Long-term weekly adrenocorticotropic hormone therapy for relapsed infantile spasms

Takeo Kato1*, Minako Ide1 and Masatoshi Nakata2

1Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
2Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto Japan

 Infantile spasms (IS) is the most recognized epileptic encephalopathy in early infancy, resulting in poor cognitive outcome. Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for IS, but the relapse rate is high. Relapse after initial ACTH therapy is a poor prognostic factor for long-term seizure control and outcome of cognitive function. Recently, several studies have reported on the long-lasting maintenance of the positive effects produced by an initial course of ACTH by using long-term weekly ACTH therapy for relapsed IS. Here, we review the clinical characteristics of five previously reported cases. Epileptic spasms and hypsarrhythmia remained completely resolved during the extended ACTH therapy and did not recur after ACTH discontinuation in all cases. Furthermore, no cognitive or neurodevelopment deterioration was observed, and no serious adverse events occurred in any patient. In conclusion, this therapy appears safe and may lead to improved psychomotor development. We believe that it may be a good alternative therapy when frequent relapses occur after a favorable response to an initial course of conventional ACTH therapy. However, further studies are required to examine the risks and benefits of this therapy for relapsed IS in a large population and in countries in addition to Japan.


Infantile spasms (IS), or West syndrome is the most recognized epileptic encephalopathy in early infancy, resulting in poor cognitive outcome1-5. The incidence of IS is estimated to be about 1 per 2000 to 4000 live births4,5. The disorder presents with a unique seizure type, epileptic spasms (ES), a characteristic electroencephalography (EEG) pattern called hypsarrhythmia, and psychomotor delay/regression. Developmental outcome is poor in patients with IS, and a majority of patients have moderate or severe mental retardation. The most important prognostic factors include the etiology of IS and the duration of hypsarrhythmia. Early control of hypsarrhythmia is crucial for improved neurodevelopmental prognosis6,7, and a recent study demonstrated that the risk of lower mental outcome in IS increases after 3 weeks duration of hypsarrhythmia7. Another prognostic indicator, sustained response to therapy without relapse, is also associated with favorable prognostic outcomes8. Thus, the goal of the treatment for IS should be to produce not only cessation of spasms but also resolution of hypsarrhythmia as rapidly as possible.

Evidence does not support the clinical efficacy of most conventional anti-epileptic drugs (AEDs) as effective treatments for IS8. The American Academy of Neurology and the Child Neurology Society concluded that natural or synthetic adrenocorticotropic hormone (ACTH) therapy is probably effective for short-duration treatment of IS and resolution of hypsarrhythmia9. Several studies have reported that the clinical response to ACTH therapy in 42–87% of patients within 2 weeks occurred without major adverse side effects, but relapse rate is high (from 30% to 72%)1,10-16. Matsumoto et al. reported that relapse after initial ACTH therapy is a poor prognostic factor for long-term seizure control17. Riikonen et al. showed that a second course of ACTH controls IS in only 23% of relapsed IS patients after the first course of ACTH therapy18. Thus, one problem with conventional ACTH therapy is a high relapse rate. Recently, several studies have reported that a successful alternative therapy, namely, long-term weekly ACTH therapy for relapsed IS after the first conventional ACTH therapy, resolves this problem19-21. The aim of this therapy is to maintain the positive ACTH effects for a long time. Okanishi et al. first reported successful long-term ACTH therapy in three patients with relapsed IS19. Inui et al. then reported one case20. We reported successful long-term weekly ACTH therapy for relapsed IS after conventional ACTH therapy in a child with tuberous sclerosis complex (TSC)21.

In our case, the patient had a series of ES and hypsarrhythmia (Figure 1A) at the age of 3 months. She was diagnosed with IS associated with TSC, and was treated with conventional synthetic ACTH therapy (0.005 mg/kg daily for 2 weeks) at 4 months of age, and a second course of ACTH therapy (0.01 mg/kg daily for 2 weeks) at 8 months of age. We could not use Vigabatrin (VGB), because this drug had not been approved for use in Japan at the point of the study. Both courses were transiently effective, but the patient relapsed. A third course of ACTH therapy (0.01 mg/kg daily for 2 weeks) was begun at age 1 year and 2 months, and long-term weekly ACTH therapy (0.01 mg/kg weekly) was continued thereafter. During this extended therapy, both ES and hypsarrhythmia remained completely resolved (Figure 1B). Therapy was continued, and dose reduction was started when the patient was 2 years and 10 months old. The AED treatment regimen did not change during long-term weekly ACTH therapy. No serious adverse events, including hypertension, infection, and irritability occurred during this therapy. Three months after discontinuing ACTH therapy, the patient developed tonic seizures; however, the attacks were well controlled by administering a combination of lamotrigine and valproate. Although focal epileptic discharges remained on EEG, no relapse of ES or hypsarrhythmia was observed afterwards (Figure 1C), and topiramate treatment was discontinued. The patient was able to stand without support and speak some words by 1 year and 5 months of age. Her developmental quotient scores were 54 and 53 at 1 year and 8 months and at 3 years and 8 months of age, respectively.


Figure 1:Interictal sleep EEG of the case 5.

The EEG data revealed hypsarrhythmia at initial presentation (A), rare spikes in the occipital regions during long-term ACTH (B) and at age 3 years (C). Interictal EEGs were done by every 6 months during and after the long-term ACTH therapy both.

The clinical characteristics of five previously reported cases, including ours, are summarized in Table 1. Because all of these cases were reported in Japan, the ACTH preparation used was synthetic. The mean age at the start of treatment and the duration of long-term weekly ACTH therapy were 19.6 months (range, 11-28 months) and 12.8 months (range, 7-21 months), respectively. The ACTH preparation contained an extremely low dose, with a mean dose of 0.0127 mg/kg/dose (range, 0.01-0.015 mg/kg/dose) during long-term weekly ACTH therapy. During this therapy, no relapse was observed for ES and hypsarrhythmia on EEG; however, three cases developed generalized tonic seizures several months after therapy was discontinued. No neurodevelopment decline was observed during this treatment. In our aforementioned case, the developmental quotient score was maintained during long-term weekly ACTH therapy and thereafter. The results of previous studies suggested a poor prognosis of cognitive function and epilepsy was likely in our patient because she had IS with TSC and experienced frequent relapses22,23. However, the resolution of both ES and hypsarrhythmia, which can damage the developing brain, may have improved her development. Thus, we suggested in that report that long-term weekly ACTH therapy may be effective and used as an alternative treatment for relapsed IS. In all cases, the response to conventional ACTH therapy for both ES and hypsarrhythmia was good. Of the all five cases, ES was resolved within 1 week after the first ACTH course in four cases, and after the second ACTH course in three cases. These results suggested that a good response to conventional ACTH therapy may be important for successful long-term weekly ACTH therapy, because long-term ACTH weekly therapy may maintain the initial effects.


Table 1:

Clinical characteristics and schedules of conventional and long-term weekly ACTH therapy in five previously reported cases

Abbreviations: Y, year; mo, month; d, day; VitB6, vitamin B6; NZP, nitrazepam; VPA, valproate; VGB, vigabatrin; CZP, clonazepam; ZNS, zonisamide; CBZ, carbamazepine; PB, phenobarbital; TPM, topiramate; TRH, thyroid release hormone; GTS, generalized tonic seizure; All remaining abbreviations are defined in the main text.

Several issues remain to be resolved when conducting long-term weekly ACTH therapy, one of which is the optimal treatment period. In four of the aforementioned cases, not our case, the duration of long-term weekly ACTH therapy was approximately 1 year. In our case, therapy was intended to be discontinued when the patient was 2 years old; however, because ES recurred, therapy was resumed. Thus, the duration of therapy in our case was approximately 2 years, as our patient discontinued ACTH therapy when she was 3 years old. We questioned whether the key to successful long-term weekly ACTH therapy was the duration of this therapy. Okanishi et al. reported that all three of their patients were able to discontinue treatment at approximately 3 years of age, although the duration of therapy was 1 year19. In general, despite having a reputation of being difficult to treat, the spasms occurring in this condition tend to spontaneously resolve with age. ES disappears in 50% of children by the age of 3 years, and hypsarrhythmia is rare after 3 years of age3,24. Considering that IS is an age-dependent, epileptic encephalopathy syndrome, we consider that the age up to which the patient receives long-term weekly ACTH therapy is more important than the duration of this therapy. Thus, we recommend continuing this therapy until the patient is 3 years of age, after which time the epileptic activity appears to be naturally suppressed.

An additional concern about long-term weekly ACTH administration is adverse effects. In general, ACTH therapy is associated with some adverse effects, including obesity, hypertension, hypertrichosis, cardiac myopathy, brain shrinkage, subdural hematoma, and immunosuppression, leading to lethal infection. However, during the ACTH therapy in our case and in the other cases examined here, no serious adverse events occurred. In two of the five cases, mild adverse effects were reported, including transient mild cardiac hypertrophy, irritability, hyperphagia, oral candidiasis, transient fever, irritability, and weight gain25. In our case, the patient experienced chickenpox during therapy without severe manifestations. She had not been previously vaccinated, and the disease was resolved by standard antiviral treatment with acyclovir. She showed normal immunoglobulin levels throughout therapy, acquiring anti-varicella zoster immunoglobulin G after the infection. Thus, these results indicated the relatively safety of the therapy regarding immunosuppression; however, further studies should be conducted because chickenpox may be life-threatening in immunosuppressed patients. In the patient’s endocrine system, her cortisol level was within the reference range, but her ACTH level was low (2.2 pg/ml; reference range 7.2 - 63.3 pg/mL). When the rapid ACTH test was carried out during long-term ACTH therapy, serum cortisol levels showed a normal response. Thus, we skipped the ACTH bolus when patients developed a fever and did not employ hydrocortisone replacement therapy. No obvious brain shrinkage was observed during therapy in our case. Additionally, because previous studies have used a synthetic ACTH preparation, the safety and efficacy of natural preparations are unknown.

Another concern is that we do not fully understand the impact of long-term weekly ACTH administration on the developing brain. Lorusso et al. reported low-dose synthetic ACTH therapy (ACTH analog tetracosactide; 1 mg intramuscularly once a week for 12 months) of adult nephrotic patients (n=80). In their study, no neuropsychiatry adverse effects were reported. However, in another report, in which adult patients (n=20) with idiopathic membranous nephropathy were treated with a synthetic ACTH analog with a total treatment period of nine months and 59 injections (1mg/dose), neuropsychiatry adverse effects, including mood disorders and agitation, in 8 patients (40%), were observed. Because all cases examined here were symptomatic IS, it remains controversial whether this therapy should be applied to other relapsed IS cases, including cryptogenic IS. In conclusion, we reviewed the successful use of long-term weekly ACTH therapy for relapsed IS after a first course of conventional ACTH therapy. This therapy may have advantages over other conventional therapies because it has the potential of eliminating the risk of ES and hypsarrhythmia, which outweights its potential adverse effects. We believe that this therapy has merits that could improve the quality of life and daily activities of patients, even in those with severe neurodevelopmental disabilities. Although it may be a good alternative therapy for patients with frequent relapses after a favorable response to conventional ACTH therapy, this therapy should be selected only if other treatments, including new AEDs such as vigabatrin, and epilepsy surgery, are not applicable or effective. Further studies will be required to determine whether the therapy has adverse effects on metabolic or endocrine systems to establish fully the safety of this therapy.

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Article Info

Article Notes

  • Published on: December 16, 2016


  • ACTH

  • Long-term weekly ACTH therapy
  • Infantile spasms
  • Relapse
  • Epileptic spasms
  • Hypsarrhythmia
  • Cognitive function


Takeo Kato
Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinanbacho, Amagasaki city, Hyogo, 660-8550, Japan, Tel: +81-6-6480-7000; Fax: +81-6-6480-7001
Email: tkokt4819@gmail.com