Friday, August 24, 2018

High-dose prednisolone for infantile spasms

John R. Mytinger.  High-Dose Prednisolone as a First-line Treatment for Infantile Spasms.  Pediatric Neurology, in press.

Infantile spasms (IS) are seizures associated with a severe infantile epileptic encephalopathy called West syndrome. Both clinical remission of IS and electrographic remission of the epileptic encephalopathy are necessary for the best possible patient-specific epilepsy and neurodevelopmental outcomes. Corticosteroids and adrenocorticotropic hormone (ACTH) are hormone therapies that have been used for the treatment of IS since the late 1950s.  By the early 1990s, the preference for ACTH for the treatment of IS was relatively uniform among US child neurologists.The superiority of ACTH over corticosteroids seemed to be confirmed with a small 1996 study reporting electroclinical remission in 13 of 15 (86.6%) children treated with high-dose natural ACTH (150 IU/m 2 /day) and only 4 of 14 (28.6%) children treated with low-dose prednisone (2 mg/kg/day).  We later learned that the rate of IS remission with corticosteroids could be improved by increasing the dose. 

The 2004 study by Lux and colleagues (United Kingdom Infantile Spasms Study [UKISS]) reported a 70% rate of clinical IS remission using high-dose prednisolone (40-60 mg/day).  This result led some members of the IS community to question the superiority of ACTH over corticosteroids. Then, in 2007, the price of a single vial of natural ACTH (H.P. Acthar Gel) in the US suddenly increased from $2,063 to $23,000.  In the years since, the cost of H.P. Acthar Gel has soared to approximately $40,000 per vial, resulting in a minimum cost of $80,000 to $120,000 for a typical one-month treatment course. These factors, as well as prednisolone's low cost (less than $40 for a one-month course), widespread availability, and ease of administration, have led to an increase in the use of high-dose prednisolone (40-60 mg/day or 4-8 mg/kg/day) for IS.

High-dose prednisolone was included as one of three recommended treatments (in addition to ACTH and vigabatrin) in the 2017 Quality Measure Set from the American Academy of Neurology and Child Neurology Society.  This measure states that ACTH, high-dose prednisolone, or vigabatrin should be used for the initial treatment of IS unless refused, contraindicated, enrolled in research, or better treated with surgery.  Consistent use of these standard treatments over nonstandard treatments (e.g. topiramate) significantly improves the rate of electroclinical remission.   ACTH, high-dose prednisolone, and vigabatrin are also tnd vice versa). Thus, even when high-dose prednisolone is the preferred initial treatment for IS, ACTH and vigabatrin are the best next treatment options.

Physicians from the Johns Hopkins Hospital took an early position in the debate about ACTH versus high-dose prednisolone. This group chose to use high-dose prednisolone or the ketogenic diet as the initial treatment of IS beginning in 2007, and they no longer offered ACTH.  In this issue of Pediatric Neurology , Gonzalez-Giraldo and colleagues from John Hopkins report their experience treating IS with high-dose prednisolone from 2006 to 2016.  In this retrospective analysis, the authors identified 87 children treated with high-dose prednisolone as the first or second treatment. The main outcome measure was clinical remission of IS by two weeks and resolution of hypsarhythmia or similar pattern between two to four weeks on a 30 minute electroencephalogram (EEG). Electroclinical remission occurred in nearly two thirds (56/87, 64.4%) of children. However, a relapse of IS occurred in 26 of 56 (46.4%) children indicating an early sustained remission rate of 34.5%.

Although the study by Gonzalez-Giraldo and colleagues gives additional support for the use of high-dose prednisolone as a first-line treatment for IS, we have yet to definitively answer the fundamental question about the relative effectiveness of ACTH versus prednisolone. Two recent randomized controlled trials, both reporting electroclinical remission as a secondary outcome measure, advance our understanding of hormone therapy but provide differing results. In 2015, Wanigasinghe and colleagues (Shri Lankan study) reported that electroclinical remission starting within two weeks and sustained for 28 days was significantly higher in children receiving high-dose prednisolone (15/48, 31.3%) compared to children receiving synthetic ACTH (6/49, 12.2%; P=0.008).  In 2017, O'Callaghan and colleagues (International Collaboration Infantile Spasms Study: ICISS) reported that electroclinical remission beginning within two weeks and sustained to day 42 was significantly higher in children receiving synthetic ACTH (76/111, 68.5%) compared to children receiving high-dose prednisolone (151/263, 57.4%; P=0.04).  The reasons for these incongruous results are unknown but considerations include differences in enrollment and study design.

In contrast to the US, where natural ACTH is used for the treatment of IS, the synthetic depot form of ACTH was used in both the Shri Lankan study and ICISS. A US clinical trial of synthetic depot ACTH (as monotherapy or dual therapy with vigabatrin) is underway (NCT03347526). This raises the possibility that we would ultimately have access to a synthetic depot ACTH in the US. However, recent history justifies some apprehension about the potential price of an FDA approved IS treatment with an orphan drug status.

Even if the US acquires access to a synthetic depot ACTH, the cost of this product is likely to be much higher than the cost of prednisolone. In addition, questions will persist about the relative effectiveness of ACTH versus high-dose prednisolone as well as synthetic versus natural ACTH. While there has been an interest within the IS community of a US randomized control trial of natural ACTH versus high-dose prednisolone essentially since the 2004 UKISS publication, the cost of H.P. Acthar Gel has made this nearly impossible. There is no incentive for an owner of H.P. Acthar Gel to support a clinical trial that may fail to show ACTH superiority over high-dose prednisolone. The approval of a lower cost synthetic depot ACTH in the US may revive interest in a US study of ACTH versus high-dose prednisolone, but drug cost may remain a barrier. Yet, a well done clinical trial has the potential to change clinical practice, whether it results in an increase in the use of ACTH for superiority or in the consistent initial use of high-dose prednisolone prior to ACTH if efficacy is similar. In an effort to confirm electroclinical remission, a future clinical trial should utilize multiple EEG reviewers (given the lack of inter-rater agreement in the determination of hypsarhythmia) and longer duration EEGs that include sleep. 

Ernesto Gonzalez-Giraldo, Carl E. Stafstrom, Anthony C. Stanfield and Eric H. Kossoff.  Treating Infantile Spasms with High-Dose Oral Corticosteroids: A Retrospective Review of 87 Children. Pediatric Neurology, in press. 


Hormonal therapy is the treatment of choice in most cases of infantile spasms (IS), but the optimal way to provide this is unclear. Intramuscular adrenocorticotropic hormone (ACTH) is historically used first-line; however, there are significant logistical and financial issues. Our institution has used high-dose prednisolone as the first-line hormonal treatment of IS since 2006 and published our early experience with 15 infants in 2009. This study updates our institutional experience over more than 10 years of continuous use.

Charts of infants who presented to the Johns Hopkins Hospital with IS and were treated with high-dose oral prednisolone (40-60 mg/day) from 1/2006-12/2016 were reviewed. Electroclinical response was defined as clinical spasm-freedom and resolution of hypsarrhythmia within two weeks of initiation of therapy. Presence of IS at 3 months and adverse effects throughout treatment were evaluated.

Over the 10-year time period, 87 infants with new-onset IS were treated. Electroclinical response was seen in 64% infants within 2 weeks; 62% were spasm-free at 3 months. Fifty two percent had side effects, primarily irritability, weight gain, and gastroesophageal reflux. Five percent had major adverse events, including gastrointestinal bleed (n=2), herpes simplex virus reactivation (n=1), and necrotizing enterocolitis (n=1).

Our results continue to demonstrate that high-dose oral prednisolone is very effective for the treatment of new-onset IS, with few major adverse effects. Oral prednisolone represents a less expensive, readily available alternative to ACTH injections.


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