Pediatric Status Epilepticus: Identification of Prognostic Factors Using the New ILAE Classification After 5 Years of Follow-Up

Objective: Status epilepticus (SE) is the most common neurologic emergency in childhood. This study aimed to report on a large cohort of pediatric patients with SE, applying the International League Against Epilepsy (ILAE) Classification for SE to identify prognostic factors.

Methods: The research team included 173 children treated at “Bambino Gesù” Children’s Hospital in Rome for SE exceeding 30 minutes (mean age 4.43 ± 4.93 years old, median 2.28, interquartile range [IQR] 0.41-7.32; follow-up for a mean of 4.9 ± 3.4 years, median 8.75, IQR 4,58-12.63). A multivariate model was constructed to predict neurocognitive outcome, recurrence of SE, development of epilepsy, and mortality. Adjusted odds ratios [ORs] were calculated with 95% confidence interval (OR, 95% CIs).

Results: The researchers observed a different prevalence of etiologies for the different semiologies (P < .05) and for each age group (P < .05), overlapping only in part with the recent ILAE classification. After SE, patients showed 69.9% epilepsy (drug-resistant in half of them), 23.1% worsening of neurologic findings on examination, 28.9% cognitive deficit, and 28.3% recurrent SE. At multivariate analysis: superrefractory SE was correlated to an increased risk of developing cognitive (OR 6.00, 95% CI 2.09, 17.31) or neurologic sequelae (OR 4.9, 95% CI 1.75, 19.77). A similar finding was observed for patients with onset in the neonatal period for cognitive (OR 4.84, 95% CI 1.13, 17.3) and neurologic sequelae (OR 9.03, 95% CI 2.40, 34.04). Recurrence of SE was associated with unknown etiology (OR 6.15, 95% CI 1.43, 26.76), and myoclonic semiology (OR 6.1, 95% CI 1.23, 29.3). Patients with acute symptomatic etiology (OR 0.12, 95% CI 0.04, 0.40) had a lower risk for developing epilepsy.

Significance: Age at onset and duration of status epilepticus (SE) were critical independent variables associated with worse neurocognitive outcome. The risk of developing epilepsy was lower after acute symptomatic and febrile SE. Semiology and age at onset correlate with etiology of SE. For this reason, ILAE classification with respect to four axes seems an appropriate advancement.

Epilepsy Research Findings: November 2019

Among the interesting research published this past month are advances in epilepsy genetics that may help predict who is at risk for developing epilepsy and a novel gene therapy concept for treating temporal lobe epilepsy. Research has also furthered our understanding of how epilepsy may impact cognition – even when seizures are controlled by medication.

In this update, we also feature the results of the “Seize the Truth about Epilepsy Perceptions” survey. This national survey of adult epilepsy patients, caregivers, and healthcare professionals explores the physical, social, emotional, and financial consequences associated with epilepsy.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • Epilepsy Genetics: Risk scores are being used to investigate the genetic risk of epilepsy in a large sample of people with and without epilepsy. The international team led by the Cleveland Clinic is using this model to work towards a more personalized method of epilepsy diagnosis and treatment. Learn more
  • Epilepsy Gene Therapy: A new gene therapy concept has been developed for the treatment of temporal lobe epilepsy. In a “proof-of-concept” study, the researchers demonstrated that strategically delivering a specific gene to the place in the brain where seizures start can suppress them on demand in animal models. Learn more
  • Understanding Epilepsy: A new, national survey of adult epilepsy patients, caregivers, and healthcare professionals (HCPs) revealed a wide range of challenges in the management of the condition. The findings range from significant disconnects that occur in conversations among patients, caregivers, and HCPs to revelations about the far-reaching impact of epilepsy. Learn more
  • Epilepsy and Cognition: A study by Stanford University School of Medicine investigators may help explain why even people benefiting from medications for their epilepsy often continue to experience bouts of difficulty thinking, perceiving, and remembering clearly. The cause is a pathological buzz of electrical brain activity, called a high-frequency oscillation, that interferes with the brain’s normal activity. Learn more
  • Seizures in Newborns: Utilizing a mouse model of hypoxic-ischemic seizures has shed light on why seizures in newborns may lead to behavioral issues and learning disabilities much later, according to a study from University of Virginia Children’s Hospital. This research suggests that the brain’s learning and memory centers are among the regions most affected by seizures caused by inadequate oxygen and blood flow. Learn more

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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.

Seizures in Babies: UVA Sheds Light on Why They Have Lifelong Effects

A doctor at University of Virginia Children’s is using an elegant new approach to mapping brain activity to shed light on what happens during seizures in newborns that can lead to behavioral issues and learning disabilities much later.

New research by UVA neonatologist Jennifer Burnsed, MD, and colleagues suggests that the brain’s learning and memory centers are among the regions most affected by seizures caused by inadequate oxygen and blood flow. That lack of oxygen and blood, called hypoxia-ischemia, is a leading cause of death and disability in newborns. It is often caused by an event around the time of birth, such as a detached placenta or umbilical cord accidents.

“When babies have these brain injuries early on, it’s really hard for us to predict outcomes, especially in the babies who are not as severely affected. A lot of them will look pretty good when they leave [intensive care] and then, several years later, when they go to school, things pop up — behavioral problems, cognitive problems, learning disabilities,” Burnsed said. “That’s one of the things that’s always frustrated me as a clinician, so we have brought that question into the lab, to try to figure out exactly what is going on in the neonatal brain.”

Seizures in Infancy in the Offspring of Women with Epilepsy

In this investigation, researchers evaluated the seizure incidence in the first year of life in infants born to mothers with epilepsy and factors contributing to the incidence of seizure.

Investigators found that seizures occurred in the progeny of 47 pregnancies by the end of a year following pregnancy (2.4%), including febrile seizures in 18, the latter rate being higher than the 0.40% and 0.59% rates recorded in the recent literature for the same situation in the general population. Infant seizures were more likely in the offspring of generalized mothers vs focal epilepsy and generalized epilepsy mothers in those who during pregnancy were not seizure-free. In infants with fetal malformations, seizures were also more likely, especially those that were not discovered until after the first postnatal month.

Such results may help to warn mothers with epilepsy about the risk that their offspring will suffer seizures in the first year of life. They also indicate the desirability of achieving maternal seizure control during pregnancy.

New Report Shows Rare Disease More Common Than Previously Thought

Approximately one in forty-two thousand children are born with a disease called CDKL5 Deficiency Disorder, according to a new medical report recently published in the journal Brain and presented last month at the 13th European Paediatric Neurology Society Congress in Athens, Greece. This means that each year there are over 100 new children born with the disease in the EU alone, and over 3,000 in the world.

The disease leads to frequent seizures shortly after birth and severe impairment in neurological development, with most affected people being unable to walk, talk or care for themselves. “When our daughter was diagnosed in 2009 they told us there were approximately 200 cases in the world”, says Carol-Anne Partridge, chair of CDKL5 UK and the International CDKL5 Alliance, which represents patient organizations from 18 countries. “Today we know that these children were simply not being diagnosed correctly,” she adds.

The study, by a medical team from the Royal Hospital for Children in Glasgow, kept track of all births in Scotland during three years and applied genetic testing to all children under 3 years of age who developed epilepsy. “We found that as many as 1 in 4 children with epilepsy have a genetic syndrome”, explains Professor Sameer Zuberi, corresponding author for the study, “and a small group of genes explains most of the cases.”

Among these genes is CDKL5, which encodes a protein necessary for proper brain functioning. Mutations in the CDKL5 gene produce CDKL5 Deficiency Disorder, with one of the first symptoms being early-onset epilepsy. There is no therapy approved for treating the disease now known to affect thousands of people.

NeuCyte to Advance Novel Compound for Treatment of Refractory Epilepsy and Related Neurological Disorders

NeuCyte, Inc. announced that it has entered into an exclusive license agreement with Trillium Therapeutics to advance an undisclosed preclinical compound with potential utility in treating refractory epilepsy in the form of Dravet syndrome and related disorders.

The compound covered by this agreement has demonstrated highly encouraging activity during studies conducted by the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP). It demonstrates a superior safety and anti-seizure efficacy profile over NINDS benchmark anti-epileptic drugs (AEDs) in eleven animal models. It has also demonstrated broad efficacy in NIH animal studies for pharmaco-resistant epilepsy.  As a result, this novel agent has gained the prestigious NINDS Red Book status and been selected as a promising lead drug candidate.

“This compound is an exceedingly promising antiseizure drug which, although in preclinical development, is quite efficacious in a wide variety of highly predictive seizure models,” said Roger J. Porter, MD, Adjunct Professor of Neurology at the University of Pennsylvania, former Deputy Director of NINDS, former Chairman of the White House Committee on Brain and Behavioral Sciences, and former President of American Epilepsy Society. “It may prove very effective for patients with epilepsy.” As a first-in-class compound with unique mechanism of action profiles, this drug candidate is likely to have activity across a variety of indications. The favorable efficacy and safety profile has also been validated by NeuCyte’s proprietary in vitro human iPSC-derived models.

Complex Neurocognitive Skills Delayed in Youth With SCN8A Variant Epilepsy

Complex neurocognitive skills, typically acquired later in development, are the most delayed skills in youth with SCN8A?related epilepsy, according to results published in Epilepsia.

Researchers analyzed 91 patients with SCN8A-related epilepsy. Analyses were conducted to identify correlations between age at seizure onset and neurodevelopmental growth. Parents and guardians provided information pertaining to their child’s medications, seizure history, comorbidities, and developmental skills based on Denver II items. Twenty-five skills were chosen, six to seven from each category (fine motor, gross motor, social motor, and language).

Researchers carried out a retrospective analysis of data from an online SCN8A community registry and used the canonical transcript to map all genetic variants collected. Spearman rank tests were used to evaluate pairwise relationships between certain seizure characteristic variables and development score.

A limitations of this study included the potential for recall error in questionnaires completed by parents and guardians. Further, cohort included was not large enough to produce statistically significant tests and prevented further stratification based on subphenotypes or mutational type.

Researchers concluded that variants of uncertain significance should be taken into consideration when evaluating children with SCN8A-related epilepsy. Researchers believe these findings provide “a clinical context at initial presentation that may be prognostic for developmental outcome.”

Diacomit is Effective as Add-on Therapy to Reduce Refractory Seizures in Dravet, Review Study Finds

Diacomit (stiripentol) is an effective add-on oral therapy to reduce the frequency and duration of seizures in patients with Dravet syndrome, a review study has found.

The study, “Stiripentol: A Novel Antiseizure Medication for the Management of Dravet Syndrome,” was published in the journal Annals of Pharmacotherapy.

Diacomit, marketed by Biocodex, is a new type of anticonvulsive medication that has been shown to reduce the frequency of seizures in patients with Dravet syndrome, especially when administered in combination with other antiseizure medications, such as Onfi (clobazam), Depacon (valproate), and topiramate (sold as Topamax among other names), or with dietary interventions such as the ketogenic diet (low-carbohydrate, high-fat diet).

This new antiseizure therapy received the designation of orphan drug in 2001 from the European Medicines Agency, followed by its approval in Europe as an add-on therapy in 2007. The U.S. Food and Drug Administration approved Diacomit in 2018 as an add-on therapy for the treatment of seizures in children with Dravet syndrome who are 2 years of age or older and already taking Onfi.

Better Seizure Control with Ketogenic Diet in Infants with Genetic Epilepsy

Infants and young children with epilepsy due to a confirmed genetic abnormality had a better response to treatment with ketogenic diet compared to patients with other types of epilepsy, according to a review of 10-year experience at Ann & Robert H. Lurie Children’s Hospital of Chicago. Results were published in Scientific Reports.

“Overall, we observed that ketogenic diet continues to be a safe, effective and well-tolerated treatment for patients under 3 years of age with drug-resistant epilepsy,” says study author John Millichap, MD, an epilepsy specialist at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Based on our experience, clinicians could consider offering ketogenic diet earlier to infants diagnosed with genetic epilepsy, perhaps even before it becomes clear that the patient is not responding to anticonvulsant medication.”

Ketogenic diet is a high fat, low carbohydrate and protein restricted diet that is rigorously medically supervised. It is widely recognized as an effective treatment for epilepsy that does not respond to medications.

“The ketogenic diet helps control seizures by reducing fluctuations of blood sugar, which reduces hyper-excitability in the brain,” explains Dr. Millichap. “At Lurie Children’s we have used it since 1963.”