The use of smartphone video to capture infantile spasms (IS) significantly reduces the time to diagnosis and treatment, according to a new study. Researchers assessed the difference in the amount of time to electroencephalogram (EEG), diagnosis and treatment of 80 infants with confirmed infantile epileptic spasms syndrome with or without accompanying video capture of their spasms. The infants whose spasms were captured on smartphone video were seen at a clinic a median of nine days earlier, had their first EEG 16 days earlier, and were diagnosed and started treatment 17 days earlier compared with the group that had no video capture. They also had a 25% greater response to initial standard treatment. “Infantile spasms are a pretty detrimental type of seizure that infants can have around 5 months of age,” explained study co-author Douglas R. Nordli III, MD, a pediatric epileptologist at the University of Chicago. “When most people hear the word ‘seizure,’ they think of a grand mal seizure involving uncontrolled movements, but this is very different. Infantile spasms involve just a slight twitch with the head going down and the arms going up, and an uncomfortable cry afterward. The description, especially for a distressed parent, is hard to relay, and seeing the video really is worth a thousand words.”
I hope that you are all enjoying the cooler temperatures, fall activities, and at least where we are, spectacular fall foliage. The end of the year is a very busy time for the epilepsy community, and this year is no different. In October alone, we have hosted a special New York City event, a Hamilton raffle, two Treatment Talks, and many CURE Epilepsy Champion events. On a personal note, my son is a CURE Epilepsy Champion and ran the Chicago Marathon for us last year. This weekend, he will be running the Marine Corps Marathon in Washington DC to raise funds for post-traumatic epilepsy research, which is important for our wounded veteran community. It will be a special race for him as he is a 1stLt in the Marine Corps. You can support his run here. As a CEO and a proud mother, I am honored to have each and every one of you supporting us as we continue our mission to find a cure for epilepsy.
As we enter the final months of our 25th anniversary year, we are undertaking exciting strategic planning and visioning on the next chapter for the organization. As we think about how to update our messaging and improve our website, we would appreciate your participation in an anonymous five-to-ten-minute brand and website survey. Thank you in advance for helping us serve the epilepsy community in ways that continually evolve to meet new needs!
Finally, as many of you know, Sudden Unexpected Death in Epilepsy (SUDEP) Action Day took place last week. It is an important day within our community to both increase education and raise awareness among those unfamiliar with this devastating and often not talked about outcome. Since CURE Epilepsy pioneered the first SUDEP research almost 20 years ago, we have funded initiatives that study why SUDEP occurs and how it can be prevented. Just as I look forward to a day when we have a world without epilepsy, I look forward to a time when no individual passes away due to SUDEP. Until that day comes, I encourage you to review our SUDEP Action Day resources and share them with your family and friends. Doing so might save a life.
With a commitment to inspire hope and deliver impact.
In this CURE Epilepsy Update, please find information on:
Over $275,000 Raised for Future Research Thanks to Hamilton Unplugged!
Thank you to everyone who was in The Room Where It Happened on Monday, October 23 for Hamilton Unplugged! With your help, we raised over $275,000 for critical epilepsy research. Guests enjoyed a phenomenal performance by Miguel Cervantes and his Broadway friends, including never-before-seen musical mashups, hilarious behind-the-scenes stories from the Hamilton stage, and more.
Thank You to Our CURE Epilepsy Champions
Thank you to our recent CURE Epilepsy Champions who have helped us raise critical epilepsy research funds and who are getting us closer to completion of the 25th Anniversary Champions Challenge – raising $425K for 25 years! Kris Sadens ran, biked, and swam in honor of his son Silas and the 10-year anniversary of Silas’ diagnosis, by participating in the Chicago Triathlon. Erin Monast, her daughter Reagan, and her family hosted the second annual Reagan’s Run, a 5K and 1-mile fun run in Eastern Pennsylvania. Champions also got out their golf clubs from coast to coast to raise funds and awareness for epilepsy in two separate events. The 5th annual Commish Open, in memory of Aiden Nichols Long, was held on September 27 in Maryland and the 3rd annual Epilepsy Awareness Golf Tournament honoring Colton Grothe and Joey Hart in Willamette Valley Oregon was held on October 9.
If you would like more information about the Champions Challenge or hosting your own unique fundraising event, click here. Every participating Champion host will receive a free raffle entry for one trip for a family of four to Epilepsy Awareness Day 2024 at Disneyland California, including airfare, hotel, epilepsy expo, and park tickets. Also, every Champion host who raises over $1,000 will receive a CURE Epilepsy Treasure Pack, with merchandise to help show your CURE Epilepsy pride.
CURE Epilepsy Discovery: Leading the Charge on Research and Awareness of Sudden Unexpected Death in Epilepsy
In our latest CURE Epilepsy Discovery, we showcase CURE Epilepsy’s work within the SUDEP space. Over the past 25 years, CURE Epilepsy has funded transformative science and significantly furthered awareness of SUDEP, and we will continue to prioritize this important area of research going forward in hopes of eventually preventing this tragic outcome. Read about some of the research and projects we have funded.
Infantile Spasms Diagnosis and Treatment Journey Inspires Children’s Book
Kate Kostolansky shares her daughter Charlotte’s infantile spasms journey and explains how these experiences inspired a children’s book designed to help newly-diagnosed families and those around them better understand infantile spasms.
Searching for Answers, Providing Support, and Understanding Grief After the Death of a Child
In observance of SUDEP Action Day on October 18, we spoke with Dr. Richard Goldstein, Associate Professor of Pediatrics at Harvard Medical School, about the program he directs conducting research into both Sudden Unexpected Death in Pediatrics (SUDP) and the grieving process of bereaved parents.
Objective: To test the hypothesis that early vigabatrin treatment in Tuberous Sclerosis Complex (TSC) infants improves neurocognitive outcome at 24 months of age.
Methods: Phase IIb multicenter randomized double-blind placebo-controlled trial of vigabatrin at first epileptiform EEG vs. vigabatrin at seizure onset in infants with TSC.
Primary outcome: Bayley-III cognitive assessment score at 24 months.
Secondary outcomes: prevalence of drug resistant epilepsy, additional developmental outcomes, and safety of vigabatrin.
Results: Of eighty-four infants enrolled, 12 were screen failures, four went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). 56 were randomized to early vigabatrin (n=29) or placebo (n=27). 19 of 27 in the placebo arm transitioned to open label vigabatrin with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups.
Interpretation: Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children; nor delay onset or lower the incidence of focal seizures and drug resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms.
Seizures can be predicted more than 30 minutes before they occur in patients with temporal lobe epilepsy, possibly opening the door to preventing seizures from happening, according to a new study. Researchers used electroencephalography (EEG), which measures electrical activity in the brain, to examine periods of potentially heightened risk for seizures known as “pro-ictal states.” The researchers were able to detect pro-ictal states in patients with temporal lobe epilepsy approximately 30 minutes or more before seizure onset. This information could lead to the development of electrical stimulation or drug therapies aimed at preventing seizures in people with this type of epilepsy. “The ability to predict seizures before they occur is a major step forward in the field of epilepsy research,” a study author stated.
New research has found that large-scale changes in the activation of neurons can be detected in the brains of people with temporal lobe epilepsy during a resting state (a state in which the brain is not stimulated by tasks or input), even when no seizure is occurring. The non-invasive approach uses EEG to detect changes in brain activity and could lead to a new method to aid in the diagnosis of epilepsy. While the brain is at rest, spontaneous waves of neuronal activation are constantly generated in a phenomenon called a “neuronal avalanche.” The researchers demonstrated that even during the resting state it is possible to detect a change in the neuronal avalanches in the brains of people with epilepsy. The researchers suggested that this method might be used as a preliminary diagnostic method, especially for difficult cases where standard scalp EEG fails to detect seizures, but additional investigations are necessary.
Researchers have discovered higher levels of immune proteins in the blood before and after an epileptic seizure. In this study, researchers discovered that levels of five inflammation markers, or proteins, were elevated in people with temporal or frontal lobe epilepsy who had experienced a seizure. Among patients with psychogenic non-epileptic seizures (PNES), however, there was no change in the protein levels. These proteins, therefore, have the potential to be future biomarkers for a diagnosis of epilepsy. Diagnosing epilepsy from a simple blood draw would provide a significant advantage over the current diagnostic standards which may include admittance to a hospital for several days with constant video and EEG surveillance.
In a new study, researchers report that sodium selenate could be the first curative drug therapy for epilepsy. The study, conducted in an animal model of drug-resistant epilepsy, revealed sodium selenate to have a long-lasting effect (after months of stopping the medication) in reducing the frequency of seizures and in 30% of cases stopping them altogether. Sodium selenate also improved other aspects of epilepsy such as memory, learning, and sensor-motor functioning. The researchers will next begin a clinical trial of sodium selenate as a curative treatment in patients with drug-resistant epilepsy. “Despite the cost of the disease and the enormous amount of research into it, there has not been a single therapy developed to prevent the development of epilepsy,” stated a study author. “This Phase 2 clinical trial, if effective, has the potential to tackle a disease that is an enormous global burden as well as being truly transformative for people who are impacted by often daily seizures, with no respite.”
Researchers at Baylor College of Medicine, including former CURE Epilepsy grantee Dr. Jeff Noebels, report that glioma tumors in the brain can interfere with the ability of surrounding neurons to handle potassium, an important ion in neuronal communication. The disruption of this normal neural function drives seizures and favors the progression of epilepsy. The team found that patients who have seizures have increased expression of genes involved in the formation of neuronal connections or synapses. In both humans with glioma and animal models, the researchers identified one of the genes, IGSF3, as the driver that mediated seizures in glioma-related epilepsy. The team found that IGSF3 suppresses the ability of these cells to take up potassium, which leads to its accumulation of this ion and then seizures. “Our studies reveal that tumor progression and seizures are triggered by disruption of potassium handling. The findings support further studies into novel strategies to control seizures and tumor growth,” stated one of the study’s authors.
Infantile spasms (IS), also called West syndrome, is a rare epilepsy syndrome associated with stereotypical spasms, developmental delay, and a telltale brainwave pattern. Medications used to treat IS are not effective in everyone with IS and are associated with side effects.
CURE Epilepsy launched the Infantile Spasms Initiative (IS Initiative) in 2013 with a team science approach to bring together groups of investigators working on diverse topics related to IS; this one-of-a-kind initiative in epilepsy research contributed immensely to today’s understanding of IS and its mechanisms.
One of the Initiative’s grantees, Dr. Chris Dulla, developed a mouse model that simulates the neuronal excitation and inhibition relevant to IS. Animal models are incredibly useful to understanding the biological mechanisms underlying IS, and by better understanding the interplay between neural excitation and inhibition in IS, there is hope that we can develop targeted therapies.
Infantile spasms (IS) is a devastating and rare epilepsy syndrome that is typically seen in the first year of a child’s life, most commonly between four and eight months of age.[1, 2] One in 2,000 children is affected by infantile spasms, and worldwide it is estimated that one baby is diagnosed with IS every 12 minutes. IS consists of the following characteristics: subtle seizures consisting of repetitive, but often subtle movements—such as jerking of the mid-section, dropping of the head, raising of the arms or wide-eyed blinks; developmental delay and cognitive and physical deterioration; and a signature disorganized, atypical brainwave pattern called “hypsarrhythmia.”[4, 5] Potential causes include brain injuries or infections, issues with brain development and malformations, gene variants, or metabolic conditions. IS can sometimes have an underlying genetic cause as well.[2, 6] Often, infants appear to develop normally until spasms start, but then show signs of regression. Some infants may have hundreds of such seizures a day.
Current treatment for IS consists of hormonal therapy such as adrenocorticotropic hormone and prednisone, and antiseizure medications such as vigabatrin. These medications are effective in approximately half of the patients with IS.[7, 8] Even infants who have been diagnosed in a timely fashion may not respond to the available treatments, or they may suffer adverse side effects. There is no reliable way to predict who will respond favorably to medications.
As there was a dire need to better understand and treat IS, because there was no advocacy group or organization dedicated to IS and no organization was focusing on finding treatments or cures, CURE Epilepsy stepped in and leveraged our expertise as well as our resources to assemble the Infantile Spasms (IS) Initiative in 2013. Committing $4 million, the Initiative brought together eight research teams working on various aspects of IS.  Team science” is a unique way of conducting research that leverages the strengths and expertise of scientists trained in different but related fields to solve a single, complex problem. CURE Epilepsy’s IS Initiative was the first team science approach in the epilepsy research community, and teams in the Initiative benefitted from sharing knowledge and resources to expedite understanding of IS.  Collectively, the Initiative studied the basic biology that may explain what causes IS, searched for biomarkers and novel drug targets, and explored ideas for improved treatments for the condition. 
One of the eight teams involved in the Initiative was led by Dr. Chris Dulla and his laboratory at Tufts University. Dr. Dulla’s team developed an animal model for IS by targeting a gene called Adenomatous polyposis coli (APC). For the epilepsies in general, animal models are crucial to understanding the biological mechanisms that cause seizures. Dr. Dulla’s team developed an animal model for IS by targeting a gene called Adenomatous polyposis coli (APC). Mice that were genetically altered to have a decrease in the activity of APC exhibited many of the features that were reminiscent of human IS. The development of this mouse model (called “APC cKO”) was an important step in IS research as it provided a way for scientists to study IS and the mechanisms that may cause it.
Broadly speaking, there are two kinds of neurons (brain cells): “excitatory” neurons that activate other neurons, and “inhibitory” neurons that restrain other neurons. A fine balance between excitation and inhibition is critical for the brain to function, and in epilepsy, this delicate balance may be disturbed. Inhibitory neurons are modulated by a neurotransmitter called gamma amino butyric acid (GABA). In the current study, Dr. Dulla’s team wanted to study GABAergic neurotransmission in the APC cKO model. Previous studies have shown a link between GABAergic neurotransmission and IS; specifically, alterations in GABAergic transmission have been found in animal models of IS [11, 12] and in human patients with IS. The ultimate goal is to better understand the interplay between excitatory and inhibitory neurotransmission in IS.
In a recent study that was published in February 2023, Dr. Dulla’s team studied inhibitory neurons (also called “interneurons,” abbreviated to “INs”). They looked at a certain kind of interneuron, called a parvalbumin-positive interneuron (PV+ IN) and studied the way these interneurons looked under the microscope (i.e., their anatomy) as well as the way they functioned (i.e., their physiology). In humans, IS has a time course in terms of when seizures start. To recreate this in their mouse model, the team studied APC cKO mice at multiple time points: in infancy (postnatal days 9 and 14), and then later, as adults, and compared them to mice that did not have the genetic mutation (i.e., “wild-type” mice).The goal of the study was to understand what happens to PV+ INs in the APC cKO mouse model of IS.
In normal brain development, an excess of PV+ INs are made, but then they disappear over time. The first discovery Dr. Dulla’s team made was that in APC cKO mice, there is an excess of PV+ IN death. The second important finding was that in APC cKO mice, the death of these PV+ INs occurred earlier in development as compared to wild-type mice. This change in the pattern of death of PV+ INs could mean that there are subtle changes taking place in the neural circuit. Since the primary role of interneurons is to keep brain activity in check, an excess of interneurons dying very quickly may mean that the excitatory neurons run amok. In contrast, other types of interneurons did not show accelerated dying, but this change was specific to PV+ INs. The change in the pattern of PV+ IN cell death in APC cKO mice was also reflected in the functioning of the brain as studied by looking at the electrical activity in the brain.14 The changes seen in the interneuron death and associated function were more pronounced at postnatal day 9 (as compared to postnatal day 14), which suggests that this is the critical period in brain development in this model, when, if GABAergic inhibition is perturbed, may lead to IS and associated symptoms.
In totality, Dr. Dulla’s findings regarding GABAergic neurotransmission and PV+ INs are complicated with respect to the sequence and timing of events. However, there is a variation in the way the inhibitory GABAergic neuronal circuitry develops and matures in APC cKO mice that suggests a critical window of events that if perturbed, may lead to spasms and behavioral impacts later on. This work positions PV + INs as a potential target to treat IS, and perhaps even offers avenues for timely diagnosis. This perturbation of inhibition during a critical period in development may contribute to spasms and seizures later in life. The development of the GABAergic circuitry depends on brain activity; hence, the changes in activity of the neural circuitry seen in APC cKO mice interneurons may contribute to long-term changes in the brain. The exact link between the PV+ IN death in early development and behavioral spasms needs to be investigated in more detail, but this work lays the foundation to continue studying inhibitory transmission in IS. Future studies will reveal if stopping this excess PV+ IN death may be a therapeutic target or a cure for Infantile Spasms.
Hrachovy RA. West’s syndrome (infantile spasms). Clinical description and diagnosis Adv Exp Med Biol. 2002;497:33-50.
Shields WD. Infantile Spasms: Little Seizures, BIG Consequences. Epilepsy Curr. 2006;6:63-69
Smith MS MR, Mukherji P. Infantile Spasms. Treasure Island (FL): StatPearls [Internet]; StatPearls Publishing Updated 2022 May 29.
Eling P, Renier WO, Pomper J, Baram TZ. The mystery of the Doctor’s son, or the riddle of West syndrome Neurology. 2002 Mar 26;58:953-955.
Lux AL. West & son: the origins of West syndrome Brain Dev. 2001 Nov;23:443-446.
Osborne JP, Edwards SW, Dietrich Alber F, Hancock E, Johnson AL, Kennedy CR, et al. The underlying etiology of infantile spasms (West syndrome): Information from the International Collaborative Infantile Spasms Study (ICISS) Epilepsia. 2019 Sep;60:1861-1869.
Knupp KG, Coryell J, Nickels KC, Ryan N, Leister E, Loddenkemper T, et al. Response to treatment in a prospective national infantile spasms cohort Ann Neurol. 2016 Mar;79:475-484.
Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013 Brain Dev. 2014 Oct;36:739-751.
Lubbers L, Iyengar SS. A team science approach to discover novel targets for infantile spasms (IS). Epilepsia Open. 2021;6:49-61.
Pirone A, Alexander J, Lau LA, Hampton D, Zayachkivsky A, Yee A, et al. APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal ?-catenin levels, neonatal spasms, and chronic seizures Neurobiol Dis. 2017 Feb;98:149-157.
Marsh E, Fulp C, Gomez E, Nasrallah I, Minarcik J, Sudi J, et al. Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females Brain. 2009 Jun;132:1563-1576.
Katsarou AM, Li Q, Liu W, Moshé SL, Galanopoulou AS. Acquired parvalbumin-selective interneuronopathy in the multiple-hit model of infantile spasms: A putative basis for the partial responsiveness to vigabatrin analogs? Epilepsia Open. 2018 Dec;3:155-164.
Bonneau D, Toutain A, Laquerrière A, Marret S, Saugier-Veber P, Barthez MA, et al. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings Ann Neurol. 2002 Mar;51:340-349.
Ryner RF, Derera ID, Armbruster M, Kansara A, Sommer ME, Pirone A, et al. Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome J Neurosci. 2023 Feb 22;43:1422-1440.
A new method of determining which brain cells lead to seizures in children has been developed. The team used noninvasive techniques and advanced computational methods to measure the electric and magnetic signals generated by neural cells to identify brain “hubs” responsible for the generation of seizures in children with epilepsy. This team retrospectively analyzed electroencephalography (EEG) and magnetoencephalography data recorded from 37 children and young adults with drug-resistant epilepsy who had neurosurgery. They then created a virtual model of the brain and virtually implanted sensors at locations where invasive EEG contacts had been placed during neurosurgery. The researchers found that the virtual sensors could non-invasively identify highly connected hubs in patients with drug-resistant epilepsy. The authors stated that the discovery could help to identify areas of the brain that generate epileptic activity in children with drug-resistant epilepsy in a non-invasive way.
New research featuring the work of a former CURE Epilepsy grantee, Dr. Chris Dulla, and colleagues suggests that the timing of the death of a subset of neurons in the brain shortly after birth may be partly to blame for infantile and epileptic spasms syndrome (a form of which is also called infantile spasms (IS) or West syndrome), a childhood epilepsy with poor outcomes. These neurons are responsible for providing inhibitory input to the brain; the lack of these neurons may lead to too much excitation and epileptic spasms. The research suggests that it may be the timing of inhibitory neuron cell death which is important, not just the fact that it occurs. This research may suggest a potential target for the future development of treatments for infantile and epileptic spasms.
A new study increases our understanding of symptoms associated with changes in the STXBP1 gene, one of the most common genetic causes of childhood epilepsies and neurodevelopmental disorders. By systematically mapping symptoms and assessing their impacts on patients and their caregivers, the researchers identified previously underreported symptoms beyond just neurological symptoms. To understand these symptoms, the researchers performed more than 24 hours of interviews among 19 caregivers of 16 individuals with STXBP1-related disorders and seven healthcare professionals. In doing so, the researchers created a so-called “disease concept model,” which is meant to determine which outcomes are relevant in everyday clinical practice. These results may serve as an important foundation for future trials assessing the effectiveness of therapeutic interventions for all related symptoms.
A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy. The new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function but can also be hijacked by disease to promote seizures. The work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings suggest for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment. “Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” stated a study author. “The study also clarified, not just how CBD counters seizures, but more broadly how neural circuits are balanced in the brain.”
In a new study using a fruit fly model of epilepsy, researchers describe a chain of events that link the brain’s immune system response to worsening seizures. The researchers used flies with a mutation in a gene known as the prickle gene, similar to the mutation in the PRICKLE gene found in humans with progressive myoclonus epilepsy with ataxia, and found that this particular mutation can lead to increases in a condition called oxidative stress. The researchers found that oxidative stress can activate the brain’s resident immune cells (called glia), which in turn triggers more severe seizures. “We have provided genetic proof that both oxidative stress and activation of the brain immune system make epilepsy worse,” stated a study author. “This is hugely significant because our data suggest that we can now repurpose exceedingly well-tolerated anti-inflammatory compounds as well as perhaps antioxidants to help control epilepsy progression.”
Objective: WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analysed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regards to survival.
Methods: We studied thirteen patients from twelve families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms and disease outcome were collected. EEG and brain MRI data were analysed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense allowing individuals to be classified into one of three genotype classes: 1) null/null 2) null/missense, 3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method.
Results: All patients experienced multiple seizure types (median onset 5 weeks, range: 1 day – 10 months); the most frequent being focal (85%), epileptic spasms (77%) and tonic seizures (69%). Ictal EEG recordings in 6/13 patients showed tonic (n=5), myoclonic (n=2), epileptic spasms (n=2), focal (n=1) and migrating focal (n=1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. 11/13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (4 deletions; 1 duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value = 0.0085, log-rank test).
Significance: Biallelic WWOX pathogenic variants cause an early-infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.
New research from Tufts University School of Medicine and the Graduate School of Biomedical Sciences suggests that the timing of the death of certain inhibitory neurons in the brain shortly after birth may be at least partly to blame for infantile and epileptic spasms syndrome (IESS), a rare but devastating form of epilepsy that develops most frequently between four and eight months of age but can emerge within weeks of birth until ages 4 or 5.
Their research in mice suggests both a potential new target for treatment and raises the hope that, in the future, early diagnosis and treatment could detect and prevent some of the most significant impairments associated with the syndrome. The research was published Jan. 30 in the Journal of Neuroscience.
In their research, the Tufts scientists focused their studies on the b-catenin signaling pathway in a mouse model, originally developed by neuroscientist and School of Medicine professor Michele Jacob, that develops a condition analogous to IESS. The mice also demonstrate intellectual disabilities and behavioral abnormalities corresponding to human autism spectrum disorder.
The researchers determined that cortical parvalbumin-positive interneuron development and function are altered in the mice. These neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system.
For 25 years, CURE Epilepsy has been funding breakthrough research to advance science to find a cure for epilepsy. A key focus of our research grants has been understanding the basic biological mechanisms that result in epilepsy, which provides foundational knowledge that will ultimately lead to a cure for epilepsy.
One initiative funded by CURE Epilepsy, the Infantile Spasms (IS) Initiative, brought together a diverse team of medical and scientific experts to rapidly advance IS research and was the first initiative of its kind in the field of epilepsy.
John Swann of Baylor College of Medicine, whose work is discussed herein, was one of the grantees involved in the IS Initiative. He has progressed his initial discoveries, demonstrating the importance of funding basic mechanisms research to put us one step closer to a cure.
Basic research provides hope for a cure for the epilepsies; by better understanding the mechanisms that cause seizures, we can develop curative treatments for the epilepsies.
Twenty-five years ago, CURE Epilepsy was founded finding a cure for epilepsy and related seizure disorders, which now impacts 3.4 million Americans and 65 million people worldwide. The founders saw a need to push the research community to think differently about epilepsy research. This resulted in a paradigm shift for the community, moving from seeking treatments and therapies that would control seizures to focusing on innovative approaches that would advance science and find a cure for epilepsy. Achieving this goal would provide freedom from seizures and the negative side effects of medications. The organization determined that it could have the largest impact by focusing on understanding the basic biological mechanisms underlying the causes of epilepsy. Understanding is the first step in the scientific process, where researchers study the brain to gain a better understanding of why and how seizures are caused. These findings create foundational knowledge that may translate to new ideas to treat epilepsy and eventually preclinical and clinical trials. Clinical trials may ultimately lead to improved and potential cures. Hence, while the benefits of basic epilepsy research are not immediate, the rewards that basic research provides in terms of our understanding epilepsy are unparalleled.
Since 1998, CURE Epilepsy has funded over 280 research grants, and many have addressed the need to learn more about the basic biological mechanisms that underlie epilepsy. Many of these grants have formed the basis for further study, learning, and advancements that may lead us to a cure. One example of this is within infantile spasms (IS), a rare and particularly severe form of epilepsy, with approximately 90% of cases diagnosed in the first year of life. Infantile spasms manifest as sudden, jerking movements of the arms and legs, and are often accompanied by an irregular brainwave pattern on the electroencephalogram (EEG) called hypsarrhythmia.These seizures are also often accompanied by significant cognitive and physical deterioration. Current therapies for IS are effective in only half of the children with IS  and are associated with negative side effects, highlighting the need to find better and more effective treatments.
In 2013, CURE Epilepsy launched the Infantile Spasms Initiative, with $4 million in funding. The IS Initiative employed a multi-disciplinary and multi-location team science approach to study the basic biological mechanisms underlying IS, search for biomarkers and novel drug targets, and develop improved treatments. Work done as part of the IS Initiative proved successful across multiple dimensions and led to more than 19 publications. More about the IS Initiative can be found here.
Understanding the basic biological mechanisms underlying IS was a key focus of the IS Initiative. One example of the IS Initiative’s success in understanding a key underlying basic mechanism is from the team led by Dr. John Swann of Baylor College of Medicine. Dr. Swann and his team discovered that treatment with a derivative of the growth hormone insulin-like growth factor 1 (IGF-1) called (1-3) IGF-1 reduced spasms and irregular brain wave patterns on the EEG in an animal model. Adding this compound to vigabatrin, an FDA-approved treatment for IS, reduced the dose of vigabatrin required to eliminate the spasms. Reducing the dosage also decreased the risk of serious side effects, including the potential for irreversible peripheral vision loss. The Swann lab patented this combination treatment and used the discovery to obtain two National Institutes of Health (NIH) grants. The NIH grants enabled Dr. Swann to build on the discoveries from the CURE Epilepsy-funded IS Initiative. In a subsequent study, data from Dr. Swann’s team revealed that the levels IGF-1 itself were lower in brain tissue from both a rat model and from infants with IS. Data also indicated that reduced expression of IGF-1 in the rat model affected the biological pathways critical for neurodevelopmental processes.
Using the learnings from the IS Initiative as a foundation, through a series of additional experiments, the team confirmed that the (1-3) IGF-1 could also cross the blood-brain barrier with much higher efficiency than the full-length IGF-1 and activate the same biological pathways as full-length IGF-1. The researchers administered it to the rats in their experiment, and successfully eliminated both the spasms and 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. You can read more about this study here.
Dr. Swann and his team have continued to build on the learnings initially funded through their CURE Epilepsy grant; recently, the team studied seizure progression in IS, and the impact of spasms on learning and memory. Infants with IS show developmental delay and behavioral abnormalities, with only 16% of patients with IS exhibiting normal intellectual development. The reasons for a delay in intellectual development could be many, though they have not yet been determined.[10,11] Additionally, the trajectory of the decline in intellectual and behavioral abilities has not yet been documented due to the variability of the condition, and limitations in assessing intellectual abilities in infants. Spasms can be subtle, making an accurate diagnosis of the exact start of the spasms challenging. Hence, whether the behavioral decline is caused by or simply associated in time with seizures in IS is an area where more research is necessary. Given the difficulties of understanding this relationship between seizures and cognitive decline in infants with IS, Dr. Swann’s team used rats with a history of spasms and assessed them in a series of tests to gauge their ability to learn and remember. Swann’s team used rats with a history of spasms and assessed them in a series of memory tests to gauge their ability to learn and remember. The team also studied their brainwaves using EEG.
Previous work by Dr. Swann’s team had developed a model to simulate IS in animal models. In this model, a substance known as tetrodotoxin (TTX) is infused into the brains of infant rats 10-12 days after birth which causes many of the characteristics of IS, including spasms, seen in humans. The research team then used tests to examine spatial and working memory. Spatial memory helps us remember locations and the relationship between locations, and working memory helps us remember a small part of the information in our minds temporarily. To better understand the brainwaves in rats that had spasms, Dr. Swann’s team performed continuous EEG recordings for a total of seven weeks after infusion of TTX. Rats with spasms were compared with rats that did not have spasms. After seven weeks of EEG recording, behavioral tests were done to test learning and memory. The study showed that rats experiencing spasms showed impairment on the behavioral tests, pointing to issues in learning and memory, which are also seen in infants with IS. EEG analysis showed that there was an increase in spasms for two weeks, and after the two weeks, spasms stabilized. Seizure progression in epilepsy has long been a topic of intense research. The current study suggests that like other seizure disorders[14,15], there may be a critical period in IS when there is a gradual increase in spasm intensity over time. A better understanding of seizure progression patterns in IS could lead to clues about therapies, management, and prognosis. This work from Dr. Swann’s lab is unique as the team did rigorous EEG monitoring and behavioral analysis; these techniques are time and labor-intensive, and seizures in IS have not been studied this deeply before. The neurological mechanisms that underlie memory disturbances and seizure progression in IS are not fully known. So, seizures could be correlated with the learning deficits, but exact details are not clear. Additional research using EEG monitoring coupled with behavioral analysis in the same animals could provide clarity into the relationship.
In conclusion, basic research provides a foundational understanding of underlying biology of a disease process from which cures for the epilepsies will be found. CURE Epilepsy has been funding basic research for 25 years with the solemission of finding a cure for epilepsy. Dr. Swann’s work as part of the IS Initiative is one example of how strategic, long-term investment in basic research can advance our knowledge by leaps and bounds.
Gibbs EL, Fleming MM, Gibbs FA. Diagnosis and prognosis of hypsarhythmia and infantile spasms Pediatrics. 1954 Jan;13:66-73.
Cowan LD, Hudson LS. The epidemiology and natural history of infantile spasms J Child Neurol. 1991 Oct;6:355-364.
Knupp KG, Coryell J, Nickels KC, Ryan N, Leister E, Loddenkemper T, et al. Response to treatment in a prospective national infantile spasms cohort Ann Neurol. 2016 Mar;79:475-484.
Lubbers L, Iyengar SS. A team science approach to discover novel targets for infantile spasms (IS). Epilepsia Open. 2021;6:49-61.
Swann J, Lee, CL., Le, JT. and Frost Jr, JD. , inventor; Combination therapies for treating infantile spasms and other treatment resistant epilepsies 2022.
Ballester-Rosado CJ, Le JT, Lam TT, Mohila CA, Lam S, Anderson AE, et al. A Role for Insulin-like Growth Factor 1 in the Generation of Epileptic Spasms in a murine model Ann Neurol. 2022 Jul;92:45-60.
Yamamoto H, Murphy LJ. Enzymatic conversion of IGF-I to des(1-3)IGF-I in rat serum and tissues: a further potential site of growth hormone regulation of IGF-I action J Endocrinol. 1995 Jul;146:141-148.
Le JT, Ballester-Rosado CJ, Frost JD, Jr., Swann JW. Neurobehavioral deficits and a progressive ictogenesis in the tetrodotoxin model of epileptic spasms Epilepsia. 2022 Dec;63:3078-3089.
Hrachovy RA, Frost JD, Jr. Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/West syndrome) J Clin Neurophysiol. 2003 Nov-Dec;20:408-425.
Wirrell EC, Shellhaas RA, Joshi C, Keator C, Kumar S, Mitchell WG. How should children with West syndrome be efficiently and accurately investigated? Results from the National Infantile Spasms Consortium Epilepsia. 2015 Apr;56:617-625.
Osborne JP, Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification Epilepsia. 2010 Oct;51:2168-2174.
Lux AL, Osborne JP. A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group Epilepsia. 2004 Nov;45:1416-1428.
Lee CL, Frost JD, Jr., Swann JW, Hrachovy RA. A new animal model of infantile spasms with unprovoked persistent seizures Epilepsia. 2008 Feb;49:298-307.
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Golomb MR, Garg BP, Williams LS. Outcomes of children with infantile spasms after perinatal stroke Pediatr Neurol. 2006 Apr;34:291-295.
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 potentialto be a promising new treatment for this severe form of epilepsy.
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 . The seizures are accompanied by significant development delays as well as cognitive and physical deterioration . Standard treatments include adrenocorticotropic hormone (ACTH)or prednisone,and the antiseizure medication vigabatrin . Unfortunately, only approximately 50% of children with IS respond to these treatments and there remains no reliable way of predicting who will respond favorably . 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  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 injuredbrains 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 , and second is that IGF-1 activates a biological pathway crucial for proper brain development and neuronal function . As hypothesized, data revealed that IGF-1 levelswere 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 .
These promising findingssuggested 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 .
After confirming that (1-3)IGF-1 could activate the same biological pathways responsible for regulating the processes involved in early brain developmentas 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.
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.
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