Clinical features and surgical outcomes in young children with focal cortical dysplasia type II

Abstract Aims To investigate clinical characteristics and surgery outcomes of young children with focal cortical dysplasia (FCD) type II. Methods Young children (onset age ≤6 years) with FCDII who underwent epileptic surgery in Children Epilepsy Center of Peking University First Hospital in 2014‐2018 were followed up for at least 6 months after surgery. Results One hundred and twelve children with FCDII were included, with median age of onset 0.9 years (0.01‐5.9), who underwent surgery at 4.1 years old (0.8‐16.2). Focal seizures were most frequent (90.2%) and epileptic spasms presented in 23 (20.5%) cases. Epileptic encephalopathy was not uncommon (12.5%), associated with earlier epilepsy onset and higher rate of bilateral onset on ictal EEG (OR = 0.213, 9.059; P = .041, .004). At the last follow‐up, 88.4% achieved seizure‐free. Before surgery, 49.1% showed moderate/severe developmental delay, associated with earlier seizure onset and higher rate of history of epileptic encephalopathy (OR = 0.740, 5.160, P = .023, .042). For 48 children with preoperatively moderate/severe developmental delay, DQ rank at 6 months postsurgery was improved in only four cases. Conclusion For young children with FCDII, they tend to present with epileptic encephalopathies and show moderate/severe developmental delay before surgery. The seizure outcome was favorable after surgery. For children with preoperatively moderate/severe developmental delay, developmental outcome at 6 months after surgery was not satisfactory.


| INTRODUC TI ON
Focal cortical dysplasia (FCD) refers to a common spectrum of malformation of cortical development (MCD). 1 It is the most common histopathologic finding in brain tissue obtained from epilepsy surgeries in children. 2 Among 464 children who underwent epilepsy surgery in Children Epilepsy Center of Peking University First Hospital from May 2014 to April 2018, two hundred and seventeen (46.8%, 217/464) were confirmed to be FCD. FCD type II, which is characterized by a combination of dysmorphic neurons and balloon cells, is the most common type of FCD, accounting for 60.8% (132/217) of FCD cases. The age at seizure onset in patients with FCD II was reported to range from neonate to 53 years old. 3,4 For children with early-onset epilepsy, longer exposure to seizures and epileptic discharges, FCD lesions, and multiple antiepileptic drugs might have detrimental effects on the developing brain.
Especially, the epileptic activities may have adverse effects on cognitive and behavioral development beyond the FCD lesions and the condition can get worse over time, which also referred to as epileptic encephalopathies. And this phenomenon is more severe and common in infancy and early childhood. 5 From the perspective of epileptic syndromes, some epileptic syndrome in infancy and childhood are classified as epileptic encephalopathy, such as infantile spasm (IS), Lennox-Gastaut syndrome (LGS), epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS), and early-onset epileptic encephalopathies (EOEEs). 6 Additionally, the plasticity of brain function should also be considered. Therefore, clinical characteristics, such as semiology of seizures and epileptic encephalopathy, as well as psychomotor developmental and surgical outcome in children with early-onset seizures would differ from older children or adults with FCD type II. 7,8 In this study, we analyzed the pre-and postsurgery data from 112 young children (epilepsy onset ≤6 years of age) with FCD type II to investigate the clinical features, as well as their seizure and developmental outcomes after surgery.

| Inclusion criteria of patients
We analyzed data from patients with refractory epilepsy who underwent surgical treatment from May 2014 to April 2018 in the Children Epilepsy Center of Peking University First Hospital.
Patients fulfilled all the following criteria were included: (a) age of seizure onset ≤6 years old; (b) drug-resistant refractory epilepsy according to the criteria defined by the International League Against Epilepsy (ILAE); 9 (c) focal lesions of FCD type II were revealed in brain magnetic resonance imaging (MRI), such as cortical thickness, signal hyperintensity (mainly on T2FLAIR and T2-weighted sequences), blurring of gray-white matter, and "transmantle" sign; 10 (d) histological confirmation of FCD type II (including FCD IIa and IIb) based on resected specimens; and (e) follow-up at least 6 months after surgery.

| Presurgical information
We reviewed clinical features, including gender, age at seizure onset, epilepsy exposure duration (calculated as the interval from age at seizure onset to age at surgery), seizure frequency, seizure types, number of antiepileptic drugs (AEDs), and history of diagnosis with any of epileptic encephalopathies. The seizure types were classified according to the operational classification by ILAE. 11 We classified epileptic encephalopathy as IS (with onset age under 1 year, epileptic spasms, psychomotor delay, and hypsarrhythmia patterns on EEG), 5,12 LGS (with onset age in childhood, multiple seizures types including tonic seizures, atonic seizures or atypical absences, cognitive impairment, as well as generalized slow spikewave patterns and bilateral fast rhythm patterns during slow sleep on EEG), 12 CSWS (with onset age in childhood, neurocognitive regression, and at least 85% continuous spikes-and-waves activities of slow-wave sleep on EEG), 12 or EOEEs (with onset from early infancy, recurrent seizures, and developmental delay, including Ohtahara syndrome, early myoclonic epileptic encephalopathy, malignant migrating partial seizures in infancy, and others). 13 The presurgical evaluation included brain MRI, FDG-PET (fluorodeoxyglucose positron emission tomography), PET-CT/MR image coregistration, long-term video EEG recordings of habitual seizures, and neuropsychological assessments. All patients underwent 3.0T MRI of epileptic sequences, including T1-weighted, T2-weighted, FLAIR, and DWI sequencing in the axial, sagittal, and coronal planes.
Interictal/ictal scalp EEGs were recorded, and the electrodes were arranged according to the international 10-20 systems. EEG data were categorized as ipsilateral (to the FCD lesion) or as bilateral/generalized. Ages and Stages Questionnaire version 3 (ASQ-3) 14

| Surgery
We collected the following surgical related data: intracranial EEG recordings (if required), age at surgery, operative site and procedures, and histopathologic diagnoses. The surgical resections were classified as follows: unilobar resection, multilobar resection, and hemispherotomy.

| Postsurgical data
The seizure outcome was classified using the Engel score 15   We evaluated the developmental outcome after surgery using ASQ-3 and the Griffiths Mental Development Scales. Based on rank changes in DQ scores, the outcomes were divided into three subcategories, that is, improved, declined, or stabilized. 16 If the rank was ascending according to the scores, we judged to be improved, otherwise, to be declined or stabilized.

| Ethics and informed consent
This study was approved by the institutional review board of the ethics committee of Peking University First Hospital. The parents of all participants had been provided written informed consent for the use of the children's information for scientific purposes.

| Statistical analysis
Categorical variables were summarized as numbers and as percent-     Comparing the seizure group versus seizure-free group, we found a higher percentage of developmental delays in seizure group before surgery (76.9% vs 45.5%; P = .032). There is no significant difference between the two groups in any of the following factors: age at onset (P = .989), age at surgery (P = .510), epilepsy exposure dura-  Table 1).

| D ISCUSS I ON
The structure and function of brain maturate continuously throughout early life shaped by the interaction of genetics, environment, and experiences. 17 For young children, the immature brain, with higher expression of excitatory neurotransmitters, remodeling synaptic patterns, incomplete myelination, and deficient local and longerrange connections, makes it vulnerable to seizure and increasing synchronization. 18 And the lesion of FCD II might result from aberrant proliferation or apoptosis of cells during the period of gestation. 19,20 The mechanism of generation is related to brain somatic variations. 21,22 The lesion could have adverse impact on the developing brain. Especially for patients with earlier seizure onset, the influence of lesion on the brain function might be much serious.

| Clinical characteristics of younger children with FCD type II different from those of older children or adults
In term of seizure types, epileptic spasms were common in young children and 61.6% of spasms showed bilateral onset on ictal EEG in our cohort. With increasing age, the proportion of spasms was reduced. [23][24][25] In the cohort reported of 62 patients with FCD II with an average onset age of 7 years, there was no patient having epileptic spasm. 23 The epileptic spasm may originate from the local cortex and rapidly spread through the subcortical structure to the bilateral hemispheres, resulting in the clinical seizures. It is age-related and may be associated with immature brain function in young children. 26 In term of scalp EEG, FCD II usually exhibits some characteristic EEG activities. The interictal EEG frequently showed rhythmic discharges concordant with the anatomic lesions. And the dischargers sometimes spread to adjacent areas, especially in type IIb. 23,27 The ictal EEG patterns reveal poly-spikes and low-voltage fast activities.
Delta brushes could be occasionally represented at seizure onset, [27][28][29] whereas the EEG abnormalities tend to be more diffuse and nonlocalized in young children. 30 We found that 12.5% cases showed bilateral discharges on interictal EEG and 11% with bilateral onset on ictal EEG. The diffuse EEG discharges in young children may be due to lower development level of young children in which local lesions more likely cause synchronization or comprehensive discharges. 31 While, for adult with FCD, EEG discharges tend to be more regional and 95% cases present concordance of ictal with interictal EEG abnormalities. 32

| Seizure outcome in young children was as favorable as older children or adults
In this study, 88.4% cases achieved seizure freedom at the last follow-up, similar to that of older children or adults. 37 The seizures relapse mostly within 12 months after surgery, 38-40 and 48.2% cases in our cohort were followed for less than 1 years, so it still needs longer follow-up. We observed higher rate of moderate/severe delay before surgery in group of patients not seizure-free.
Low level of development may reflect widespread disturbance of cerebral function. 41 And seizure outcomes also related to higher rate of history of epileptic encephalopathy and multilobar lesions in our study. Malmgren 47 and only patients with seizure-free showed improvement. 16,48 It might due to the reduced effects of frequent seizures, AEDs, and devastating EEG discharges on brain function. And the removal of epileptogenic zone could also interrupt its reaction to the surrounding region, which could carry chance to achieve neurodevelopmental progress. 46 Especially for young children in rapid developmental stage, earlier acquisition of seizure-free is necessary for neurodevelopment, and long-term outcome might be better with strong brain plasticity. Chen et al 49  This study had some limitations. It may be biased as it was a retrospective study that was conducted at a single tertiary epilepsy treatment center and with relatively small number of patients. In term of neurodevelopment, it would be more comprehensive to interpreting the developmental outcomes by analyzing changes in different aspects of psychomotor development and the quality of life. And more valid and applicable assessment for different age of patients might be useful for longitudinal follow-up. Importantly, longer follow-up after surgery is needed to better assess outcomes.

| CON CLUS IONS
For young children with FCD type II, epileptic spasms and bilateral EEG discharges were more common than older children or adults.
Young children also tend to present with epileptic encephalopathies and show moderate to severe developmental delay before surgery.
The seizure outcome was favorable after surgery, even for those with epileptic encephalopathy and severe developmental delay, but of those, developmental outcome at 6 months after surgery was not satisfactory.

ACK N OWLED G M ENTS
We thank all the families of these children for their participation and

CO N FLI C T O F I NTE R E S T
None of the authors have any conflict of interest to disclose.