Epilepsy Surgery in Infants up to 3 Months of Age: Safety, Feasibility, and Outcomes: A Multicenter, Multinational Study

Summary, originally published in Epilepsia

Objective: Drug-resistant epilepsy (DRE) during the first few months of life is challenging and necessitates aggressive treatment, including surgery. Because the most common causes of DRE in infancy are related to extensive developmental anomalies, surgery often entails extensive tissue resections or disconnection. The literature on “ultra-early” epilepsy surgery is sparse, with limited data concerning efficacy controlling the seizures, and safety. The current study’s goal is to review the safety and efficacy of ultra-early epilepsy surgery performed before the age of 3 months.

Methods: To achieve a large sample size and external validity, a multinational, multicenter retrospective study was performed, focusing on epilepsy surgery for infants younger than 3 months of age. Collected data included epilepsy characteristics, surgical details, epilepsy outcome, and complications.

Results: Sixty-four patients underwent 69 surgeries before the age of 3 months. The most common pathologies were cortical dysplasia (28), hemimegalencephaly (17), and tubers (5). The most common procedures were hemispheric surgeries (48 procedures). Two cases were intentionally staged, and one was unexpectedly aborted. Nearly all patients received blood products. There were no perioperative deaths and no major unexpected permanent morbidities. Twenty-five percent of patients undergoing hemispheric surgeries developed hydrocephalus. Excellent epilepsy outcome (International League Against Epilepsy [ILAE] grade I) was achieved in 66% of cases over a median follow-up of 41 months (19–104 interquartile range [IQR]). The number of antiseizure medications was significantly reduced (median 2 drugs, 1–3 IQR, p < .0001). Outcome was not significantly associated with the type of surgery (hemispheric or more limited resections).

Significance: Epilepsy surgery during the first few months of life is associated with excellent seizure control, and when performed by highly experienced teams, is not associated with more permanent morbidity than surgery in older infants. Thus surgical treatment should not be postponed to treat DRE in very young infants based on their age.

Study: ‘Rethink’ Use of Antiseizure Medications after Hospital Discharge in Neonates

Summary, originally published on healio.com

Researchers observed no difference in functional neurodevelopment or epilepsy among children aged 24 months regardless of whether antiseizure medication was discontinued or maintained in infants at discharge once seizures ceased.

Results of the comparative effectiveness study were published in JAMA Neurology.

“These results support discontinuing antiseizure medications (ASMs) for most neonates with acute symptomatic seizures prior to discharge from the hospital, an approach that may represent an evidence-based change in practice for many clinicians,” Hannah C. Glass, MDCM, MAS, a pediatric neurologist, founding codirector of the neurointensive care nursery and director of neonatal critical care services at the University of California, San Francisco Benioff Children’s Hospital, and colleagues wrote.

Cognitive Outcome in Children With Infantile Spasms Using a Standardized Treatment Protocol: A Five-Year Longitudinal Study

Abstract, originally published in Seizure

Aim: To evaluate the long-term developmental trajectory of children with infantile spasms (IS) and identify the clinical protective and risk factors associated with their cognitive outcome.

Methods: We analyzed the five-year follow-up results of 41 children (13 female) from the previously published cohort (n = 68) recruited in a multicenter randomized controlled trial for 2-years, examining the effect of an adjunctive therapy (Flunarizine) on standardized IS treatment. The children were subsequently monitored in an open-label study for additional 3 years. The Vineland Adaptive Behavior Scale, second edition, and either the Stanford-Binet Intelligence Scale, Fifth Edition (SB5) or the Bayley Scales of Infant Development, second edition (BSID-II) were used as cognitive outcome measures.

Results: Etiology [cause of epilepsy] was the strongest predictor of outcome. Children with no identified etiology (NIE) showed a progressive improvement of cognitive functions, mostly occurring between 2 and 5 years post-diagnosis. Conversely, symptomatic etiology was predictive of poorer cognitive outcome. Developmental delay, other seizure types (before and after IS diagnosis), and persistent electroencephalographic abnormalities following treatment were predictive of poor cognitive outcome.

Interpretation: Given the 5-year cognitive improvement, children with IS should undergo a developmental assessment before school entry. Factors influencing their cognitive outcome emphasize the importance of thorough investigation and evidence-based treatment.

Modification of Classification of Seizures for Seizures in the Neonate

Position paper by the ILAE Task Force on Neonatal Seizures
Abstract, originally published in Epilepsia

Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be electrographic-only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults.

A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group.

The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic-only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non-motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group.

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.


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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?