CURE-funded grant yields Dravet syndrome discovery

A recent CURE-funded grant has taken a step forward in the search for therapeutic mechanisms to combat Dravet syndrome, a type of epilepsy that is currently difficult to treat and has no known cure.[1] A CURE-funded team has discovered that RNA-stimulators have the capability of fully restoring functionality to the Scn1a gene (in rodents), which may in turn prevent or reverse the symptoms of Dravet syndrome.

CURE researcher Dr. Antonello Mallamaci of the Scuola Internazionale Superiore di Studi Avanzati is leading the team that seeks to restore functionality to Scn1a, by creating “Scn1a-stimulating RNA devices” to stimulate Scn1a activity.

The team sees great potential in being able to use these devices to compensate for the reduction in Scn1agene functionality. Next steps include plans to test these RNA-stimulators in the Dravet syndrome mouse that has similar symptoms to humans with Dravet syndrome and in human tissue from individuals with Dravet syndrome. There are also plans to create a specialized “tool” called a viral vector that can deliver these RNA-stimulators directly into affected brain areas, pushing this research ever closer to achieving a viable human therapy.

Dravet syndrome is a rare epilepsy that begins in infancy, is lifelong and often leads to developmental disability.[2] It is most often caused by a mutation or deletion in the Scn1a gene, a gene that codes for an important sodium channel whose function is essential in normal transmission of electrical signals within the brain.[3],[4] The loss of functionality of this gene can lead to brain activity and hyperexcitability that characterizes seizures and epilepsy.[5]

Through the critical work of researchers like Dr. Mallamaci, new therapeutic approaches for epilepsy are within our reach. This exciting research has been made possible by funding from CURE as we strive ever closer to our goal of producing treatments and cures for epilepsy to achieve “no seizures, no side effects.”

____________________

[1] Wirrel EC. Treatment of Dravet syndrome. Can J Neurol Sci 2016: 43 Suppl 3:S13-18.

[2] Dravet C. The core Dravet syndrome phenotype. Epilepsica 2011; 52(2):3-9.

[3] Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia 2011; Suppl 2:24-9

[4] Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest 2005; 115(8): 2010-2017.

[5] Chopra R, Isom LL. Untangling the Dravet syndrome seizure network: The changing face of a rare genetic epilepsy. Epilepsy Curr 2014; 14(2):86-89.

The Established Status Epilepticus Treatment (ESETT) Clinical Trial

The Established Status Epilepticus Treatment Trial (ESETT) is a multicenter, randomized, double-blind, comparative effectiveness study of fos-phenytoin, levetiracetam, and valproic acid in subjects with benzodiazepine-refractory status epilepticus. Patients will be recruited by two national emergency research networks:  Neurology Emergency Treatment Trials (NETT) network and Pediatric Emergency Care and Applied Research Network (PECARN).  Each network has successfully undertaken a Status Epilepticus treatment trial under exception from informed consent (EFIC) rules.

Objectives: The primary objective is to determine the most effective and/or the least effective treatment of benzodiazepine-refractory SE among patients older than 2 years. There are three active treatment arms being compared: fosphenytoin (FOS), levetiracetam (LEV), and valproic acid (VPA). The second objective is comparison of three drugs with respect to secondary outcomes. Final objective is to ensure that the trial is informative for treatment of ESE in children by describing the effectiveness, rate of adverse reactions of these drugs in children.

Participating Sites: Patients will be recruited by two national emergency research networks: Neurology Emergency Treatment Trials network(NETT) and Pediatric Emergency Care and Applied Research Network (PECARN). Each network has successfully undertaken a SE treatment trial under EFIC rules.

Eligibility Criteria

Inclusion Criteria: Patient witnessed to seize for greater than 5 minute duration prior to treatment with study drug; Patient received adequate dose of benzodiazepines. The last dose of a benzo was administered in the 5-30 minutes prior to study drug administration. The doses may be divided.; continued or recurring seizure in the Emergency Department; Age 2 years or older

Exclusion Criteria: Known pregnancy; Prisoner; Opt-out identification; Treatment with a second line anticonvulsant (FOS, PHT, VPA, LEV, phenobarbital or other agents defined in the MoP) for this episode of SE; Treatment with sedatives with anticonvulsant properties other than benzodiazepines (propofol, etomidate, ketamine or other agents defined in the MoP); Endotracheal intubation; Acute traumatic brain injury; Known metabolic disorder; Known liver disease; Known severe renal impairment; Known allergy or other known contraindication to FOS, PHT, LEV, or VPA; Hypoglycemia < 50 mg/dL; Hyperglycemia > 400 mg/dL; Cardiac arrest and post-anoxic seizures

Taking anti-epileptic drug Topiramate in early pregnancy increases risk of oral clefts, according to a Neurology study

According to authors Sonia Hernandez-Diaz et al. in the study “Topiramate use early in pregnancy and the risk of oral clefts” [1]:

The increased risk of oral clefts associated with use of Topiramate early in pregnancy was more pronounced in women with epilepsy who used higher doses.

[The study’s objective was] to assess the relative risk of oral clefts associated with maternal use of high and low doses of Topiramate during the first trimester for epilepsy and nonepilepsy indications.

Science Daily reports [2]:

Approximately one out of every 1,000 infants are born with an oral cleft, but among infants exposed to low doses of Topiramate (median 100-mg daily dose) in the first trimester, that risk was 2.1 out of every 1,000 live births. Among women taking higher dose Topiramate (median 200-mg daily dose), the risk was much higher — 12.3 for every 1,000 live births.

Women with epilepsy on Topiramate have the highest relative risk of giving birth to a baby with cleft lip or cleft palate, likely due to the higher doses of Topiramate when used for controlling seizures.

Folic Acid May Limit Autism Traits in Children of Epileptic Women

According to a Norwegian biobank study “Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero” [1]:

Children exposed to antiepileptic drugs in utero had a significantly lower risk of autistic traits if the mother used periconceptional folic acid supplements.

The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008. The study included 104,946 children.

In the 335 children exposed to antiepileptic drugs, the risk for autistic traits was significantly higher at 18 months of age and 36 months of age when their mothers had not used folic acid supplements compared with children of mothers who had used supplements.

[The study concluded that] fertile women using AEDs should take folic acid supplements continuously.

Growth hormone releasing hormone may play a role in inhibiting seizures

According to the study, “Interactions between GHRH and GABAARs in the brains of patients with epilepsy and in animal models of epilepsy” [1]:

[Researchers] propose that growth hormone releasing hormone (GHRH) may exert an antiepileptic effect.

The primary finding of this study is that growth hormone releasing hormone expression was significantly increased in the brains of both patients with temporal lobe epilepsy and in two mouse models of epilepsy induced by either kainic acid or pentylenetetrazol.

In addition, growth hormone releasing hormone co-localized with presynaptic and postsynaptic inhibitory neurons. Interestingly, [researchers] confirmed that growth hormone releasing hormone and activate ?-aminobutyric acid (GABA) receptors (GABAARs) interacted.

Therefore, [researchers] propose that growth hormone releasing hormone participates in anti-epileptic processes by increasing ?-aminobutyric acid levels and activating ?-aminobutyric acid receptors.

Ablation of hippocampal granule cells could halt progression of epilepsy

According to a study from Bethany E. Hosford et al., “Ablation of peri-insult generated granule cells after epilepsy onset halts disease progression,” [1]:

Targeted ablation of newborn granule cells can produce a striking improvement in [temporal lobe epilepsy] disease course, and the treatment can be effective when applied months after disease onset.

Ablation halted epilepsy progression relative to untreated epileptic mice; the latter showing a significant and dramatic 300% increase in seizure frequency. This increase was prevented in treated mice.

Ablation did not, however, cause an immediate reduction in seizures, suggesting that peri-insult generated cells mediate epileptogenesis, but that seizures per se are initiated elsewhere in the circuit.

SPREAD Clinical Trial: Study of Predictive Biomarkers for Rational Management of Drug-resistant Epilepsy Associated With Focal Cortical Dysplasia (SPREAD)

Focal Cortical Dysplasias (FCDs) are neurodevelopmental disorders that represent a major cause of early onset drug-resistant epilepsies with cognitive and behavioral impairments, carrying a lifelong perspective of disability and reduced quality of life. Despite a major medical and socio-economic burden, rationale therapeutic strategies are still under debate. Surgical removal of the epileptogenic brain area (Epileptogenic Zone) is the most successful treatment, yet it fails to control FCD-associated seizures in as much as 40% of cases. Precise definition and complete resection of the Epileptogenic Zone are the main determinants of outcome. In current practice of French centers, up to 80% FCD-patients require an intracranial EEG (icEEG) recording to accurately define the epileptogenic zone. However, the indications for icEEG in MRI-visible FCD remain empirical and are essentially based on expert opinion.

Eligibility Criteria

Inclusion Criteria:

  • Adult or pediatric patient suffering from drug-resistant focal epilepsy?
  • Age more than 2 years old;
  • Brain MRI suggestive of FCD or normal?
  • Standardized presurgical evaluation available including medical history, scalp video-EEG, 3T MRI, FDG-PET, Neuropsychological tests?
  • Inpatient in one of the participating centers for recording seizure during long term scalp video-EEG and / or SEEG-monitoring?
  • Resective surgery with a minimal post-operative follow-up of 12 months?
  • Histopathologic evidence for FCD or non-pathologic findings (normal histology or mMCD type II).
  • Patient, parents or legally representative who have given written informed consent to allow the study data collection procedures.

 

Exclusion Criteria:

  • Brain MRI suggestive of another type of lesion?
  • Difficulty to read or understand French, or inability to understand the information;
  • Pregnant or breastfeeding woman;
  • Subject under judicial protection.
  • Other lesion discovered on histological examination?
  • FCD type 3, dual pathology, ambiguous or unavailable neuropathological findings
  • Lack of longitudinal pre- and post-surgical follow-up.

The Association Between Hyponatremia and Osteoporosis in Patients With Epilepsy Clinical Trial

The study investigates the association between normalization of serum sodium levels and bone markers in patients with epilepsy and chronic hyponatremia.

The study is a randomized, single blinded, placebo controlled study where participants will be randomized to either treatment with salt tablets or placebo tablets through 4 months. At the beginning and end of the 4 months bone markers will be measured.

The investigators null-hypothesis is that there will be no difference in bone markers before or after the intervention.

Eligibility Criteria

Ages Eligible for Study: 18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Epilepsy requiring treatment for at least 2 years
  • Known hyponatremia (2 subsequent s-sodium values < 136 mmol/l)
  • Age 18-80 years
  • Danish speaking
  • Signed form of prior consent

 

Exclusion Criteria:

  • Pregnancy and breastfeeding
  • Known osteoporosis. DXA scan < -2.5 T-score. Z-score is used for patients 50 years or younger.
  • Undergoing treatment for osteoporosis
  • Undergoing treatment with salt tablets
  • Known SIADH
  • Severe concomitant disease such as cancer or ischemic heart disease
  • Alcohol, drug or substance abuse

Clobazam Clinical Trial: Use for Epilepsy and Anxiety

This study is an open label, adjunctive, proof of concept, pilot clinical trial. Pediatric patients with epilepsy and clinically significant anxiety will be recruited and if enrolled will receive active treatment, involving flexible dose titration of clobazam and will be monitored for a period of four months. The study will be monitored and overseen by the Johns Hopkins Hospital Institutional Review Board.

Eligibility Criteria

Ages Eligible for Study: 6 Years to 17 Years (Child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Established diagnosis of epilepsy, characterized by focal seizures with suspected or documented localization in the temporal lobe. All participants will have active epilepsy that requires treatment with anticonvulsant medication.
    • Although it is not necessary to be seizure free, a seizure baseline period will be established in the 60 days prior to enrollment into the study.
    • Current regimen of anticonvulsant drugs must have been stable for 30 days prior to entry into the study.
  • No episodes of seizure clusters of status epilepticus within 30 days prior to entry into the study.
  • Established symptoms of anxiety with functional impairment.
  • Baseline behavioral criteria for inclusion will include subscale scores above the norm for age and gender on one of the following:
    • Pediatric Anxiety Rating Scale (PARS).
    • Multidimensional Anxiety Scale (MASC)
  • Male or female participants equal to or above age 6 and below age 18 at the start of the study. No exclusion will be made on the basis of gender or minority status.
  • Good general health as determined by medical history and physical examination.
  • Ability to swallow pills (participant will receive pill swallowing instruction if necessary). The medicine may be cut into pieces and/or mixed with applesauce.
  • If female of childbearing age, a negative urine or serum pregnancy test must be established or assured at baseline. Additionally, the participant must agree to use abstinence or appropriate contraception methods or be otherwise incapable of pregnancy for the duration of the study. Pregnancy test results will be shared with parent or guardian. Pregnancy status (or prevention) and abstinence or contraception methods will be addressed throughout the study for females of childbearing age as well as for post-pubertal males.
  • Previous subjects who failed at any point to meet continuation criteria and withdrew early may be considered for re-enrollment by the PI on a case-by-case basis.
  • Participant or legal caregiver capable of providing informed consent and fully capable of monitoring the subject’s disease process and compliance with treatment.

 

Exclusion Criteria:

  • Previous allergic or hypersensitivity reactions to Onfi® or benzodiazepines
  • Active substance abuse or dependence within 30 days of enrollment
  • DSM-V diagnosis of psychotic illness or imminent risk of harm to self or others.
  • Current use of antidepressants
  • Current standing use of benzodiazepines (except as “rescue” medicine)
  • Serious or unstable medical or neurologic conditions such as HIV, liver or kidney disease, cancer or diabetes.
  • Participation in a previous experimental drug study within 30 days of baseline visit.
  • Estimated IQ<70 as indicated by initial clinical assessment (rendering rating scales invalid)
  • Insufficient capacity of caregiver or legal guardian to understand and appropriately consent for study procedures

Personalized epilepsy seizure prediction a possibility with AI, according to EBioMedicine report

According to research findings, “Epileptic Seizure Prediction Using Big Data and Deep Learning: Toward a Mobile System” [1]:

Deep learning in combination with neuromorphic hardware can provide the basis for a wearable, real-time, always-on, patient-specific seizure warning system with low power consumption and reliable long-term performance.

Harnessing the recent breakthroughs in deep learning techniques and in building specialized processing chips, [researchers] have demonstrated that seizures can now be predicted by a portable device. [The] system automatically learns patient-specific pre-seizure signatures, and, in real time, warns of oncoming seizures.

Data for the study were collected for a previous clinical trial of an implanted seizure advisory system. This study may serve as a benchmark for new work exploring deep learning enabled seizure prediction.