Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Efficacy of long term weekly ACTH therapy for intractable epilepsy Takehiko Inui a,1,2, Tomoko Kobayashi b,1, Satoru Kobayashi a,c, Ryo Sato a,b, Wakaba Endo a,b, Atsuo Kikuchi b, Tojo Nakayama b, Mitsugu Uematsu b, Masaru Takayanagi d, Mitsuhiro Kato e, Hirotomo Saitsu f, Naomichi Matsumoto f, Shigeo Kure b, Kazuhiro Haginoya a,b,⇑ a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, 20 Shishioto, Akiu Yumoto, Taihaku-ku, Sendai-shi, Miyagi 982-0241, Japan b Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan c Department of Pediatrics, Nagoya City West Medical Center, Nagoya, Japan d Department of Pediatrics, Sendai City Hospital, Sendai, Japan e Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan f Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan Received 9 May 2014; received in revised form 8 July 2014; accepted 9 July 2014
Abstract Background: Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for infantile spasms, and is effective for many other intractable epilepsies. While spasms may respond to ACTH for weeks, a substantial proportion of patients develop recurrent seizures over a yearly period. To maintain efficacy, we treated two children with intractable epilepsy with weekly ACTH therapy for 1 year and described the changes in clinical seizures, electroencephalograms, developmental assessments and side effects. Subjects and methods: A girl with infantile spasms due to lissencephaly and a boy with atypical absence seizures were studied. In both cases, seizures were frequent and resistant to antiepileptic drugs; electroencephalograms showed continuous epileptiform activities, and the patients’ development was delayed and stagnant prior to ACTH treatment. The initial ACTH therapy (daily 0.015 mg/kg for 2 weeks, 0.015 mg/kg every 2 days for 1 week, 0.0075 mg/kg every 2 days for 1 week), was transiently effective in both cases. The second-round ACTH therapy consisted of the initial ACTH therapy protocol followed by weekly ACTH injections (0.015 mg/kg or 0.0075 mg/kg) for 1 year. Both cases were followed for at least 1 year after therapy. Results: In both patients, clinical seizures were completely controlled during and 1 year after the second-round AHCH therapy. Continuous epileptiform discharges disappeared, while intermittent interictal epileptiform discharges remained. Both patients showed some developmental gains after achieving seizure control. No serious side effects were recorded. Conclusion: Further studies are warranted to determine if a long-term weekly ACTH is a safe and effective treatment for intractable epilepsy. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: ACTH; Intractable epilepsy; Infantile spasms; Atypical absence seizure; LIS1; Lissencephaly
⇑ Corresponding author at: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, 20 Shishioto, Akiu Yumoto, Sendai 982-0241, Japan. Tel.: +81 22 398 2221; fax: +81 22 397 2697. E-mail address: [email protected] (K. Haginoya). 1 These authors contributed equally to this report. 2 Address: 20 Shishioto, Akiu Yumoto, Sendai 982-0241, Japan.
1. Introduction Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for infantile spasms [1]. Despite its high response rate (42–87%) [2], a high proportion of patients (30–72%) suffer relapses [3]. Data on the optimum
http://dx.doi.org/10.1016/j.braindev.2014.07.004 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
2
T. Inui et al. / Brain & Development xxx (2014) xxx–xxx
treatment for spasm relapse are lacking. Possible treatment options include returning to a previously effective protocol, returning to a previously effective agent at the maximum dose, or implementing a new treatment agent [2]. Even if the treatment of relapse is effective, another relapse after the second-round treatment is a major problem [4]. ACTH therapy is also effective for epilepsies other than infantile spasms [5–9]. In many reports, short-term efficacies are relatively good, but high relapse rates are often reported. In this report, we attempted to maintain the efficacy of ACTH therapy with weekly ACTH injections in patients with a relapse of intractable epilepsies. 2. Patients and ACTH treatment protocol We describe two children with intractable seizures, who relapsed after treatment (Table 1). The initial ACTH therapy protocol consisted of daily intramuscular injections of synthetic ACTH-Z (zinc hydroxide suspension of tetracosactide) at a dose of 0.015 mg/kg (0.6 IU/kg) for 2 weeks, then reduced gradually over 2 weeks. The second-round of ACTH therapy began after informed consent was obtained from both parents. Its protocol consisted of the initial protocol for 4 weeks, followed by weekly intramuscular ACTH injections at the dose of 0.0075 mg/kg or 0.015 mg/kg (0.3 and 0.6 IU/kg) for 1 year. The therapy was not given when the patient had a fever. Both cases were followed over 1 year after the treatment. Adverse events including hypertension, infection, irritability, hyperglycemia, hypokalemia, elevation of liver enzymes, brain atrophy, and intracranial hemorrhage were recorded. 3. Case reports 3.1. Case 1 A 3-year-old female was born normally at 40 weeks of gestation. Her birth weight was 2,922 g, and her family history was unremarkable. At 2 months, she presented with frequent generalized clonic seizures. Her brain magnetic resonance imaging (MRI) revealed lissencephaly (Fig. 1-A). At 3 months, she manifested a series of spasms and the electroencephalogram evolved into hypsarrhythmia (Fig. 1-B). At 3 months, she was started on ACTH therapy. Spasms and hypsarrhythmia disappeared in few days (Fig. 1-C), but returned at 8 months (Fig. 1-D). At that time, she did not have head control. At 11 months, she was started on the second-round of ACTH therapy. Her seizures and hypsarrhythmia disappeared in 4 weeks of treatment. Weekly ACTH therapy was continued for 1 year. During this period, clonazepam was
ceased. No side effects were observed. Her electroencephalogram showed 12–14 Hz-fast waves over both frontal areas (Fig. 1-E). One year after the therapy, she had no seizures and her electroencephalogram exhibited the same pattern with rare spike-waves (Fig. 1-F). She had head control at 1 year 7 months, and could maintain a seated position at 3 years. 3.2. Case 2 A 5-year-old male was born normally at 38 weeks of gestation. His birth weight was 2,924 g, and his family history was unremarkable. At 10 months, rhythmic myoclonus was observed in the extremities. At 2 years 5 months, he presented with frequent atypical absence seizures and occasional partial seizures. His electroencephalogram showed repetitive spike and spike-and-wave discharges over both centro-temporal areas (Fig. 2-A). He was diagnosed with an atypical benign partial epilepsy variant [10]. At 2 years 11 months, his electroencephalogram showed continuous diffuse spike-and-wave (Fig. 2-B). He was started on ACTH therapy. His atypical absence seizures and spike-wave discharges disappeared in few days (Fig. 2-C), but returned 1 month after the therapy (Fig. 2-D). At that time, he could crawl but could not stand with support. At 3 years 6 months, the second-round of ACTH therapy was begun. His atypical absence seizures were controlled in few days. Weekly ACTH therapy was continued for 1 year. The therapy was skipped three times for mild infection, but no other side effects were observed. During this period, zonisamide was added for epileptic discharges, resulted in no efficacy. After the therapy, his electroencephalogram had few spikeand-wave discharges over both central areas (Fig. 2-E). His action myoclonus ameliorated. One year after the therapy, he has rare and questionable partial seizures, but no atypical absence seizures. His electroencephalogram has no paroxysmal activity (Fig. 2-F). He can now stand with support and reach to people. 4. Discussion Our study demonstrates seizure cessation following weekly ACTH therapy in two patients with intractable epilepsies, which recurred after short-term ACTH therapy. These results are consistent with several previous studies. Okumura et al. reported that 13 of 15 patients with generalized intractable seizures became seizure free after ACTH treatment, but 9 patients suffered relapse [9]. Oguni et al. reported that 19 of 30 patients with epileptic spasms without hypsarrhythmia became seizure free after ACTH treatment, but 9 patients experienced recurrence [5]. These facts indicate that while ACTH may be effective for seizure cessation, its effects may also be transient in about half of those who respond.
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
T. Inui et al. / Brain & Development xxx (2014) xxx–xxx
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Table 1 Summary of both cases. Case 1
Case2
Etiology
Lissencephaly
Unknown
Genetic testing
LIS1 p.W261X
ATN1, UBE3A: no causative mutation CGH array (SurePrint G3 CGH + SNP Microarray Kit 4 180 K (ISCA)(Agilent)): negative Whole exome sequencing (including KCNT1, SCN8A, FOXG1, KCNQ2, SCN1A, SCN2A, STXBP1, SPTAN1, CDKL5, PCDH19, MECP2, GNAO1, CASK, SLC35A2, ALG13, GABRB3, HDAC4, DNM1, CHD2, SYNGAP1, GRIN2A, QARS): no pathogenic mutation
Metabolic testing
Serum amino acid: not specific Spinal fluid lactate, pyruvate: not rised Enzyme activity of PPT-1, TTP-1: normal
Epileptic syndrome
Infantile spasms
ABPE variant
Seizure type
Spasm
Atypical absence Partial seizure
Age at onset of seizure
2 mo
2 y and 5 mo
Treatment before initial ACTH
PB
ZNS, CZP, ESM, VPA, TPM, DZP, CLB, NZP, LEV, LTG
3 mo 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Spasms disappeared in 4 d 8 mo VPA, CZP, ZNS, TPM
2 y 11 mo 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Atypical absence seizures disappeared in 4 d 3 y 1 mo LOF, AZA, PHT, KBr, Ketogenic diet
11 mo No head control, no social smile 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Then 0.015 mg/kg, weekly for 1 y VPA, CZP, TPM Cease CZP after seizure control
3 y 6 mo Crawl, cannot stand with support 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Then 0.0075 mg/kg weekly for 1 y AZA, ESM, LOF Add ZNS for EEG abnormality (no effect)
Spasms disappear in 6 d None 1.28 mg/kg
Atypical absence seizures disappear in 10 d 3 times for infection 0.93 mg/kg
Adverse effect
No remarkable adverse effect
Mild upper respiratory tract infection, 3 times
Follow up period after therapy
1 y 4m
1y
Seizure prognosis
No seizure
No atypical absence seizure Rare and questionable partial seizure
Developmental prognosis
Pursuit, social smile, sit alone
Stand with support
Initial ACTH therapy Age at start Dosage
Efficacy Relapse Treatment after relapse Secondary ACTH therapy Age at start Development before therapy Dosage
Antiepileptic drugs at the start of therapy Change of antiepileptic drugs during therapy Efficacy Therapy skipped Total dose
Involuntary movement
Improved myoclonus
Abbreviations: CGH=comparative genomic hybridization; PPT-1, palmitoyl-protein thioesterase 1; TTP-1, tripeptidyl peptidase 1; ABPE, atypical benign partial epilepsy; ACTH, adrenocorticotropic hormone; y, year(s); mo, month(s); PB, phenobarbital; ZNS, zonisamide; CZP, clonazepam; ESM, ethosuximide; VPA, valporate; TPM, topiramate; DZP, diazepam; NZP, nitrazepam; LEV, levetiracetam; LTG, lamotrigine ; LOF, ethyl loflazepate; AZA, acetazolamide; PHT, phenytoin; KBr, potassium bromide; d, day(s); EEG, electroencephalogram; Hyps, hypsarrhythmia; CLB, clobazam.
Okanishi et al. treated relapsed West syndrome with weekly or biweekly ACTH with excellent efficacy and few side effects [3]. This result, taken together with our findings, indicates that seizure relapse following ACTH
therapy may be reduced safely with long-term, weekly ACTH therapy. The patients in this report achieved perfect seizure control 1 year after the therapy. During weekly ACTH
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
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Fig. 1. Brain imaging and electroencephalograms during sleep in case 1. (A) Axial T1-weighted magnetic resonance image at the level of the basal ganglia. Frontal pachygyria and occipital agyria conforming posterior dominant grade 3 classical lissencephaly, consistent with the LIS1 mutation, are seen. (B) Before ACTH therapy, hypsarrhythmia was evident. (C) After the first round of ACTH therapy. High voltage spikes and waves were observed, but hypsarrhythmia had disappeared. (D) Before the second-round of ACTH therapy, hypsarrhythmia recurred. (E) After weekly ACTH therapy, 12–14-Hz fast waves were seen over both frontal areas. (F) One year after the completion of weekly ACTH therapy, the pattern was the same as in (E).
therapy, there were some changes in anticonvulsants regimen in both patients. However, since drugs were changed after the seizure control in both patients, and had no effect on electroencephalogram, second-round ACTH therapy was considered as the most probable cause of the successful seizure control during and after the therapy. Our patients’ development was stagnant when their seizures appeared, but their development resumed when their seizures were controlled. These changes in
development suggest that seizure control was critical for development in these patients. There were no serious adverse effects from ACTH therapy in our patients. The total ACTH dose correlates with the incidence of adverse effects, and in our protocol the total ACTH dose was 0.9–1.3 mg/kg (36–52 IU/kg), which is lower than used in high-dose protocols [2]. Thus low-dose weekly ACTH therapy may be indicated in cases of intractable, ACTH-responsive epilepsy. Further studies are warranted to determine its efficacy,
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
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Fig. 2. Electroencephalograms during sleep in case 2. (A) At the age of 2 years 5 months, repetitive spike and spike-and-wave discharges were seen over both centro-temporal areas. (B) Before the initial ACTH therapy, diffuse continuous high-voltage spike-and-wave discharges with maximum voltage were observed over the centro-temporal areas. (C) After initial ACTH therapy, spike-and-wave discharges disappeared. (D) After the recurrence, diffuse continuous high voltage spike-and-wave discharges recurred. (E) After weekly ACTH therapy, few spike-and-wave discharges were observed over both central areas. (F) One year after the end of ACTH therapy, no paroxysmal activity was seen.
indicated seizure type, the optimum dose and duration of ACTH therapy. References [1] Go CY, Mackay MT, Weiss SK, Stephens D, Adams-Webber T, Ashwal S, 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;78:1974–80.
[2] Pellock JM, Hrachovy R, Shinnar S, Baram TZ, Bettis D, Dlugos DJ, et al. Infantile spasms: a U.S. consensus report. Epilepsia 2010;51:2175–89. [3] Okanishi T, Sugiura C, Saito Y, Maegaki Y, Ohno K, Togari H. Long-term weekly ACTH therapy for relapsed West syndrome. Pediatr Neurol 2008;38:445–9. [4] Mohamed BP, Scott RC, Desai N, Gutta P, Patil S. Seizure outcome in infantile spasms – a retrospective study. Epilepsia 2011;52:746–52. [5] Oguni H, Funatsuka M, Sasaki K, Nakajima T, Yoshii K, Nishimura T, et al. Effect of ACTH therapy for epileptic spasms without hypsarrhythmia. Epilepsia 2005;46:709–15.
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T. Inui et al. / Brain & Development xxx (2014) xxx–xxx [6] Haberlandt E, Weger C, Sigl SB, Rauchenzauner M, Scholl-Bu¨rgi S, Rosta´sy K, et al. Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes. Pediatr Neurol 2010;42:21–7. [7] Inutsuka M, Kobayashi K, Oka M, Hattori J, Ohtsuka Y. Treatment of epilepsy with electrical status epilepticus during slow sleep and its related disorders. Brain Dev 2006;28:281–6. [8] Fujii A, Oguni H, Hirano Y, Osawa M. Atypical benign partial epilepsy: recognition can prevent pseudocatastrophe. Pediatr Neurol 2010;43:411–9.
[9] 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. [10] Kobayashi S, Inui T, Wakusawa K, Tanaka S, Nakayama T, Uematsu M, et al. A case of atypical benign partial epilepsy with action myoclonus. Seizure 2013;22:242–5.
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Case Report
Efficacy of long term weekly ACTH therapy for intractable epilepsy Takehiko Inui a,1,2, Tomoko Kobayashi b,1, Satoru Kobayashi a,c, Ryo Sato a,b, Wakaba Endo a,b, Atsuo Kikuchi b, Tojo Nakayama b, Mitsugu Uematsu b, Masaru Takayanagi d, Mitsuhiro Kato e, Hirotomo Saitsu f, Naomichi Matsumoto f, Shigeo Kure b, Kazuhiro Haginoya a,b,⇑ a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, 20 Shishioto, Akiu Yumoto, Taihaku-ku, Sendai-shi, Miyagi 982-0241, Japan b Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan c Department of Pediatrics, Nagoya City West Medical Center, Nagoya, Japan d Department of Pediatrics, Sendai City Hospital, Sendai, Japan e Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan f Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan Received 9 May 2014; received in revised form 8 July 2014; accepted 9 July 2014
Abstract Background: Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for infantile spasms, and is effective for many other intractable epilepsies. While spasms may respond to ACTH for weeks, a substantial proportion of patients develop recurrent seizures over a yearly period. To maintain efficacy, we treated two children with intractable epilepsy with weekly ACTH therapy for 1 year and described the changes in clinical seizures, electroencephalograms, developmental assessments and side effects. Subjects and methods: A girl with infantile spasms due to lissencephaly and a boy with atypical absence seizures were studied. In both cases, seizures were frequent and resistant to antiepileptic drugs; electroencephalograms showed continuous epileptiform activities, and the patients’ development was delayed and stagnant prior to ACTH treatment. The initial ACTH therapy (daily 0.015 mg/kg for 2 weeks, 0.015 mg/kg every 2 days for 1 week, 0.0075 mg/kg every 2 days for 1 week), was transiently effective in both cases. The second-round ACTH therapy consisted of the initial ACTH therapy protocol followed by weekly ACTH injections (0.015 mg/kg or 0.0075 mg/kg) for 1 year. Both cases were followed for at least 1 year after therapy. Results: In both patients, clinical seizures were completely controlled during and 1 year after the second-round AHCH therapy. Continuous epileptiform discharges disappeared, while intermittent interictal epileptiform discharges remained. Both patients showed some developmental gains after achieving seizure control. No serious side effects were recorded. Conclusion: Further studies are warranted to determine if a long-term weekly ACTH is a safe and effective treatment for intractable epilepsy. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: ACTH; Intractable epilepsy; Infantile spasms; Atypical absence seizure; LIS1; Lissencephaly
⇑ Corresponding author at: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, 20 Shishioto, Akiu Yumoto, Sendai 982-0241, Japan. Tel.: +81 22 398 2221; fax: +81 22 397 2697. E-mail address: [email protected] (K. Haginoya). 1 These authors contributed equally to this report. 2 Address: 20 Shishioto, Akiu Yumoto, Sendai 982-0241, Japan.
1. Introduction Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for infantile spasms [1]. Despite its high response rate (42–87%) [2], a high proportion of patients (30–72%) suffer relapses [3]. Data on the optimum
http://dx.doi.org/10.1016/j.braindev.2014.07.004 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
2
T. Inui et al. / Brain & Development xxx (2014) xxx–xxx
treatment for spasm relapse are lacking. Possible treatment options include returning to a previously effective protocol, returning to a previously effective agent at the maximum dose, or implementing a new treatment agent [2]. Even if the treatment of relapse is effective, another relapse after the second-round treatment is a major problem [4]. ACTH therapy is also effective for epilepsies other than infantile spasms [5–9]. In many reports, short-term efficacies are relatively good, but high relapse rates are often reported. In this report, we attempted to maintain the efficacy of ACTH therapy with weekly ACTH injections in patients with a relapse of intractable epilepsies. 2. Patients and ACTH treatment protocol We describe two children with intractable seizures, who relapsed after treatment (Table 1). The initial ACTH therapy protocol consisted of daily intramuscular injections of synthetic ACTH-Z (zinc hydroxide suspension of tetracosactide) at a dose of 0.015 mg/kg (0.6 IU/kg) for 2 weeks, then reduced gradually over 2 weeks. The second-round of ACTH therapy began after informed consent was obtained from both parents. Its protocol consisted of the initial protocol for 4 weeks, followed by weekly intramuscular ACTH injections at the dose of 0.0075 mg/kg or 0.015 mg/kg (0.3 and 0.6 IU/kg) for 1 year. The therapy was not given when the patient had a fever. Both cases were followed over 1 year after the treatment. Adverse events including hypertension, infection, irritability, hyperglycemia, hypokalemia, elevation of liver enzymes, brain atrophy, and intracranial hemorrhage were recorded. 3. Case reports 3.1. Case 1 A 3-year-old female was born normally at 40 weeks of gestation. Her birth weight was 2,922 g, and her family history was unremarkable. At 2 months, she presented with frequent generalized clonic seizures. Her brain magnetic resonance imaging (MRI) revealed lissencephaly (Fig. 1-A). At 3 months, she manifested a series of spasms and the electroencephalogram evolved into hypsarrhythmia (Fig. 1-B). At 3 months, she was started on ACTH therapy. Spasms and hypsarrhythmia disappeared in few days (Fig. 1-C), but returned at 8 months (Fig. 1-D). At that time, she did not have head control. At 11 months, she was started on the second-round of ACTH therapy. Her seizures and hypsarrhythmia disappeared in 4 weeks of treatment. Weekly ACTH therapy was continued for 1 year. During this period, clonazepam was
ceased. No side effects were observed. Her electroencephalogram showed 12–14 Hz-fast waves over both frontal areas (Fig. 1-E). One year after the therapy, she had no seizures and her electroencephalogram exhibited the same pattern with rare spike-waves (Fig. 1-F). She had head control at 1 year 7 months, and could maintain a seated position at 3 years. 3.2. Case 2 A 5-year-old male was born normally at 38 weeks of gestation. His birth weight was 2,924 g, and his family history was unremarkable. At 10 months, rhythmic myoclonus was observed in the extremities. At 2 years 5 months, he presented with frequent atypical absence seizures and occasional partial seizures. His electroencephalogram showed repetitive spike and spike-and-wave discharges over both centro-temporal areas (Fig. 2-A). He was diagnosed with an atypical benign partial epilepsy variant [10]. At 2 years 11 months, his electroencephalogram showed continuous diffuse spike-and-wave (Fig. 2-B). He was started on ACTH therapy. His atypical absence seizures and spike-wave discharges disappeared in few days (Fig. 2-C), but returned 1 month after the therapy (Fig. 2-D). At that time, he could crawl but could not stand with support. At 3 years 6 months, the second-round of ACTH therapy was begun. His atypical absence seizures were controlled in few days. Weekly ACTH therapy was continued for 1 year. The therapy was skipped three times for mild infection, but no other side effects were observed. During this period, zonisamide was added for epileptic discharges, resulted in no efficacy. After the therapy, his electroencephalogram had few spikeand-wave discharges over both central areas (Fig. 2-E). His action myoclonus ameliorated. One year after the therapy, he has rare and questionable partial seizures, but no atypical absence seizures. His electroencephalogram has no paroxysmal activity (Fig. 2-F). He can now stand with support and reach to people. 4. Discussion Our study demonstrates seizure cessation following weekly ACTH therapy in two patients with intractable epilepsies, which recurred after short-term ACTH therapy. These results are consistent with several previous studies. Okumura et al. reported that 13 of 15 patients with generalized intractable seizures became seizure free after ACTH treatment, but 9 patients suffered relapse [9]. Oguni et al. reported that 19 of 30 patients with epileptic spasms without hypsarrhythmia became seizure free after ACTH treatment, but 9 patients experienced recurrence [5]. These facts indicate that while ACTH may be effective for seizure cessation, its effects may also be transient in about half of those who respond.
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
T. Inui et al. / Brain & Development xxx (2014) xxx–xxx
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Table 1 Summary of both cases. Case 1
Case2
Etiology
Lissencephaly
Unknown
Genetic testing
LIS1 p.W261X
ATN1, UBE3A: no causative mutation CGH array (SurePrint G3 CGH + SNP Microarray Kit 4 180 K (ISCA)(Agilent)): negative Whole exome sequencing (including KCNT1, SCN8A, FOXG1, KCNQ2, SCN1A, SCN2A, STXBP1, SPTAN1, CDKL5, PCDH19, MECP2, GNAO1, CASK, SLC35A2, ALG13, GABRB3, HDAC4, DNM1, CHD2, SYNGAP1, GRIN2A, QARS): no pathogenic mutation
Metabolic testing
Serum amino acid: not specific Spinal fluid lactate, pyruvate: not rised Enzyme activity of PPT-1, TTP-1: normal
Epileptic syndrome
Infantile spasms
ABPE variant
Seizure type
Spasm
Atypical absence Partial seizure
Age at onset of seizure
2 mo
2 y and 5 mo
Treatment before initial ACTH
PB
ZNS, CZP, ESM, VPA, TPM, DZP, CLB, NZP, LEV, LTG
3 mo 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Spasms disappeared in 4 d 8 mo VPA, CZP, ZNS, TPM
2 y 11 mo 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Atypical absence seizures disappeared in 4 d 3 y 1 mo LOF, AZA, PHT, KBr, Ketogenic diet
11 mo No head control, no social smile 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Then 0.015 mg/kg, weekly for 1 y VPA, CZP, TPM Cease CZP after seizure control
3 y 6 mo Crawl, cannot stand with support 0.015 mg/kg daily for 14 d, 0.015 mg/kg every 2 d for 7 d 0.0075 mg/kg every 2 d for 7 d Then 0.0075 mg/kg weekly for 1 y AZA, ESM, LOF Add ZNS for EEG abnormality (no effect)
Spasms disappear in 6 d None 1.28 mg/kg
Atypical absence seizures disappear in 10 d 3 times for infection 0.93 mg/kg
Adverse effect
No remarkable adverse effect
Mild upper respiratory tract infection, 3 times
Follow up period after therapy
1 y 4m
1y
Seizure prognosis
No seizure
No atypical absence seizure Rare and questionable partial seizure
Developmental prognosis
Pursuit, social smile, sit alone
Stand with support
Initial ACTH therapy Age at start Dosage
Efficacy Relapse Treatment after relapse Secondary ACTH therapy Age at start Development before therapy Dosage
Antiepileptic drugs at the start of therapy Change of antiepileptic drugs during therapy Efficacy Therapy skipped Total dose
Involuntary movement
Improved myoclonus
Abbreviations: CGH=comparative genomic hybridization; PPT-1, palmitoyl-protein thioesterase 1; TTP-1, tripeptidyl peptidase 1; ABPE, atypical benign partial epilepsy; ACTH, adrenocorticotropic hormone; y, year(s); mo, month(s); PB, phenobarbital; ZNS, zonisamide; CZP, clonazepam; ESM, ethosuximide; VPA, valporate; TPM, topiramate; DZP, diazepam; NZP, nitrazepam; LEV, levetiracetam; LTG, lamotrigine ; LOF, ethyl loflazepate; AZA, acetazolamide; PHT, phenytoin; KBr, potassium bromide; d, day(s); EEG, electroencephalogram; Hyps, hypsarrhythmia; CLB, clobazam.
Okanishi et al. treated relapsed West syndrome with weekly or biweekly ACTH with excellent efficacy and few side effects [3]. This result, taken together with our findings, indicates that seizure relapse following ACTH
therapy may be reduced safely with long-term, weekly ACTH therapy. The patients in this report achieved perfect seizure control 1 year after the therapy. During weekly ACTH
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
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Fig. 1. Brain imaging and electroencephalograms during sleep in case 1. (A) Axial T1-weighted magnetic resonance image at the level of the basal ganglia. Frontal pachygyria and occipital agyria conforming posterior dominant grade 3 classical lissencephaly, consistent with the LIS1 mutation, are seen. (B) Before ACTH therapy, hypsarrhythmia was evident. (C) After the first round of ACTH therapy. High voltage spikes and waves were observed, but hypsarrhythmia had disappeared. (D) Before the second-round of ACTH therapy, hypsarrhythmia recurred. (E) After weekly ACTH therapy, 12–14-Hz fast waves were seen over both frontal areas. (F) One year after the completion of weekly ACTH therapy, the pattern was the same as in (E).
therapy, there were some changes in anticonvulsants regimen in both patients. However, since drugs were changed after the seizure control in both patients, and had no effect on electroencephalogram, second-round ACTH therapy was considered as the most probable cause of the successful seizure control during and after the therapy. Our patients’ development was stagnant when their seizures appeared, but their development resumed when their seizures were controlled. These changes in
development suggest that seizure control was critical for development in these patients. There were no serious adverse effects from ACTH therapy in our patients. The total ACTH dose correlates with the incidence of adverse effects, and in our protocol the total ACTH dose was 0.9–1.3 mg/kg (36–52 IU/kg), which is lower than used in high-dose protocols [2]. Thus low-dose weekly ACTH therapy may be indicated in cases of intractable, ACTH-responsive epilepsy. Further studies are warranted to determine its efficacy,
Please cite this article in press as: Inui T et al. Efficacy of long term weekly ACTH therapy for intractable epilepsy. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2014.07.004
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Fig. 2. Electroencephalograms during sleep in case 2. (A) At the age of 2 years 5 months, repetitive spike and spike-and-wave discharges were seen over both centro-temporal areas. (B) Before the initial ACTH therapy, diffuse continuous high-voltage spike-and-wave discharges with maximum voltage were observed over the centro-temporal areas. (C) After initial ACTH therapy, spike-and-wave discharges disappeared. (D) After the recurrence, diffuse continuous high voltage spike-and-wave discharges recurred. (E) After weekly ACTH therapy, few spike-and-wave discharges were observed over both central areas. (F) One year after the end of ACTH therapy, no paroxysmal activity was seen.
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T. Inui et al. / Brain & Development xxx (2014) xxx–xxx [6] Haberlandt E, Weger C, Sigl SB, Rauchenzauner M, Scholl-Bu¨rgi S, Rosta´sy K, et al. Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes. Pediatr Neurol 2010;42:21–7. [7] Inutsuka M, Kobayashi K, Oka M, Hattori J, Ohtsuka Y. Treatment of epilepsy with electrical status epilepticus during slow sleep and its related disorders. Brain Dev 2006;28:281–6. [8] Fujii A, Oguni H, Hirano Y, Osawa M. Atypical benign partial epilepsy: recognition can prevent pseudocatastrophe. Pediatr Neurol 2010;43:411–9.
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