Prevention of West Syndrome With Low-dose Adrenocorticotropin Hormone (ACTH) (PREVENT-WS)

West syndrome (WS) is a specific type of epilepsy (or seizure disorder) that has three features: infantile spasms (type of seizure), loss of milestones, and a specific pattern on electroencephalogram (EEG or brain wave test) called hypsarhythmia. The purpose of this study is to detect pre-hypsarhythmia in infants at high-risk for WS and determine whether treatment with ACTH will prevent WS.

The long-term neurological sequelae of intractable epilepsy that begins in infancy are devastating. A true anti-epileptogenic treatment trial is needed. The intervention proposed herein will succeed because it is based on solid clinical observations, uses a medication that is clearly effective in practice, and it relies on a highly reliable time-tested surrogate marker of epilepsy: the EEG. The study is focused on a very specific condition, West syndrome (WS), defined by infantile spasms, hypsarhythmia, and developmental regression. Conventional antiepileptic drugs are not only inadequate in controlling spasms, but unable to spare the developing brain from epileptogenic insults or to modify disease progression. Early recognition of spasms and prompt adrenocorticotropin hormone (ACTH) therapy offer the best option for electroclinical cessation of spasms and for favorable long term developmental outcome. Neonatal hypoxic ischemic encephalopathy (HIE) and cystic periventricular leukomalacia (PVL) have been identified as significant risk factors for WS. Focal epileptiform discharges or multifocal spikes in the EEG often precede WS and is highly predictive of future progression to hypsarhythmia. There is a paucity of well-designed adequately powered randomized controlled trials to show the efficacy of different dosages and durations of ACTH in WS. Furthermore, for 160 years since the first description of WS, not a single study has utilized a preemptive strategy to halt the evolution of epileptogenic process from perinatal brain injury to abnormal EEG followed by WS.

Hypothesis 1: A specific EEG pattern, pre-hypsarhythmia, appears 4-8 weeks prior to development of hypsarhythmia and reliably predicts development of WS in infants with HIE or PVL.

Aim 1. To identify infants at high risk for developing WS.

Hypothesis 2: Preemptive ACTH will halt the evolution of hypsarhythmia and improve the EEG patterns in infants with pre-hypsarhythmic EEG.

Aim 2. To determine whether a low dose ACTH improves EEG, we will repeat EEG one month after a 2 week course of daily ACTH.

Design: A single treatment arm exploratory study utilizing a two-stage "minimax optimal" design that yields a first stage sample size of 12 that requires 4 or more successes to proceed (and n=16 in stage 2; total n=28 over 2 years) using EEG as the surrogate biomarker for clinical response. The two-stage design exposes the smallest number of infants to treatment and provides information on adverse events and short-term clinical response with a short duration and at a low cost.

• SOREL L, DUSAUCY-BAULOYE A. [Findings in 21 cases of Gibbs' hypsarrhythmia; spectacular effectiveness of ACTH]. Acta Neurol Psychiatr Belg. 1958 Feb;58(2):130-41. French. No abstract available.
• Okumura A, Watanabe K. Clinico-electrical evolution in pre-hypsarrhythmic stage: towards prediction and prevention of West syndrome. Brain Dev. 2001 Nov;23(7):482-7.
• Suzuki M, Okumura A, Watanabe K, Negoro T, Hayakawa F, Kato T, Itomi K, Kubota T, Maruyama K. The predictive value of electroencephalogram during early infancy for later development of West syndrome in infants with cystic periventricular leukomalacia. Epilepsia. 2003 Mar;44(3):443-6.
• Philippi H, Wohlrab G, Bettendorf U, Borusiak P, Kluger G, Strobl K, Bast T. Electroencephalographic evolution of hypsarrhythmia: toward an early treatment option. Epilepsia. 2008 Nov;49(11):1859-64. Epub 2008 Jul 9.
• Watanabe K, Iwase K, Hara K. The evolution of EEG features in infantile spasms: a prospective study. Dev Med Child Neurol. 1973 Oct;15(5):584-96. No abstract available.
• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10.

Inclusion Criteria:

• Infants with an abnormal EEG at 3 months corrected age and one or more of the following diagnoses:

  1. Periventricular leukomalacia (PVL)
  2. Neonatal intraventricular hemorrhage (IVH)
  3. Neonatal hypoxic ischemic encephalopathy (HIE)

Exclusion Criteria:

• Infants with any of the following diagnoses:

  1. Genetic abnormality
  2. Progressive degenerative metabolic condition
  3. Other symptomatic epileptic encephalopathy (e.g. Ohtahara syndrome)