ACTH therapy for infantile spasms with chronic renal failure

A one-year-old female patient with infantile spasms who suffered from chronic renal failure was treated with ACTH for the control of frequent tonic spasms. She received 0.005 mg/kg of ACTH for 7 days and then 0.01 mg/kg for 12 days daily. From 12 days after initiation of the treatment, tonic spasms and hypsarrythmia observed on electroencephalography disappeared. During the ACTH treatment, hypertension and gastric bleeding developed, and persisted even with antihypertensive drugs and a H2-blocker treatments. During the ACTH therapy, the serum cortisol level was higher than that in control subjects. Recent advances regarding the metabolism of cortisol have shown that the inactivation of cortisol is impaired in patients with chronic renal failure and that clearance of cortisol from serum is decreased in such patients. It is suggested that the same mechanism was involved in the present patient during the ACTH therapy and that adverse effects of ACTH were related to the high cortisol level in the serum. We conclude that the dose and duration of ACTH therapy should be determined by careful monitoring for the adverse effects of ACTH, and that the serum cortisol level might be a predictor of the side effects of ACTH therapy in a patient with chronic renal failure.     

Changes in thyroid function during ACTH therapy in patients with infantile spasms

Serum triiodothyronine (T3), free T3, thyroxine (T4) and free T4 levels were measured before and immediately after daily ACTH-Z therapy (0.01 mg/kg/day, 1-2 weeks) for patients with 9 cases of infantile spasms and one case of myoclonus epilepsy. In some of them, serum reverse T3 (rT3) and thyroxine binding globulin (TBG) levels were also measured. All patients became seizure free after ACTH-Z therapy. Before ACTH-Z therapy, all of the hormone levels were within normal limits. Serum T3 and free T3 levels were markedly decreased after daily ACTH-Z therapy, and serum T4, free T4 and TBG levels were moderately decreased after the therapy. 1-6 weeks after the daily treatment, all of these hormone levels returned to pretreatment levels. Serum rT3 levels did not change after ACTH-Z therapy. These results suggest that the effect of long-term daily ACTH-Z therapy is very critical to the immature brain, and conventional ACTH-Z therapy has to be reconsidered.     

Changes in anterior pituitary function during ACTH therapy of patients with infantile spasms

Serum cortisol, prolactin (PRL), TSH, GH, LH and FSH levels were measured before and immediately after daily ACTH-Z therapy (0.01 mg/kg/day, 1-2 weeks) for 5 patients with infantile spasms and one patient with myoclonus epilepsy. Total number of ACTH-Z therapy were 8 times, and all patients became seizure free after ACTH-Z therapy. In 6 occasions, TRH, LH-RH and insulin tolerance tests were performed before and after daily ACTH-Z therapy. Serum cortisol levels were significantly increased after daily ACTH-Z therapy but all other hormone levels were significantly decreased. In TRH and LH-RH tolerance tests, peak levels and increments of PRL, LH and FSH were significantly decreased after daily ACTH-Z therapy and those of TSH were mildly decreased. In one case insulin tolerance test revealed an adequate decrease of blood glucose before and after ACTH-Z therapy, and there was a poor GH response after ACTH-Z therapy. Daily ACTH-Z therapy was thought to suppress secretion of anterior pituitary hormones.     

Hypothalamo-pituitary-adrenal function in infantile spasms: effects of ACTH therapy

The metyrapone test was used to study the hypothalamo-pituitary-adrenal function in ten children with infantile spasms, before and after ACTH treatment. The hypothalamo-pituitary-adrenal response was normal before ACTH treatment in almost all children. After ACTH, the responses of two children were suggestive of a diminished pituitary reserve; three were suggestive of decreased adrenal as well as decreased pituitary reserve, and one suggested either adrenal hyperplasia with normal pituitary reserve, or appropriate response to a developing medical stress. We suggest that, in children being treated with ACTH, the dosage of ACTH should be gradually tapered, AM cortisol levels should be monitored, and high-dose steroids should be included when treating medical stress.     

Treatment of infantile spasms with long-term low dose ACTH]

We investigated the effect of long-term, low-dose ACTH in 13 patients (10 boys and 3 girls) with infantile spasms who were treated with low-dose ACTH (mean: 0.0081 mg/kg/day). Two patients (one boy and one girl) received this therapy twice because of relapse of tonic spasms. ACTH was injected intramuscularly every morning for 30 days, after which dosage was tapered. The mean observation period was 53.9 months. Complete cessation of seizures was attained in 13 of 15 treatment trials. In one trial, complete cessation was not attained but the number of attacks decreased to less than one-third of that before treatment. In only one trial was treatment not effective. EEG showed good response to this treatment. The side-effects of this therapy were hypertension in 6 patients, hypokalemia in 7, and emotional outburst in 7. Emotional outburst appeared during the early phase of therapy, while the other two side-effects appeared in the later phase and disappeared when ACTH-tapering was begun. Brain shrinkage observed on CT scan was mild in all trials. Five patients have had no relapse. The total dose of ACTH was significantly larger in the group with good outcome than in the group with poor outcome.     

Effectiveness of once-daily high-dose ACTH for infantile spasms

There is insufficient evidence to recommend a specific protocol for treatment of infantile spasms (IS) and a lack of standardization among, and even within, institutions. Twice-daily dosing (for the first two weeks) of high-dose natural ACTH for IS is used by many centers and recommended by the National Infantile Spasms Consortium (NISC). Conversely, it is our practice to use once-daily dosing of high-dose natural ACTH for IS. In order to determine the effectiveness of our center's practice, we retrospectively reviewed 57 cases over the past four years at Boston Children's Hospital (BCH). We found that 70% of infants were spasm-free at 14 days from ACTH initiation and 54% continued to be spasm-free at 3-month follow-up. Electroencephalogram showed resolution of hypsarrhythmia (when present on the pretreatment EEG) in all responders. Additionally, once-daily dosing of ACTH was well tolerated. We performed a meta-analysis to compare our results against the reports of published literature using twice-daily high-dose ACTH for treatment of IS. The meta-analysis revealed that our results were comparable to previously published outcomes using twice-daily ACTH administration for IS treatment. Our experience shows that once-daily dosing of ACTH is effective for treatment of IS. If larger prospective trials can confirm our findings, it would obviate the need for additional painful injections, simplify the schedule, and support a universal standardized protocol.     

Influence of ACTH therapy on overnight sleep polygrams in infantile spasms

Overnight sleep polygrams were recorded before and during therapy in nine patients with infantile spasms. Results showed that ACTH therapy increased the waking time and decreased rapid eye movement sleep. Thus it caused sleep disturbance in patients with infantile spasms. During ACTH therapy the number of rapid eye movements/min and the pulse rate decreased significantly. Body movements/min also decreased, but not significantly. These results suggest that ACTH therapy may inhibit functions of the central nervous system. The respiratory rate increased during ACTH and clonazepam therapy, probably in association with the decrease or the absence of seizures. These findings indicate the necessity for further studies on whether ACTH therapy is really of value in patients with infantile spasms, and show that if ACTH is given, the period of therapy should be as short as possible.     

Suppressed pituitary ACTH response after ACTH treatment of infantile spasms

Suppression of an adrenocorticotropic hormone (ACTH) response to insulin hypoglycemia has been reported in ACTH-treated adults. There are no guidelines for withdrawal of ACTH treatment in children. After observing suppressed morning cortisol in several children, insulin tolerance tests were performed in five children within 48 hours after tapered withdrawal of ACTH treatment for myoclonic seizures. ACTH response, as determined by cortisol and beta-endorphin radioimmunoassay, was adequate in four of the children. One child showed low basal levels and minimal elevation during hypoglycemia for both beta-endorphin (0 to 3 pg/ml) and cortisol (3.6 to 4.4 micrograms/dL) on initial testing, but normal responses six weeks later. Measurement of beta-endorphin response supported a central basis for suppression in the child, who had had an adrenal hemorrhage during gram-negative sepsis while on ACTH. ACTH release is transiently suppressed in some children after exogenous ACTH treatment. Tapered withdrawal and stress coverage is recommended.     

CT and ACTH treatment in infantile spasms

Computed tomography of 8 cases with West's syndrome before, during and after ACTH treatment are reported. The scans, performed at the third week of therapy, showed consistent widening of the sulci, cisterns and ventricles in all the patients. Of these, 2 patients underwent ICP monitoring which showed higher than normal values. A return to the normal ICP values in association with the disappearance of the CT findings was observed in both cases. It is concluded that widening of the sulci, cisterns and ventricles are not findings of atrophy, but a condition of initial communicating hydrocephalus, which is in accordance with the hypotheses of Riikonen and Lyen.     

ACTH versus vigabatrin therapy in infantile spasms: a retrospective study.

ACTH is the standard treatment for infantile spasms (IS) in North America. Recent reports showed that vigabatrin is a valuable treatment for IS, but comparative studies with ACTH are limited. In this study, we compare the effectiveness of ACTH versus vigabatrin on IS. Our results support that vigabatrin is as effective as and better tolerated than ACTH. Because of their similar efficacy, we believe that vigabatrin should be the first intention drug for the treatment of IS.     

Acute-onset transient hydrocephalus after suspension of ACTH therapy for infantile spasms: A case report

A baby with infantile spasms (West's syndrome) who developed acute-onset transient hydrocephalus 10 days after suspending ACTH treatment is described. Hydrocephalus is an unusual complication of A CTH therapy, the more common complication being benign intracranial hypertension. The probable common pathogenic mechanism of altered CSF reabsorption which may lead to the two different clinical states, depending on age of patient, is discussed.

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Sommario Vierte descritto un lattante affetto da S. di West che ha manifestato idrocefalo ad insorgenza acuta, dopo spspensione di ACTH. È noto che l'ACTH può essere causa di ipertensione intracranica benigna piuttosto che di idrocefalo. Viene discusso il probabile comune meccanismo patogenetico legato ad un alterato riassorbimento del liquido cefalorachidiano, che condurrebbe ai due diversi quadri clinici in rapporto alla età del paziente.

     

ACTH therapy in infantile spasms: relationship between dose of ACTH and initial effect or long-term prognosis

The relationship between the dose of ACTH and the initial effect was investigated in 41 children with infantile spasms. More than 0.015 mg (0.6 IU)/kg/day of ACTH was needed for a good initial response of seizures and electroencephalographic abnormalities. The relationship between the dose of ACTH and long-term prognosis was investigated in 29 patients. There was no relationship between the daily or total ACTH dosage, provided the dose was greater than 0.015 mg (0.6 IU)/kg/day, and the outcome of seizures and electroencephalographic abnormalities; however, ACTH 0.04-0.06 mg (1.6-2.4 IU)/kg/day and a total ACTH dose of 1.1-1.5 mg (44-60 IU)/kg resulted in better mental development than smaller doses of ACTH. Side effects of ACTH increased with dosage. Too small or too large a dose of ACTH does not lead to better mental development. The proper dose of ACTH should be used with careful attention to potential side effects.     

Advances in therapy of infantile spasms. Current knowledge of actions of ACTH and corticosteroids

The anticonvulsant actions of ACTH and corticosteroids in the treatment of infantile spasms have been well documented during the past 29 years. In the past decade neuropeptides have been studied intensively and an understanding of their actions has been gained. Most of the actions of ACTH are well documented in animal experiments and cytochemical studies. Some proceedings of modern steroid research are here reviewed. In the treatment of infantile spasms, the principal mechanism of the therapeutic action of ACTH and corticosteroids is unknown. Clinical data concerning their effects, site and mode of action, on brain and CSF neurochemical activity are still scant and controversial. Some mechanisms probably involved in the therapeutic effects are reviewed. It seems that a disturbance of the central neural transmitter regulation at a specific phase of brain development may be the underlying cause for infantile spasms.     

Therapeutic efficacy of ACTH in symptomatic infantile spasms with hypsarrhythmia

The records of twenty-six infants with both symptomatic infantile spasms and classic hypsarrhythmia were reviewed to determine the efficacy of various ACTH dosages and time of initiation of therapy. Mean age of infantile spasm onset was 6.4 months. Most patients (13) had sustained perinatal hypoxic-ischemic insults. Seventeen patients (65%) had complete cessation of spasms. Between these responders and the 9 nonresponders there was no difference in duration of spasms prior to treatment (2.6 and 2.0 months) or mean ACTH dose (87.4 and 84.5 U/m², respectively). Infants treated with high-dose ACTH (> 100 U/m²) did not have an improved response rate. The most favorable outcomes were associated with spasm onset at > 8 months of age (all of whom were responders, regardless of dose) or when treatment was started within 1 month of onset of infantile spasms with > 80 U/m² ACTH (88% responders). Infants treated more than 2 months after onset often did not respond (57%) regardless of dose. Nonresponders with spasm onset at < 4 months of age had the worst prognoses; all had poorly controlled seizures and regressed developmentally. Although all infants in the study were neurologically abnormal, development either improved or did not deteriorate in most responder infants following spasm resolution and one-half remained seizure free. Nonresponder infants continued to have infantile spasms or other seizure types. These data suggest that ACTH is valuable in the treatment of significantly impaired infants with symptomatic infantile spasms, but the most important determinants of outcome may be age of onset and rapidity of treatment rather than dosage.     

Effect of ACTH therapy for epileptic spasms without hypsarrhythmia

PURPOSe: We analyzed the short- and long-term effects of adrenocorticotropic hormone (ACTH) therapy for patients with epileptic spasms (ESs) who did not meet the criteria of West syndrome (WS). METHODS: The subjects were 30 patients, including 13 boys and 17 girls, who had received ACTH therapy between 1970 and 2003. We excluded patients with WS, but included those with a history of WS who no longer showed hypsarrhythmia at the period of ACTH therapy. The age at onset of ESs and at ACTH therapy ranged from 2 to 82 months with a median of 18 months, and from 11 to 86 months with a median of 29 months, respectively. RESULTS: Excellent and poor responses were obtained in 19 (63%) and 11 (37%) patients, respectively, as a short-term effect. Although the patients could be subclassified into five subgroups according to the previous reports, no difference was seen in short- term response to ACTH. Among 17 of the 19 patients with excellent short-term outcomes and a follow-up of >1 year after the ACTH therapy, eight patients have continued to be seizure free (29%; excellent long-term effect), whereas the remaining nine patients had a recurrence of seizures (complex partial seizures, four; generalized tonic seizures, three; ESs, two) at 9 months to 198 months (median, 49 months) after ACTH therapy. In addition, nine of the 17 patients demonstrated a localized frontal EEG focus after the ACTH therapy, although most of these had previously shown diffuse epileptic EEG abnormality. CONCLUSIONS: ACTH therapy is worth trying for patients with resistant ESs, even without features of WS. However, the long-term effect is uncertain because recurrences of various types of seizures, including focal, were frequently observed.