A blond woman cradles her infant in her arms, trying to soothe them.

CURE Epilepsy Infantile Spasms Initiative: Using Team Science to Discover Novel Targets

Key Points:

  • Infantile spasms (IS) is a rare debilitating pediatric epilepsy syndrome marked by distinct observable symptoms.
  • CURE Epilepsy directed its unique resources to establish a team science-based initiative to support research into this devastating disorder.
  • The IS Initiative has successfully accelerated advancements in IS research and underscored the advantages of working as part of such a formal collaboration.

Deep Dive:

Dr. John Swann, Ph.D

Infantile spasms is a rare, devastating epilepsy disorder that generally begins within the first year of life. The condition is typified by seizures with sudden jerking motions or head bobs and often, though not always, an atypical EEG marked by a chaotic pattern of brain waves (hypsarrhythmia). The seizures are accompanied by significant developmental delays and cognitive and physical deterioration. Current standardized treatments include a hormone (ACTH, prednisone) or the antiseizure medication vigabatrin. Unfortunately, only 50% of children suffering from IS respond to these treatments, and there remains no reliable way of predicting who will respond favorably.

Launched in 2013, CURE Epilepsy’s IS Initiative was an innovative interdisciplinary program designed to advance findings that could lead to better treatments for IS. It brought together eight research groups from different institutions who functioned as a united team, collaborating and sharing data to accelerate understanding of IS in an effective and efficient fashion. Collectively, the investigators studied the basic biology underlying IS, searched for biomarkers as well as novel drug targets, and developed improved treatments. The availability of several widely accepted rodent models of IS allowed for cross-testing of promising targets and therapeutic interventions. The initiative generated 19 publications to date, 7 additional manuscripts in preparation, 3 federal grants from the National Institutes of Health (NIH), and even a patent, published in October 2018.

One exciting project was led by John Swann at the Baylor College of Medicine. Building on previous findings, Dr. Swann’s team focused its efforts on discovering novel drug targets and devising better treatment strategies to arrest the spasms as well as the associated developmental delay. The team was able to show that treatment with (1-3) IGF-1, a derivative of the growth hormone insulin-like growth factor 1 (IGF-1), diminished the spasms and irregular brain wave pattern in an animal model. Importantly, adding this compound to vigabatrin, one of the standard IS treatments, reduced the dose of vigabatrin required for the complete elimination of the spasms, thereby decreasing the risk of serious side effects, the most serious of which is irreversible loss of peripheral vision. These data allowed the Swann lab to patent the novel combination treatment and to obtain two NIH grants. One, worth a total of ~$350,000 over 5 years, aims to investigate the molecular basis for the combination therapy. The second grant seeks to establish a specific IS rodent model for identifying more effective, less toxic therapies.

In addition to the more concrete evidence of increased knowledge of IS reflected in the publications, federal grants, and patents, the CURE Epilepsy IS initiative yielded numerous intangible benefits. The most significant of these was the active collaboration among teams that might otherwise have been competing. Such interactions facilitated rapid dissemination of results among teams, cross-fertilization of ideas between basic scientists and clinicians, and mentoring of junior investigators. All these factors served to accelerate basic research that will hopefully benefit patients and their families who suffer from IS. Learnings also indicated the need for a dedicated project manager and more transparent real-time communications with the investigators. CURE Epilepsy has applied these valuable insights to its ongoing Post-Traumatic Epilepsy Initiative, funded by the US Department of Defense.

You can read more about our work and the full paper here.


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

Mortality in Infantile Spasms: A Hospital-Based Study

Abstract, published in Epilepsia

Objective: To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). The team describe the overall goals of care for those who died.

Methods: Researchers reviewed the charts of IS patients born between 2000 and 2011, focusing on potential risk factors for mortality, including cause, neurologic impairment, medication use, persistence of epileptic spasms, and comorbid systemic involvement. For patients who died, the team described cause of death and resuscitation status or end-of-life care measures.

Results: Of the 150 IS patients identified and followed over a 12 year period, 25 (17%) of them died, 13 before 5 years of age. Analysis demonstrated that developmental delay, identifiable cause, hormonal use for IS, persistence of epileptic spasms, treatment with multiple antiseizure medications, refractory epilepsy, respiratory system comorbidity, and the need for a feeding tube placed directly into the stomach were significant risk factors for mortality.

Significance: Mortality at this single-center IS cohort was 17%, and persistence of epileptic spasms and comorbid respiratory system disorders were the most important determinants of mortality. Early deaths were related to neurological impairments/comorbidities. SUDEP was more common in children who died after 5 years of age than in those who died younger than 5 years.

A blond woman cradles her infant in her arms, trying to soothe them.

Levetiracetam (Keppra®) Versus Phenobarbital (Solfoton®) for Seizures in Newborn Children: A Randomized Controlled Trial

Abstract, published in Pediatrics

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration–approved therapies for neonatal seizures, which are seizures that occur in newborn children. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in newborn children. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures.

METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the pattern of brain waves by 2 neurophysiologists.

RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam. A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. Although more adverse effects were seen in subjects randomly assigned to phenobarbital, they were not statistically significant.

CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

Le Bonheur Children’s Hospital Launches Infantile Epilepsy Center

Le Bonheur Children’s Hospital has launched an Infantile Epilepsy Center that focuses on the potentially devastating diagnosis of infantile spasms and other rare epilepsies that affect children under two-years-old.

The seizures typically present as small involuntary movements, crunches or spasms and require a rapid diagnosis to prevent developmental delay or worsening of prior development.

“Infants are not just small children,” said Sarah Weatherspoon, MD, an assistant professor of Pediatric Neurology at the University of Tennessee Health Science Center and Director of the Infantile Epilepsy Center at Le Bonheur Children’s. “Infantile epilepsy requires specific techniques, diagnostics and treatments.”

The center is part of Le Bonheur’s Comprehensive Epilepsy Program and includes neurology, neurodiagnostics, neuropsychology, neuroradiology, neuro-ophthalmology, genetics, clinical nutrition, pediatrics and speech therapy/feeding assessment.

CURE Ally Dr. Marcelo Diaz-Bustamante Works to Find a CURE for his Daughter’s Epilepsy

Dr. Marcelo Diaz-Bustamante of Johns Hopkins University is not only a devoted father; he is also a devoted researcher studying infantile spasms, a severe form of childhood-onset epilepsy. Dr. Diaz-Bustamante’s daughter Myriam was diagnosed with the disorder in 2016.

Infantile spasms is a hard-to-treat form of epilepsy that normally starts in the first year of life and is characterized by subtle seizures, abnormal brain activity, and developmental delay or regression.

Faced with Myriam’s daunting diagnosis, Dr. Diaz-Bustamante had his daughter’s genes sequenced as part of CURE’s Epilepsy Genetics Initiative (EGI). EGI examines genetic information to uncover the causes of epilepsy and advance precision medicine. Amazingly, gene sequencing pinpointed the cause of Myriam’s infantile spasms to a mutation in a GABA receptor, which is a type of neuronal receptor important in maintaining the balance of excitatory and inhibitory activity in the brain. After learning of this mutation, Dr. Diaz-Bustamante changed his research focus to devote himself to studying this infantile spasms-causing mutation.

Since his daughter’s diagnosis, Dr. Diaz-Bustamante has formed a deep connection with CURE. He has hosted a CURE-sponsored seminar at Johns Hopkins University and has participated in CURE’s Day of Science events. Dr. Diaz-Bustamante credits CURE with providing both education about and a human face to epilepsy, creating a feeling that he and his family are not alone in their fight.

In fact, Dr. Diaz-Bustamante believes the biggest challenge facing parents whose child has been diagnosed with infantile spasms is a lack of hope; “It is difficult to remain hopeful with all of the scary information available on the internet, coupled with many pediatricians’ lack of knowledge about the disorder.” Still, he is hopeful about the future of epilepsy research, noting that growth in the field over the past 10 years has been exponential with heightened understanding of epilepsy and increased research into new treatments and therapies.

While Myriam has gone through more than 5 different types of treatments and therapies to control her spasms, we are happy to report that she is finally experiencing some improvement. However, Myriam still has a long road ahead of her. There is a continuing need for the devotion of research and resources to uncover the causes of childhood epilepsy. As Dr. Diaz-Bustamante notes, “We have the tools to investigate the causes of epilepsy, but if there isn’t enough money for research, we can’t investigate potential treatments.” CURE agrees. We thank Dr. Diaz-Bustamante for his devotion to finding a cure for infantile spasms.

Woman sitting at a laptop participating in a CURE webinar.

Webinar: Diagnostic and Treatment Challenges of Infantile Spasms

This webinar focuses on the challenges of diagnosing and treating Infantile Spasms, and how advances in epilepsy medicine and technology have improved this process. This presentation will also examine currently available treatment options.

The presenter is Dr. Shaun Hussain, Assistant Professor of Pediatrics at UCLA, Director of the UCLA Infantile Spasms Program, and inaugural recipient of the Elsie and Isaac Fogelman Endowed Chair in Pediatric Neurology. His clinical and research endeavors focus on Infantile Spasms and other forms of severe pediatric epilepsy, including Lennox-Gastaut syndrome and Dravet syndrome.

Dr. Hussain’s presentation is followed by an interactive Q&A session, where viewers asked questions like:

  • What are the consequences of Infantile Spasms if they are not controlled?
  • How are Infantile Spasms treated and how often are treatments effective?
  • Could a ketogenic diet help control my child’s Infantile Spasms?

Study: Detailed Magnetic Resonance Imaging (MRI) Analysis in Infantile Spasms

Purpose: To evaluate initial magnetic resonance imaging (MRI) abnormalities in infantile spasms, correlate them to clinical characteristics, and describe repeat imaging findings.

Methods: A retrospective review of infantile spasm patients was conducted, classifying abnormal MRI into developmental, acquired, and nonspecific subgroups.

Results: MRIs were abnormal in 52 of 71 infantile spasm patients (23 developmental, 23 acquired, and 6 nonspecific) with no correlation to the clinical infantile spasm characteristics. Both developmental and acquired subgroups exhibited cortical gray and/or white matter abnormalities. Additional abnormalities of deep gray structures, brain stem, callosum, and volume loss occurred in the structural acquired subgroup. Repeat MRI showed better definition of the extent of existing malformations.

Conclusion: In structural infantile spasms, developmental/acquired subgroups showed differences in pattern of MRI abnormalities but did not correlate with clinical characteristics.

New Direction For Precision Medicine In Epilepsy

In a new approach to precision medicine research, scientists used bioinformatics tools to identify common features of genes associated with infantile spasms compared to other forms of early life epilepsy. Their analysis, published in PLOS ONE, reveals that infantile spasms are not only unique clinically, but also biologically. Focus on specific biological mechanisms underlying the genes that cause infantile spasms could help find new targets for treatment.

‘Our novel approach marks a paradigm shift in precision medicine from single gene discovery to grouping genes by their underlying biology,’ says lead author Anne Berg, PhD, epilepsy specialist at Ann & Robert H. Lurie Children’s Hospital of Chicago and Research Professor in Pediatrics at Northwestern University Feinberg School of Medicine. ‘To develop new treatments, we can start looking at mechanisms common to many associated genes, instead of trying to therapeutically target one gene at a time. With this approach, we are starting to ask why certain genes are involved, which might help us understand why some treatments are effective and others are not. Such an approach could ultimately help us choose the treatment that mostly precisely matches the genetic signature and biology of the child’s epilepsy.’

‘We used bioinformatics tools to perform what is called gene set enrichment analysis, which means that we looked at common molecular properties of genes that lead to infantile spasms and other types of seizures,’ says Dr. Berg. ‘We examined how these genes function in the cell, in what processes they are involved, where in the cell they are expressed. We found that the genes associated with infantile spasms are uniquely involved in developmental functions within the cell body, which might be linked to why spasms tend to start at the same time in an infant’s development.’

When it comes to Infantile Spasms, families face difficult choices

When Mickie was born, she was a beautiful, normal, healthy baby. Then she began having seizures at the age of three months. Soon thereafter, she was diagnosed with intractable epilepsy and infantile spasms (IS), and her parents were forced to make agonizing decisions about her care.

After eight different medications failed to stop Mickie’s seizures, physicians suggested that a major surgery might be her only hope. Without it, her seizures could eventually prove debilitating or even fatal. The day before Mickie’s first birthday, she underwent brain surgery and has not had a seizure since. Today Mickie is active and healthy but still recovering from the damage inflicted by epilepsy. She undergoes regular therapies to improve her speech and must take anti-seizure medication every day.

Mickie’s quality of life improved with surgery, but for far too many children with infantile spasms, these results are not possible. That is why we hope you consider CURE during your annual holiday giving so that we can continue to drive research forward.

CURE’s Infantile Spasms (IS) Initiative has advanced disease-modifying therapies for kids like Mickie by focusing on the underlying pathology of this syndrome. In a groundbreaking, multidisciplinary “team science” approach, CURE awarded $4.2 million in grants to investigators to advance cutting-edge research to find a cure for IS. This collaborative, milestone-driven project examined potential therapeutic pathways and biomarkers in order to improve treatment options and decrease lifelong disabilities that often result from IS. With additional resources we can build on the important work done by our preeminent investigators.

This year, as you consider your annual holiday giving, we hope you will consider CURE and its impact on kids like Mickie and the hundreds of thousands of other children with epilepsy.

Our work inspires and gives meaning to parents of children with IS. “CURE gives children their best chance,” Mickie’s mother, Kristie, says. “It offers hope for families with intractable epilepsies, and pulls all the parts together. CURE is a vital link in the chain that connects mothers like me to the leading-edge research that is pushing us closer to a cure.”

Your ongoing support will help ensure that the finest scientific minds continue working together to move us closer to our ultimate goal: no seizures, no side effects, and a cure for epilepsy. 

Mickie’s mother, Kristie Griess, considers Mickie’s journey the definition of a miracle and founded her own nonprofit – Mickie’s Miracles – aimed at creating awareness, education, and advocacy around pediatric epilepsy. She is also a passionate supporter of CURE.

Vigabatrin evaluated for focal seizures in tuberous sclerosis in recent study

A study, “Vigabatrin for focal seizures in tuberous sclerosis,” found that [1]:

Vigabatrin (VGB) is used for focal seizures in tuberous sclerosis (TS) and may be an effective therapy in patients who fail to respond adequately to other anti-seizure medications while awaiting definitive epilepsy surgery.

Vigabatrin is well-established as the first-line therapy for infantile spasms in association with tuberous sclerosis, but less is known about its role in focal seizures due to tuberous sclerosis.

[Researchers] retrospectively identified 22 patients with tuberous sclerosis who received Vigabatrin for focal seizures, starting Vigabatrin in June 1989 and continuing through the present time. Nineteen (86%) had a history of infantile spasms and all except the two oldest, born in 1986, received Vigabatrin for infantile spasms. Eleven of these individuals exhibited improvement in or resolution of infantile spasms. Sixteen out of 17 with infantile spasms remained on Vigabatrin to treat focal seizures.

The risk for vision loss due to photoreceptor toxicity continues to limit prolonged use.