Efficacy and Safety of Fenfluramine Hydrochloride (Fintepla®) for the Treatment of Seizures in Dravet Syndrome: A Real-world Study

Abstract, originally published in Epilepsia

Objective: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS.

Methods: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months.

Results: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥ 50% reduction of convulsive seizures, 24 (53.3%) had a ≥ 75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA.

Significance: In this real-world study, fenfluramine provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

NAYZILAM® (midazolam) nasal spray

Important Update on NAYZILAM® Availability

NAYZILAM® (midazolam) nasal spray, a rescue medicine manufactured by UCB, is experiencing a manufacturing delay.

This shortage is expected to be temporary, lasting until the end of October 2020. If you need medication and are having challenges finding it at your pharmacy, please do one of the following:

  • Contact your physician
  • Contact: UCBCares® at (844) 599 2273
  • Email: UCBCares@ucb.com

If you have any questions or concerns, please contact your physician.

Study Finds Sleep Abnormalities Are a Major Issue in up to ¾ of Children With Drug-Resistant Epilepsy

Abstract, originally published in Seizure

Purpose: This study aims to assess the prevalence of sleep abnormalities in children with drug-resistant epilepsy (DRE) and characterize their polysomnographic profile and to further compare it with well-controlled epilepsy (WCE) and age-matched typically developing children (TDC).

Methods: A cross-sectional study consisting of 40 children in each group (DRE, WCE, and TDC) was conducted. Children’s sleep habits questionnaire (CSHQ) and modified pediatric Epworth daytime sleepiness scale (MPEDSS) were administered to all three groups. Thirty-five children each in the DRE and WCE group and 17 TDC underwent single night polysomnography (PSG).

Results: The prevalence of sleep abnormalities by the administration of CSHQ in DRE group was 72.5% (95% C.I-58.7 to 86.3%, mean score: 47.5 ± 7.1) compared to 32.5% (42.4 ± 6.2) and 15% (37.3 ± 5) in WCE and TDC groups respectively (P = 0.01). On MPEDSS, 52.5% of children in the DRE group had excessive daytime sleepiness compared to 12.5% in WCE and 5% in TDC groups respectively (p-0.03). On overnight PSG, sleep efficiency and REM sleep duration were significantly reduced in the DRE group in comparison to WCE and TDC. N2 duration, REM latency, arousal, and apnea-hypopnea index were significantly increased in the DRE group when compared to WCE and TDC groups.

Conclusion: Sleep-related problems are major comorbidity in up to three-fourths of patients with DRE and sleep architecture is significantly affected particularly in the DRE group.

Study Finds That Psychotherapy via Telehealth Is a Viable Treatment Option for Psychogenic Nonepileptic Seizures (PNES)

Abstract, originally published in Epilepsia

Objective: Previous studies have shown the effectiveness of manual-based treatment for psychogenic nonepileptic seizures (PNES), but access to mental health care still remains a problem, especially for patients living in areas without medical professionals who treat conversion disorder. Thus, we evaluated patients treated with cognitive behavioral therapy–informed psychotherapy for seizures with clinical video telehealth (CVT). We evaluated neuropsychiatric and seizure treatment outcomes in veterans diagnosed with PNES seen remotely via telehealth. We hypothesized that seizures and comorbidities will improve with treatment.

Methods: This was a single–arm, prospective, observational, cohort, consecutive outpatient study. Patients with video–electroencephalography–confirmed PNES (n = 32) documented their seizure counts daily and comorbid symptoms prospectively over the course of treatment. Treatment was provided using a 12–session manual–based psychotherapy treatment given once per week, via CVT with a clinician at the Providence Veterans Affairs Medical Center.

Results: The primary outcome, seizure reduction, was 46% (P = .0001) per month over the course of treatment. Patients also showed significant improvements in global functioning (Global Assessment of Functioning, P = < .0001), quality of life (Quality of Life in Epilepsy Inventory–31, P = .0088), and health status scales (Short Form 36 Health Survey, P < .05), and reductions in both depression (Beck Depression Inventory–II, P = .0028) and anxiety (Beck Anxiety Inventory, P = .0013) scores.

Significance: Patients with PNES treated remotely with manual-based seizure therapy decreased seizure frequency and comorbid symptoms and improved functioning using telehealth. These results suggest that psychotherapy via telehealth for PNES is a viable option for patients across the nation, eliminating one of the many barriers of access to mental health care.

Preparing Adolescents With Epilepsy to Manage Care Through Adulthood

Article, originally published on UofMHealth

As children with epilepsy get older, managing their own care is critical to their independence, ability to drive, go to college, seek employment and eventually start a family if they choose to do so.

And as more children with the neurological disorder survive into adulthood, ensuring a smooth transition in care is even more important.

Now, clinicians at Michigan Medicine have developed a tool to help them better prepare adolescents and young adults to take ownership of their disease well before the time comes.

Through a customized screening tool for 16 to 26 year-olds, doctors are effectively able to monitor their patients’ development of knowledge and self-management skills regarding their condition, according to a report in Epilepsia Open. This structure allows providers to proactively address gaps in readiness that may impact long term health outcomes.

Localizing Epilepsy ‘Hotspots’

Article, originally published on PennToday

By applying tools of machine learning and network analysis, the Davis Lab in the Penn Epilepsy Center was assisted by a team of Penn interns this summer to target the ‘missing electrode problem,’ identifying regions of the brain that cause epilepsy.

One percent of the U.S. population, or three million people, lives with epilepsy. Approximately one-third of those will have a drug-resistant form of epilepsy that, often, demands surgery. The challenge: Localizing where their seizures are coming from before surgery has historically been done with the implantation of EEG electrodes in the brain—an extraordinarily invasive procedure that comes with its own set of limitations.

Enter, the lab of Kathryn Davis, an assistant professor of neurology in the Penn Epilepsy Center at the Perelman School of Medicine.

“The problem with intracranial EEG electrodes is mainly a sampling issue. To solve this problem, we are leveraging information captured from whole-brain neuroimaging to better localize the seizure onset zone,” says Andrew Revell, a fifth-year MD/Ph.D. student in the Davis Lab, who explains that implanted electrodes can miss the areas implicated in seizure generation. “When planning for epilepsy surgery to remove the seizure onset zone, you want to precisely localize the seizure generating areas and avoid eliminating any functional brain tissue, such as areas associated with hand movement or language generation. This is where an MRI can help.”

The Davis lab is studying how an MRI of the brain may help with the sampling issue of intracranial EEG, or the so-called “missing electrode problem,” where surgical limitations and safety restrict implantation of the entire brain. Patients routinely undergo an MRI of their brain before implantations, but they may also participate in research scans to acquire different imaging sequences, such as High-Angular Resolution Diffusion Imaging (HARDI). With these MRI sequences, the lab is modeling how the brain is connected, building networks of the brain, and making predictions of seizure activity in regions where electrodes were not implanted. They take an interdisciplinary approach, drawing from their expertise in imaging analysis, machine learning, network analysis, and signal analysis to solve a very relevant clinical problem.

Polytherapy, Improved Medication Adherence Reduce Risk for SUDEP in Swedish Cohort

Article, originally posted on Healio

Polytherapy, especially the use of three or more antiepileptic drugs, correlated with a substantially decreased risk for sudden unexpected death in epilepsy, according to findings from a nationwide case-control study conducted in Sweden.

The findings, which were published in Neurology, also demonstrated a link between statin use and a decreased risk for sudden unexpected death in epilepsy.

“There is an urgent need to reduce the risk of sudden unexpected death in epilepsy (SUDEP),” the researchers wrote. “Risk factors related to drug treatment may represent opportunities for prevention.”

Olafur Sveinsson MD, PhD, of the departments of neurology and clinical neuroscience at the Karolinska Institute in Sweden, and colleagues performed the population-based, case-control study to determine the relationship between AEDs, selective serotonin reuptake inhibitors (SSRIs) and “other potentially relevant drugs” and SUDEP risk.

“These results provide support for the importance of medication adherence and intensified AED treatment for patients with poorly controlled GTCS in the efforts to reduce SUDEP risks and suggest that comedication with statins may reduce risks,” Sveinsson and colleagues wrote.

Risk-Benefit Assessment of Treatment of Epileptic Women of Childbearing Age With Valproic Acid

Abstract, originally published in Seizure

Aim: Valproic acid (VPA) is a widely used anti-epileptic drug (AED) of demonstrated efficacy. However, its teratogenic effects have resulted in many regulatory agencies recommending that it should not be administered to women of childbearing age unless they are taking contraceptives. The aim of this study was to determine the willingness of candidate patients to change their treatment and to monitor the evolution of their attitude.

Methods: We identified patients aged between 15 and 45 years old who had been diagnosed with epilepsy and were being treated with VPA. A shared decision-making visit was arranged, during which variables related to their epilepsy were recorded. The patients were informed about the teratogenic effects of VPA and the risks/benefits of a change in treatment. The patient, or legal guardian, then freely chose the course of treatment that they wished to follow. On a follow-up visit, six months later, seizure control and tolerance to the chosen treatment were recorded. The variables related to each patient’s willingness to their change treatment were analysed.

Results: A total of 60 patients, with a median age of 32.7 years, were included in the study. Of these, 25 (41.7%) suffered some form of intellectual disability. Only one (1.7%) had poor seizure control. After the initial visit, 41 patients (68%) opted to continue with the VPA treatment, six opted to stop receiving VPA, and 13 decided to switch to another AED. The median age of the patients who opted to change treatment was significantly lower than that of those who opted to continue with the VPA treatment (29.1 vs. 34.4, p = 0.024). The absence of intellectual disability (p = 0.047) and a length of treatment of less than five years (0.016) were both significantly associated with the decision to change treatment. Of the 19 patients who changed treatment, nine (47%) returned to the initial treatment with VPA.

Conclusions: Despite being informed of the teratogenic risk associated with VPA, a significant number of patients and legal guardians opted to continue with this treatment; the reasons given for this were the low possibility of pregnancy and the risk of breakthrough seizures. In almost half the cases studied, the pharmacological alternatives to VPA were poorly tolerated and did not provide a good level of seizure control.

Controlling Seizure Effects Using a New Potassium Channel Activator

Article, originally posted on News-Medical.net

A group from The Mount Sinai Hospital / Mount Sinai School of Medicine have identified and characterized a novel potassium-channel activator, GiGA1, capable of selectively opening a subset of potassium channels to produce an antiseizure effect in animal models.

This study presents an integrated approach to GIRK1-specific activators, employing both computational modeling and subsequent biochemical and physiological studies. The resultant seizure mitigation produced in an acute epilepsy mouse model demonstrates a potential role for this compound in the treatment of brain disorders.

Silencing ‘Poison Exon’ Eliminates Deadly Seizures in Mice

Article, published on SpectrumNews.com (featuring the work of former CURE Grantee, Dr. Lori Isom)

A new treatment curbs deadly seizures in a mouse model of Dravet syndrome, a severe form of epilepsy, according to a new study. A clinical trial is evaluating the drug’s safety in children with the syndrome.

The new drug, which consists of short pieces of RNA called ‘antisense’ molecules, counteracts the effects of SCN1A mutations. The molecules boost the expression of the intact copy of SCN1A, allowing cells to produce normal levels of the sodium channel the gene encodes. They do so by silencing a ‘poison exon’ in SCN1A, a sequence of DNA that ordinarily limits the gene’s expression.

In model mice of Dravet syndrome, the drug significantly decreased the frequency of SUDEP, the new work found, lowering their likelihood of having a fatal seizure during the first 90 days of life from 77 to 3 percent.