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).

First Known Case of Double Somatic Mosaicism Reported in Girl with Dravet Syndrome

A genetic phenomenon called double somatic mosaicism was found for a first time in a girl with Dravet syndrome, a case study reports.

The study, “Double somatic mosaicism in a child with Dravet syndrome,” was published in Neurology Genetics.

Dravet syndrome, a severe type of epilepsy usually evident during the first year of life, is in about 80% of cases tied to known mutations in the SCN1A gene, which encodes for a sub-unit of a sodium channel called NaV1.1 that is involved in the transmission of electrical signals in the brain.

In about 20% of Dravet patients, however, the disorder’s cause  is unclear. In these cases, it has been proposed that genetic alterations taking place in very early fetal development, and not inherited from the parents, may be the underlying reason.

Investigators at the University of Washington examined whether somatic mosaicism — a phenomenon in which an individual has cells that are genetically different due to a mutation taking place during very early fetal development (shortly after the embryo formed) — could be the reason why some people develop idiopathic (unknown cause) Dravet syndrome.

They used a highly sensitive technique known as deep sequencing to analyze SCN1Aand seven other genes previously linked with the disease (SCN2A, SCN8A, HCN1, GABRA1, GABRG2, STXBP1, and PCDH19) using DNA they isolated from blood or saliva of 20 patients with this type of Dravet syndrome.

“We detected double mosaicism in SCN1A in a patient with Dravet syndrome. Comprehensive studies of disease-relevant tissue will be required to gain a more accurate picture of somatic mosaicism levels and how this affects disease severity,” the scientists concluded.

Epilepsy Research Findings: July 2019

This month’s edition of epilepsy news features recent research suggesting that inducing a seizure prior to surgery is just as effective for pinpointing the brain region where seizures originate as a spontaneous seizure as a spontaneous seizure. In addition, CURE Post-Traumatic Epilepsy initiative members Dr. Oleskii Shandra and Dr. Stefanie Robel published work indicating that the amount of a certain type of cell may increase in the brain following repeated, mild TBIs, causing epilepsy.

Safety updates on several anti-epileptic drugs were reported, including results showing pregabalin may be associated with increased suicidal behavior and other hazards, and that certain drugs used to treat epilepsy may increase the risk of dementia. Studies also highlight the need for improved counseling for safe and effective contraception for women with epilepsy, and the need for resources for people with epilepsy in low-income countries.

Summaries of all highlighted studies follow below. We have organized the findings into Research and Discoveries and Also Notable.

Research and Discoveries

Inducing Seizures to Stop Seizures
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Causing seizures by stimulating the brain may be a convenient and more cost-effective way to determine the brain region where seizures are originating prior to surgery.

New Research Could Help Predict Seizures Before They Happen
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A new study has found a pattern of molecules that appears in the blood before a seizure happens, which may lead to the development of an early warning system.

Pregabalin Associated with Increased Suicidal Behavior and Other Hazards 
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Gabapentinoids, a class of drugs used to treat epilepsy and other neurological disorders, are associated with an increased risk of suicidal behavior, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.

Study Furthers Understanding of the Development of Epilepsy Following Mild Traumatic Brain Injury (TBI)
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Featuring the work of CURE PTE Initiative members Dr. Oleskii Shandra and Dr. Stefanie Robel

A type of cell in the brain called an “atypical astrocyte” may increase following trauma, causing epilepsy following repeated, mild TBIs, according to a study by Drs. Oleskii Shandra and Stefanie Robel.

Even People with Well-Controlled Epilepsy May Be at Risk for Sudden Death
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Featuring the work of former CURE Grantee Elizabeth Donner

A new study shows the risk of Sudden Unexpected Death in Epilepsy (SUDEP) may apply to individuals whose epilepsy is well-controlled. Previous, smaller studies showed that SUDEP risk was highest among those with severe, difficult-to-treat epilepsy, however, this study suggests a sizeable minority of SUDEP occurred in patients thought to be treatment-responsive or to have benign epilepsies. The study found that SUDEP occurred in people who had not taken their last dose of epilepsy medication, those who were sleep deprived, and those who had not had a seizure in at least a year.

Anticholinergic Drugs May Increase Risk of Dementia 
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A study suggests that the possible link between anticholinergic drugs and an increased risk of dementia is strongest for certain classes of anticholinergic drugs, including antiepileptic drugs such as oxcarbazepine and carbamazepine.

Research into Cannabis Dosage Shows Reduced Seizures in Children with Severe Epilepsy
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Medicinal cannabis oil containing both cannabidiol (CBD) and a small amount of tetrahydrocannabinol (THC) can reduce or end seizures in children with severe, drug-resistant epilepsy, a study by the University of Saskatchewan has found.

Also Notable

The World Health Organization (WHO) Highlights the Scarcity of Treatment for Epilepsy in Low-Income Countries
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Three quarters of people living with epilepsy in low-income countries do not get the treatment they need, increasing their risk of dying prematurely and condemning many to a life of stigma, according to WHO.

Bringing Neuromodulation Therapies to Drug-Resistant Epilepsy Patients
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Researchers at the University of Alabama at Birmingham found that creating an epilepsy neuromodulation clinic improved access for patients and communication with referring physicians, achievement of expected outcomes for reducing or eliminating seizures, and the ability to train future providers in programming neuromodulation devices.

Encoded Therapeutics Gets $104M to Propel ‘Precision Gene Therapy’ for Dravet Syndrome
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Encoded Therapeutics received $104 million to fund a precision gene therapy for Dravet syndrome. The company will also use the funds to advance its preclinical programs and come up with new treatments for severe genetic disorders.

Improved Counseling Needed for Safe, Effective Contraception in Women With Epilepsy
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Over a third of women with epilepsy do not use highly effective contraception, despite the important, negative consequences of unintended pregnancy such as elevated risk of having offspring with congenital malformations. There is a need for more readily available information and counseling on safe and effective contraception for this community.

Immediate Outcomes in Early Life Epilepsy: A Contemporary Account

RATIONALE: Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts.

METHODS: Children with newly diagnosed epilepsy and onset <3 years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1?year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome.

RESULTS: Seven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5?months (interquartile range (IQR): 4.2-16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (<12 months). Of 680 children followed at least 6?months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes.

CONCLUSION: Early-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles.

Potassium Bromide Should be Considered for Treatment of Refractory Epilepsy, Study Says

Potassium bromide (KBr) can control certain types of epileptic seizures and should be considered as an option for the treatment of children with refractory epilepsy, a study says.

The findings of the study, “Potassium Bromide in the Treatment of Pediatric Refractory Epilepsy,” were published in the Journal of Child Neurology.

Dravet syndrome is a severe type of drug-resistant epilepsy that usually emerges during the first year of life and is characterized by seizures, cognitive deficits, and increased mortality.

In this study, a group of researchers from the Chiba Children’s Hospital in Japan set out to examine the efficacy and tolerability of KBr for the treatment of children with refractory epilepsy.

Treatment was found to be effective in more than half of the children diagnosed with generalized epilepsy (59.1%) and focal epilepsy (55.6%). In addition, KBr also led to significant improvements in seizure control among the two children who had been diagnosed with Dravet syndrome.

The treatment was more effective in children who had tonic seizures (72.2%), generalized tonic-clonic seizures (66.6%), or secondary generalized seizures (75.0%). KBr therapy was less effective among children who had focal seizures (46.2%), infantile spasms (20.0%), or myoclonic seizures (0%).

Adverse effects, which included drowsiness, excitement and skin rashes, were reported in 13 (31.0%) children participating in the study.

Zogenix Ready to Resubmit Fintepla for Rare Epilepsy to FDA

In April, the FDA issued a Refuse to File (RTF) letter to Zogenix for its New Drug Application (NDA) for Fintepla (fenfluramine hydrochloride). The drug was developed to treat seizures associated with Dravet syndrome, a rare form of epilepsy characterized by frequent and prolonged seizures.

The company at the time indicated the application, which was submitted in February, was not “sufficiently complete to permit a substantive review.” The FDA had two concerns, the first over non-clinical studies that were not submitted over chronic administration of the drug, and what Zogenix indicated as an incorrect version of a clinical dataset.

Now, the company announced that after its Type A meeting with the FDA on May 30, it plans to resubmit its NDA for Fintepla. Based on the meeting, the company will resubmit the NDA without the inclusion of the new chronic toxicity studies requested in the original RTF letter. In terms of the second issue, Zongenix ran a root cause analysis to explain the incorrect clinical dataset originally submitted and discussed that analysis with the agency.

“We are very pleased with the outcome of our meeting with the FDA and appreciate their thoughtful approach in considering the totality of the data from our drug development program, along with additional clinical and non-clinical literature that will be referenced in our re-submission,” stated Stephen J. Farr, president and chief executive officer of Zogenix. “We now have the clarity required to successfully resubmit our Fintepla NDA, which we will anticipate will occur in the third quarter.”

Clinical Evolution and Epilepsy Outcome in Three Patients with CDKL5-Related Developmental Encephalopathy

Objective: To further characterize CDKL5-related disorder, previously classified as an early-onset seizure variant of Rett syndrome, which is currently considered a specific and independent early-infantile epileptic encephalopathy.

Results: Researchers describe the epileptic phenotype and neurocognitive development in three girls with CDKL5 mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. The patients differed regarding age at epilepsy onset, seizure frequency, duration of “honeymoon periods”, as well as EEG features. The “honeymoon period”, defined as a seizure-free period longer than two months, represented, in this case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the “honeymoon period”, the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5 disorder was compared between the three girls, focusing on the relationship between electroclinical features and neurological development.

Significance: These findings suggest that CDKL5 mutations likely play a direct role in psychomotor development, whereas epilepsy is one of the clinical features associated with this complex disorder.

Epilepsy Research Findings: June 2019

This month’s round-up of epilepsy news features an announcement about a new antiepileptic rescue medication, NAYZILAM®. This therapy is the first FDA-approved nasal treatment option for people with epilepsy who experience episodes of frequent seizure activity.

We also highlight many research advances, from the discovery of a compound found in fruit and honey which can inhibit seizures to the development of a new drug to treat Dravet syndrome. Research in the cannabidiol (CBD) space has also advanced, with the creation of a synthetic form of CBD which may be easier to purify and does not need to be cultivated from hemp plants.

In more sobering news, reports over the past month show that one-third of epilepsy cases go without appropriate treatment for up to three years following diagnosis. In addition, people with psychogenic nonepileptic seizures (PNES) as well as epileptic seizures may be at a higher risk for sudden unexpected death in epilepsy (SUDEP)during the years immediately following diagnosis with PNES.

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

Treatment Advances

FDA Approves NAYZILAM® Nasal Spray to Treat Intermittent, Stereotypic Episodes of Frequent Seizure Activity in People Living with Epilepsy in the US
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The FDA has approved a New Drug Application for UCB’s newest antiepileptic drug NAYZILAM® (midazolam) nasal spray. This therapy is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern in individuals with epilepsy who are 12 years of age and older.

Study Advances More Effective Laser Ablation and Standard Epilepsy Surgery 
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In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy. These researchers discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

Research Discoveries

Brain Network Activity can Improve in Epilepsy Patients after Surgery
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Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery. The study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

New Drug Could Help Treat Neonatal Seizures
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A new drug that inhibits neonatal seizures in rodent models could open new avenues for epilepsy treatment in human newborns. Researchers have found that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons.

Research Looks to Halt Stress-Induced Seizures Following Brain Injury
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The likelihood of developing epilepsy increases significantly with a traumatic brain injury. Stress and anxiety increase that likelihood even more dramatically. Researchers have been able to demonstrate that an injured brain responds differently to stress hormones than a healthy brain. The research team showed abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, found a way to stop this activity from occurring.

Synthetic Version of Cannabidiol (CBD) Treats Seizures in Rats
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A synthetic, non-intoxicating analogue of CBD was found to be effective for treating seizures in rats. Researchers note the synthetic CBD alternative is easier to purify than a plant extract, eliminates the need to use agricultural land for hemp cultivation, and could avoid legal complications associated with cannabis-related products.

AZD7325 Has Seizure-Protective Effect in Mouse Model of Dravet Syndrome, Study Says
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Treatment with AZD7325, a compound that stimulates an inhibitory receptor in the brain, has a seizure-protective effect in a mouse model of Dravet syndrome. This treatment significantly increased the temperature threshold animals could withstand without experiencing any seizures during a hyperthermia-induced seizure test.

Children’s Brains Reorganize after Epilepsy Surgery to Retain Visual Perception
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Children can keep their full ability to process and understand visual information after brain surgery for severe epilepsy, according to a study funded by the National Eye Institute, part of the National Institutes of Health. This new report from a study of children who underwent epilepsy surgery and suggests that the lasting effects on visual perception can be minimal, even among children who lost tissue in the brain’s visual centers.

One-Third of Epilepsy Cases Go Untreated up to 3 Years After Diagnosis
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A small yet substantial subset of patients with newly diagnosed epilepsy go without appropriate treatment approximately 3 years after diagnosis. This gap in treatment may be increasing the risk for medical events and hospitalization in these patients.

Study Suggests ‘High Risk Period’ for SUDEP for People with Psychogenic Nonepileptic Seizures in Addition to Epileptic Seizures 
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Findings of a recently published study suggest that patients with comorbid epileptic seizures (ES) and Psychogenic Nonepileptic Seizures (PNES) can die from SUDEP and that there may be a high?risk period after the diagnosis of PNES is made. The authors state such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

Also Notable

Fralin Biomedical Research Institute Neuroscientist Awarded Grant to Study Epilepsy
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Featuring CURE Grantee Dr. Sharon Swanger

Dr. Sharon Swanger of the Fralin Biomedical Research Institute was recently awarded a $1.7 million grant through the National Institute of Neurological Disorders and Stroke to study the role of glutamate receptors in the thalamus – an area of the brain involved in seizure generation. “If we can figure out how each [receptor] subtype functions and modulate select subtypes, then maybe we can target therapies to the circuit where the disease originated while leaving healthy circuits intact,” said Dr. Swanger.

Tool Helps GPs Predict Risk of Seizures in Pregnancy
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Doctors, midwives, and others can use a new risk calculator to identify those pregnant women at high-risk of seizures and to plan early referral for specialist input. The specialist could determine the need for close monitoring in pregnancy, labor, and after birth, and assess antiepileptic drug management, according to new research in PLOS Medicine. The study authors added that the model’s performance is unlikely to vary with the antiepilepsy drug dose management strategy – and that it could save maternal and infant lives.

Development of Epilepsy Prediction Device to Improve Independence for People with Epilepsy
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The University of Sydney’s Faculty of Engineering and Information Technologies is developing a system, NeuroSyd, which aims at real-time monitoring and processing of brain-signals while driving in a group of people living with epilepsy. NeuroSyd will be developed to deliver an early warning of the likelihood of an epileptic seizure.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy
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Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalized tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks. Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo. Another phase 3 trial in May 2018 was successful, showing that a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo.

AZD7325 Has Seizure-Protective Effect in Mouse Model of Dravet Syndrome, Study Says

Treatment with AZD7325, a compound that stimulates the activity of a specific type of receptor in the brain, has a seizure-protective effect in a mouse model of Dravet syndrome, a study has found.

The study was published in The Journal of Physiology.

In this study, a group of researchers from Northwestern University in Chicago, Illinois, set out to test the effects of AZD7325, a potentiator of a subtype of GABAA receptors containing the alpha 2 or 3 subunits, in different strains of a mouse model of Dravet syndrome. Of note, GABAA receptors are composed of numerous different subunits, which determine the receptors’ affinity to certain molecules, among other properties.

Treatment with AZD7325 significantly increased the temperature threshold animals were able to withstand without experiencing any seizures during an hyperthermia-induced seizure test. This seizure-protective effect was present in all three doses tested (10 mg/kg; 17.8 mg/kg; and 31.6 mg/kg) and was not associated with sedative side effects.