Epilepsy Research Findings: July 2018

This month’s promising epilepsy news includes the FDA approval of the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with Dravet Syndrome and Lennox-Gastaut Syndrome, two forms of epilepsy that are challenging to treat. This decision brings hope to families facing these difficult diagnoses. In addition, a report discusses epilepsy genetics and the utility of next-generation sequencing in the diagnosis of early-life epilepsies.

In more sobering news, a study shows that the incidence of Sudden Unexpected Death in Epilepsy (SUDEP), once thought to be greater in adults than in children, may be the same in both populations. However, we have included a report discussing the recent discovery of a potential biomarker for SUDEP, which could lead to preventative measures for this devastating occurrence.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome 

The US Food and Drug Administration (FDA) approved EPIDIOLEX® (cannabidiol/CBD) for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients two years of age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of antiepileptic drugs.

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New Technique Fine-Tunes Treatment for Severe Epilepsy Cases 

An advance by researchers will enable surgeons to more precisely target areas of the brain which cause debilitating symptoms in a subset of epilepsy patients. The technology, called magnetoencephalography or MEG, measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and researchers have developed a novel way to employ it.

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Treating Refractory Epilepsy with Transcutaneous Vagal Nerve Stimulation 

This study found that transcutaneous vagal nerve stimulation (t-VNS) had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients.

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Sunovion Announces Health Canada Approval of Aptiom (eslicarbazepine acetate) as Monotherapy to Treat Partial-Onset Seizures in Adults with Epilepsy

Health Canada approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy.

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Diagnostic Advances

Next-Generation Sequencing May Improve Pediatric Epilepsy Treatment

Next-generation sequencing can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy, according to a study published in CNS Neuroscience & Therapeutics.

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Prediction Method for Epileptic Seizures Developed 

Scientists have proposed a generalized, patient-specific seizure-prediction method that can alert epilepsy sufferers of the likelihood of a seizure within 30 minutes, according to a paper published in Neural Networks.

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Research Discoveries

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

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Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk. This would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

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Also Notable

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

This study reports that levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

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Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report. NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

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Generic Antiepileptic Drugs — Safe or Harmful in Patients with Epilepsy?

Sufficient evidence indicates that most generic antiepileptic drugs (AEDs) are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. This report recommends administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

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Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

Epilepsy is common among elderly individuals, and health care expenditures among this growing group are two times higher than in those without epilepsy.

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Mechanism Leading to Cortical Malformation from Brain-Only Mutations Identified

Focal malformations of cortical development (FMCDs) are a heterogeneous group of brain cortical abnormalities. These conditions are the most common causes of medically refractory epilepsy in children and are highly associated with intellectual disability, developmental delay, and autism-spectrum disorders. Despite a broad spectrum of cortical abnormalities in FMCDs, the defective migration of neuronal cells is considered a key pathological hallmark.

A Korean research team led by [CURE grantee] Professor Jeong Ho Lee at the Korea Advanced Institute of Science and Technology (KAIST) has recently investigated the molecular mechanism of defective neuronal migration in FMCDs.

The research team previously demonstrated that brain-only mutations in the mechanistic target of rapamycin (MTOR) gene causes focal cortical dysplasia, one major form of FMCDs leading to intractable epilepsy in children. However, the molecular mechanisms by which brain-only mutations in MTOR lead to cortical dyslamination and defective neuronal migration in FMCDs remain unclear.

Next-Generation Sequencing May Improve Pediatric Epilepsy Tx

Next-generation sequencing (NGS) can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy (DRE), according to a study published CNS Neuroscience & Therapeutics.

Jing Peng, Ph.D., from Central South University in China, and colleagues conducted genetic testing on 273 pediatric DRE patients with no obvious acquired etiology; 74 underwent whole-exome sequencing (WES), 141 had epilepsy-related gene panel testing, and 58 had clinical WES gene panel testing. Frequency of seizures, outpatient visits, and hospitalization was also assessed.

The researchers found that a genetic diagnosis was made in 86 patients (31.5 percent; 93 likely disease-causing mutations in 33 genes). By testing type, detection rates were 32.6% for the epilepsy-related gene panel, 44.8% for the clinical WES gene panel, and 17.3% for WES. Also, 34 patients accepted therapy based on their mutant genes, after which 52.9% became seizure-free and 38.2% experienced seizure reduction. Hospitalization incidents were significantly lower for patients after testing than before regardless of positive or negative genetic results.

CURE Discovery: New Cause of Severe Childhood Epilepsy Found – Genetic Mutation in the CUX2 Gene

CURE Grantee Dr. Gemma Carvill has identified a new cause of epilepsy: a mutation in the gene CUX2. Dr. Carvill’s discovery was recently published in the Annals of Neurology.1

The discovery provides an important advance in our understanding of the causes of a class of severe childhood epilepsies. This class includes childhood epileptic encephalopathy, an aggressive and severe group of treatment-resistant epilepsy disorders in which children can have profound cognitive and neurological deficits.2,3

Dr. Carvill began her research into the ways specific genetic mutations lead to childhood epileptic encephalopathy in 2015 as the result of a 1-year CURE Taking Flight Award. This award program encourages young investigators to conduct independent research which could lead to a cure for epilepsy. When Dr. Carvill recieved the CURE Taking Flight Award, she was a Postdoctoral Fellow at the University of Washington.

Dr. Carvill studied the ways genetic mutations lead to epilepsy. Her initial findings suggested that mutations in a class of genes important in determining the structure of DNA could impact several genes involved in epilepsy, making this class of genes a potential target of future epilepsy therapy development.

Since receiving her CURE award, Dr. Carvill’s career has certainly “taken flight” – she is now Assistant Professor of Neurology and Pharmacology at Northwestern University. Still, Dr. Carvill has remained committed to her quest to understand the genetic mechanisms behind severe childhood epilepsy. In her latest study, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital, located in France, to identify de novo mutations in the gene CUX2 as a new cause of epilepsy. De novo mutations are changes present only in the affected patient and not in their healthy parents. CUX2 is important in binding DNA and promoting the expression of certain target genes. Mutations in CUX2 cause errors in this process that can lead to epilepsy.

Dr. Carvill’s report details her international study of 9 patients aged 6 months to 21 years who first began having seizures early in life. To identify the mutation in the CUX2 gene, Dr. Carvill and her team used, among other techniques, a test called whole exome sequencing. This test analyzes a person’s genes to identify changes in their DNA. All 9 patients had the same CUX2 mutation. The team found that the majority of these patients had severe treatment-resistant epilepsy that started early in life, severe intellectual disability, and did not have speech appropriate for their age.

Besides finding an important genetic cause of severe childhood epilepsy, which can now be targeted for the development of therapeutic interventions, Dr. Carvill’s collaboration with Dr. Lesca highlights the importance of international efforts to identify new genes important in epilepsy. As Dr. Carvill notes, these genetic mutations are very rare and therefore collaborative efforts with multiple patient populations make it more likely that a rare genetic mutation can be identified and studied.

In the future, Dr. Carvill plans to further explore the genetic mechanisms behind these devastating childhood epilepsies. Her goal, which we at CURE share, is that treatments and cures can be found for all of the amazing children affected by epilepsy and their wonderful families, too.

Citations

1 Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol2018; 6 [Epub ahead of print]
2 Cross H and Guerrini R. The epileptic encephalopathies. Handb Clin Neurol 2013; 111:619-626.
3 Jehi L, Wylie E, Devinsky O. Epileptic encephalopathies: Optimizing seizure control and developmental outcome. Epilepsia 2015; 56(10):1486-1489.

The adult motor phenotype of Dravet syndrome is Associated with Mutation of the STXBP1 Gene and Responds Well to Cannabidiol Treatment

Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult; that is why Cannabidiol emerged as valid option for treatment of this condition.

Elevated Cerebrospinal Fluid Protein in POLG-Related Epilepsy: Diagnostic and Prognostic Implications

SIGNIFICANCE: Our results indicate that there is disruption of the blood brain barrier in POLG-related disease, as evidenced by a raised cerebrospinal fluid protein and a raised CSF/serum ratio of albumin. We also find that raised cerebrospinal fluid protein is a common finding in patients with POLG disease. Our data suggest that the presence of blood brain barrier dysfunction predicts a poorer outcome, and elevated cerebrospinal fluid protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.

OBJECTIVE: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients.

METHODS: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries–Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF barrier.

RESULTS: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months).

Clinical trial: Rolandic Epilepsy Genomewide Association International Study (REGAIN)

Approximately 25% of child patients have Rolandic Epilepsy or RE, also known as Benign Epilepsy with Centrotemporal Spikes (BECTS). RE has a complex genetic basis, probably made up of combinations of susceptibility variants in different genes. Children with RE quite often have other symptoms that affect their speech, attention, reading ability or coordination. The goal of this study is to find the genetic basis for susceptibility to seizures and associated comorbidities for RE using genomewide association approaches.

We know that RE has a genetic basis and we recently discovered the genetic cause of the EEG pattern seen in RE. The goal of REGAIN is to now find the genetic basis for susceptibility to seizures and the associated symptoms above. Our hope is to be able to improve diagnosis and understand why each child with RE is different, and perhaps point us towards new treatments that are more effective and have fewer side effects.

We will compare the genetic code of 3,000 children with RE against a similar number of people not affected by epilepsy. With the proposed large sample of participants, we will be able to pinpoint the exact changes that might lead to seizures or attention problems for example. Learning the genetic basis for these problems will deepen our understanding of the mechanisms and lead to new treatments or cures.

Estimated study start date: June 1, 2018
Estimated study completion date: December 31, 200

Eligibility Criteria

Ages Eligible for Study: 6 Years to 25 Years (Child, Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Sampling Method: Non-Probability Sample

Inclusion Criteria:

  • Diagnosis of Rolandic Epilepsy in accordance with the following international criteria:
    • Age of first afebrile seizure 3-12 years
    • Seizures comprising focal sensorimotor seizures affecting the vocal tract and face, with or without involvement of the arm
    • Predominant sleep-related seizures
    • EEG interictal centro-temporal spikes with normal background
  • Current age 6-25 years

 

Exclusion Criteria:

  • No history of focal seizure
  • Normal EEG or abnormal background features on EEG
  • Known structural causes (stroke, tuberous sclerosis, infection, post-infectious or metabolic)
  • Primary diagnosis of autism or global learning disability
  • Focal central neurological deficit on clinical exam,
  • Unable to provide informed consent
  • Unable to provide blood sample

Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses: Work Featuring CURE Grantee Annapurna Poduri

Epilepsy genetics is an emerging field with increasing therapeutic implications resulting from genetic findings. Despite an overall enthusiasm for precision medicine in epilepsy and other disciplines, there remains no consensus on the approach to genetic testing. A recent study by Berg et al demonstrated a relatively similar diagnostic yield of epilepsy next-generation sequencing (NGS) gene panels compared with whole-exome sequencing (27% vs 33%). Although the utility of NGS panels are consistently demonstrated to our knowledge, no study has systematically evaluated the variability in genes tested among clinically available NGS panels. We compared the potential diagnostic yield of commercially available NGS epilepsy panels to detect the genetic findings identified in a recently published cohort of early-life epilepsy.

Dr. Annapurna Poduri [a CURE grantee] and colleagues from Boston Children’s Hospital compared 10 commercially available NGS gene panels from three major vendors (Athena Diagnostics, Ambry Genetics and GeneDx).

Genetic Literacy Series: Primer Part 2—Paradigm Shifts in Epilepsy Genetics

This is the second of a 2?part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy.

In Part 1, we covered types of genetic variation, inheritance patterns, and their relationship to disease. In Part 2, we apply these basic principles to the case of a young boy with epileptic encephalopathy and ask 3 important questions: (1) Is the gene in question an established genetic etiology for epilepsy? (2) Is the variant in this particular gene pathogenic by established variant interpretation criteria? (3) Is the variant considered causative in the clinical context? These questions are considered and then answered for the clinical case in question.

Epilepsy Research Findings: May 2018

This month I would like to share with you several promising treatment and diagnostic advances, and research discoveries. The FDA recently recommended supporting the approval of the New Drug Application for cannabidiol-based drug Epidiolex and also approved Medtronic’s deep brain stimulation therapy for drug-resistant epilepsy. Recent research has also provided the promise of new genetic insight for children with epileptic encephalopathy, and has brought us closer to understanding how to repair a “leaky” blood-brain barrier associated with epilepsy. In contrast to these exciting results, we have also learned that individuals with epilepsy are at an increased risk of dying from suicide and accidents, and a new study has highlighted the high direct costs associated with epilepsy for children with the disorder.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

TREATMENT ADVANCES

GW Pharmaceuticals and U.S. Subsidiary Greenwich Biosciences Announces FDA Advisory Committee Unanimous Recommendation of Support for Epidiolex

GW Pharmaceuticals plc, along with its U.S. subsidiary Greenwich Biosciences, announced that the Peripheral and Central Nervous System Drugs Advisory Committee of the U.S. Food and Drug Administration unanimously recommended supporting the approval of the New Drug Application (NDA) for the investigational cannabidiol oral solution (CBD), also known as Epidiolex®, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients two years of age and older. If approved, Epidiolex would be the first pharmaceutical formulation of purified, plant-based CBD.

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Medtronic Receives FDA Approval for Deep Brain Stimulation Therapy for Medically Refractory Epilepsy

Medtronic plc, the global leader in medical technology, announced that the U.S. Food and Drug Administration has granted premarket approval for Medtronic’s Deep Brain Stimulation (DBS) therapy as adjunctive treatment for reducing the frequency of partial-onset seizures in individuals 18 years of age or older who are refractory or drug-resistant to three or more antiepileptic medications. DBS therapy for epilepsy delivers controlled electrical pulses to a target in the brain called the anterior nucleus of the thalamus, which is part of a network involved in seizures.

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Zynerba Pharmaceuticals Announces Twelve Month Data from STAR 2 Study in Patients with Focal Seizures

Zynerba Pharmaceuticals, Inc reported new longer term open label clinical data from its STAR 2 Study in patients with focal seizures. “The data continues to suggest that focal seizures may be reduced with longer-term exposure to transdermally-delivered CBD,” said Dr. Liza Squires, Zynerba’s Chief Medical Officer. “In this population of patients, the use of ZYN002 for an additional 12 months in STAR 2 was well tolerated and appeared to result in clinically meaningful seizure reductions both across and within the originally randomized STAR 1 groups.”

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Zynerba Pharmaceuticals Initiates Open-Label Phase 2 Trial of ZYN002 in Developmental and Epileptic Encephalopathies

Zynerba Pharmaceuticals announced that it has initiated the Phase 2 BELIEVE 1 clinical trial, an open label study to assess the safety and efficacy of ZYN002 administered as a transdermal gel to children and adolescents with developmental and epileptic encephalopathy.

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DIAGNOSTIC ADVANCES

New Testing Provides Better Information for Parents of Children with Epileptic Encephalopathy

Advances in genetic testing offer new insights to parents who have a child with a rare but serious form of epilepsy, epileptic encephalopathy. New ways of sequencing the human genome mean geneticists and genetic counselors have much more to say to parents who wonder if future children might carry the disease, says Dr. Heather Mefford, Associate Professor of Pediatrics (genetic medicine) at University of Washington School of Medicine and Deputy Scientific Director of the Brotman Baty Institute for Precision Medicine, co-senior author of findings published in the New England Journal of Medicine.

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RESEARCH DISCOVERIES

Repairing a Leaky Blood-Brain Barrier in Epilepsy

In a study of rodent brain capillaries published in the Journal of Neuroscience, Björn Bauer and colleagues identified a seizure-triggered pathway that contributes to blood-brain barrier dysfunction in epilepsy. The blood-brain barrier is a filtering mechanism that lets nutrients into the brain but keeps toxins out. Understanding how a “leaky” blood-brain barrier can lead to seizures is necessary to develop strategies to plug the leak.

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Hope for New Treatment of Severe Epilepsy

Researchers at Lund University in Sweden succeeded in reducing epileptic activity in the hippocampus. In many severe cases of epilepsy, this is the part of the brain where epileptic seizures start. The researchers used a method known as chemogenetics, which enables them to reduce activity in the specific areas and nerve cells involved in an epileptic seizure, whereas other parts and cells in the body remain unaffected. This is in contrast to current drugs that affect more or less all parts and cells of the body, potentially leading to side-effects.

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Epilepsy Does Not Impact Likelihood of Pregnancy

Women with epilepsy, without previous infertility and related disorders, were as likely to conceive as their counterparts without epilepsy, according to findings recently published in JAMA Neurology. Dr. Page B. Pennell and colleagues found that 60.7% of women with epilepsy became pregnant versus 60.2% of the control group without epilepsy.

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Increased Risk of Suicide and Accidental Death Found for People with Epilepsy

A new study has shown that people diagnosed with epilepsy in England and Wales are at increased risk of dying from suicide and accidents. Though the risks of dying from suicide and accidents for people with epilepsy are low in absolute terms (0.3-0.5%), they are higher than in people without epilepsy, says Dr. Hayley Gorton from The University of Manchester.

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ALSO NOTABLE

What Modern Day Challenges Affect Epilepsy Treatment?

Researchers recently published an article in The Lancet Neurology discussing the difficulties facing seizure detection in patients with epilepsy. In a recent study, Christian Elger and Christian Hoppe determined that a key challenge facing patients is that over 50% of patients under-report the number of seizures they experience, which has a serious impact on how well doctors are able to determine what treatments are most suitable for them. This also calls into question much of the previously published research on epilepsy treatments.

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Study Finds a High Direct Cost of Epilepsy in Children

A study of children aged 17 years using data from the Medical Expenditure Panel Survey-Household Component found that medical expenditure among children with epilepsy is high. The high expenditure is essentially driven not only by inpatient expenditure but also by home healthcare, outpatient, and medication healthcare expenditures.

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