CURE Epilepsy Discovery: Identifying a Promising Novel Treatment for Infantile Spasms

Key Points:

John Swann, PhD, and his team explored an underlying cause of infantile spasms (IS), a devastating epileptic encephalopathy (an epilepsy syndrome that can lead to deterioration of the brain) that typically begins within the first year of life. This new research, funded by the National Institutes of Health (NIH), was a direct result of Dr. Swann’s findings from his work as a member of the CURE Epilepsy Infantile Spasms Initiative, conducted from 2013-2017.
Standard treatments for IS work in only approximately 50% of patients and can have severe side effects. The need for additional effective therapies drove Dr. Swann and his team to explore a more effective treatment with fewer or, ideally, no side effects.
Through extensive experimentation with an established rat model of IS and parallel studies in human tissue removed during epilepsy surgery, Dr. Swann observed very low levels of an important growth factor in the brain which has the potential to be a promising new treatment for this severe form of epilepsy.

Deep Dive:

Infantile spasms (IS) is a rare catastrophic form of epilepsy with approximately 90% of the cases beginning within the first year of life [1,2]. The condition is characterized by seizures with sudden brief jerking movements of the arms and legs or head bobs and often, though not always, an atypical, chaotic pattern of brain waves on the electroencephalogram (EEG) known as hypsarrhythmia [3]. The seizures are accompanied by significant development delays as well as cognitive and physical deterioration [2]. Standard treatments include adrenocorticotropic hormone (ACTH) or prednisone, and the antiseizure medication vigabatrin [4]. Unfortunately, only approximately 50% of children with IS respond to these treatments and there remains no reliable way of predicting who will respond favorably [4]. Even if these treatments diminish IS symptoms for a specific patient, they can have serious side effects. Therefore, scientists have been searching for other drug targets with the ultimate goal of developing alternative therapies.

One of these scientists is Dr. John Swann, Professor of Pediatrics at the Baylor College of Medicine, Director of the Gordon and Mary Cain Pediatric Neurology Research Foundation, and Principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, who leveraged findings from his work as part of the CURE Epilepsy Infantile Spasms Initiative (2013-2017). With additional funding from NIH, Dr. Swann and his team used a previously developed rat model of IS [5] that mirrors many of this disorder’s symptoms, to investigate spasms that result from pediatric brain injuries, such as those suffered during a traumatic birth.

He and the team wanted to determine if the level of a substance known as insulin-like growth factor-1 (IGF-1) was altered in the injured brains of both their rat model and in IS patients, the latter using brain tissue from IS patients who had undergone neurosurgery to stop their seizures. The rationale behind this experiment was based on two observations. The first is that the level of IGF-1 in the cerebrospinal fluid of IS patients with preexisting brain damage is low [6], and second is that IGF-1 activates a biological pathway crucial for proper brain development and neuronal function [7]. As hypothesized, data revealed that IGF-1 levels were lower in brain tissue from both the rat model and from infants with IS. Data also showed that reduced expression of IGF-1 in the rat model affected the biological pathways critical for neurodevelopmental processes [8].

These promising findings suggested that increasing the amount of IGF-1 in the brains of the rat model might alleviate at least some of the symptoms of IS. To test this idea, the researchers employed a shorter version of IGF-1 called (1-3)IGF-1 which is a natural breakdown product of IGF-1 that can cross the blood-brain barrier with much higher efficiency than the full-length IGF-1 [9].

After confirming that (1-3)IGF-1 could activate the same biological pathways responsible for regulating the processes involved in early brain development as full-length IGF-1, the researchers administered it to their rat model and successfully eliminated both the spasms as well as the hypsarrhythmia in most rodents. This exciting finding suggests that this smaller (1-3)IGF-1 or perhaps an IGF-1-like drug may one day be used to treat IS patients immediately after the condition is diagnosed. This new approach could potentially reduce or even eliminate the associated neurodevelopmental and cognitive effects of this devastating disorder without the side effects of the currently available treatments. Dr. Swann states that this research and subsequent additional funding from NIH to continue the work would not have been possible without his participation in the CURE Epilepsy Infantile Spasms Initiative.

Literature Cited:

Pellock, JM et al. Infantile spasms: a US consensus report. Epilepsia 2010; 51: 2175-2189
Cowan, L.D. & Hudson, L.S. The epidemiology and natural history of infantile spasms. Child Neurol. 1991; 6(4): 355-364.
Gibbs, E.L., Fleming, N.M, & Gibbs, F.A. Diagnosis and prognosis of hypsarrhythmia and infantile spasms. Pediatrics 1954; 13(1): 66-73.
Knupp, K.G. et al. Response to treatment in a prospective national infantile spasms cohort. Neurol. 2016; 79(3): 475-484.
Lee, C.L. et al. A new animal model of infantile spasms with unprovoked persistent seizures. Epilepsia 2008; 49(2): 298-307.
Riikonen, R.S. et al. Insulin-like growth factor-1 is associated with cognitive outcome in infantile spasms. Epilepsia 2010; 51(7): 1283-1289.
O’Kusky, J. & Ye, P. Neurodevelopmental effects of insulin-like growth factor signaling. Neuroendrocrincrinol. 2012; 33(3): 230-251.
Ballester-Rosado, C.J. et al. A role for insulin-like growth factor 1 in the generation of epileptic spasms in a murine model. Neurol. 2022; 92(1): 45-60.
Yamamoto, H. & Murphy, L.J. Enzymatic conversion of IGF-1 to des(1-3)IGF-1 in rat serum and tissues: a further potential site of growth hormone regulation of IGF-1 action. Endocrinol. 1995; 146(1): 141-148.

A Pioneering Study Discovers an Underlying Cause for Infantile Spasms and Points to a Novel Therapy

Article published by Texas Children’s Hospital

Featuring the research of former CURE Epilepsy grantee Dr. John Swann

Infantile spasm (IS) is a severe epileptic syndrome of infancy and accounts for 50% of all epilepsy cases that occur in babies during the first year of life. Current treatment options for this disorder are limited and most affected infants grow up to have developmental delays, intellectual disabilities and other types of severe epilepsy. A groundbreaking study, conducted in the laboratory of Dr. John Swann, director of the Gordon and Mary Cain Pediatric Neurology Research Foundation labs, investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and professor at Baylor College of Medicine, has found that the levels of insulin growth factor -1 (IGF-1) and its downstream signaling are reduced in the brains of both IS patients and animal models. Furthermore, they found that the administration of an IGF-1 analog to an IS animal model successfully eliminated spasms and abnormal brain activity. This exciting study, published in the Annals of Neurology, has the potential to transform the treatment landscape for babies with infantile spasms.

Dr. Swann is a leading expert in epilepsy research and a few years back, his team’s pioneering discoveries resulted in an FDA-approved treatment for severe epilepsy among tuberous sclerosis patients. He and his team have had a longstanding interest and experience in studying infantile spasms, an epileptic disorder diagnosed in roughly 2500 babies in the United States each year.

Predictors of Outcome Among 31 Children with Infantile Spasms Syndrome

Abstract found in John Libbey Eurotext

Objective: Infantile spasms syndrome is a severe epileptic encephalopathy. Management of infantile spasms remains challenging because of pharmacoresistant forms and relapsing seizures. A high number of patients with this syndrome have neurodevelopmental delay. The main objective of our study was to determine predictors to measure the neurodevelopmental outcome of patients with infantile spasms.

Methods: We prospectively evaluated 31 patients with infantile spasms from 2014 to 2017 at three hospitals in Tbilisi, Georgia. Various demographic data were evaluated at the first visit; video-EEG, brain MRI and neurodevelopmental evaluation were performed upon admission. A diary to record spasms was provided and completed by all parents/caregivers. Seizures were recorded on video and the phenomenology of infantile spasms was studied. Children were followed for one and two years after the first assessment.

Results: Neurodevelopmental deterioration was revealed in 61.1% on the second and 53% on the third evaluation in patients with onset of spasms before seven months of age. The mean score on the ASQ communication domain was low among structural cases. Eleven patients with pre-existing delay had developmental regression based on the second evaluation (Fisher’s exact test: 7.2; df 1; p=0.01).

Significance. Our study reveals that age at onset of infantile spasms at less than seven months, pre-existing developmental delay, low ASQ scores and structural abnormalities on MRI are predictors of poor developmental outcome. Our data suggest that clinicians should inform parents at the first clinical evaluation about prognosis, and intervention should be started as early as possible in order to improve development.

Risk of Vigabatrin-Associated Brain Abnormalities on MRI: A Retrospective and Controlled Study

Summary, originally published in Epilepsia

Objective: Vigabatrin (VGB) is the first-line treatment for infantile spasms (IS). Previous studies have shown that VGB exposure may cause vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM). Based on previous studies, this study aimed to go further to explore the possible risk factors and the incidence of VABAM. In addition, diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) were compared to explore whether DWI should be used as a routine examination sequence when MRI is performed in children receiving VGB.

Methods: Children with IS receiving VGB were selected as the study subjects. Whether VABAM occurred or not was categorized as the VABAM group and the non-VABAM group, respectively. Their general clinical data and medication exposure were collected. The possible risk factors of VABAM and different MRI sequences were compared and statistically analyzed.

Results: A total of 77 children with IS were enrolled in the study, of which 25 (32.5%) developed VABAM. Twenty-three of the 25 VABAM cases have a peak dosage of VGB between 50 and 150 mg/kg/day. The earliest observation time of VABAM was 30 days. Regression analysis of relevant risk factors showed that the peak dosage of VGB was the risk factor for VABAM. Comparison between different MRI sequences showed that DWI is more sensitive than T2WI to the evaluation of VABAM.

Significance: In our study, the occurrence of vigabatrin-associated brain abnormalities on magnetic resonance imaging was 32.5%, indicating a higher incidence than in most previous reports. In addition, we once again verified that the peak dosage of Vigabatrin was the risk factor of vigabatrin-associated brain abnormalities on magnetic resonance imaging. Caution should be exercised that our data also suggest that vigabatrin-associated brain abnormalities on magnetic resonance imaging may occur even using the conventional dosage of Vigabatrin (ie, 50–150 mg/kg/day). Therefore, even when using the conventional dosage of Vigabatrin, regular MRI examination should be required. Furthermore, DWI sequence should be used as a routine examination sequence when MRI is performed in children with IS who are receiving Vigabatrin.

Confirmation of Infantile Spasms Resolution by Prolonged Outpatient EEGs

Abstract, originally published in Epilepsia Open

Objective: There is no consensus on the type or duration of the post-treatment EEG needed for assessing treatment response for infantile spasms (IS). We assessed if outpatient electroencephalograms (EEGs) are sufficient to confirm infantile spasms (IS) treatment response.

Methods: Three-year retrospective review identified new onset IS patients. Only presumed responder to IS treatment at 2-weeks with a prolonged (> 90 min) outpatient EEG to assess treatment response, and at least 3 mo follow-up were included. Hypsarrhythmia, electroclinical spasms, and sleep were evaluated for the first hour and for the duration of the EEG.

Results: We included 37 consecutive patients with new onset IS and presumed clinical response at 2-weeks post treatment. Follow-up outpatient prolonged EEGs (median:150 min, range:90-240 min) were obtained 14 days (IQR:13-17) after treatment initiation. EEGs detected ongoing IS in 11 of 37 (30%) of presumed early responders. Prolonged outpatient EEG had a sensitivity of 85% (confidence interval [CI] 55-98%) for detecting treatment failure. When hypsarrhythmia and/or electroclinical spasms were not seen, EEG had a negative predictive value 92% (CI:75-99%) for confirming continued IS resolution. Outpatient EEG combined with clinical assessment, however identified all treatment failures at two-weeks. Compared to the entire prolonged EEG, the first hour recording missed IS in 45% (5/11). While sleep was captured in 95% (35/37) of the full EEG recording, the first hour of recording captured sleep in only 54% (20/37).

Significance: IS treatment response can be confirmed with a clinical history of spasm freedom and an outpatient prolonged EEG without evidence for ongoing spasms (hypsarrhythmia/electroclinical spams on EEG). Outpatient prolonged EEG, but not routine EEGs, represent an alternative to inpatient long-term monitoring for IS post-treatment EEG follow-up.

What is the Optimal Duration for Vigabatrin Monotherapy in Patients With Infantile Spasms: 6 Months or Longer?

Abstract, originally published in Seizure

Vigabatrin (VGB) is approved as monotherapy for pediatric patients with Infantile Spasms (IS). Duration of VGB use should be limited because of the risk of retinal and neurotoxicity, but the optimal length of treatment is unknown. Our study aimed to determine the risk of spasms relapse after 6 months of VGB as first-line therapy in IS patients deemed VGB good responders. The participants were 44 infants with IS who demonstrated both absence of clinical spasms and hypsarrhythmia four weeks after starting VGB, obtained from two cohorts: 29 patients from a multicenter prospective cohort and 15 patients from a retrospective single-center cohort. We divided them post hoc into two groups according to the duration of VGB treatment: 6-month group (n=34) and >6-month group (n=10) and compared outcome between the two groups. No patient in either group had a relapse of spasms. For patients with non-identified etiology (NIE) in the 6 months treatment group, no other seizure types were observed. Late epilepsy, in the form of focal seizures, emerged in only 5/37 patients (3/30 in the 6-month treatment group; 2/7 in the extended treatment group); all within the first 6-9 months after VGB initiation. Our study provides substantial evidence that a shortened VGB course of 6 months could be sufficient to treat and prevent relapse of spasms in children with IS, particularly those with NIE.

Adrenocorticotropic Hormone, Oral Steroids Superior for New-onset Infantile Spasms

Article, published in Healio

Adrenocorticotropic hormone and oral steroids demonstrated superiority compared with non-standard therapy for the initial treatment of infantile spams in a prospective, multicenter observational cohort study published in Neurology.

“There are three recommended first treatments for infantile spasms: oral corticosteroids (typically prednisolone in the United States), adrenocorticotropic hormone (ACTH) and vigabatrin. Each medication has a different proposed mechanism of action,” the researchers wrote. “Our published analysis of a rigorous prospective multicentered observational study of infants with infantile spasms (the National Infantile Spasms Consortium; NISC) suggested the superiority of ACTH over other treatments. However, our findings were based on a preliminary analysis of an active registry and did not fully account for treatment selection bias and center-to-center variations.”

“We provide real-world head-to-head comparisons of different treatments for infantile spams. Among children with infantile spasms, treatment with anything other than the three recommended therapies resulted in a dismal response: Only 4 of 51 were free from treatment failure,” Dr. Zachary Grinspan and colleagues wrote. “By our estimates, ACTH would have led to freedom from failure in 20 of the 51 and oral steroids would have led to freedom from failure in 19 of the 51. The E-values were high (9.2 and 9), suggesting that unmeasured confounding is unlikely to explain away these findings.”

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

Abstract, published in Seizures

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.

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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