Brain & Development 37 (2015) 733–737 www.elsevier.com/locate/braindev

Case Report

ACTH therapy on intractable epilepsy in Hemiconvulsion–Hemiplegia–Epilepsy syndrome Shuichi Shimakawa a,⇑, Shohei Nomura a, Motoko Ogino a, Miho Fukui a, Mitsuru Kashiwagi b, Takuya Tanabe c, Hiroshi Tamai a a Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan Department of Pediatrics, Hirakata Municipal Hospital, Hirakata, Osaka, Japan c Department of Pediatric Neurology, Tanabe Children’s Clinic, Hirakata, Osaka, Japan b

Received 9 September 2014; received in revised form 9 November 2014; accepted 13 November 2014

Abstract Introduction: In the chronic phase of Hemiconvulsion–Hemiplegia–Epilepsy (HHE) syndrome, developing epilepsy may be intractable. Herein, we report a case where adrenocorticotropic hormone (ACTH) ceased an intractable habitual partial seizure in a patient with HHE syndrome. Case report: A developmentally normal one-year-old girl presented with left focal motor status epilepticus in the clinical course of rotavirus infection. She was diagnosed with HH syndrome. At 4 months after status epilepticus, she developed partial seizures that occurred daily, and which resulted in a stooped posture, head rotation to the right, and contraction of both upper limbs predominantly in the left arm. At this time, she was diagnosed with idiopathic HHE syndrome. Her seizures were not reduced by sodium valproate, clonazepam, clobazam, zonisamide, phenytoin, phenobarbital, topiramate, lamotrigine, or liposteroid. At the age of 7, ACTH therapy was performed. On the 10th day of ACTH therapy, the habitual seizure was ceased. However, partial seizures characterized by left arm contraction then developed. Treatment with 350 mg/day lamotrigine prevented this emerging seizure. She has been free of both seizure types for more than one year, with no serious adverse effects of ACTH therapy. Conclusion: We suggest that ACTH therapy may be useful for patients with HHE, although further studies are required. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Hemiconvulsion–Hemiplegia–Epilepsy syndrome; Adrenocorticotropic hormone therapy; Lamotrigine; Treatment

1. Introduction Hemiconvulsion–Hemiplegia–Epilepsy (HHE) syndrome is an uncommon outcome of prolonged focal status epilepticus in childhood. The prolonged focal motor seizure usually occurs during the course of a febrile ill-

⇑ Corresponding author at: Department of Pediatrics, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. Tel.: +81 72 683 1221; fax: +81 72 684 5798. E-mail address: [email protected] (S. Shimakawa).

ness and is followed by hemiplegia ipsilateral to the side of convulsions. Intractable epilepsy may develop at a time remote from the initial presentation [1]. There is some evidence that surgical treatment of delayed intractable epilepsy in HHE syndrome is beneficial [1,2]. Herein, we report a patient with HHE syndrome who developed an intractable partial seizure. Although many antiepileptic drugs were ineffective, her seizure was ceased by adrenocorticotropic hormone (ACTH) therapy. ACTH may be useful for treatment of chronic stage partial seizures in HHE patients.

http://dx.doi.org/10.1016/j.braindev.2014.11.003 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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2. Case report A previously healthy, developmentally normal oneyear-old girl presented with left focal clonic motor status epilepticus prolonged for forty five minutes, which developed a day after onset of vomiting, diarrhea, and fever during the clinical course of rotavirus infection. Impairment of consciousness lasted five days, and left focal motor seizures, which were prolonged for several minutes, occurred repeatedly on the second to fourth day after initial status epilepticus. She developed left sided hemiparesis after recovery. CT images at three days after status epilepticus showed an affected right cerebral hemisphere cortex with swelling. Follow-up MRI at 12 months later showed right cerebral hemisphere atrophy and severe right-sided hippocampal atrophy. There was no hyperintensity signal on right hippocampi coronal T2 fluid attenuated inversion recovery imaging (Fig. 1). She was diagnosed with HH syndrome. At 4 months after status epilepticus, she developed a daily epileptic seizure characterized by impaired consciousness, stooped posture, head rotation to the right, and contraction of both upper limbs pre-

dominantly in the left arm during wakefulness. Her seizures occurred daily in 2–3 events per cluster in 1–2 clusters per day with a cluster duration of 40 s. At this time she was diagnosed with idiopathic HHE syndrome at another hospital. Her seizure was not ceased by sodium valproate, clonazepam, clobazam, zonisamide, phenytoin, phenobarbital, topiramate, lamotrigine, or liposteroid. She was referred to our hospital at the age of 7. At that time, 16 mg/day of clobazam, 100 mg/ day of lamotrigine, and 50 mg/day of topiramate were administered. Interictal EEG showed multi-focal abnormalities located in the frontal pole to the frontal region, and high amplitude spikes or spikes and waves in the left hemisphere. On video-EEG monitoring, ictal EEG showed generalized low-amplitude spike bursts arising predominantly from the right hemisphere, followed by high amplitude spikes and waves in the right hemisphere, which corresponded to her habitual seizure (Fig. 2). Although 800 mg/day potassium bromide was added, her seizure was not ceased. After informed consent was obtained, ACTH therapy (synthetic ACTH, zinc hydroxide suspension of tetracosactide acetate [Cortrosyn-Z (Daiichi-Sankyo, Japan)]) was initiated

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Fig. 1. Neuroradiological feature. (a) CT images at three days after status epilepticus. Right cerebral hemisphere cortex with swelling is shown. (b) Follow-up MRI at 12 months later shows atrophy of right cerebral hemisphere. (c) There was no obvious hyperintensity signal on right hippocampus on coronal T2 fluid attenuated inversion recovery imaging at 12 months follow-up. L, left; R, right.

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Fig. 2. Ictal EEG of the habitual seizure showing generalized low-amplitude spike burst arising predominantly from the right hemisphere, followed by high amplitude spike and wave in the right hemisphere. Her habitual seizure occurred in clusters (open arrow). Ictal video: before the attack, she sat on her bed. (1) Her head began to stoop and rotate to the right, and (2) simultaneously, her arms (predominantly left arm) began to contract. (3) She then showed a stooped posture with continued arm contraction. (4) The stooped posture and arm contraction were terminated. We obtained permission of the publication of her photographs from patients’ parents.

as daily intramuscular injections (0.0125 mg/kg) for two weeks, which was then gradually tapered off over one week. At the 10th day of ACTH therapy, the habitual seizure ceased. However, partial seizures characterized by left arm contraction developed on the same day, and continued daily. Paroxysmal discharge was not found in interictal EEG. However, on video-EEG monitoring, ictal EEG showed generalized high-amplitude spike bursts arising predominantly from the left hemisphere, followed by high amplitude slow waves in the left hemisphere, which corresponded to the newly emerged seizure (Fig. 3). On ictal EEG record, this partial seizure duration was 2–3 s and occurred 15 times per

day. As the seizure was thought to be ACTH-induced, clobazam was discontinued. However, as the seizure continued to occur after termination of ACTH therapy, the dose of lamotrigine was increased to 350 mg/day, which prevented the newly emerged seizure and allowed us to reduce topiramate dose to 25 mg/day. The 350 mg/ day lamotrigine and 25 mg topiramate therapy has ceased her seizure for more than one year, which has increased her quality of life as she has not fallen. Adverse events of ACTH therapy including irritability, central obesity, and hypokalemia (serum potassium level was 3 mEq/l) were observed. However, no serious adverse events occurred.

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Fig. 3. Ictal EEG of newly emerging seizure developing during ACTH therapy showing generalized high-amplitude spike burst arising predominantly from the left hemisphere, followed by high amplitude slow wave in the left hemisphere. Ictal video: (1) the beginning of left arm contraction. (2) Left arm was contracted and lifted. (3) Left arm contraction was terminated. We obtained permission of the publication of her photographs from patients’ parents.

3. Discussion We report a girl who developed intractable partial seizure of idiopathic HHE ceased by ACTH therapy. To our knowledge, this is the first report of ACTH therapy in a patient with idiopathic HHE. Although two-third of patients developing HH syndrome will develop epilepsy that is typically intractable [2], there are no treatment guidelines for delayed seizures of children with HHE syndrome. Surgical treatment of delayed intractable epilepsy in HHE syndrome may be beneficial in HHE patients with hippocampal sclerosis detected on MRI and anterior temporal ictal onset on video-EEG monitoring of the delayed epileptic seizure [2]. However, the clinical characteristics of our patient did not match these criteria. Although many anti-epileptic drugs were ineffective, ACTH therapy and lamotrigine ceased her intractable seizure, suggesting that this strategy may be useful for treatment of intractable seizures in HHE patients. The efficacy of ACTH against intractable seizures other than epileptic spasms has been reported [3,4]. However, there are limited data on the efficacy of ACTH therapy against intractable seizures other than epileptic spasms, or on improving cognition and quality of life [5]. Further studies are required to examine efficacy of ACTH therapy for delayed epileptic seizure in

HHE patients. Partial seizure, irritability, central obesity, and hypokalemia (serum potassium level was 3 mEq/l) have been previously reported in patients receiving ACTH therapy [3,4,6]. Although there are no reports of older subjects developing ACTH-induced seizures, we believe the partial seizures in our case were induced by ACTH treatment, as follows: (1) both brief tonic seizures and focal motor seizures induced by ACTH were described, (2) no new epileptic focus was revealed by inter-ictal EEG, and (3) ACTH-induced seizures occurred at 9–11 days of consecutive ACTH injection in previous reports [6]. Other adverse events of ACTH therapy can occur. However, no serious adverse events have been reported with ACTH therapy for childhood epileptic spasms or seizures other than epileptic spasms [3,4,7]. Importantly, no serious adverse effects of ACTH therapy occurred in our case. Thus, ACTH therapy might be safe in childhood for treatment of seizures other than epileptic spasms. Idiopathic HHE was recently considered an acute encephalopathy with inflammation-mediated status epilepticus (AEIMSE) [8–10], and inflammation has been implicated in the pathophysiology of AEIMSE. In an experimental immature rat seizure model, seizure threshold was decreased one month after status epilepticus when lipopolysaccharide was administered with kainic

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acid, suggesting a role of neuroinflammation in longterm changes in brain excitability (termed remote-onset seizures) [10]. Once seizure activity emerges and recurs, it can perpetuate inflammation, thus activating a vicious cycle that in turn fosters aberrant hyperexcitability [10]. Therefore, anti-inflammatory strategies can affect the course of AEIMSE. However, the use of steroids and immunoglobulins was reported to have no effect on AEIMSE [10]. Although the mechanisms underlying the antiepileptic action of ACTH are unknown, ACTH and corticosteroids exhibit immunomodulatory properties [4]. In our case, the ictal spike-wave of the habitual seizure before ACTH therapy was left-sided predominant. The epileptogenesis in the hemisphere contralateral to the atrophic change is interesting. However, because laterality of epileptic focus was not diagnosed by scalp EEG, we could not deny that the epileptic focus may be located on the affected hemisphere. According to Nabbout et al., maturation of interhemispheric commissures is incomplete at the age when idiopathic HH syndrome normally occurs [10]. As our case was referred to our hospital at 7 years, the ictal spike-wave activity with left-sided predominance might be the result of maturation of interhemispheric commissures after remote seizure onset, and might not show the localization of epileptic focus. In summary, ACTH therapy prevented habitual intractable seizures in our case, and she has been free from seizures for more than one year following subsequent lamotrigine administration. ACTH therapy may

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be useful for prevention of seizures developing at the chronic phase in HHE patients, although further evaluation is required. References [1] Tenney JR, Schapiro MB. Child neurology: hemiconvulsion– hemiplegia–epilepsy syndrome. Neurology 2012;79:e1–4. [2] Kim DW, Kim KK, Chu K, Chung CK, Lee SK. Surgical treatment of delayed epilepsy in hemiconvulsion–hemiplegia– epilepsy syndrome. Neurology 2008;70:2116–22. [3] Okumura A, Tsuji T, Kato T, Natsume J, Negoro T, Watanabe K. ACTH therapy for generalized seizures other than spasms. Seizure 2006;15:469–75. [4] Verhelst H, Boon P, Buyse G, Ceulemans B, D’Hooghe M, Meirleir LD, et al. Steroids in intractable childhood epilepsy: clinical experience and review of the literature. Seizure 2005;14:412–21. [5] Gayatri NA, Ferrie CD, Cross H. Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms. Cochrane Database Syst Rev 2007;1:CD005222. [6] Fukui M, Shimakawa S, Tanabe T, Nomura S, Kashiwagi M, Azumakawa K, et al. Partial seizures during ACTH therapy in a cryptogenic West syndrome patient. Brain Dev 2014;36:80–3. [7] Fukui M, Shimakawa S, Kuki I, Kawawaki H, Mogami Y, Suzuki Y, et al. Effect of adrenocorticotropic hormone therapy for epileptic spasms developing after the age of 1 year. Seizure 2014;23:521–6. [8] Nabbout R. FIRES and IHHE: delineation of the syndromes. Epilepsia 2013;54:54–6. [9] Nabbout R. Autoimmune and inflammatory epilepsies. Epilepsia 2012;53:58–62. [10] Nabbout R, Vezzani A, Dulac O, Chiron C. Acute encephalopathy with inflammation-mediated status epilepticus. Lancet Neurol 2011;10:99–108.

ACTH therapy on intractable epilepsy in Hemiconvulsion-Hemiplegia-Epilepsy syndrome.

In the chronic phase of Hemiconvulsion-Hemiplegia-Epilepsy (HHE) syndrome, developing epilepsy may be intractable. Herein, we report a case where adre...
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