T	MEG	21	15	Lt anterior T lobectomy and amygdalohippocampectomy	2	2	Improved—language delay	1
14	123	111	CBM—lt F FCD; epidermal nevus syndrome	Y	2	0	Hyps; lt F, lt C, lt hemispheric	MEG	55	54	Lt functional hemispherectomy	3	1	Stable—GDD	1
15	113	101	CBM—lt O FCD	Y	1	0	Modified hyps; lt hemispheric	No	2; 12	11	Total hemispherectomy, followed by revision; complication: CSVT	2	1	Improved—GDD	1
16	82	59	CBM—lt T FCD; VUS in POLG, VUS in CLN6, and VUS in TBC1D24	N	13	0	Lt hemihyps; lt T, lt central, and lt hemispheric discharges	PET	30	16	Lt T lobectomy	2	1	Improved—normal development	1
17	107	62	CBM—rt F FCD	N	5	1	Hyps; rt F	PET and MEG	48	43	Rt F, T, and partial P lobectomy	4	1	Stable—ADHD, mild ID	1
18	55	56	Encephalomalacia—lt MCA infarct	N	7	1	Lt hemihyps; lt T and lt hemispheric discharges	No	18	11	Lt functional hemispherectomy	2	2	Improved—GDD	1
19	76	71	CBM—Rt O partial hemimegalencephaly	Y	5	0	Modified hyps; rt T, lt T, rt C, rt P, lt P, rt O, lt O	No	5	3	Rt hemispherectomy	3	0	Improved—GM delay	1
Median (range)	82 (35-175)	66 (12-122)			5 (1-13)	0 (0-9)			18 (2-61); 24 (12-71)	15 (3-69)		3 (1-5)	2 (0-5)		1 (1-5)

Abbreviations: ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; ASMs, antiseizure medications; C, central; CBM, congenital brain malformation; CSVT, cerebral sinus venous thrombosis; F, frontal; FCD, focal cortical dysplasia; GDD, global developmental delay; GM, gross motor; hemihyps, hemihypsarrhythmia; hyps, hypsarrhythmia; lt, left; MCA, middle cerebral artery; O, occipital; P, parietal; PCA, posterior cerebral artery; PMG, polymicrogyria; rt, right; T, temporal; VUS, variant of uncertain significance.

Diagnosis and Treatment of Infantile Epileptic Spasms Syndrome

The median age at the onset of infantile epileptic spasms syndrome ranged from 1 to 13 months with a median age of 5 months. The lead-time to treatment (the time from the onset of spasms to the initiation of medical treatment) ranged from 0 to 9 months. Seventeen patients (89%) were treated within 1 month of the onset of spasms. Eleven patients (58%) were successfully treated with medical therapy (defined by cessation of spasms and resolution of hypsarrhythmia on EEG). Nine of these patients were successfully treated with vigabatrin monotherapy. Two were successfully treated with vigabatrin followed by ACTH. The number of antiseizure medications (not including hormonal therapy) that were used prior to surgery ranged from 1 to 5 with a median of 3.

Preoperative Evaluation

All patients underwent brain MRI and video EEG. All 19 patients had hypsarrhythmia or modified hypsarrhythmia on EEG at the time of diagnosis of infantile epileptic spasms syndrome. Hypsarrhythmia was considered modified if any of the following features were present: asymmetry, consistent focal discharge, episodes of voltage attenuation, excessive rapidity, excessive slowing, fragmentation, increased interhemispheric synchronization, increased periodicity, or predominant high-voltage bilaterally asynchronous slow activity.¹⁹ All 19 patients had focal or lateralizing ictal or interictal features on at least 1 EEG prior to undergoing epilepsy surgery. Fourteen patients (74%) had focal activity that was ipsilateral or concordant to their MRI lesion. Five patients (26%) had focal activity that was both ipsilateral and contralateral to their MRI lesion. Five patients (26%) underwent PET scan, 2 patients (10%) underwent MEG scan, 4 patients (21%) underwent both PET and MEG scans.

Surgical Treatments

Fourteen patients (74%) had ongoing seizures/spasms at the time of surgery. Surgery was performed prophylactically in the 5 patients (26%) who were not having seizures at the time of surgery. Nine patients (47%) underwent hemispherectomy and 10 patients (53%) underwent lobectomy/lesionectomy. The age at surgery ranged from 2 to 61 months with a median age of 18 months. The duration of epilepsy prior to surgery ranged from 3 to 69 months with a median of 15 months. Eight patients were operated on within 12 months of seizure onset, 7 patients were operated on within 13-24 months of seizure onset, and 4 patients were operated on over 24 months after seizure onset. Three patients (16%) underwent 2 surgeries. One patient who underwent hemispherectomy at 2 months of age underwent further disconnection of residual tracts 10 months later and is now seizure-free. One patient who underwent lesionectomy at 5 months of age underwent hemispherectomy 19 months later and is now seizure free. One patient who underwent lobectomy at 17 months of age underwent corpus callosotomy 54 months later and is now ILAE class 4; although the second surgery that this patient underwent was a palliative disconnective surgery (which was an exclusion criteria of the study), this patient was included in the study because the initial resective surgery that the patient underwent was intended to be curative, and thus we felt that his outcome (although relatively poor) should be included in this cohort. For patients who underwent a second surgery, the duration of their epilepsy prior to surgery was calculated as the time between onset of seizures and date of second surgery.

Postsurgical Outcomes

Outcomes were assessed at patients’ most recent follow-up visit, at which time the time since surgery ranged from 12 to 122 months with a median follow-up of 66 months. For patients who underwent a second surgery, this time was calculated from the time of the second surgery. Fifteen patients (79%) were considered ILAE seizure outcome class 1 (completely seizure free; no auras), 3 patients (16%) were considered ILAE seizure outcome class 4 (4 seizure days per year to 50% reduction of baseline seizure days ± auras), and 1 patient (5%) was considered ILAE seizure outcome class 5 (less than 50% reduction of baseline seizure days to 100% increase of baseline seizure days ± auras). Of the 15 patients who were considered ILAE class 1, 5 did not have seizures at the time of surgery, which was performed prophylactically. The percentage of patients who were ILAE class 1 at the most recent follow-up decreased with increasing duration of epilepsy prior to surgery: 8 of 8 (100%) of patients operated on within 12 months of seizure onset were ILAE class 1, 5 of 7 patients (71%) who underwent surgery after a duration of epilepsy of 13-24 months were ILAE class 1, and 2 of 4 patients (50%) who underwent surgery after a duration of epilepsy over 24 months were ILAE class 1. All patients (100%) who underwent hemispherectomy were ILAE class 1. Two patients who underwent lesionectomy and had ongoing seizures (class 4) were undergoing workup for a second epilepsy surgery at the time of their last follow-up (patients 3 and 11). The number of antiseizure medications at last follow-up ranged from 0 to 5 with a median of 2. Developmental outcome was improved in 14 of 19 (74%) and stable in 5 of 19 patients (26%). Despite this, 12 patients (63%) had global developmental delay at most recent follow-up visit. One patient (5%) had normal development.

Discussion

Our study found excellent seizure freedom rates and improved developmental outcomes following epilepsy surgery. Patients who underwent earlier epilepsy surgery had better seizure freedom rates and developmental outcomes, as did patients who underwent hemispherectomy.

Diagnosis and Medical Treatment of Infantile Epileptic Spasms Syndrome

The median age at onset of infantile epileptic spasms syndrome was 5 months, which is consistent with previously reported cohorts of patients with infantile epileptic spasms syndrome.^7,12,14 Seventeen patients (79%) had a lead time to treatment of 1 month or less. In 1 patient, diagnosis and treatment was delayed by 4 months as the family did not attend the initial appointment for EEG and consultation. In 1 patient, diagnosis and treatment was delayed by 9 months as spasms were misdiagnosed as gastroesophageal reflux. Delay in treatment is independently associated with poorer developmental outcomes.²² A lead time to treatment less than 1 month is associated with a 50% improvement in neurodevelopmental outcome relative to a lead time to treatment of >1 month.²³ Previous reports of median lead time to treatment in patients with infantile epileptic spasms syndrome are of 1-3 months.^24,25,26

The relatively short lead time to treatment in our cohort reflects rapid diagnosis and initiation of treatment. This is striking for a condition that can be subtle and difficult to diagnose. The rapid diagnosis and initiation of treatment of infantile epileptic spasms syndrome in our cohort may be due to education around infantile epileptic spasms syndrome and rapid access to EEG and consultation with a Paediatric Neurologist for patients with suspected infantile epileptic spasms syndrome at the Hospital for Sick Children. As some patients in our cohort had large structural brain lesions, some patients had abnormal neurologic examinations, development, or epilepsy prior to the diagnosis of infantile epileptic spasms syndrome, and thus clinicians and parents were likely attuned to the appearance of spasms. This leads to the question of whether serial EEGs should be performed as a screening measure in patients considered high risk for infantile epileptic spasms syndrome (i.e., patients with tuberous sclerosis, hypoxic ischemic encephalopathy, trisomy 21, perinatal stroke, and other risk factors for infantile epileptic spasms syndrome).²⁷

Preoperative EEG

All 19 patients had hypsarrhythmia or modified hypsarrhythmia on EEG at the time of diagnosis of infantile epileptic spasms syndrome but had focal or lateralizing ictal patterns or interictal epileptiform discharges on at least 1 EEG prior to undergoing epilepsy surgery. Fourteen patients (74%) had focal activity that was ipsilateral or localizable to their MRI lesion. Five patients (26%) had focal activity that was both ipsilateral and contralateral to their MRI lesion. Generalized EEG patterns such as hypsarrhythmia or multifocal interictal epileptiform discharges should not be considered a contraindication to epilepsy surgery in patients with an epileptogenic lesion identified with neuroimaging or neurophysiologic testing. Resective surgery has been demonstrated to be successful despite a generalized EEG pattern such as hypsarrhythmia, multifocal, or discordant EEG features.^10,16,28-30

Surgery—Timing and Procedure

Epilepsy surgery is a well-established, cost-effective, and often underutilized treatment modality for selected patients with refractory epilepsy.^31,32 Seizure freedom rates in pediatric patients who undergo epilepsy surgery range from 60% to 75%.³³

The duration of epilepsy prior to surgery ranged from 3 months to 5.7 years, with a median of 15 months, which is similar to previously reported cohorts.^12,14,15,34 Seventy-nine percent of patients were ILAE class I (seizure free) at their most recent follow-up. This percentage increased to 89% in patients who underwent epilepsy surgery within 12 months of seizure onset, compared with 70% of patients who underwent epilepsy surgery after 12 months of seizure onset.

All 10 patients who underwent hemispherectomy were seizure free at the most recent follow-up, compared with 5 of 9 patients (55%) who underwent lobectomy or lesionectomy. Two patients with class 4 outcomes were undergoing workup for a second epilepsy surgery at the time of their last follow-up. We hypothesize that some patients may have recurrent seizures after lobectomy or lesionectomy because of incomplete resection of the epileptogenic zone, which is more difficult to delineate in disorders of neuronal migration than in patients with encephalomalacia. The extent of the epileptogenic zone may be underestimated by MRI, resulting in incomplete surgical resection. PET and invasive electrode monitoring have been suggested to mitigate this,²⁸ although other studies have suggested that invasive monitoring is not required, permitting earlier surgery without the risks of invasive monitoring.¹¹ Another explanation for recurrent seizures is the presence of undetected multifocal epileptogenic lesions, complex neuronal networks involving the remaining tissue or contralateral hemisphere, or an underlying genetic predisposition epilepsy.

One patient (patient 11) who underwent right temporal lobectomy for a right temporal focal cortical dysplasia also harbored a pathogenic variant in DEPDC5, which is known to cause familial focal epilepsy. This patient continued to have seizures at last follow-up (class 4) and is being considered for repeat surgery. This raises the question as to whether patients with underlying genetic etiologies should be considered for resective surgery and whether genetic testing should be routinely performed prior to surgery. Ferri et al³⁵ and Baulac et al³⁶ reported favorable outcomes in 5 patients with DEPDC5 who underwent epilepsy surgery and suggest that an underlying genetic etiology should not preclude epilepsy surgery.

Development

Development was abnormal in 18 of 19 patients (95%) following surgery despite improved seizure control. Following surgery, developmental outcome was improved in 14 of 19 (74%) and stable in 5 of 19 (26%) patients. No patients had further developmental regression.

Shorter duration of epilepsy/infantile epileptic spasms syndrome was associated with improved surgical outcomes in our cohort, although this must be interpreted with caution in a small cohort of 19 patients. As neuronal plasticity facilitates recovery from damage caused by the epileptic encephalopathy, early surgical intervention may alter the natural history of epilepsy by halting the adverse effects of ongoing epileptic encephalopathy and the establishment of wider epileptogenic networks on the unaffected brain.

Limitations

We acknowledge the limitations of our study, including the retrospective design, single-center study, descriptive statistics, and small sample size. There was a limited follow-up interval in some cases as some patients underwent surgery recently compared with the time of data collection. However, no patients were lost to follow-up. Our study is also limited by the heterogeneous etiologies of infantile epileptic spasms syndrome and heterogeneity in the surgical procedure that was performed in our patients. As not all patients underwent both pre- and postsurgical neuropsychological evaluation, developmental assessment was based on a subjective retrospective review of clinical notes by 1 author in these cases. Developmental delay at the time of diagnosis may not have been assessed reliably given that development is hard to assess in early infancy and may have been confounded by the effect of unrecognized spasms prior to diagnosis.

Conclusions

Our study found excellent seizure freedom rates and improved or stable developmental outcomes following epilepsy surgery in patients with a history of infantile epileptic spasms syndrome with a structural lesion detected on MRI brain. Patients who underwent earlier epilepsy surgery had improved seizure freedom rates as did patients who underwent hemispherectomy. We hypothesize that early surgical intervention shortens the duration of active epilepsy, limiting the potentially irreversible effects of ongoing seizures and antiseizure medications on brain development. Patients should be referred for surgical assessment early.

Future studies are needed to prospectively examine long-term seizure freedom and neurodevelopmental outcomes of patients with infantile epileptic spasms syndrome who undergo epilepsy surgery. Currently, genetic testing is not routinely performed as part of the presurgical evaluation. Identifying causative genes in patients evaluated for epilepsy surgery may improve presurgical decision making by identifying patients who are good and poor candidates for epilepsy surgery. Further work is needed to investigate the potential use of genetic testing in epilepsy surgery evaluation.

Footnotes

Author Contributions

JG, PJ, WR, and CG contributed to data acquisition, analysis, and interpretation. JG drafted the manuscript. All authors contributed to conception and design of the study and critically revised the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article

Ethical Approval

Research ethics approval was obtained from the Hospital for Sick Children Research Ethics Board (REB 1000061134).

ORCID iDs

Jennifer V. Gettings

Puneet Jain

References

Trevathan

Murphy

Yeargin-Allsopp

. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia (Copenhagen). 1999;40(6):748-751.

Wirrell

Shellhaas

Joshi

Keator

Kumar

Mitchell

. How should children with West syndrome be efficiently and accurately investigated? Results from the National Infantile Spasms Consortium. Epilepsia (Copenhagen). 2015;56(4):617-625.

Mackay

Weiss

, et al. Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2012;78(24):1974-1980.

Appleton

Peters

ACB

Mumford

Shaw

. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia. 1999;40(11):1627-1633.

Knupp

Coryell

Nickels

, et al. Response to treatment in a prospective national infantile spasms cohort. Ann Neurol. 2016;79(3):475-484.

O'Callaghan

FJK

Edwards

Alber

, et al. Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. Lancet Neurol. 2016;16(1):33-42.

Pellock

Hrachovy

Shinnar

, et al. Infantile spasms: a U.S. consensus report. Epilepsia (Copenhagen). 2010;51(10):2175-2189.

Saemundsen

Ludvigsson

Rafnsson

. Autism Spectrum disorders in children with a history of infantile spasms: a population-based study. J Child Neurol. 2007;22(9):1102-1107.

Kang

Rhie

, et al. Seizure outcome of infantile spasms with focal cortical dysplasia. Brain Dev. 2013;35(8):816-820.

10.

Chugani

Shewmon

Shields

, et al. Surgery for intractable infantile spasms: neuroimaging perspectives. Epilepsia (Copenhagen). 1993;34(4):764-771.

11.

Erdemir

Pestana-Knight

Honomichl

, et al. Surgical candidates in children with epileptic spasms can be selected without invasive monitoring: a report of 70 cases. Epilepsy Res. 2021;176:106731.

12.

Iwatani

Kagitani-Shimono

Tominaga

, et al. Long-term developmental outcome in patients with West syndrome after epilepsy surgery. Brain Dev. 2012;34(9):731-738.

13.

Kramer

Sue

Mikati

. Focal features in West syndrome indicating candidacy for surgery. Pediatr Neurol. 1997;16(3):213-217.

14.

Yum

Lee

Hong

Kim

. Surgical treatment for localization-related infantile spasms: excellent long-term outcomes. Clin Neurol Neurosurg. 2010;113(3):213-217.

15.

Asarnow

LoPresti

Guthrie

, et al. Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev Med Child Neurol. 1997;39(7):430-440.

16.

Gowda

Salazar

Bingaman

, et al. Surgery for catastrophic epilepsy in infants 6 months of age and younger. J Neurosurg Pediatr. 2010;5(6):603-607.

17.

Dorfer

Ochi

Snead

, et al. Functional hemispherectomy for catastrophic epilepsy in very young infants: Technical considerations and complication avoidance. Childs Nerv Syst. 2015;31(11):2103-2109.

18.

Shields

Shewmon

Peacock

LoPresti

Nakagawa

Yudovin

. Surgery for the treatment of medically intractable infantile spasms: a cautionary case. Epilepsia (Copenhagen). 1999;40(9):1305-1308.

19.

Lux

Osborne

. A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group. Epilepsia. 2004;45(11):1416-1428.

20.

Wieser

Blume

Fish

, et al. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia (Copenhagen). 2001;42(2):282-286.

21.

Bélanger

Joannie

. Evaluation of the child with global developmental delay and intellectual disability. Paediatr Child Health. 2018;23(6):403-410.

22.

O’Callaghan

FJK

Lux

Darke

, et al. The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study. Epilepsia (Copenhagen). 2011;52(7):1359-1364.

23.

Widjaja

McCoy

Snead

. Neurodevelopmental outcome of infantile spasms: a systematic review and meta-analysis. Epilepsy Res. 2014;109:155-162.

24.

Hussain

Lay

Cheng

Weng

Sankar

Baca

. Recognition of infantile spasms is often delayed: The ASSIST study. J Pediatr. 2017;190:215-221.e1.

25.

Sanmaneechai

Sogawa

, et al. Treatment outcomes of West syndrome in infants with Down syndrome. Pediatr Neurol. 2013;48(1):42-47.

26.

Surana

Symonds

Srivastava

, et al. Infantile spasms: etiology, lead time and treatment response in a resource limited setting. Epilepsy Behav Rep. 2020;14:100397.

27.

Kotulska

Kwiatkowski

Curatolo

, et al. Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP trial. Ann Neurol. 2021;89(2):304-314.

28.

Chugani

Ilyas

Kumar

, et al. Surgical treatment for refractory epileptic spasms: the Detroit series. Epilepsia (Copenhagen). 2015;56(12):1941-1949.

29.

Wyllie

Lachhwani

Gupta

, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology. 2007;69(4):389-397.

30.

Karakas

Wilfong

Riviello

Curry

Ali

. Epileptic spasms in a large hypothalamic hamartoma cohort. J Child Neurol. 2021;36(4):304-309.

31.

Lim

Bowen

Snead

, et al. Access to surgery for paediatric patients with medically refractory epilepsy: a systems analysis. Epilepsy Res. 2013;107(3):286-296.

32.

Widjaja

Schinkel

, et al. Cost-effectiveness of pediatric epilepsy surgery compared to medical treatment in children with intractable epilepsy. Epilepsy Res. 2011;94(1):61-68.

33.

Widjaja

Jain

Demoe

Guttmann

Tomlinson

Sander

. Seizure outcome of pediatric epilepsy surgery: systematic review and meta-analyses. Neurology. 2020;94(7):311-321.

34.

Taussig

Dorfmüller

Save

, et al. Hemispherotomy for isolated infantile spasms following perinatal ischemic stroke. Eur J Paediatr Neurol. 2015;19(5):597-602.

35.

Ferri

Bisulli

Mai

, et al. A stereo EEG study in a patient with sleep-related hypermotor epilepsy due to DEPDC5 mutation. Seizure. 2017;53:51-54.

36.

Baulac

Ishida

Marsan

, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5mutations. Ann Neurol. 2015;77(4):675-683.