Steroids in Infantile Spasms Syndrome

Infantile spasms syndrome (ISS) is a severe epileptic encephalopathy characterized by epileptic spasms, developmental stagnation and/or regression, and the electroencephalogram finding of hypsarrhythmia.[1] Early recognition and treatment of ISS are essential, in order to improve seizure outcomes and preserve the neurodevelopmental trajectory. Treatment of ISS includes the use of anti-seizure medications (i.e., vigabatrin) and hormonal therapy in the form of prednisolone or adrenocorticotropic hormone (ACTH).[1] In a recent systematic review and network analysis, treatment with ACTH and high-dose prednisolone were found to be more effective at achieving electroclinical and clinical remission in ISS when compared to other treatments (i.e., vigabatrin).[1] An additional meta-analysis demonstrated that the effectiveness of ACTH was not statistically different than high-dose prednisolone (4 to 8 mg/kg/day) for ISS and that ACTH was less cost-effective.[2] Although, vigabatrin remains the standard treatment for ISS associated with Tuberous Sclerosis Complex.[3] Despite the growing evidence that supports the use of hormonal therapy for ISS, there are challenges with the administration of this therapy, particularly ACTH.[4] Decreased availability, difficulties with administration, high cost, and side effect profile limit the use of ACTH for ISS.[24] Therefore, there is a growing need to determine whether other forms of steroid therapy can be used for the treatment of ISS. The reported rates of electroclinical remission with oral prednisolone, from various studies from India are variable, 26.7% to 44.8%.[5678] These studies, in general, had long lag times to treatment and a high proportion of children with “symptomatic” etiology. These rates are lower than those reported in developed countries (59% to 80%).[49] In this issue of the Annals of Indian Academy of Neurology, Deswal et al. (2022)[10] examine the use of oral dexamethasone versus high-dose prednisolone for the management of ISS in an open-label randomized control trial. The rationale for this pilot study was to compare the efficacy of both treatments and determine whether dexamethasone may be a promising alternative treatment for ISS. Dexamethasone was chosen due to its ease of administration, potency, low cost, CNS bioavailability, favorable pharmokinetics, and availability in most countries. Children with ISS between the ages of 3 months and 3 years were randomized to receive either oral dexamethasone (0.6 mg/kg/day divided into four doses) or high-dose oral prednisolone (4 mg/kg/day divided into two doses) and were followed up at 2 weeks. At the end of 2 weeks, the authors found no difference between oral prednisolone and dexamethasone with regard to spasm cessation, electroclinical remission, greater than 50% reduction of spasms, time to cessation of spasms, and side effect profile. Despite being underpowered, there appeared to be a trend with regard to electroclinical remission with oral dexamethasone (65% vs. 40%, P = 0.21) and the number of children who achieved clinical spasm cessation at 2 weeks (65% vs. 40%, P = 0.21). However, these findings are preliminary and will need to be confirmed with adequately powered randomized control trials. Nevertheless, Deswal et al.[10] (2022) should be commended for their efforts, in helping to pave the way for alternative treatments for children with ISS. There were limitations to this trial, however, including a small sample size, short duration of follow-up, and over-representation of structural aetiologies in the cohort (i.e., 75% to 90%). Further, 50% to 80% of the cohort also had a history of perinatal asphyxia, which was felt to be high and may limit the generalizability to all-comers with ISS.[10] The time lag to diagnosis and thus treatment lag in both groups was also prolonged, upwards of 2 months, which may adversely affect treatment responses.[1] Delayed recognition and treatment of ISS in this study highlight the ongoing challenges with identifying this devastating epileptic encephalopathy. There is a need for better education of healthcare professionals and caregivers about ISS so that treatment delays can be avoided. Given that the study participants were only followed for 2 weeks in duration, it is unclear whether spasm cessation and electroclinical response were short-lived. Further studies should therefore evaluate long-term electroclinical responses as well as developmental outcomes, which were not evaluated in the present study. Moreover, children were included in this trial up to the age of 3 years, which would be an atypical age for the onset of ISS, and thus likely had refractory epileptic spasms in the context of an evolving Lennox Gastaut syndrome. It is also unclear if patients with late-onset spasms (>1 year age at onset) were enrolled. It is unknown if these patients behave similarly to usual infantile spasms with respect to treatment responses. Future studies aimed at evaluating the efficacy of dexamethasone should have stricter inclusion criteria (i.e., include smaller age ranges and stricter diagnostic criteria for ISS). Finally, as Deswal et al.[10] (2022) illustrate there are few studies to which one can compare the results of this present trial, with previous studies being limited by small numbers, various treatment regimens, administration routes, and treatment responses. Given the novelty of dexamethasone, there is also the need to determine the most appropriate dose and duration for the treatment of ISS and whether certain aetiologies are more responsive to treatment. Comparing the use of oral dexamethasone to other forms of therapy will also be required. Overall, the results presented by Deswal et al.[10] (2022) provide some promise for alternative forms of hormonal therapy for the treatment of ISS. However, additional larger randomized control studies will be needed to confirm these preliminary findings. We are also excited about the establishment of the South Asian West Syndrome research group. Inter-regional collaboration in this part of the world would be critical to answering several research questions related to ISS through well-planned and adequately powered studies.

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