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.”

Possible Role of SCN4A Skeletal Muscle Mutation in the Loss of Breathing During Seizure

SCN4A gene mutations cause a number of neuromuscular phenotypes including myotonia. A subset of infants with myotonia-causing mutations experience severe life-threatening episodic laryngospasm [a spasm of the vocal cords that makes it difficult to speak or breathe] with apnea.

This research team recently identified similar SCN4A mutations in association with sudden infant death syndrome. Laryngospasm has also been proposed as a contributory mechanism to some cases of sudden unexpected death in epilepsy (SUDEP). The team reports an infant with EEG-confirmed seizures and recurrent apneas. Whole-exome sequencing identified a known pathogenic mutation in the SCN4A gene that has been reported in several unrelated families with myotonic disorder.

This study proposes that the SCN4A mutation contributed to the apneas in our case, irrespective of the underlying cause of the epilepsy. They suggest this supports the notion that laryngospasm may contribute to some cases of SUDEP, and implicates a possible shared mechanism between a proportion of sudden infant deaths and sudden unexpected deaths in epilepsy.

Stoke Therapeutics Observational Study of Children and Adolescents Living with Dravet Syndrome

Stoke Therapeutics, Inc. announced enrollment of the first patient in an observational study of children and adolescents ages 2 to 18 with Dravet syndrome. BUTTERFLY is a two-year observational study that is designed to evaluate seizure frequency and non-seizure comorbidities associated with the disease, including motor and speech impairment, intellectual and developmental disabilities, behavioral deficits and abnormal sleep patterns. Data from the study will support clinical development plans for the company’s lead therapeutic candidate, STK-001, an investigational new treatment for Dravet syndrome.

Epilepsy Research Findings: August 2019

The past month has been filled with interesting research discoveries, including work done by CURE Grantee Dr. William Nobis and colleagues to advance our understanding of the areas of the brain that may be important in Sudden Unexpected Death in Epilepsy (SUDEP). In the field of epilepsy genetics, a large-scale study identified new epilepsy-associated genetic variants by examining the genetic make-up of more than 17,000 people with epilepsy. There is also intriguing research news looking at why cilantro, used in traditional medicine, may work to combat seizures.

Summaries of these research discoveries are below.

Plus, get epilepsy research news all month by downloading the new CURE mobile app! Find the details here.

Research Discoveries

  • SUDEP: A study featuring the work of CURE Grantee Dr. William Nobis and colleagues suggests that an area of the brain called the amygdala plays a role in dysfunctional breathing during seizures and possibly SUDEP. Learn More
  • Epilepsy Genetics: In one of the largest studies of its kind to examine the genetic make-up of individuals with epilepsy, scientists discover rare genetic variants associated with epilepsy. Learn More
  • Herbal Treatments: A study examines how the molecular action of cilantro, which is used as a traditional anticonvulsant medication, can help combat seizures. Learn More
  • Dementia and Epilepsy: Patients with dementia who are registered in the Swedish dementia registry were found to have increased rates of epilepsy. Learn More
  • Multiple Sclerosis and Epilepsy: Patients with multiple sclerosis have a higher risk of developing seizures compared with the general population. Learn More
  • SCN8A-Related Epilepsy: A study featuring the work of CURE Grantee Dr. Gemma Carvill and colleagues identified a set of neurons in the brains of mice that have a SCN8A gene mutation similar to humans that may be critical targets for therapeutic intervention. Learn More

Introducing the CURE Epilepsy Research Mobile App for research updates in the palm of your hand! Download today. iOS | Android

FDA-Approved Donepezil Protects Against Seizures in a Mouse Model of Dravet Syndrome

De novo loss-of-function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early-life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. This research team previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants.

In the present study, the team evaluated the therapeutic potential of donepezil, a reversible acetylcholinesterase inhibitor approved by the FDA, in a mouse model of Dravet syndrome (Scn1a +/-). The team found that donepezil conferred robust protection against induced seizures in Scn1a +/- mutants.

Study on Challenges in Patients with Juvenile Myoclonic Epilepsy Points to a Need of Closer Follow-Up

BACKGROUND: Patients with juvenile myoclonic epilepsy (JME) may have uncontrolled seizures. The purpose of this study was to investigate the use and challenges with antiepileptic drugs (AEDs) and the patients’ view of these challenges.

METHOD: A questionnaire about the use of AEDs, adherence to therapy, and quality of life was given to patients with JME recruited from Drammen Hospital. Data regarding AEDs were confirmed from medical records at Drammen Hospital, Norway (2007-2018). Additional clinical interviews were performed, and a mixed method approach was applied.

RESULTS: Ninety patients with defined JME diagnosis, 54/36 women/men aged 14-39 (mean: 25) years, were included. Only 29 (33%) were seizure-free. Within the last year, 21% experienced generalized tonic-clonic seizures (GTCS), and 68% had myoclonic jerks. Seventy-six (84%) used AEDs, 78% in monotherapy. A total of 10 AEDs were used;: most commonly valproate (n = 33), lamotrigine (n = 27), and levetiracetam (n = 21). Two-thirds of valproate users were men while all other AEDs were used more in females than in men. Valproate and levetiracetam displayed better efficacy against GTCS than lamotrigine. One-third often/sometimes forgot their medication nonintentionally while 14% had intentional poor adherence. The majority reported good quality of life (76%). No significant correlations between the use of AEDs, use of valproate, poor adherence, quality of life score, and seizure freedom were demonstrated. Half of the patients had serum concentrations measured every year, and two-thirds thought this was important. Qualitative interviews elucidated treatment challenges in JME;, adverse effect burden, adherence, and activities of daily life.

CONCLUSION: Despite the use of antiepileptic drugs in the majority of patients, only one-third were seizure-free. Other challenges included polypharmacy, the use of valproate in women, and variable adherence. This points to a need for closer follow-up in patients with juvenile myoclonic epilepsy.

Mysterious Sunflower Syndrome is Spotlighted at Massachusetts General Hospital

Sunflower syndrome [is] a rare form of epilepsy that, in a new study, researchers at Massachusetts General Hospital are working to understand – and treat. Sunflower syndrome compels those who suffer from it to turn toward bright light and wave one hand, fingers spread, in front of their eyes. It’s usually the same hand every time. This unique behavior is coupled with abrupt lapses in consciousness that last several seconds.

“About half of the kids do it both indoors and outdoors. It’s pretty crippling,” said Dr. Elizabeth Thiele, director of the pediatric epilepsy program at MassGeneral Hospital for Children. She has fielded calls from patients around the world and seen dozens of them, including a 7-year-old boy who obsessively drew pictures of the sun.

She said her latest work measuring brain activity in sunflower patients, which has not been published, shows only a fraction of a second elapses between the start of the hand-waving and the onset of the seizure, not nearly long enough for the action to create a seizure. It demonstrates, she said, that the waving is part of the seizure and is not provoking it.

Thiele is launching a four-month study of 10 patients to test whether an appetite suppressant banned two decades ago, Fenfluramine, might be effective in controlling the syndrome. Fenfluramine, often combined with another medication and sold as a popular diet pill known as Fen-Phen, was pulled from sales after reports the drugs caused significant heart damage.

But Fenfluramine was not banned in Belgium, and researchers have demonstrated that low doses taken for years have significantly reduced seizures in another drug-resistant form of epilepsy, Dravet syndrome, without producing heart damage. Now, federal regulators are considering whether to allow Fenfluramine back on the market to treat Dravet in the United States, possibly preparing the way for sunflower patients.

The Onset of Pediatric Status Epilepticus Peaks Mid-Morning and is Lowest at Night

PURPOSE: To evaluate whether the onset of pediatric refractory status epilepticus (rSE) is related to time of day.

METHOD: This study analyzed the time of day for the onset of rSE in this prospective observational study performed from June 2011 to May 2019 in pediatric patients (1 month to 21 years of age). The research team evaluated the temporal distribution of pediatric rSE utilizing a cosinor analysis and calculated the midline estimating statistic of rhythm (MESOR) and amplitude. MESOR is the estimated mean number of rSE episodes per hour if they were evenly distributed. Amplitude is the difference between MESOR and maximum rSE episodes/hour, or between MESOR and minimum rSE episodes/hour. We also evaluated the temporal distribution of time to treatment.

RESULTS: The researchers analyzed 368 patients (58% males) with a median (p25 – p75) age of 4.2 (1.3 9.7) years. The MESOR was 15.3 (95% CI: 13.9-16.8) and the amplitude was 3.2 (95% CI: 1.1-5.3), p = 0.0024, demonstrating that the distribution is not uniform, but better described as varying throughout the day with a peak in the morning (11 am-12 pm) and trough at night (11 pm-12 am). The duration from rSE onset to application of the first non-benzodiazepine antiseizure medication peaked during the early morning (2 am-3 am) with a minimum during the afternoon (2pm-3pm) (p = 0.0179).

CONCLUSIONS: The distribution of pediatric status epilepticus onset is not uniform during the day. Pediatric status epilepticus onset shows a 24-h distribution with a peak in the mid-morning (11am-12pm) and a trough at night (11pm-12am).