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.

Marinus Announces Ganaxolone Orphan Epilepsy Program Updates Including Planned Clinical Program in Tuberous Sclerosis Complex

Marinus Pharmaceuticals, Inc. announced clinical and regulatory updates for its orphan seizure programs in tuberous sclerosis complex (TSC), CDKL5 deficiency disorder (CDD) and PCDH19-related epilepsy (PCDH19-RE).

“The decision to expand our epilepsy program in TSC was strategically informed by the discovery of a new potential epilepsy biomarker, Allo-S, in our Phase 2 study in PCDH19-related epilepsy,” said Scott Braunstein, M.D., Chief Executive Officer of Marinus. “This led us to additional analyses that identified TSC as another rare genetic disorder that may be similarly impacted by Allo-S levels. We look forward to initiating a Phase 2 trial in the first half of 2020 to provide a potential targeted treatment option for these patients with limited approved therapies.”

Marinus intends to initiate a Phase 2, open label study to evaluate the safety and tolerability of adjunctive ganaxolone treatment in patients with seizures associated with TSC. Patient stratification from the Company’s PCDH19-related epilepsy Phase 2 trial identified a subpopulation of patients with improved ganaxolone responses, those with low levels of allopregnanolone-sulfate (Allo-S). Based on these data, the Company performed a biomarker analysis to identify other rare genetic epilepsies that may benefit from the GABAA-receptor modulatory effects of ganaxolone and today announced TSC as the next planned orphan epilepsy program to study the effect of ganaxolone on seizures as well as the expanded utility of a potential biomarker.

The planned Phase 2 study will be conducted at approximately 4-6 sites in the United States and enroll approximately 20-40 patients ages 2 to 65.  Patients will undergo a 4-week baseline period followed by a 12-week treatment period.  The primary endpoint for the study is percent change in 28-day primary seizure frequency through the end of the 12-week treatment period relative to the 4-week baseline period.

News from American Epilepsy Society Meeting 2019

Sepsis Linked to Elevated Risk for New-Onset Epilepsy in Young Individuals

Patients with sepsis, particularly younger patients and those with chronic kidney disease, may be at an elevated risk for new-onset epilepsy, according to research presented at the 2019 American Epilepsy Society Annual Meeting, held December 6-10, 2019, in Baltimore, Maryland.

Researchers conducted a population-based, retrospective, matched-cohort study to estimate the risk for new-onset epilepsy among patients hospitalized in the intensive care unit (ICU) for sepsis treatment. Researchers collected data from the patients in the Discharge Abstract Database between 2010 and 2015.

“These findings indicate that sepsis may be an unrecognized epilepsy risk factor,” the researchers concluded. “Possible mechanisms include damage to the blood-brain barrier as a result of renal dysfunction, persisting inflammation after the acute episode, and increased risk of cardiovascular events following sepsis.”

Learn more

Variable Long-Term Cognitive Changes in Pediatric Epilepsy

Children with pediatric epilepsy who undergo surgery may experience changes in verbal and nonverbal IQ, particularly when associated with abnormal electroencephalogram (EEG), according to research presented at the 2019 American Epilepsy Society Annual Meeting.

Researchers sought to assess the long-term, postsurgery cognitive outcomes of patients with pediatric epilepsy. Investigators assessed 24 participants, all of whom had pharmacoresistant epilepsy. Participants underwent a neuropsychological evaluation that included intellectual functioning assessments (overall IQ, verbal IQ, and nonverbal IQ), as well as an evaluation of postsurgical seizure status.

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Teenagers With Epilepsy Frequently Post Online Messages Related to Suicide

Using artificial tools to collect and analyze conversations and comments about epilepsy posted online, researchers revealed that 7.8% of all posts by teenagers with epilepsy were related to suicide, compared with 3.2% of adult posts, according to study results presented at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that roughly 30%-50% of patients with epilepsy may suffer from depression and the incidence of suicide in this population was found to be approximately 12%, which is 22% higher than the general population.2 The goal of the current study was to assess the major motivations for suicide thoughts among teenagers and adults with epilepsy, using artificial tools to analyze online conversations.

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Apnea and Arrhythmia Associated With Increased Mortality Among Patients With Epilepsy

Cardiac arrhythmias with or without apnea among patients with epilepsy are associated with increased mortality risk.  This risk may play an important role in cases of sudden unexpected death in epilepsy (SUDEP), according to study results presents at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that cardiac arrhythmias and apnea may play a significant part in cases of SUDEP, the second most common cause potential life-years lost in patients with epilepsy. The incidence rate of SUDEP is 1.16 cases per 1000 patients, but may be higher in those with intractable epilepsy.

Learn more