A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms

Purpose: ACTH is currently the standard first‐line therapy for new‐onset infantile spasms, but it has significant side effects. We hypothesized the ketogenic diet (KD), previously reported as beneficial for intractable infantile spasms, would have similar efficacy, but better tolerability than ACTH when used first‐line. Methods: We conducted a retrospective chart review of all infants started on the KD (n = 13) and high‐dose ACTH (n = 20) for new‐onset infantile spasms at our institution since 1996. Results: Infants were spasm‐free in 8 of 13 (62%) infants treated with the KD within 1 month, compared to 18 of 20 (90%) treated initially with ACTH, p = 0.06. When effective, median time to spasm freedom was similar between ACTH and the KD (4.0 vs. 6.5 days, p = 0.18). Those treated with ACTH were more likely to have a normal EEG at 1 month (53% vs. 9%, p = 0.02), however, use of the KD led to EEG normalization within 2–5 months in all eight who became spasm‐free. In the five children in whom the KD was unsuccessful, four became spasm‐free subsequently with ACTH or topiramate immediately. Side effects (31% vs. 80%, p = 0.006) and relapse rate after initial success (12.5% vs. 33%, p = 0.23) were lower with the KD. Discussion: In this retrospective study, the KD stopped spasms in nearly two‐thirds of cases, and had fewer side effects and relapses than ACTH. ACTH normalized the EEG more rapidly, however. Further prospective study of the KD as, with a 2‐week time limit if unsuccesful, first‐line therapy for infantile spasms is warranted.     

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.     

ACTH and prednisone in childhood seizure disorders

We treated 116 children with ACTH or prednisone. Fifty-two had infantile spasms with hypsarhythmia, and 64 had other types of intractable seizures. ACTH completely controlled seizures in all patients with infantile spasms and hypsarhythmia and 74% of those with other types of seizures. Prednisone controlled 51% of patients with infantile spasms and none with other seizures. Serious side effects were minimal for both drugs, and recurrent seizures occurred in 40 to 50% of patients within 4 to 14 months after completion of therapy.     

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.     

Reduced ACTH Content in Cerebrospinal Fluid of Children Affected by Cryptogenic Infantile Spasms with Hypsarrhythmia

In view of the therapeutic efficacy of adrenocorticotropic hormone (ACTH) in the treatment of infantile spasms (IS) with hypsarrhythmia, we studied the cerebrospinal fluid (CSF) levels of ACTH in 15 children (4-10 months) affected by IS with hypsarrhythmia (eight cryptogenic forms, seven secondary to perinatal distress) and in age-matched controls. Lumbar puncture was performed in all but one case before any kind of treatment. In another case, CSF was collected 3 weeks after a spontaneous remission. Both ACTH and beta-endorphin (beta-EP), the other peptide related to the same precursor (proopiomelanocortin), were measured by specific radioimmunoassay after gel chromatography. While beta-EP levels were unchanged in the two groups of patients, ACTH concentrations of cryptogenic (3.75 +/- 2.40 fmol/ml, Mean +/- SD p less than 0.05) and secondary (6.36 +/- 3.70, NS) forms were lower than in controls (10.90 +/- 5.79). On the other hand, ACTH was higher in the case studied after therapy (9.0) and in the case presenting a spontaneous clinical and EEG remission (15.0). These data indicate that in children affected by IS with hypsarrhythmia (mainly of cryptogenic type), CSF levels of ACTH are lower, while levels of beta-EP remain normal. It would therefore appear that central ACTH content may play a possible role in the pathogenesis of IS with hypsarrhythmia.     

Long-Term Prognosis of Patients with Infantile Spasms Following ACTH Therapy

The influence of ACTH on the prognosis of patients with infantile spasms remains controversial. We have examined retrospectively the long-term benefits of initially successful ACTH therapy in patients treated at this institution between 1961 and 1974. Individuals with equivocal or minimal improvement during ACTH therapy were excluded from this study. Eighteen affected infants showed a favorable early response consisting of cessation of seizures for at least 3 weeks during ACTH therapy and concurrent disappearance of the hypsarhythmic EEG pattern. Modal age at last follow-up was 5 years (range, 15 months to 16 years). Infantile spasms recurred in 7 patients (39%), and 8 patients subsequently had other seizure types. All epileptiform (spike) activity disappeared from the EEGs of 8 patients during ACTH therapy, but in 4 of these cases epileptiform activity was present in later tracings. In the remaining 10 patients the hypsarhythmic pattern disappeared in association with ACTH therapy, but the EEG remained epileptiform (often only in sleep). Later EEGs were free of epileptiform activity in 5 of the 10 patients whose tracings contained spike discharges in the early follow-up period. Four patients (22%) were seizure free and without intellectual impairment when last evaluated.     

Two cases of myocarditis appearing during ACTH therapy for infantile spasms]

We experienced two cases of myocarditis occurring during ACTH therapy for infantile spasms. Myocarditis cases occurred during the reduction of ACTH doses, and viral infection was suspected. Steroid replacement therapy was effective in the both cases. It is important to consider that ACTH therapy for infantile spasms could sometimes lead to severe myocarditis.     

ACTH Therapy for Infantile Spasms: A Combination Therapy with High-Dose Pyridoxal Phosphate and Low-Dose ACTH

Summary: Combination therapy consisting of high-dose pyridoxal phosphate (40–50 m/kg/day) and low-dose synthetic ACTH (0.01 mg/kg/day) was prescribed in 28 children with infantile spasms. Monotherapy with pyridoxal phosphate provided excellent seizure control in 3 of the 28 (11%) patients. ACTH was subsequently added to the regimen of the remaining 25 patients. As of 1 month after discontinuing the ACTH treatment, 21 of the 25 (84%) patients had experienced no seizures. The mean interval until seizure control was achieved was 4.1 days after the start of treatment with ACTH. The 21 patients have been monitored for a mean of 34.9 months (range 2–81 months); 6 patients (29%) have had recurrences of infantile spasms, and 10 (48%) have experienced normal development. Fourteen of the 28 patients (50%) have had transient increases in liver enzymes, but none of the patients developed more serious side effects.     

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.     

Pyruvate carboxylase deficiency: acute exacerbation after ACTH treatment of infantile spasms

Pyruvate carboxylase deficiency results in congenital lactic acidosis. We report the significant finding in a child with infantile spasms controlled with adrenocorticotrophin hormone (ACTH) but who then developed severe lactic acidosis; pyruvate carboxylase deficiency was subsequently diagnosed. Blood lactate, pyruvate, and alanine levels were elevated, as well as cerebrospinal fluid alanine. Plasma alanine concentration was doubled by ACTH therapy. Fibroblasts contained extremely low pyruvate carboxylase activity. The patient died at 12 weeks of age after recurrent episodes of profound acidosis. At autopsy, the brain manifested cystic degeneration and demyelination. Pyruvate carboxylase deficiency is associated with neonatal onset of acidosis, delayed development, seizures, hypotonia, recurrent profound acidosis, and early death. The dramatic rise in plasma alanine content coincident with ACTH therapy suggest that ACTH played a role in precipitating the catastrophic metabolic acidosis.     

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.     

The prognostic value of EEG patterns in epilepsies with infantile spasms

By scoring EEG patterns (hypsarrhythmia = 10, absence of sleeping patterns = 10, focal epileptic discharge = 5, general-treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EEG did not have any ending ACTH therapy free of seizures showed lower scores compared to those infants relapsing after the end of ACTH treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EED did not have any prognostic significance. Using EEG scores it might be possible to separate non-responders and responders after 3 weeks of ACTH therapy, thus shortening ACTH treatment in non-responding infants.     

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.     

Use of ACTH and prednisolone in infantile spasms: Experience from a developing country

BACKGROUND: Adrenocorticotrophic hormone (ACTH) and prednisone are both used to treat infantile spasms (IS) in West syndrome. In many countries, ACTH is expensive and difficult to obtain whereas, prednisone or prednisolone are cheap, given orally and easily available. AIMS: The purpose of this retrospective data analysis was to compare the efficacy and cost of ACTH and prednisolone in the treatment of IS from the perspective of a developing country. METHODS: Patients admitted with West syndrome in Children's Hospital, Islamabad, between January 1995 and December 2001 were included in the analysis. The diagnosis was made after eliciting a history of characteristic seizures and detecting hypsarrhythmia on the EEG. Parents were offered the use of either ACTH administered by intramuscular injection or prednisolone given orally. ACTH was expensive and difficult to obtain whereas prednisolone was cheap and easily available. RESULTS: One hundred and five children were included in the study. Sixty-three were boys and their age ranged from 2 months to 3 years with a mean of 11 months. Thirty-three children received ACTH injections; 27 showed improvement and 11 remained spasms free after discontinuation of injections. Seventy-two patients were given oral prednisolone, 51 responded and 17 remained spasms free after oral steroids were stopped. Overall outcome was similar in both groups. The cost of ACTH injection was more than 100 times the cost of oral prednisolone. CONCLUSION: No significant difference was seen in the final outcome in both treatment groups. Since prednisolone is inexpensive, easily available and given orally, it is the preferred mode of therapy.     

Clinical Effects of Thyrotropin-Releasing Hormone for Severe Epilepsy in Childhood: A Comparative Study with ACTH Therapy

We investigated the effects and side effects of thyrotropin-releasing hormone (TRH) on severely epileptic children to evaluate the clinical usefulness of TRH in the treatment of epilepsy and compared them with the results of ACTH therapy. The subjects were 64 patients admitted consecutively between 1980 and 1986. Their seizures were frequent, more than one a day or more than one a week. The subjects were divided into two groups; 33 patients treated with ACTH and 31 treated with TRH. The mean follow-up periods in TRH and ACTH therapy were 8 months and 3.0 years, respectively. The daily dose of TRH-t 0.5-1 mg was administered intravenously (i.v.) or intramuscularly (i.m.) for 1-4 weeks. The follow-up periods were 3-12 months (mean 6 months). In the TRH group, complete control of seizures was achieved in 7 of 13 (53.7%) of those with infantile spasms, and marked improvement of EEGs were observed in 8 of 13 (61.5%) of them. In the ACTH group, seizure cessation was observed in 75% of infantile spasms. Of the patients who received ACTH, 66.7% had various side effects, including pneumonia, huge subcutaneous abscess, hypokalemia, cataracts, and brain shrinkage as shown on computed tomography (CT), whereas only 16.7% of the patients treated with TRH had transient reduction of urine volume without other laboratory and physical abnormalities. The results of the study indicated that some patients who received TRH had cessation of infantile spasms and improved EEG findings with no serious side effect. Because of the untoward side effects of ACTH therapy, TRH is considered a possible new treatment for children with infantile spasms.     

Electroencephalography complexity in infantile spasms and its association with treatment response

ObjectiveTo investigate the potential of EEG multiscale entropy and complexity as biomarkers in infantile spasms.MethodsWe collected EEG data retrospectively from 16 newly diagnosed patients, 16 age- and gender-matched healthy controls, and 15 drug-resistant patients. The multiscale entropy (MSE) and total EEG complexity before anti-epileptic drug (AED) treatment, before adrenocorticotropic hormone (ACTH) treatment, 14 days after ACTH therapy, and after 6 months of follow-up were calculated.ResultsThe total EEG complexity of 16 newly diagnosed infantile spasms patients was lower than the 16 healthy controls (median [IQR]: 351.5 [323.1–388.1] vs 461.6 [407.7–583.4]). The total EEG complexity before treatment was higher in the six patients with good response to AED than the 10 patients without response (median [IQR]: 410.0 [388.1–475.0] vs 344.5 [319.6–352.0]). The total EEG complexity before and after 14-days of ACTH therapy was not different between 13 ACTH therapy responders and nine non-responders. After 6-months follow-up, the total EEG complexity of ACTH therapy responders were higher than non-responders (median [IQR]: 598.5 [517.4–623.3] vs 448.6 [347.1–536.3]).ConclusionsThe total EEG complexity before AED and 6 months after ACTH are associated with spasm-freedom.SignificanceThe total EEG complexity is a potential biomarker to predict and monitor the treatment effect in infantile spasms.     

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.     

Oxytocin reduces metyrapone-induced ACTH secretion in human subjects

The inhibitory action of oxytocin (OT) on adrenocorticotropin (ACTH) secretion has been disputed. Thus we evaluated the effect of exogenous OT on the elevated blood ACTH levels in normal human subjects. Metyrapone, a blocker of cortisol secretion, was given to enhance ACTH release. This experimental model was chosen because metyrapone-induced ACTH activation depends on diminution of the negative feed-back of cortisol, which is an important physiological mechanism in the control of ACTH secretion. A striking decline in plasma cortisol levels and a 10-fold rise in the mean plasma ACTH concentration was observed within 20 h after the beginning of metyrapone treatment (750 mg orally every 4 h). The administration of OT (2 IU as a i.v. bolus plus 4 IU infused in 2 h) significantly reduced the metyrapone-induced plasma ACTH rise. Since the effect of OT was evident when ACTH secretion was enhanced by a reduced cortisol-dependent negative feed-back, confirmation of the inhibitory action of OT on the ACTH secretory system in man is provided.     

CSF protein profile in infantile spasms. Influence of etiology and ACTH or dexamethasone treatment

CSF proteins in 107 children ranging from 3 to 24 months of age were analyzed by means of quantitative zone electrophoresis on agarose gel. Subjects included 50 children with infantile spasms, 41 children without CNS disease serving as controls, and 16 infants with acute aseptic meningitis who demonstrated the protein pattern of blood-CSF barrier disturbance. Children with infantile spasms were subdivided into several groups according to etiological categories: symptomatic (pre-, peri-, and postnatal), doubtful, and cryptogenetic. Before any treatment was started, these children showed the protein profile of increased permeability of the blood-CSF barrier, especially for albumin. There was an association between the severity of the changes and the etiological category. Changes were most marked in the symptomatic group, intermediate in the doubtful group, and slight in the cryptogenetic group. No child with infantile spasms of doubtful or unknown etiology revealed changes of the immunoglobulin-containing gamma fractions. Ten children who had received adrenocorticotropic hormone (ACTH) or dexamethasone for 2-11 weeks no longer showed any protein leakage into the CSF. The period of ACTH or dexamethasone treatment was characterized by the following findings: the disappearance or reduction of hypsarrhythmia; the reappearance of normal cerebrovascular permeability for protein; and the occurrence of reversible dilatation of the subarachnoid and intraventricular spaces.     

Restoration of ACTH/cortisol and LH responses to naloxone by chronic dopaminergic treatment in Parkinson's disease

Summary Naloxone is unable to stimulate ACTH/cortisol secretion in patients with de novo Parkinson's disease, suggesting a reduced endogenous opioid control of the hypothalamic-pituitary-adrenal axis in parkinsonian patients. In the present study we examined whether Parkinson's disease also impairs the secretion of LH, which is under the inhibitory control of different opioid peptides than ACTH/cortisol. In addition, we examined whether a chronic dopaminergic therapy for at least one year with levodopa (450 mg/day) plus benserazide (112.5 mg/day) in 3 divided oral doses/day of Madopar modifies the ACTH/cortisol and/or the LH response to naloxone (4 mg as an i. v. bolus plus 10 mg infused in 2 hours). Ten parkinsonian patients (aged 52–62 years) and 8 normal controls (50–60 years) were tested with naloxone and in a different occasion with normal saline. The parkinsonian patients were tested both before and after dopaminergic treatment. Tests started at 09.00 h and lasted 2.5 hours. Basal ACTH/cortisol and LH levels were similar in all groups. During saline tests, ACTH/cortisol levels showed a slight physiological decline in all groups, whereas LH levels remained constant. Naloxone administration significantly increased the plasma levels of ACTH/cortisol and LH in the normal controls, but not in the parkinsonian patients before the dopaminergic treatment. In contrast, dopaminergic therapy restored significant ACTH/cortisol and LH responses to naloxone in parkinsonian patients. In fact, after levodopa plus benserazide, naloxone-induced ACTH, cortisol and LH increments in parkinsonian patients were significantly higher than before therapy and were indistinguishable from those observed in the normal controls. These data suggest that in men Parkinson's-related dopaminergic alterations may underlie the defective endogenous opioid control of ACTH/cortisol and LH secretion.