High-dose Corticotropin (ACTH) Versus Prednisone for Infantile Spasms: A Prospective, Randomized, Blinded Study

, Abstract Objective— To compare the efficacy of corticotropin (ACTH) (150 U/m 2 /day) and prednisone (2 mg/kg/day), given for 2 weeks, in suppressing clinical spasms and hypsarrhythmic electroencephalogram (EEG) in infantile spasms (IS). ACTH and prednisone are standard treatments for IS. ACTH at high doses causes severe dose- and duration-dependent side effects, but may be superior to prednisone, based on retrospective or uncontrolled studies. Blinded prospective studies have shown equal efficacy of prednisone and low-dose ACTH, and low versus high-dose ACTH. Design— A prospective, randomized, single-blinded study. Subjects and Methods— Patient population consisted of consecutive infants fulfilling entry criteria, including the presence of clinical spasms, hypsarrhythmia (or variants) during a full sleep cycle video-EEG, and no prior steroid/ACTH treatment. Response required both cessation of spasms and elimination of hypsarrhythmia by the end of the 2-week treatment period, as determined by an investigator “blinded” to treatment. Treatment of re-sponders was tapered off over 12 days; those failing one hormone were crossed-over to the other. Results— Of 34 eligible infants, 29 were enrolled. Median age of patients was 6 months. Twenty-two infants were “symptomatic” with known or suspected cause, and seven were cryptogenic (two normal). Of 15 infants randomized to ACTH, 13 responded by both EEG and clinical criteria (86.6%); and urine Additional studies were obtained guided clinical observations. Before beginning treatment, serum were

pattern, response to hormonal therapy, and poor outcome distinguish IS from a variety of other myoclonic epilepsies of infancy. 1,2[3][4][5]7 Therefore, IS continues to attract research concerning both pathogenesis and therapy.
IS is generally resistant to conventional anticonvulsants.However, in 1958, Sorel 9 reported on the efficacy of corticotropin (ACTH) for the seizures, and ACTH and a synthetic glucocorticoid (GC), prednisone, have become the standard therapy for IS.1][12] However, a double-blinded series 13 demonstrated equal efficacy of short courses of 20 to 30 U ACTH and prednisone in the treatment of IS.
Further issues of ACTH dose and duration of treatment have not been resolved.High doses of ACTH (150 U/m 2 body surface/day) have been advocated, based on a response rate of >80% in uncontrolled trials. 10,14Low-dose ACTH (<40 U/day) has been found effective in retrospective studies. 15,16A recent controlled study comparing high-dose long duration ACTH to low-dose (20-30 U/day) short treatment found equal efficacy of both regimens. 17verall response rate (50%), however, was quite low.
We compared the efficacy of 2-week courses of high-dose ACTH and prednisone for the treatment of IS.The study was a single-blinded comparison of response, using video-EEG as the objective measure of response to treatment.

1.
IS was defined according to Jeavons. 6Because an outcome of mental retardation could not be assessed on presentation, the criterion was not used.

2.
Cryptogenic IS was defined as the absence of etiology despite a battery of tests described below.An abnormal developmental status did not preclude defining an infant as having cryptogenic IS, because drug effects or deterioration with the onset of IS could not be excluded.

Study Population
Infants with clinical IS and no previous steroid or ACTH treatment were considered for the study if parents were willing to consent to randomized treatment.All subjects underwent a 24-hour video-EEG to ascertain the presence of hypsarrhythmia or its variants, 8,18 and the presence and frequency of epileptic myoclonic events.Thirty-six consecutive infants met clinical and EEG criteria for entry.Two were ineligible for ACTH/GC treatment due to severe hypertension (1), and resolution of spasms after shunt placement (1).The remaining 34 patients were eligible for the study.Twenty-nine were entered into the study, and five were not, due to parental refusal (2), unavailability of legal guardian (2), and other issues (1).

Study Design
The study was approved by the Childrens Hospital Los Angeles Institutional Review Board.
Patients who met clinical and electrographic criteria were entered into the study subsequent to an informed consent signing by parents or legal guardians.A computer-generated random-number list determined treatment.No stratification was employed.
An evaluation for the etiology of IS was undertaken in all infants.This consisted, at a minimum, of the prenatal and postnatal history, physical and neurological exams, neuroimaging (computed tomography or magnetic resonance imaging), blood amino acids, lactate and pyruvate, and urine organic acids.Additional studies were obtained guided by clinical observations.Before beginning treatment, serum electrolytes, glucose, and blood pressure were measured.
Treatment lasted for 2 weeks (Table 1).ACTH (ACTHARGEL, Rhône-Poulenc-Rorer, Collegeville, PA; 150 U/m 2 /day) was given intramuscularly in two divided doses.Prednisone (2 mg/kg/day) was given orally in two divided doses.Seizure frequency was monitored by parents who maintained seizure diaries.Side effects such as hypertension and hyperglycemia were monitored: glycosuria was checked on each specimen for the duration of treatment, and blood pressure was measured bi-weekly.Irritability and voracious appetite were the most frequent side effects, but no infant required stopping or modifying treatment.
After 2 weeks, a repeat video-EEG was performed, and clinical and EEG response assessed.
Video-EEG lasted 4 to 24 hours, always including a full sleep-wake cycle.For a patient to be considered a responder to treatment, both video-EEG and clinical responses were necessary: clinical response consisted of a complete cessation of IS events.Electrographic response consisted of resolution of the hypsarrhythmic pattern on both sleep and wake EEG.
The emergence of background slowing or other epileptiform patterns was considered a positive response.Video-EEG studies were interpreted by an investigator (E.J.H.) who was not informed of treatment assignment.
Infants with persistent IS or hypsarrhythmia were offered the alternative treatment.
Responders were tapered off ACTH or prednisone as described in Table 1.

Statistical Considerations
Treatment groups were compared using the χ 2 test.The Mann-Whitney test was used to determine potential differences (eg, age) between treatment groups, and the effect of discrepancy in mean age among treatment groups was analyzed using the Mantel-Haenszel test.

Results
Patient characteristics are summarized in Tables 2 and 3. Ethnic background was representative of the Childrens Hospital Los Angeles patient population.There were twelve infants with Hispanic surnames (six in each treatment group).Eleven infants were white non-Hispanic (five in the ACTH group), three were Asian, and three African-American.
Twenty-two infants had "symptomatic" IS, with known or suspected cause, and seven had cryptogenic IS, but only two were entirely developmentally and neurologically normal at the time of diagnosis.Of 29 subjects, 15 were randomized to ACTH and 14 to prednisone.Mean age of the prednisone group was higher than that of the ACTH group (7.5 vs 5.1 months), but the difference did not reach statistical significance (P = .06Mann-Whitney test).Cryptogenic etiology, male sex, other seizures, or duration of IS did not differ significantly between treatment groups.
Of 15 infants randomized to ACTH, 13 responded by both EEG and clinical criteria (86.6%); seizures stopped in an additional infant, but EEG remained hypsarrhythmic (considered a failure).Four of 14 patients (28.6%) given prednisone responded by both EEG and clinical criteria.No patient had clinical response only.The different response rate between treatment groups was significant: P = .002χ 2 test).The difference between ACTH and prednisone remained significant even after accounting for the potential confounding effect of age.Weighted relative response adjusted for age (Mantel-Haenszel test) was 3.94 (confidence interval 1.44 -10.77;P = .0026).
The two infants who failed ACTH received prednisone for 2 weeks, and one responded by both clinical and EEG criteria.Of the 10 infants who failed prednisone, nine received ACTH (for 2 weeks), and eight responded (88%).Two of the five infants who were ineligible for the study received ACTH and responded.The remaining infants received prednisone, valproate, or clonazepam, which did not control the IS within a 2-week period.
Length of follow-up period was insufficient for comparing cognitive outcome and development of other seizures in the ACTH and prednisone-treated infants.This type of comparison was further confounded by the fact that nine infants initially randomized to prednisone went on to receive ACTH.IS recurred by clinical and EEG criteria in two infants in the ACTH group, and seven infants in each group eventually developed other seizure types (Tables 2 and 3).
Two ACTH-treated infants and one prednisone-treated infant have normal neurologic and cognitive development as of last contact (Tables 2 and 3).These include the two who were considered normal on presentation.The third is an infant with cryptogenic IS and abnormal exam on presentation who was treated with ACTH.

Discussion
In this prospective, randomized, single-blinded study, high-dose 19 ACTH was significantly superior to prednisone in terminating IS and normalizing the EEC No demographic or etiologic differences between treatment groups confounded this effect.The prednisone group was slightly older, but, when age was accounted for, the efficacy of ACTH remained significantly higher than that of prednisone (weighted relative response 3.94, Mantel-Haenszel test P = .0026).Moreover, younger age at onset has been associated with a worse prognosis, so that somewhat older infants (the prednisone group) would be expected to have a more favorable response.
The protocol design utilized a short-term (2-week) treatment.The rationale for this duration was based on two lines of observation: first, IS has a significant spontaneous remission rate. 204][5]7,20 Thus, prolonged (3 to 10 months) therapy with a large number of agents has been reported as "effective" (reviewed in Reference 5).Further, in the majority of studies describing the time-course of treatment responses, patients who benefitted from therapy did so within the first week or two. 9,13In the current study, median response time for ACTH was 2 days, and for prednisone, 3.5 days.No patient responded clinically more than I week after treatment began.Follow-up EEGs were obtained only at the end of treatment, precluding evaluation of the time-course of elimination of hypsarrhythmia.In a single case, ACTH treatment abolished clinical spasms in 2 days, yet video-EEG continued to show a modified hypsarrhythmia pattern on the 15 th day of treatment (the patient was considered a failure).These results suggest that the short length of treatment did not bias outcome: both ACTH and prednisone exerted their therapeutic effects within days.
In a recent report, Hrachovy et al 20 compared ACTH in a regimen comparable to ours, to a low-dose (20 or 30 U/day) regimen.They found comparable efficacy of both ACTH dosage schedules, but had a low response rate (50%) overall.In a previous controlled, blinded, randomized study, the same authors described the equivalence of short-term low-dose ACTH and prednisone. 13The response rate (33% to 42% before cross-over) was substantially lower that obtained in other studies using high-dose ACTH, and was comparable to that obtained with prednisone in the current study.
The reasons for the different response rates are obscure.Hrachovy et al emphasized that clinical outcome measures were unreliable. 9,13,17,20They advocated EEG response criteria, ie, the elimination of hypsarrhythmia and its variants. 9,18The current study employed both EEG and clinical measures.Posttreatment EEGs, encompassing a minimum of a complete sleep cycle revealed persistent hypsarrhythmia during slow-wave sleep in only one patient who was free of clinical spasms.
Whether the response rate to ACTH or prednisone differs in infants with the "cryptogenic" versus the "symptomatic" form of IS is a complex issue.2][3][4][5] With the advent of contemporary diagnostic tools, the number of infants with apparently cryptogenic IS has drastically declined.This has made comparison of results of older and more recent studies difficult.Conversely, previously normal infants may lose developmental milestones at the onset of continuous abnormal neuronal activity (hypsarrhythmia) with resulting abnormal neurological examination.In the current study, seven infants (24%) had no definite etiology for their IS.Only two (7% of total) were neurologically normal, and responded to ACTH and prednisone.Five infants had abnormal neurologic examinations (cognitive, motor, or both) in the absence of etiology for their IS.The three infants randomized to prednisone failed to respond; of the two such infants assigned to ACTH, one responded.This response pattern was not significantly different from that of infants with "symptomatic" IS.
3][24][25] ACTH may function as a promoter of adrenal glucocorticoid secretion: high-dose ACTH may result in higher or more sustained plasma Cortisol. 10Alternatively, ACTH may exert therapeutic effects directly on the central nervous system, in addition to or independent of Cortisol release. 11,12,22ACTH analogues devoid of steroidogenic effects, however, are not effective for IS. 26,27Both agents, acting via a negative feedback loop, suppress the synthesis and secretion of corticotropin-releasing hormone (CRH) (reviewed in 5).CRH is a potent convulsant in the rodent, with age-specific potency during infancy. 23,24ACTH is more effective than prednisone in suppression of CRH gene expression, and affects cortical as well as hypothalamic CRH levels. 28 The minimal effective dose of ACTH remains un-clear.Ito et al 16 reported the results of retrospective analysis of patient response to graded ACTH doses.Based on nine patients, they concluded that 0.6 U/kg/day (6 units for a 10-kg infant) resulted in seizure cessation (8/9), and 0.8 U/kg/day eliminated hypsarrhythmia.Beyond that "threshold" dose, no dose effect was seen. 16Authors in this country 10,19,21 and abroad 14 strongly advocate high-dose ACTH, based on both response and plasma hormone data. 10 is a form of epilepsy that is age-specific to infancy. 31It is triggered at a vulnerable developmental stage in the setting of a previously stressed or injured central nervous system. 59,11,14,21 Recently, prolonged duration of IS before treatment was correlated with graver intellectual prognosis. 32In the current study, IS duration before treatment did not predict short-term response rate.Further studies on the relative efficacy of ACTH and prednisone on long-term cognitive outcome of infants are needed.These require a population of neurologically normal ("cryptogenic") infants.Given the small number of such infants in clinical series, a prospective multi-center collaborative effort is indicated.
In conclusion, using a 2-week regimen, high-dose ACTH is superior to prednisone for suppression of clinical spasms and hypsarrhythmia in IS.Further studies of the mechanisms by which ACTH acts are needed. 5,31These may point the way to the development of novel, more direct therapies for age-specific epilepsies such as IS.Glycosuria: all specimens.
Blood-pressure: twice a week.

B. Tapering schedules:
ACTH: For 3 days 30 U/M 2 in the morning.
For 3 days 15 U/m 2 in the morning.
For 3 days 10 U/m 2 in the morning.
For 6 days 10 U/m 2 every other morning.
Prednisone: For 3 days the morning dose (1 mg/kg) only.
For 6 days half the morning dose (0.5 mg/kg) only.

Characterisitcs of Infants Treated With Prednisone
Pediatrics.Author manuscript; available in PMC 2011 May 24.