Gladstone researchers Jorge Palop and Keran Ma are collaborating with Jesse Hanson from Genentech to develop therapies for Alzheimer's disease and Dravet syndrome.

New Small Molecule to Treat Alzheimer’s Disease and Dravet Syndrome

Gladstone researchers, in collaboration with Genentech, a member of the Roche group, have shown therapeutic efficacy of a new experimental drug in mouse models of Alzheimer’s disease and a rare genetic form of epilepsy known as Dravet syndrome. The small molecule increases the activity of a subset of neurotransmitter (NMDA) receptors that are found at synapses, the connection points between neurons. These receptors are known to support cognition and memory by enhancing communication between neurons. The new research shows that enhancing the activity of synaptic NMDA receptors helps restore the brain’s rhythms to normal patterns, and improves memory.

“Before now, we haven’t had ideal tools to enhance synaptic NMDA receptors,” said Gladstone Associate Investigator Jorge Palop, Ph.D., senior author of the study, which was published in the journal Cell Reports. “Now, the ability to specifically target these receptors opens up a lot of new possibilities for treating cognitive disorders.”

“This is the first time we’ve explored what this type of experimental drug does in animal models,” said Jesse Hanson, a scientist at Genentech and lead author of the new paper. “It was very gratifying to see an effect on both the brain’s electrical activity and the animals’ behavior.”

Abnormal activity of NMDA receptors has been long implicated in neuropsychiatric, epileptic, and neurodegenerative disorders. But previous compounds for altering NMDA receptor function worked by binding to all subtypes of NMDA receptors, and either completely blocked the receptors or put them in a permanently active state. Researchers have theorized that modulating the receptors only at active synapses may help diverse cognitive diseases by potentiating synaptic function and increasing neuronal communication.

FANS Trial Testing Ketone Supplementation to Help Control Seizures in Children With Angelman Syndrome

A clinical trial is evaluating the safety and tolerability of a nutritional formulation containing the ketone beta-hydroxybutyrate (BHB) as a treatment to help control seizures in children with Angelman syndrome.

More information about the trial, called Nutritional Formulation for Angelman Syndrome (FANS), is available here.

The protocol of this trial was described in a paper, titled “Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial,” published in the journal Trials.

Seizures that are resistant to medication are estimated to occur in more than three-quarters of people with Angelman syndrome (AS). Certain dietary interventions, the ketogenic diet in particular, have shown considerable efficacy at controlling these seizures. This diet involves eating very few carbohydrates (sugars and starches) and consuming more fats.

Generally, cells in the body will preferentially use carbohydrates — particularly glucose — as an energy source. When carbohydrates are unavailable, the body will instead use fat for energy in a process called ketosis. This process, in turn, generates molecules called ketones, such as BHB.

While it is not entirely known why ketones are beneficial, a number of hypotheses have suggested that ingesting ketones leads to a metabolic shift that results in increased inhibition of cell toxicity and ultimately to a dampening of overall neuron excitability and decreased seizure activity.

Although the “keto diet” can help control seizures, many people with AS experience digestive problems and difficulty in feeding, which make it difficult for them to adhere to the diet and get enough nutrition.

In the FANS trial, instead of going on a ketogenic diet, participants will be given a nutritional formulation that is directly supplemented with BHB. The idea is that directly consuming the ketones could produce similar benefits as a ketogenic diet, but be easier to manage.

The trial will be conducted in the Angelman Syndrome clinic at Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center (in Nashville, Tennessee) in collaboration with sponsor Disruptive Nutrition. The study is being funded by the Foundation for Angelman Syndrome Therapeutics (FAST).

Dravet Syndrome: Treatment Options and Management of Prolonged Seizures

Over time, with careful delineation of Dravet syndrome, doctors have gained experience in treatments most likely to lead to improvement in seizures, as well as those that should be avoided. Sodium valproate, clobazam, stiripentol, and topiramate are all medications that may lead to benefit, as well as the ketogenic diet. Bromides may be utilized in resistant cases. However, equally important are outlining prompt rescue treatment for prolonged seizures and avoidance of precipitants. Newer agents including cannabidiol and fenfluramine have been demonstrated to be of benefit in clinical trials. This study proposes an algorithm for management, but appreciate that the positioning of newer agents is yet to be established.

Key Points

  • An early accurate diagnosis is key to optimal treatment in Dravet syndrome
  • Prompt rescue treatment with personalized protocols for prolonged seizures is key, as well as avoidance of precipitants of seizures
  • Clobazam, stiripentol, valproate, and more recently cannabidiol appear to be effective treatments
  • Fenfluramine is a promising agent demonstrating specific efficacy in trials and should be considered for the future
Daniel Vogt

Tuberous Sclerosis Study Gives Insight into Autism and Epilepsy

A new study published in Nature Communications on a rare genetic disease provides insights into autism, epilepsy and cognitive impairment.

The disorder, tuberous sclerosis, causes benign tumors on the skin and multiple organs, including the heart, kidneys and lungs. About half of people with tuberous sclerosis also have autism spectrum disorder and roughly 90% have seizures.

“Tuberous sclerosis is caused by mutations in two genes that turn off a protein called ‘MTOR,’” Dr. Daniel Vogt said. “When MTOR is on at the wrong times, autism is a consequence. Understanding how MTOR regulates development and function of brain cells is important in understanding both how autism develops and the neuropsychiatric symptoms of tuberous sclerosis.”

As part of the study, Vogt and his team created knockout mice that lacked TSC1, one of the two genes responsible for tuberous sclerosis. The scientists found that certain cells had higher levels of MTOR. The team validated these findings by comparing them to other mice that still had the TSC1 gene.

“This analysis made clear MTOR is really important in the pathway,” Vogt said. “This was really a big surprise for the field.”

The team also found that in mice without the TSC1 gene had an imbalance in normal brain activity that causes seizures. The authors believe this may contribute to the relatively high likelihood of epilepsy in individuals with tuberous sclerosis.

Overview of STXBP1-Related Developmental and Epileptic Encephalopathy

Researchers from the University of Antwerp, Belgium, and numerous international collaborators report a comprehensive overview of the phenotypic and genetic spectrum of Syntaxin-binding protein 1 (STXBP1) encephalopathy.

COMMENTARY. This paper provides a comprehensive phenotypic and genetic analysis of individuals with STXBP1 pathogenic variants. Although most patients with STXBP1-related disease present with epilepsy, others may have primarily movement disorders such as an ataxia-tremor-retardation syndrome. In some selected patients with drug resistant epilepsy, surgical intervention has been reported to successfully reduce seizure frequency. Although profound intellectual disability is highly associated with STXBP1 variants, autism spectrum disorder is rarely seen. Management typically includes anticonvulsants for seizure control and early intervention with physiotherapy, occupational, speech and or behavioral therapy to treat the complex neurodevelopmental aspects of the disorder.

Depression and Anxiety in Children with Epilepsy and Other Chronic Health Conditions: National estimates of Prevalence and Risk Factors

OBJECTIVE: This study estimates the national prevalence of depression and anxiety among children with epilepsy and determines which demographic variables and comorbidities increase the risk of these psychopathologies. It also compare the rates of depression and anxiety in pediatric epilepsy with those of other chronic health conditions in childhood.

METHODS: This team used the 2009-2010 National Survey of Children with Special Health Care Needs to identify children with epilepsy with and without depression and anxiety. They assessed demographic factors and comorbidities associated with depression and anxiety using weighted multivariable logistic regressions. The rates of psychiatric comorbidity in children with chronic conditions other than epilepsy were also determined.

RESULTS: The final sample included 1042 children over the age of five with epilepsy. After applying the sampling weights, we estimated that 283,000 children between 5 and 17 years of age have epilepsy in the United States (U.S.). Among these children, 25% have depression and/or anxiety. This figure was not significantly different from the rates seen among children with asthma (16.5%) or allergies (21.6%) but was significantly lower than the rate seen among children with migraines (43.2%). In our analyses of children with epilepsy, low-income children (regardless of race) and children whose needs for specialist care were unmet (relative to those whose needs were met) were more likely to have depression. Low-income black children were less likely to have anxiety than high-income white children. Gender, age, and epilepsy severity were unrelated to depression or anxiety.

CONCLUSIONS: One in four U.S. children with epilepsy has depression and/or anxiety. Therefore, physicians should consider the various factors that are related to depression and anxiety in children with epilepsy so that at-risk children can be screened and managed appropriately.

Open-label, Uncontrolled Retrospective Study Provides Eevidence that Perampanel (Fycompa) May Help in Adults with Lennox-Gastaut Syndrome

Purpose: Perampanel (PER) was added to the anticonvulsant regimen of 71 patients with Lennox-Gastaut Syndrome (LGS) to evaluate its efficacy against seizures and its tolerability.

Method: This team evaluated at 3 month intervals 62 with pure LGS and 9 with LGS-like epileptic encephalopathy (28 females, 43 males, mean age 40.1 ± 11.5 yrs, median 38, range 20–71) in whom PER was introduced by 2 mg steps at 2- to 4-week intervals up to 6 mg/day, with possible dose reduction or increases after that. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.

Results: Mean PER exposure was 538.9 days ± 425 (median 429), with 44 patients (62%) on PER at last follow-up. About 2/3 of patients were responders, including 35.2% that had a at least a 75% decrease in their seizures. Among these 16.9% had a 90% or greater decrease. No improvement was seen in 14 patients; 5 had a less than 50 % response, and 6 had seizure aggravation. Therefore, 25 (35.2%) were considered non-responders. Half of the patients developed at least one side-effect. Significant negative changes in behavior were noted in 1/3 of the cases, including irritability (8.5%) and aggressivity (7%). In contrast, 4 patients reported positive behavioral and psychological well-being side-effects.

Conclusions: This retrospective, open-label study provides evidence that perampanel (PER) may significantly help in Lennox-Gastaut syndrome (LGS). PER should be tried in LGS patients who are not satisfactorily controlled. Its use may be limited in some patients due to behavioral side-effects occurring, particularly at doses at or above 6 mg/d.

Epilepsy Research Findings: December 2019

This month, the FDA approved XCOPRI, a new medication to treat partial-onset seizures in adults. This type of seizure is often difficult to control, so we are thrilled to see this treatment advancement.

Additional promising research news includes the advancement of a method of predicting seizure risk. Also, for individuals affected by Lennox-Gastaut syndrome, a new Amazon Alexa skill offers engaging, interactive play options.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • New Treatment: The FDA approved SK Lifescience’s XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults. Learn More
  • Seizure Prediction: The new seizure risk assessment tool from Rice University, EpiSAT, received its first validation. The automated machine-learning algorithm correctly identified changes in seizure risk — improvement, worsening, or no change — in more than 87% of cases by analyzing seizure diaries. This prediction rate is as good or better than specialized epilepsy clinicians predicting seizure risk using patient histories. Learn More
  • New Technology: Eisai Inc. launched Ella the Jellyfish, the first Amazon Alexa skill designed for those affected by Lennox-Gastaut syndrome. This skill features capabilities such as interactive play, listening, and creative activities. Learn More
  • Status Epilepticus: New findings from a team, which included CURE Scientific Advisory Members Dr. Jaideep Kapur and Dr. Dan Lowenstein, reveal that levetiracetam (Keppra), fosphenytoin (Cerebyx), and valproate (Depakote) are equally safe and effective in treating patients with status epilepticus. Learn More
  • Post-Traumatic Epilepsy: Researchers from the University of California, Irvine (UCI) developed a cell therapy to improve memory and prevent seizures in mice following traumatic brain injury. In the study, the UCI team transplanted a cell type that can generate inhibitory brain activity into mouse brains. This process formed new connections with injured brain cells and prevented the mice from developing seizures. Learn More
  • Febrile Seizures: A study examined the cognitive functioning in children ages 4-5 who experienced febrile seizures. The research found that children with early onset of febrile seizures (especially those with recurrent febrile seizures) may be at heightened risk for poorer verbal and processing speed function, and possibly at risk for other cognitive dysfunctions. The findings suggest that these children would likely benefit from neuropediatric and neuropsychological follow-up, regardless of if they are still having febrile seizures. Learn More

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

Two children happy at a table together.

The Puzzling Link Between Autism and Infantile Spasms

Children with infantile spasms were not likely to have a sibling who also had infantile spasms, other forms of epilepsy, or autism spectrum disorder (ASD), a retrospective cohort study showed.

Of 475 patients with video-confirmed infantile spasms in a large clinical database, 294 had at least one sibling; of those, one patient had a sibling with infantile spasms, five had a sibling with another form of epilepsy, and six had a sibling with ASD, reported Shaun Hussain, MD, of the UCLA Mattel Children’s Hospital in Los Angeles, and colleagues, at the American Epilepsy Society annual meeting.

Autism affects approximately 35% of children who have infantile spasms and the link between the two disorders is unclear. They may share genetic susceptibility or it’s possible that infantile spasms cause ASD, Hussain suggested.

“The big issue out there is that in most cases of autism, there is no obvious cause,” Hussain said. “Although we believe genetics play a big role — and countless genes have been linked to autism — we can’t identify a gene mutation in the vast majority of cases.” Most children with autism also have a normal MRI and a normal, or nearly normal, EEG, he noted.

Study Results Support Safety and Efficacy of Fenfluramine as a Patient Option for Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens

Researchers investigated the safety and efficacy of fenfluramine for treating patients with Dravet syndrome who have frequent seizures despite taking a stiripentol-inclusive antiepileptic drug regimen. They conducted a double-blind, placebo-controlled, parallel-group randomized clinical trial at multiple centers randomizing patients with 6 or more convulsive seizures during the 6-week baseline period to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. Outcomes revealed a 54.0% greater reduction in mean monthly convulsive seizure frequency in correlation to receiving oral fenfluramine (0.4 mg/kg/d; maximum 17 mg/d) vs placebo among patients with Dravet syndrome who were taking stiripentol-containing antiepileptic drug regimens.

Among patients who were taking fenfluramine (vs placebo), a significantly greater proportion experienced a clinically meaningful (over 50%) or profound (over 75%) reduction in monthly convulsive seizure frequency. Adverse events most commonly encountered were decreased appetite, pyrexia, fatigue, and diarrhea; there was no patient who developed valvular heart disease or pulmonary hypertension. These findings support the safety and efficacy of adjunctive fenfluramine as a new treatment option for these patients.