The effect of ACTH therapy upon infantile spasms

March 1980 TheJournalofPEDIATRICS

485

The effect of A CTH therapy upon infantile spasms Fifty-five infants with infantile spasms and hypsarrhythmia, who were treated with A CTH using 80 units im every other day f o r a mean period of ten months, were studied retrospectively and showed better results than infants using so-called nonsteroidal anticonvulsants or A C T H and steroids" in other doses and with other time intervals. The study showed that the treatment with A C T H within the first month of onset of spasms produced a higher incidence o f spasm-free state while on treatment, a shorter duration of spasms while on treatment, and a higher incidence o f a spasm-free state when off treatment, compared to a similar regimen of A C T H begun after seizures had persisted f o r mote than a month. The vahte of early treatment o f infantile spasms suggests that the treatment o f this disease should be regarded as a medical emergency.

William D. Singer, M.D.,* Edward F. Rabe, M.D., and Jerome S. Hailer, M.D.,

Boston, Mass.

INFANTILE SPASMS represent a seizure disorder ot infancy consisting of lightning flexor or extensor spasms of the extremities, trunk, and neck. They coexist with the characteristic diffusely abnormal electroencephalographic pattern known as hypsarrhythmia. 1 Infantile spasms have been considered a refractory seizure disorder, with a poor prognosis for seizure control and normal intellectual development. High mortality is also associated with this syndrome. Treatment of these patients with conventional anticonvulsants, as well as with nitrazepam, diazepam, clonazepam, chlortetracycline, ketogenic diet, ACTH, and corticosteroids, has produced generally poor seizure control. ~ In addition, all treatment modalities have been associated with extremely high recurrence rates. 2 Treatment has had no effect on the developmental retardation which frequently accompanies the disorder? ~ The present study presents the results of a standardized treatment regimen using ACTH, substantiates the method as superior to any other described, and emphasizes the importance of early diagnosis and treatment as important factors contributing to the superior results. From the New England Medical Center Hospital, Tufts University School of Medicine. *Reprint address: New England Medical Center Hospital, Department of Pediau'ic Neurology, 171 Harrison A ve, Box 393, Boston, MA 02111.

0022-3476/80/030485 +05500.50/0 9 1980 The C. V. Mosby Co.

MATERIALS AND M E T H O D S The records of 89 patients with infantile spasms treated between 1961 and 1974 were reviewed. From these, patients were selected for intensive review based on the following criteria: uniformity of treatment regimen, follow-up period of at least one year, seizure disorder characterized by massive myoclonic jerks, extensor spasms or a combination of the two, and an electroencephalographic pattern of hypsarrhythmia. Fifty-five patients fulfilled these criteria. From their charts, the following data were extracted: age at onset of massive myoclonic jerks, the time between onset of spasms, onset of treatment, and cessation of spasms, and incidence of spasm recurrence after ACTH was discontinued. Data concerning probable etiology, the developmental level when first evaluated, and at the most recent visit, and the results of neuroradiologic studies of the patients, were collected but are not presented here. The initial treatment consisted of ACTH 40 units im daily during a hospitalization of two weeks. Concomitantly, parents were trained in the administration of the drug. At home, ACTH was given intramuscularly in doses of 80 units of ACTH gel every other day for a minimum of three months, or for one month after complete control was achieved, whichever came later. The average period of ACTH treatment was ten months (range, six to 14 months). We requested EEGs at monthly intervals during

VoL 96, No. 3, part l, pp. 485-489

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The Journal of Pediatrics March 1980

Table 1. Incidence of spasm control in two groups of patients according to duration of ACTH treatment Early treatment group Group I n = 31

Duration o f treatment (too)

No. patients

< 1 1--1.9 2-2.9 3--3.9 4--4.9 5-5.9

10 17 24 25 26 27

"

Late treatment group--Group I I n = 24

32 55 77 81 84 87

the ACTH therapy. These were done both awake and asleep, with bipolar and referential montages. The ACTH dosage was discontinued gradually. During this period of decreased dosage, if spasms recurred, or, if after initial improvement, the EEG returned to an hypsarrhythmic pattern, ACTH was immediately increased to 80 units every other day and was again maintained at this level until spasms were controlled for one month or until the EEG pattern improved significantly. It was never necessary to discontinue ACTH because of adverse side effects. Hirsuitism, seborrheic dermatitis, cushingoid changes, and cutaneous pigmentation were accepted as tolerable and reversable side effects in those patients exhibiting these signs. All of these signs, when exhibited, disappeared when ACTH was stopped. Patients not receiving another anticonvu|sant because of seizures predating the development of infantile spasms were given an anticonvulsant, usually phenobarbital concurrently with ACTH. This was done because of the high incidence of other seizures accompanying and following the development of infantile spasms? ~ All patients were repeatedly evaluated by members of the pediatric neurology staff. Intervals between examinations were lengthened as the clinical course continued. Follow-up period averaged 53 months; the range was 13 to 129 months. The statistical method used to compare the significance of differences of incidence of events between two groups was the chi squared~; P values of chi squared were determined from the tables of Fisher and Yates. 8 The significance of differences when a total sample of less than 50 patients was used was determined by the Fisher testy RESULTS The modal age of onset of symptoms was five months, the r~nge one week to 22 months. The mean age at onset

No. patients

%

2 2 6 13 14 14

8 8 25 54 58 58

P value o f x ~

< < < < < <

0.025 0.001 0.001 0.050 0.050 0.020

of treatment was 8.4 months, the range, one week to 35 months. Thirty-four patients were male. Review of the past histories revealed that there were 47 patients (85%) for whom possible etiologic factors could be identified, and eight in whom none was evident. Fifteen patients had congenital encephalopathies, i.e., retardation or motor abnormalities not associated with pre- or perinatal insults. Among the remaining 32 cases, pre- or postnatal events which may have been etiologic occurred, and included bacterial CNS infections, postnatal brain trauma, congenital structural abnormalities of the CNS, metabolic disorders, and hypoxic encephalopathy. No common antecedent agent or event occurred in all patients. Abnormalities noted on initial evaluation, which indicated abnormal neurologic function, occurred in 36 patients (65%). These abnormalities included developmental retardation (36 patients), spasticity of any distribution (14 patients), microcephaly (five patients), and tuberous sclerosis (four patients); athetosis, Down syndrome, and hypotonia (two patients each); and arthrogryposis multiplex congenita, neurofibromatosis, macrocephaly, and meningomyelocoele without hydrocephalus (one patient each). Patients were grouped according to the intervals between onset of spasms and the onset of ACTH therapy. Group I patients, numbering 31, were those treated within one month of onset of spasms; Group II patients, numbering 24, were those treated after one month or more of spasms: The modal duration in Group I patients before the treatment was two weeks (range: three days to four weeks), and in Group II patients, eight weeks (range: six weeks to 21 months). In Table I is shown the incidence of spasm control of the two groups monthly during the first six months of treatment. The incidence of control was significantly greater in Group I patients than in Group II patients in every comparison. Six months after treatment was started, 87% of Group I and 58% of Group 1I patients

Volume 96 Number 3, part 1

A C T H for infantile spasms

487

Table II. Comparis0n of incidence of spasm-free state at two ages in patients treated with ACTH vs nonsteroid-treated )atients

Spasm-freeat t yr Study No. 1 2 3 4

Treatment

Source of data

Nonsteroid anticon- References 1 and l0 vulsants ACTH Groups I + II present study ACTH Group I present study ACTH Group II present study

No. studied

i

%

3vr I No. studied %

Comparison studyNo. 1 vs.

1 yr

P values I

3 yr

30

l0

68

47

46

76

41

71

Study No. 2

< 0.001

< 0.002

30 16

83 62

22 19

86 53

Study No. 3 Study No. 4

<0.001 <0.001

< 0.005 < 0.700 (NS)

NS = Not significant9 were spasm-free. This difference is highly significant (P < 0.020). This shows that patients treated within the first month of the appearance of spasms had a shorter duration of spasms after treatment was begun, and a higher incidence of the spasm-free state on treatment, than did patients who were treated after their spasms had been endured for more than a month. Spasms occurred in five patienis during dosage reduction. This resulted in an immediate increase in ACTH to 80 units every other day, which was continued for a minimum of one spasm-free month. Four patients ceased having spasms on this dose increment; only one, a Group II patient, did not respond favorably. When ACTH was stopped, relapse occurred in 9.7% of patients--3.7% in Group I and 21.4% in Group 11. This difference was not significant. Thirty-seven (67%)of the patients remained spasm-free after treatment Was stopped, 84% in Group I and 46% in Group II. This difference is highly significant (P < 0.005), and further emphasizes the value of early treatment. The value of this regimen for treating infantile spasms was assessed by comparing our results with those of Other investigators, It was possible to find six reports With data presented in a form enabling us to compare our data with ttiose of others. Two reports describe the results Of treatment using nonsteroid therapy,'- 10 and four reports documented experience Using ACTH and steroids? .... In none of these was it possible to determine how 10ng spasms existed before treatment was started. In Table II is summarized a comparison between the data from this study and the data from the reports Of either untreated patients or patients treated with tetracycline, barbiturates, Or hydantoins (Study 1). The Outcome for such a grgu p of patients likely repi-esents the natural history of this disorder, since none of these agents has been proven to affect the course of the disease. This group of patients is labeled "nonsteroid-treated patients." The

ages at which comparisons were made were chosen because the previous investigators reported their data at 1 and 3 years of age. Data in Table II show that the method of ACTH administration used in this study renders more patients spasm-free than would result from the na{ural course of the disorder. These differences are all statistically significant, in all comparison groups at age one year, and in the early-treated group at age 3 years. The late-treated ACTH group, however, has an incidence of Spasms at 3 years of age similar to that of the nonsteroidtreated patients. in Table lII we Present a comparison of the data from the present Study with a compilation of data from 238 patients treated elsewhere with ACTH or steroids? .... 1~ Five other series of ACTH and steroid-treated patients are availablel~-1~ but the data were not adequate for comparison. o n e series of clonazepam-treated patients was available'-'~ this too was incomplete. In Tables Ill and IV, the data are presented so that comparisons can be made between groups using three endpoint criteria; incidence of patients spasm=free on ACTH/steroids, incidence of relapse of spasms after ACTH/steroids were stopped, and incidence of patients remaining spasm-free after ACTH/steroids were stopped: Data in Table IV show that Group 1 patients, or Group I plus II, had a t'avorable incidence of all endpoint criteria, at a statistically significant level, when compared with the published series. However, Group II patients were not statistically superior to the other series in any of the three endpoint criteria. ~ Two other findings are of interest. A seCond type of seizure occurred in 36 patients (65%). Twenty-one infants (38%) had other seizures preceding infantile spasms, one Group Ii patient developed infantile 9 and grand mal seizures concomitantly, and 14 patients (25%) developed the second seizure type subsequent to the development of infantile spasms. There was no significant differ-

488

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The Journal of Pediatrics March 1980

Table III. Incidence of control of spasms in present study and previously reported studies

Author

Present study Grou~ I Group II Willoughby et alI' Stamps et aP 2 Jeavons and Bowers~ Jeavons and Bowers~ Harris) 3 Danielsen14 Dobbs and Baird 1~ Rail16 Bray 17 Millichap and Bickford u Pauli et a119 Domermuth and Kovacs20

Seizure-free on medication

Relapse after A C TH-steroids D/C

A nticonvulsant age n t

No. of patients

ACTH ACTH ACTH ACTH ACTH Steroids ACTH ACTH ACTH ACTH ACTH and cortisone ACTH and steroids ACTH and steroids Clonazepam

31 24 24 60 38 18 75 23 42 34 10

27 14 6 i8 26 13 45 14 8 6 2

87 58 25 30 68 72 60 60 19 18 20

1 3 4 9 14 10 15 6 * * *

21 14 42

4 3 11

19 21 26

* * *

3.7 21.4 67 50 54 77 33 43

Patients controlled after ACTH-steroids D~

C

26 11 2 9 12 3 30

8

84 46 8 15 32 17 40 34

*Not reportedl

ence in incidence of a second seizure type occurring before or after the onset of infantile spasms, or of it occurring at all, between Group I and Group II patients. In addition, among these 55 patients, only one died, a mortality rate of 1.8%. The death occurred several months after Stopping ACTH, and was believed due to an aspiration p n e u m o n i a . A separate analysis showed that this method of treatment did not change the widely known poor prognosis for the intellectual development of these infants.

DISCUSSION Sorel and De Saucy-Bouloy ~ in 1958 described the treatment of infantile spasms in seven patients, in six of these, spasms stopped quickly, and two of them attained normal development and a normal EEG. The authors discussed the importance of early treatment in effecting these i'esults. Danieisen, TM in 1965, reported the results of A C T H treatment in 23 children. He concluded that the effect upon mental development was doubtful, but was impressed with the good effects on seizure control and EEG. He stated that steroid treatment was to be regarded as the best avaiiable method for treating infantile spasms, and that it should be instituted as soon after the onset of spasms as possible. The present study pi'oves th e value of early treatment of infantile spasms with ACTH. Treatment instituted within the first month of spasms, as Contrasted with a later onset of treatment, produces a shorter period of spasms, a decreased incidence of spasms

six months after the onset of treatment, and a lower incidence of spasms during an average observation period of 53 months after the onset of spasms. The cases grouped under nonsteroid therapy included both untreated patients and patients treated with anticonvulsants which have no proven positive effect upon the course of the disease. These cases, we believe, represent the natural course of infantile spasms. Accepting this, and comparing the differences in incidence of the spasm-free state at two age intervals, between A C T H and nonsteroid treated patients (Table II), we pos!ulate that A C T H accelerates a change in physiology which aging also accomplishes eventually, and thus yields a similar incidence of the spasm-free state at three years of a g e i n both non-steroid and Group II ACTH-treated patients. However, early use of A C T H (Group I patients), produces a quicker cessation of spasms, and a significantly higher incidence of the spasm-flee state at age three years compared to either the late treated A C T H patients (Group II, 86% versus 53%) or the nonsteroid-treated patients (86% Versus 47%): Tkis observation suggests that A C T H produces a physiologic change similar to maturation, but at a more rapid rate and significantly more often. What A C T H does at a m e m b r a n e or molecular level in this situation is unknown. The reason for the superior results of our method of A C T H treatment, over others reported, may only be conjectured. Three observations should be emphasized: 56% of the patients in this study were treated within one

Volume 96 Number 3, part 1

489

A C T H f o r infantile spasms

Table IV. C o m p a r i s o n o f results o f t r e a t m e n t a m o n g three groups o f A C T H / s t e r o i d - t r e a t e d patients according to three criteria

Study groups-% exhibiting symptoms Group I (n = 31) Criteria Spasm-free on ACTH/ steroid

Relapse rate after ACTH/steroid stopped

Spasm-free after AC.TH/ steroid stopped

Group H (n = 24)

No.

%

No.

%

27

87.1

14

58.3

1

26

3.7

83.9

3

11

21.4

45.8

Group I and H (n = 25) No. [ 41

4

37

Literature series (n = 238)

%

No.

%

74.5

122

51.3

9.7

67.3

58

64

47.5

26.9

Comparisons Group I vs II Group I vs Lit. Group II vs Lit Groups I, II vs Lit. Group I vs II Group I vs Lit. Group II vs Lit. Groups I, iI vs Lit Group I vs II Group I vs Lit. GrouP II vs Lit. Groups I, I1 vs Lit.

P values < < < < < < < < < < < <

0.020 0.001 0.700 0.005 0.250 0.001 0.200 0.001 0.005 0.001 0.100 0.001

(NS) (NS) (NS)

(NS)

NS = Not significant. m o n t h o f the onset o f spasms. In other series this time interval was difficult to determine. The average treatment period was ten months. A l t h o u g h it is impossible to state

9.

accurately the duration o f treatment in other series, m a n y

10.

received A C T H fo r only one or two m o n t h s . The dose o f A C T H used in this study was higher than the usually stated dose. -~T h e s e three factors seem to be the most likely

11.

variables favoring the superior outcome o f spasm control

12.

in this series. The most significant observation in this study was the i m p o r t a n c e o f early diagnosis and treatment to control spasms. It is for this reason that we regard the therapy o f infantile spasms as a medical emergency.

REFERENCES 1. Gibbs EL, Gleming M, and Gibbs FA: Diagnosis and prognosis of hypsarrhythmia and infantile spasms. Pediatrics 13:66, 1954. 2. Lacey JR, and Penry JK: Infantile spasms, New York. 1976. Raven Press, pp 107-111. 3. Jeavons PM, Harper JR, and Bowers BD: Long-term prognosis of infantile spasms: the follow-up report on 112 cases, Dev Med Child Neurol 12:413, !970. 4. Jeavons PM, Bower BD, and Demitrakoidi M: Long-term prognosis of 150 cases of "west X syndrome." Elilepsia 14:153, 1973. 5. Jeavons PM, and Bower BD: Infantile spasms: Review of the literature in the study of 112 cases. Clinics and Developmental Medicine No. 15, London, 1964, Spastics Society and William Heinemann, Ltd. 6. Druckman R, and Chao D: Massive spasms m infancy and Childhood. Epilepsia 4:61, 1955. 7. Hays WL: Statistics for psychologists. Holt, Rinehart, and Winston, New York. 1963, pp 596-8. 8. Croxton F: Elementary statistics with application in medi-

13. 14.

15.

16. 17.

18.

19.

20.

21.

cine and biological sciences, Appendix VI, pp. 328-9, Dover Publications. Langley R: Practical statistics. Dover Publications Inc. New York. 1971. "Fisher's Test". pp. 292-313. Jeavons PM, and Bowers BD: The natural history of infantile spasms. Arch Dis Child 36:17. 1961. Willoughby JA. Thurston DE and Holowach J: Infantile myoclonic seizures: An evaluation of ACTH and corticosteroid therapy, J PEDIATR 69:1136. 1966. Stamps FW. Gibbs EL. Rosenthal IM. and Gibbs FA: Treatment of hypsarrhythmia with ACTH. JAMA 171:408. 1959. Harris R. Some EEG observations in children with infantile spasms treated with ACTH, Arch Dis Child 39:564. 1964. Danielsen J: Infantile spasms and hypsarrhythmia treated with corncosteroids. Acta Neurol Scand 41(Suppl 131:489. 1965 Dobbs JM. and Baird HW: The use of corticotropin and a corticosteroid in panems with minor motor seizures. Am J Dis Child 100:584. 1960. Rail L: Treatment of infantile spasms with ACTH. Med J Aust 2:708. 1963. Bray PF: The influence of adrenal steroids and corticotropin on massive myoclonic seizures of infancy, Pediatrics 169:174. 1963. Millichap JG. and Bickford RG: Infantile spasms, hypsarrhythmia, and mental retardation: Response to corticotropin and its relation to age and etiology in 21 patients.dAMA 182:523. 1962. Pauli L. O'Neil R. Ybanez M. and Livingston S: Minor motor epilepsy: Treatment with corticotropin (ACTH/ and steroid therapy, JAMA 172:1408. 1960. Dumermuth G. and Kovacs E: The effect of clonazepam (RO5-40231 in the syndrome of infantile spasms with hypsarrhythmia and petit real variant or Lennox syndrome. Acta Neurol Scand. 53(Suppl 49/:26. 1973. Sorel L and De Saucy-Bouloy A: A p r o p o s de 21 cas d'hypsarrhythmie de Gibbs: son traitment speetculaire par I'ACTH. Acta Neurol Psychiat Belg 58:130. 1958.