Use of ACTH Fragments in Children with Infantile Spasms

Abstract

Referring to the article of Pente/la et al in this issue of Neuropediatrics we report on experiences with ACTH therapy in infantile spasms. In addition we want to point out the reasons which led us to use ACTH fragments for therapeutic trials in children with infantile spasms.Adrenocorticotropic hormone (ACTH) has been a useful drug in the treatment of petit mal since 1950 (Klein and Livingstone 1950). The compound was successfully used in its natural form with 39 amino acids (ACTHI-39) and in its fragmented form with 24 amino acids (ACTHI-24), the latter being the most common and most frequently applied form of ACTH. We recently completed a prospective study on infan.. tile spasms and Lennox syndrome (Lagenstein et al 1978a, b) in which we administered an ACTH-fragment consisting of 23 amino acids (ACTHI-23). All the ACTH molecules mentioned caused marked hypercortisolaemia which was not sig.. nificantly different when induced by ACTHI-23 (Willig et al 1978). As a result maximal stimulated adrenals led to severe side efTects -these are familiar from Cushing's disease.Conventional ACTHI-24 was very efTective upon infantile spasms (Singer et al 1980). Particularly in infantile spasms beginning within the first year of life, and in centrencephalic myoclonic-astatic petit mal cases of older children ACTH seems to be a suitable drug and also seems to be most effective if it is applied within the first month of the spasm onset as far as infantile spasms are concemed.In spite of good seizure control with ACTH, physicians he.. sitate to administer corticotropins because the side effects may appear even more impressive than the seizures them.. selves when treatment is carried out for aperiod of 3 to 6 months at an ACTH dose of80 IV per day.After one of our patients on ACTH therapy had died from pneumonia, we strongly considered how the side effects could be reduced withoutjeopardizing the positive effects ofACTH. Our own observations during the hormonal seizure treatment led us to the conclusion that the therapeutical aministration ofACTH has a direct effect on the central nervous system and not via the adrenocortical hormones: a) Dose-dependency in relation to the effect of ACTH From the tenth treatment day on ACTH led to a maximal cortisol level of 100 J.1g/dl on average with large individual fluctuations. The moment of therapy success was not con.. nected to the level of cortisol. One patient who showed the highest cortisol plasma level (440 Jlg/dl) did not react to the ACTH therapy. This was an indication that ACTH has a direct effect upon the brain and possibly does not have an effect via the adrenal cortex. The fact that only 15 IU ACTH is required in order to achieve a maximal adrenocortical effect also supports this theory. In addition, the results which have been reported in the literature clearly indicate that therapy success is dependent on the ACTH dose level. In our opinion these facts indicate that ACTH acts directly on the brain. b) Investigations of adrenocortical insufficiencyWe had the opportunity of...

Acth treatment of infantile spasms: Mechanisms of its effects in modulation of neuronal excitability

“…Earlier clinical studies have shown that shorter fragments (4-9) of ACTH, which failed to release adrenal steroids, were not efficacious for infantile spasms (Willig and Lagenstein, 1982;Pentella et al, 1982). Currently available information explains the apparent discrepancy: new information about the binding of ACTH fragments to melanocortin receptors shows that while the 4-10 fragment used here activates these receptors, the 4-9 fragment does not (Adan and Gispen, 1997;Gantz et al, 1993).…”

Infantile spasms.

“…There is much anecdotal evidence but little scientific basis for the use of ACTH or corticosteroids; a recent report has valiantly attempted to explain and rationalise the multiple aetiologies, efficacy of hormonal treatment, and even spontaneous resolution of infantile spasms.40 In addition there is considerable variation in the preparation, dose, and duration of treatment and relapses are common, whether on or off treatment. 26 [41][42][43][44][45] More importantly these drugs are associated with frequent, severe, and potentially fatal side effects. Drug related mortality may be as high as 5%.46 ACTH and corticosteroids have also not been shown conclusively to improve the long term outcome of either the development of chronic epilepsy (which occurs in over 65% of children) or mental retardation.…”

Effect of Antiepileptic and Antimyoclonic Drugs on Serotonin Receptors in vitro

“…It is interesting that, at all neurotransmitter receptors for which ACTHI-,, and ACTH1-24 have shown activity, the nonsteroidal fragments ACTHk9 or ACTHk,, (Schwyzer, 1980) have been less active. This may be clinically relevant since ACTHI-39, ACTHI-24, and ACTH,,, are effective against infantile spasms (Singer et al, 1980), whereas ACTHk9 and ACTHk,, are not (Willig and Lagenstein, 1982;Pentella et al, 1982). Only the long fragments potently increase cyclic-AMP, stimulate phosphoinositide hydrolysis and inhibit protein kinase phosphorylation, enhance lipid fluidity of synaptic plasma membranes, and stimulate protein synthesis (Jolles et al, 1980;Van Dongen et al, 1985).…”