Brain & Development xxx (2020) xxx–xxx www.elsevier.com/locate/braindev Case Report Effect of total callosotomy on KCNQ2-related intractable epilepsy Ayako Yamamoto a,⇑, Yoshiaki Saito a,b, Yoshitaka Oyama a, Yoshihiro Watanabe a, Azusa Ikeda a, Rumiko Takayama c, Hiroko Ikeda c, Saoko Takeshita a, Ichiro Takumi d,e, Toshiyuki Itai f, Satoko Miyatake f, Naomichi Matsumoto f a Department of Pediatrics, Yokohama City University Medical Center, 4-57 Urafune, Minami-ku, Yokohama 232-0024, Japan Division of Child Neurology, Yokohama Medical and Welfare Center, Konan, 4-6-20 Konan-ku, Yokohama 234-0054, Japan c Department of Pediatrics, National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan d Department of Neurological Surgery, Nippon Medical School Musashi Kosugi Hospital, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8553, Japan e Department of Neurosurgery, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan f Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-2606, Japan b Received 21 February 2020; received in revised form 18 May 2020; accepted 18 May 2020 Abstract Aim: To describe beneficial effects of callosotomy on KCNQ2-related intractable epilepsy. Case report: Our patient was a 10-year-old girl who had developed epilepsy during the neonatal period, accompanied by a suppression-burst pattern on the electroencephalography (EEG). The patient showed profound psychomotor developmental delay since early infancy. Daily seizures of versive posturing and ocular deviation were transiently controlled by carbamazepine and valproate at the age of 1 year; however, the seizures gradually increased to up to 50 times per day. Ictal EEG and positron emission tomography revealed an epileptic focus in the left frontal lobe at age 5 years. Total callosotomy resulted in marked reduction of epileptic seizures thereafter, as well as improved responses to external auditory and visual stimuli. Whole exome sequencing at age 9 identified a de novo missense variant in KCNQ2 (NM_172107.3:c.563A > C:p.(Gln188Pro)). Conclusion: This case supports that epilepsy surgery could benefit children with epileptic encephalopathy, even with the etiology of channelopathy. Ó 2020 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. Keywords: KCNQ2; Early-onset epileptic encephalopathy; Callosotomy; Epilepsy surgery; Channelopathy 1. Introduction KCNQ2 encodes a Kv7.2 subunit protein of the voltage-gated potassium channel, which is expressed almost exclusively in neurons in the brain [1]. It has been identified as the causative gene for benign familial neonatal epilepsy, as well as early-onset epileptic ⇑ Corresponding author. E-mail address: aa885178@yahoo.co.jp (A. Yamamoto). encephalopathy (EOEE) with manifestation of intractable epilepsy and moderate-to-profound psychomotor developmental delay [2–4]. The differential severity between these phenotypes results from the degree of impairment in the inward potassium current for the repolarization of neuronal membrane potentials, which is dependent on the site and the type of amino acid replacement due to missense mutations [5]. The EOEE phenotype typically presents with neonatal focal-onset convulsions, with ictal electroencephalog- https://doi.org/10.1016/j.braindev.2020.05.005 0387-7604/Ó 2020 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. Please cite this article in press as: Yamamoto A et al. Effect of total callosotomy on KCNQ2-related intractable epilepsy. Brain Dev (2020), https:// doi.org/10.1016/j.braindev.2020.05.005 2 A. Yamamoto et al. / Brain & Development xxx (2020) xxx–xxx raphy (EEG) of focal voltage attenuation followed by recruiting theta or spike-wave activities [4,6]. Interictal EEG reveals a suppression-burst pattern or random asynchronous attenuation during the first week of life [3,7]. Interestingly, the epilepsy is initially intractable but often becomes responsive to antiepileptics during infancy, particularly to the agents with sodium channel-blocking properties [3,8]. Seizure remission rate has been reported as 47%–67% [3,4], which is considerably high among children with EOEE or Ohtahara syndrome. The remaining patients suffer from refractory epilepsy, for which there is no consensus for a treatment option. Herein, we report the case of a girl with KCNQ2-related EOEE, for which total callosotomy resulted in significant reduction of daily seizures. 2. Case report Our patient, a Japanese female, was born to nonconsanguineous parents at 38 gestational weeks. The patient was delivered by cesarean section due to fetal distress (Fig. 1). Her body weight was 2405g, and head circumference was 32.5 cm. Apgar scores at 1 and 5 min were 8 and 10, respectively. No family history of epilepsy, including neonatal seizures, was reported. The patient manifested poor sucking and tachypnea and developed episodes of respiratory arrest, smacking, ocular deviation, facial twitching, and focal or generalized tonic convulsions around day 1 after birth. Despite treatment with phenobarbital and midazolam, the seizures, lasting 0.5–3 min, reappeared daily starting on day 7. On day 3, brain magnetic resonance imaging (MRI) revealed a thin corpus callosum and high signal intensity at bilateral globus pallidus on T1-weighted images (Fig. 2A). EEG showed a suppression-burst pattern on day 6 (Fig. 3A). These findings were interpreted to represent hypoxic-ischemic brain damage due to the fetal distress. Then, EEG findings evolved to a dysrhythmic background activity with high-voltage slow waves and multifocal spikes and polyspikes. These became equivalent to hypsarrhythmia, at times, when asynchrony and asymmetry worsened in the follow-up recordings. After initiating 5 mg/kg/d carbamazepine (CBZ) on day 34, the seizures disappeared immediately, and tube feeding could be terminated. Although tonic seizures emerged at age 2 months with a frequency of 5–10 times per day, an increase in the dosage of CBZ and the addition of valproate mitigated them (Fig. 1). The patient began to chuckle well around age 1 year, though she still did not have head control and could not perform ocular tracking of moving objects. Tonic seizures, refractory to antiepileptics including levetiracetam, zonisamide, and lamotrigine, up to 20– 40 times per day, with upward gaze and desaturation, were observed at age 3. Gelastic seizures also appeared at age 4. Ictal EEG during a tonic seizure identified a preceding activity originating at the left fronto-central areas, followed by a diffuse attenuation (Fig. 3B). MRI showed anterior-predominant cerebral atrophy and periventricular white matter lesions (Fig. 2B–D). Although these findings appeared symmetrical, cerebral images using the arterial spin-labeling technique revealed relative hyperperfusion in the left frontocentral areas (Fig. 2E, F). Positron emission tomography at age 5 revealed hypometabolism in the medial and inferior portion of the left frontal lobe, not identical to the area of hyperperfusion (Fig. 2G, H). Fig. 1. Clinical course of the patient. Please cite this article in press as: Yamamoto A et al. Effect of total callosotomy on KCNQ2-related intractable epilepsy. Brain Dev (2020), https:// doi.org/10.1016/j.braindev.2020.05.005 A. Yamamoto et al. / Brain & Development xxx (2020) xxx–xxx 3 raise her head in the prone position, and usage of arms and hands improved. Her psychomotor development was still profoundly delayed, however. The seizures were transiently suppressed for 1 month and then recurred at a rate of several times per day for 5 years thereafter (Fig. 1). Interictal EEG showed a clearer posterior background activity during wakefulness (Fig. 3D) and less prominent epileptiform discharges during sleep (Fig. 3E) compared to the findings during the presurgical period (Fig. 3B, C). Blood and urine screening tests for congenital metabolic disorders were unremarkable. When the patient was 9, whole exome sequencing identified a missense variant of NM_172107.3:c.563A > C:p.(Gln188Pro) in KCNQ2. This variant is not registered in the public database (Human Genetic Variation Database [HGVD]; http://www.hgvd.genome.med.kyoto-u.ac.jp/); the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP6500; https://evs.gs. washington.edu/EVS/); the Exome Aggregation Consortium ([ExAC]; http://exac.broadinstitute.org/) Browser; the Tohoku Medical Megabank Organization (ToMMo) Japanese reference panel (https://ijgvd.megabank.tohoku.ac.jp/); or the 575 in-house normal Japanese control exomes at Yokohama City University. The protocol of genetic examination was approved by the Ethical Committee of Yokohama City University, and informed consent was obtained from the parents. SIFT predicted this variation as pathogenic. Sanger sequencing and paternity testing using microsatellite markers confirmed that KCNQ2 was a de novo variant. According to the ACMG guideline for the interpretation of sequence variants, this variant was classified as ‘‘likely pathogenic” (i.e., this variant satisfies as follows: PS2, de novo variant; PM1, located in a mutational hotspot; PM2, absent from controls; PP3, suggested its deleterious effect by several in silico programs). 3. Discussion Fig. 2. Neuroimaging of the patient at 13 days old (A), 3 years old (B– F), and 5 years old (G and H). (A) High signal intensity is noted in the globus pallidum bilaterally on T1-weighted magnetic resonance imaging. (B–D) (B) T1-weighted image. Pallidal high intensity has been disappeared. (C, D) Fluid-attenuation inversion recovery images. Atrophy of the frontal and parietal lobes and signal change in the periventricular white matter are seen. (E, F) Cerebral perfusion image using the arterial spin-labeling technique revealed relative hyperperfusion in the left frontal lobe and hypoperfusion in the right frontoparietal and lateral temporal lobes, as well as bilateral anterior temporal lobes (arrows; asterisks in F indicate the inferior horn of lateral ventricles). (G, H) Positron emission tomography revealed hypometabolism in the medial and inferior portions of the left frontal lobe. Our neurosurgeons and the family chose a palliative epilepsy surgery of callosotomy when the patient was 5 years old. Soon after the surgery, the patient could Clinical characteristics of the present patient were typical for the KCNQ2-related EOEE, including the epilepsy phenotype of focal-onset seizures during the first day of life, suppression-burst pattern on EEG, beneficial effect of CBZ in the control of epilepsy, pallidal high signal on T1-weighted images taken in the first week of life, and profound developmental delay [3]. Gln188 is located within the extracellular domain between transmembrane segments S3 and S4; the S1– S4 domains are responsible for the gating charge formation against the potassium ion influx into the ion pore, which is surrounded by the tetrameric intramembrane loops between S5 and S6 domains. Therefore, the alteration of polar residue Gln to nonpolar Pro may affect the pore-gating function, resulting in the dominant negative effect on the channel current. Please cite this article in press as: Yamamoto A et al. Effect of total callosotomy on KCNQ2-related intractable epilepsy. Brain Dev (2020), https:// doi.org/10.1016/j.braindev.2020.05.005 4 A. Yamamoto et al. / Brain & Development xxx (2020) xxx–xxx Fig. 3. Electroencephalography (EEG) of the patient at 13 days old (A), 4 years and 10 months old (B, C), and 9 years and 9 months old (D, E). (A) A suppression-burst pattern is seen. Focal epileptiform discharges are also noted in the left or right central areas. (B) Ictal EEG during wakefulness, with a seizure type of ocular gazing followed by versive rotation of the neck to the right, and successive flexion of right arm and extension of left arm. Preceding fast activity with a low amplitude (square) emerges at the F3 area, followed by diffuse desynchronization during the tonic phase. (C) Sleep EEG reveals continual, asynchronous, and irregular slow activity with spikes over the frontal, central, and parietal areas bilaterally. (D) Posterior background activity of 5–6 Hz is evident, with rare paroxysms at left frontal and right occipital areas. (E) The background activity is more asymmetric and epileptiform discharges are more focal compared to the findings in (D). Widespread, asynchronous slow wave activity with multifocal spikes still persists but is less continual. Higher frequency components have also increased in the background activity. Please cite this article in press as: Yamamoto A et al. Effect of total callosotomy on KCNQ2-related intractable epilepsy. Brain Dev (2020), https:// doi.org/10.1016/j.braindev.2020.05.005 A. Yamamoto et al. / Brain & Development xxx (2020) xxx–xxx Sodium channel blockers may possibly act through a coupling interaction between the colocalized sodium and potassium channels [3]. In addition, some patients may experience a spontaneous remission of the epilepsy during infancy. This could be explained by the developmental evolution of Kv7.2 and Kv7.3 proteins to form a tetrameric channel structure, that is, expression of Kv7.2 begins earlier than Kv7.3 during the fetal period and rapidly decreases after birth and as the patient approaches school age, whereas expression of Kv7.3 increases after birth [1,9]. Although these trends could be seen to some degree in the present patient, the epilepsy recurred and remained refractory. This unfavorable outcome may be compatible with a hypothesis that epilepsy may be more sensitive to medication if causative mutations are located close to the pore-forming domain [3]. Four years before the confirmation of KCNQ2 variant, callosotomy was chosen for the patient with an aim to reduce the abundant seizure episodes that were harmful for her quality of life. The benefit of a neurosurgical option is generally limited for the treatment of epilepsies due to channelopathy [10]; however, the trial in this patient has retrospectively proven beneficial. This may have a relationship to the alteration of seizure semiology with age in this patient. Seizures during neonatal and the early infantile periods consisted of focal/unilateral tonic components in extremities, ocular deviation, and versive rotation of the neck, whereas the tonic seizures after age 3 years appeared without these focal or lateralized signs. This may correspond to the rapid generalization of ictal desynchronization on EEG, in contrast to the unilateral recruiting activity that could either generalize or migrate to the contralateral hemisphere, which is a well-recognized ictal finding in KCNQ2-related EOEE [6,7]. In conclusion, total callosotomy may be included in the therapeutic option for epileptic encephalopathy due to KCNQ2 variants, particularly when bilateral synchrony of epileptiform discharge is suspected in the pathogenesis of the fulminant seizure episodes. Conflict of interest 5 JP19ek0109301, JP19ek0109348 and JP19kk020515 (N. Matsumoto); JSPS KAKENHI, Japan, grant numbers JP17H01539 (N. Matsumoto) and JP19H03621 (S. Miyatake); and grants from the Ministry of Health, Labor and Welfare (N. Matsumoto) and the Takeda Science Foundation, Japan (N. Matsumoto). The authors declare no competing interests. References [1] Tinel N, Lauritzen I, Chouabe C, Lazdunski M, Borsotto M. 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Epilepsy surgery for patients with genetic refractory epilepsy: a systematic review. Epileptic Disord 2018;20:99–115. The authors claim no conflict of interest. Acknowledgments This work was supported by AMED, Japan, under grant numbers JP19ek0109280, JP19dm0107090, Please cite this article in press as: Yamamoto A et al. Effect of total callosotomy on KCNQ2-related intractable epilepsy. Brain Dev (2020), https:// doi.org/10.1016/j.braindev.2020.05.005