Hussain, S. A. (2018), Treatment of infantile spasms. Epilepsia Open. . doi:10.1002/epi4.12264
The treatment of infantile spasms is challenging, especially in the context of the following: (1) a severe phenotype with high morbidity and mortality; (2) the urgency of diagnosis and successful early response to therapy; and (3) the paucity of effective, safe, and well‐tolerated therapies. Even after initially successful treatment, relapse risk is substantial and the most effective therapies pose considerable risk with long‐term administration. In evaluating any treatment for infantile spasms, the key short‐term outcome measure is freedom from both epileptic spasms and hypsarrhythmia. In contrast, the most important long‐term outcomes are enduring seizure‐freedom and measures of intellectual performance in later childhood and adulthood. First‐line treatment options—namely hormonal therapy and vigabatrin—display moderate to high efficacy but also exhibit substantial side‐effect burdens. Data on efficacy and safety of each class of therapy, as well as the combination of these therapies, are reviewed in detail. Specific hormonal therapies (adrenocorticotropic hormone and various corticosteroids) are contrasted. Those etiologies that prompt specific therapies are reviewed briefly, as are an array of second‐line therapies supported by less‐compelling data. The ketogenic diet is discussed in greater detail, with a focus on the limitations of numerous available studies that generally suggest that it is efficacious. Special discussion is allocated to cannabidiol—the investigational therapy that has received the most attention, and which is already in use in the form of various artisanal cannabis extracts. Finally, a treatment algorithm reflecting the concepts and controversies discussed in this review is presented.
Hormonal therapy is the most effective single therapy for short‐term treatment of infantile spasms
Although highly effective in the setting of tuberous sclerosis complex (TSC), short‐term response to vigabatrin is lower in the setting of other etiologies
Based on one study, combination therapy (hormonal therapy plus vigabatrin) appears to be more efficacious than hormonal therapy alone; this finding needs replication
Surgical resection is a favorable option for highly selected patients with well‐defined cortical lesions
An array of second‐line therapies exhibit lower efficacy and should be reserved for refractory cases
From the article
With the exception of IS in the setting of tuberous sclerosis complex (TSC, discussed below), there is relatively broad consensus that hormonal therapy is the most effective class of initial treatment for IS. However, there is considerable debate as to the best agent, dose, and duration of treatment. The most popular hormonal therapies include natural adrenocorticotropic hormone (ACTH, a 39 amino acid peptide), synthetic ACTH (sACTH, a truncated peptide spanning the first 24 N‐terminal residues), prednisolone, and prednisone (the prodrug of prednisolone). Although some investigators have reported favorable response rates using extremely low‐dose sACTH,16 the highest short‐term response rates have been observed with ACTH administered at high dose (150 U/m2 body surface area/day, divided into 2 daily doses). In a pivotal randomized controlled trial, Baram and colleagues demonstrated that short‐term response (freedom from ES and hypsarrhythmia on treatment day 14) was far superior with this regimen of ACTH in comparison to a “traditional” dose of prednisone (2 mg/kg/day).19 In contrast, a sequence of studies have suggested—but not proven—that higher dose regimens of prednisolone are as effective as ACTH. In the UKISS study, Lux et al. reported no difference in response rate between prednisolone (40–60 mg/day) and a “moderate” dose of sACTH (0.50–0.75 mg on alternate days), although treatment allocation was not randomized.20 Similarly, in an arguably underpowered retrospective analysis, Kossoff and colleagues reported that efficacy of high‐dose prednisolone (40–60 mg/day) was similar to historical experience with high‐dose natural ACTH.21 Similarly, in a relatively small study evaluating short‐term efficacy of “very high dose” prednisolone (8 mg/kg/day; max 60 mg/day) followed by high‐dose natural ACTH in prednisolone nonresponders, the EEG‐confirmed response to prednisolone (63%) was comparable to the reported ACTH response in most contemporary studies. However, among the 10 prednisolone nonresponders, 4 children then responded to ACTH, though 2 subsequently relapsed, and none of the 4 ACTH responders exhibited enduring hypsarrhythmia on day 14 when ACTH was initiated. More recently, in a large‐scale prospective observational study conducted by the National (United States) Infantile Spasms Consortium without randomized treatment allocation, Knupp and colleagues reported that response rates to natural ACTH (most with high‐dose protocol; 150 U/m2/day) and oral corticosteroids (most with high‐dose prednisolone; 40–60 mg/day) were statistically indistinct, although there was a trend favoring ACTH. In a follow‐up analysis that carefully adjusted for prescribing bias, response rates for ACTH and corticosteroids were nearly identical. In the only contemporary randomized controlled trial comparing high‐dose prednisolone (40–60 mg/day) with moderate‐dose sACTH (0.5–0.75 mg on alternate days), Waningasinghe and colleagues found that response to prednisolone was superior, although the response rate to sACTH was inexplicably low (36%). It is critical to note that high‐dose ACTH has not been compared to high‐dose prednisolone in an adequately powered randomized controlled trial. Perhaps more importantly, all of the aforementioned comparisons have focused on short‐term outcomes. Only a handful of studies have evaluated long‐term epilepsy and developmental outcomes,6, and none permits adequate comparison of competing hormonal therapies. In the United States, the choice between ACTH and prednisolone is especially contentious given the enormous disparity in cost between these agents. Whereas the cost of a typical course of ACTH exceeds 100,000 USD, a typical course of prednisolone costs less than 100 USD.
Although the comparative effectiveness of ACTH, sACTH, and prednisolone is subject to ongoing debate, there is general agreement that all hormonal therapies exhibit similar—and substantial—adverse event profiles. The chief risks are immunosuppression, which can be severe and potentially lethal, as well as hypertension, with the potential to yield congestive heart failure. As such, avoidance of infectious contacts and screening for asymptomatic hypertension are key safety measures to be enacted during any course of hormonal therapy. In addition, a subset of clinicians (1) prescribe antibiotic prophylaxis for pneumocystis pneumonia, (2) screen for asymptomatic hyperglycemia, (3) monitor serum potassium given modest risk of hypokalemia, and (4) screen for adrenal or pituitary insufficiency after a course of hormonal therapy.
Whereas it is well established that ACTH stimulates endogenous cortisol production in the adrenal cortex, and that both cortisol and prednisolone (a close structural analog) exert similar corticosteroid effects, the precise mechanisms by which hormonal therapies impact ES and hypsarrhythmia are unknown. It is important to note that the debate surrounding ACTH and prednisolone is in part fueled by the hypothesis that ACTH may act via cortisol production as well as corticosteroid‐independent mechanisms mediated by central melanocortin receptors.29