Findings From Comprehensive Drug Repurposing Screening To Treat Epileptic Encephalopathy Published In Epilepsia

Pairnomix, LLC announced on March 26, 2018 that results from a comprehensive drug repurposing screen performed for a patient with SCN8A epilepsy were published as an original research article online and in an upcoming print issue of Epilepsia, the official journal of the International League Against Epilepsy (ILAE) and a leading, authoritative source for current research results on all aspects of epilepsy.

The study, A Comprehensive Approach to Identifying Repurposed Drugs to Treat SCN8A Epilepsy details rigorous efforts to identify repurposed drug options for a patient with epileptic encephalopathy caused by the SCN8A R1872Q genetic mutation. Whereas most drug repurposing studies focus on one or a few select compounds, this research highlights a broader approach using high-throughput technologies to screen hundreds of on-market drugs in a single experiment. In this study, 90 drugs were identified to have a significant effect in cellular studies; the majority of these drugs have never been implicated as having effects on ion channels or epilepsy and therefore represent potentially novel mechanistic activity.

Gregory Stewart, PhD, Chief Scientific Officer at Pairnomix, remarked, “We are very pleased to share these results and the research approach we have undertaken to identify drug options for physicians to consider in their medical management of patients with the SCN8A R1872Q variant. Our work demonstrates the utility of comprehensive, high-throughput drug screens to identify new drug options for patients that are available for immediate clinical use.”

Epilepsy Research with Patients in Mind

To mark Purple Day on 26 March, Dr Sam Lyle, Family Engagement Officer for the Changing Agendas on Sleep, Treatment and Learning in Childhood Epilepsy (CASTLE) Programme at King’s College London, blogs about conducting research into treating epilepsy in children with family engagement in mind.

The CASTLE study is focused on rolandic epilepsy, which is the most common type of childhood epilepsy and affects around one in six children with the condition in the UK. Children with rolandic epilepsy find that their learning, sleep, behaviour, self-esteem and mood are often affected, and the condition can cause stress in the family.

Treating epilepsy with drugs to reduce seizures has been the traditional goal of medical treatment. However, simply reducing seizures doesn’t necessarily make much difference to the way children and parents feel. What we do know is that active participation by patients and their carers in health research is associated with better outcomes – which is of course better for all concerned. As a result, we are  working in partnership with children and young people with the condition, as well as parents and carers, through our advisory panels. The panels help the researchers by using their experiences to directly inform how the research should be designed, carried out and shared with others.

Study: Final Safety, Tolerability, and Seizure Outcomes in Patients with Focal Epilepsy Treated with Adjunctive Perampanel for up to 4 Years in an Open?Label Extension of Phase III Randomized Trials: Study 307

Significance: Long?term (?4 years) adjunctive perampanel treatment did not raise new safety/tolerability signals and was associated with markedly improved seizure control, particularly in patients with SGS at baseline.

Objective: To evaluate long?term safety/tolerability and seizure outcomes in patients with focal seizures treated with adjunctive perampanel in the open?label extension (OLEx) Study 307 (ClinicalTrials.gov identifier: NCT00735397).

Methods: Patients could enter the OLEx after completing one of the double?blind, phase III studies. Safety/tolerability and seizure outcomes (median percent reduction in seizure frequency per 28 days, and 50% responder and seizure freedom rates) were analyzed during the OLEx in cohorts with the same minimum perampanel exposure for all focal seizures and secondarily generalized seizures (SGS). An additional sensitivity analysis accounted for early dropouts from the OLEx.

Results: Of 1480 patients randomized across the double?blind studies, 1218 enrolled in the OLEx. The majority of patients (65.4%?80.9%) received a last daily dose of perampanel 12 mg and completed long?term assessment on the same, or one fewer, concomitant antiepileptic drug compared with baseline. The long?term safety/tolerability profile was consistent with the double?blind studies.

Vitamine D in Drug Resistant Epilepsy (EPI-D) Clinical Trial

Brief Summary: Almost all patients with epilepsy living in the region of Paris have vitamin D deficiency, which is severe in 1/3 of the cases. The impact of this deficiency on epilepsy is unknown, despite the suggested benefits of vitamin D therapy including better seizure control and improvement of comorbidities (fatigue, anxiety, depression) in drug-resistant patients. Recommendations for vitamin D supplementation based on the serum level in the general population cannot be applied to patients with epilepsy due to interference of antiepileptic drugs in the vitamin D metabolism. Animal models, mechanisms of action studies and ecological information provide objective data for a direct antiepileptic effect of vitamin D. Human studies seem to confirm the antiepileptic effect of vitamin D but there are no controlled studies on large populations.

The investigators aim to assess prospectively the effect of the treatment of vitamin D deficiency providing a high level of evidence. The investigators hypothesize that the treatment of vitamin D deficiency will result in significant reduction of seizure frequency, and improvement of comorbid symptoms as well as quality of life.

Anticipated Study Start Date: April 2018
Estimated Study Completion Date: April 2020

Eligibility Criteria

Ages Eligible for Study: 15 Years and older (Child, Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria

  • Age > 15 years
  • Drug-resistant epilepsy (see definition above)
  • Having at least 6 unprovoked seizures in the previous 3 months
  • Epilepsy syndrome unequivocally established
  • Ability to reliably quantify the seizure frequency
  • Antiepileptic treatment stable for 3 months prior to inclusion
  • No vitamin D treatment in the 6 months prior to inclusion vitamin D supplemental diet
  • Medication compliance (confirmed by plasma levels if available)
  • Agreeing to participate in the study
  • Having a social insurance
  • Parental agreement if patient below the age to be able to give consent (or guardian if protected adult)

 

Exclusion Criteria

  • Progressive brain pathology
  • Status epilepticus in the 2 years prior to inclusion,
  • epilepsy surgery planned in the current year
  • Pregnancy or breast-feeding
  • Treatments influencing the metabolism of vitamin D other than anticoagulants (rifamicin, isoniazid, ketoconazole, 5-FU, leucovorin)
  • Known hypersensitivity to vitamin D, patients with a history of granulomatosis (especially sarcoidosis)
  • Contraindication to treatment with Uvedose referring to the summary of product characteristics
  • Current or past hypercalcemia or situations accompanied by increased vulnerability to hypercalcemia as arrhythmia or digitalis therapy, subjects with calcium lithiasis
  • Moderate renal impairment with creatinine clearance <60 mL/mn assessed by MDRD
  • Participation in other studies of other experimental drugs within 30 days before enrollment in the study
  • Abuse of alcohol or drugs

BIS-001-ER for the Treatment of Adult Focal Impaired Awareness Seizures (FIAS) Clinical Trial

Brief Summary: The purpose of this study is to examine safety signals and demonstrate seizure reduction in adults with FIAS treated with BIS-001ER as an add-on therapy in an in-patient and out-patient study design.

Primary Outcome Measures: Effect of BIS-001ER on Seizure Count Reduction in average daily seizure count between baseline (pre-treatment) and evaluation (on treatment) video EEG monitoring periods.

Anticipated Study Start Date: April 2, 2018
Estimated Study Completion Date: November 30, 2018

Eligibility Criteria

Ages Eligible for Study: 18 Years to 65 Years (Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria

  • Speak English with sufficient proficiency to read and comprehend the Informed Consent document, and to communicate with study staff.
  • Be able to consent to participate by signing the Informed Consent document after a full explanation of the nature and purpose of this study.
  • Have signed the Informed Consent before any study-specific procedures are performed.
  • Be males or females between 18 – 65 years of age.
  • Have a diagnosis of FIAS type epilepsy with or without additional focal aware or non-aware seizures with generalization.
  • Have a current minimum average of 5 countable seizures / week to enroll in study.
  • Have at least 5 focal impaired awareness seizures during the 96-hour baseline VEM period.
  • Be receiving stable doses (for at least 4 weeks) of one to four currently marketed anti-epileptic drugs (AEDs), with or without vagus nerve stimulation (in which case the patient should be on the same stimulation parameters for at least 4 weeks).
  • Have a negative urinary pregnancy test upon admission to the site on Day 1.
  • Be in good general health in the judgment of the Principal Investigator based upon medical history, physical examination, standard 12-lead ECG, and clinical laboratory evaluations obtained within the two weeks prior to enrollment.
  • Be able to comply with all study-specified procedures.
  • Weight between 40 and 120 kg.

 

Exclusion Criteria

  • Has taken Huperzine A within the past year.
  • Is planning to become pregnant or impregnate spouse, not using an acceptable method of birth control (defined as use of double-barrier birth control methods, use of oral contraceptives, or surgical sterilization), pregnant or nursing.
  • Have non-epileptic events that could be confused by the patient and/or study staff as epileptic seizures.
  • Has seizures that are difficult to count; for example, seizure clusters defined as multiple seizures with at least one seizure within 30 minutes of the previous seizure.
  • Have less than the 5 minimum accepted seizures required during baseline evaluation period screen.
  • Have a history of only seizure clusters, for example, seizure clusters defined as multiple seizures with at least one seizure within 30 minutes of the previous seizure.
  • Has attempted suicide within the past 2 years.
  • Has a history of status epilepticus in the 6 months previous to enrollment.
  • Has a pre-existing medical condition (including an existing progressive or degenerative neurological disorder including brain tumor, active encephalitis, active meningitis or abscess) or takes medications that, in the Principal Investigator’s opinion, could interfere with the participant’s suitability for participation in the study.
  • Has a history or evidence of significant psychiatric disturbance or illness, including alcohol or drug abuse within the past 2 years, or symptoms of psychosis (hallucinations, delusions) in the last 5 years.
  • Has had any clinical laboratory abnormalities within the past two months, prior to screening, considered of clinical significance by the Principal Investigator.
  • Is on concomitant therapy with non-AEDs that are cholinergic.
  • Has participated in any clinical investigational drug or device study within four weeks prior to study entry.
  • Inability to complete seizure diary.
  • Is currently taking or has taken Epigallocatechin gallate (EGCG) within the past 14 days, or consume foods or drinks containing EGCG; including green, white, oolong teas and certain black teas, or food containing >100grams of carob powder within the past 14 days.

Worn like a helmet, a new brain scanner aims to make it easier to treat kids with epilepsy

A brain scanner now used to guide treatment of patients with epilepsy and other neurological disorders is bulky and challenging to use on fidgety young children — but researchers hope it might soon be replaced by a new machine that’s not much bigger than a bike helmet.

Scientists at University College London have created a prototype of a lightweight, easier-to-use version of a magnetoencephalography, or MEG, brain scanner. These machines monitor the magnetic field created when neurons communicate with each other, allowing physicians to see how the brain functions from one second to the next.

They’re used to diagnose patients, and are particularly helpful for determining how to treat people with epilepsy who haven’t responded to anti-seizure medications and need surgery. The MEG scans help doctors to pinpoint the source of seizures and map nearby critical areas to avoid during surgery.

“Up until now, people have had to lie on big scanners and we say, ‘Act naturally, but whatever you do, don’t move your head,’” said Gareth Barnes, who is developing the new scanner and works as a professor at UCL’s Wellcome Trust Center for Neuroimaging. He said the new scanner could be used in research to glean more insights into how the brain works in patients with neurological conditions. The researchers published a paper Wednesday about the new device in Nature.

Study: Clustering of spontaneous recurrent seizures separated by long seizure-free periods: An extended video-EEG monitoring study of a pilocarpine mouse model

Abstract: Seizure clustering is a common and significant phenomenon in patients with epilepsy. The clustering of spontaneous recurrent seizures (SRSs) in animal models of epilepsy, including mouse pilocarpine models, has been reported. However, most studies have analyzed seizures for a short duration after the induction of status epilepticus (SE). In this study, we investigated the detailed characteristics of seizure clustering in the chronic stage of a mouse pilocarpine-induced epilepsy model for an extended duration by continuous 24/7 video-EEG monitoring. A seizure cluster was defined as the occurrence of one or more seizures per day for at least three consecutive days and at least five seizures during the cluster period. We analyzed the cluster duration, seizure-free period, cluster interval, and numbers of seizures within and outside the seizure clusters. The video-EEG monitoring began 84.5±33.7 days after the induction of SE and continued for 53.7±20.4 days. Every mouse displayed seizure clusters, and 97.0% of the seizures occurred within a cluster period. The seizure clusters were followed by long seizure-free periods of 16.3±6.8 days, showing a cyclic pattern. The SRSs also occurred in a grouped pattern within a day.

We demonstrate that almost all seizures occur in clusters with a cyclic pattern in the chronic stage of a mouse pilocarpine-induced epilepsy model. The seizure-free periods between clusters were long. These findings should be considered when performing in vivo studies using this animal model. Furthermore, this model might be appropriate for studying the unrevealed mechanism of ictogenesis.

Brain Stethoscope Listens For Silent Seizures

By converting brain waves into sound, even non-specialists can detect ‘silent seizures’ – epileptic seizures without the convulsions most of us expect. See video here.

When a doctor or nurse suspects something is wrong with a patient’s heart, there’s a simple way to check: put a stethoscope over the heart and listen to the sounds it makes. Doctors and nurses can use the same diagnostic tool to figure out what’s going on with the heart, lungs, stomach and more, but not the brain – although that could change with a new device.

Josef Parvizi, above, a professor of neurology, Chris Chafe, a professor of music, and colleagues have tested a method for detecting seizures that transforms brain waves into sound.

Over the past several years, Stanford neurologists have been working with a specialist in computer music to develop a brain stethoscope – not a stethoscope per se, but rather an algorithm that translates the brain’s electrical activity into sounds.Now, the same team has shown that medical students and nurses – non-specialists, in other words – can listen to the brain stethoscope and reliably detect so-called silent seizures – a neurological condition in which patients have epileptic seizures without any of the associated physical convulsions. The group published the work March 21 in the journal Epilepsia.

‘This technology will enable nurses, medical students and physicians themselves to actually assess their patient right there and they will be able to determine if the patient is having silent seizures,’ said Josef Parvizi, a professor of neurology and neurological sciences.

‘Missing Mutation’ Found in Severe Infant Epilepsy

Researchers have discovered a “missing mutation” in severe infant epilepsy — long-suspected genetic changes that might trigger overactive, brain-damaging electrical signaling leading to seizures. They also found early indications that specific anti-seizure medications might prevent disabling brain injury by controlling epilepsy during a crucial period shortly after birth.

“These are still early days, but we may be able to use this knowledge to protect the newborn brain and improve a child’s long-term outcome,” said study leader Ethan M. Goldberg, MD, PhD, a pediatric neurologist at Children’s Hospital of Philadelphia.

Goldberg collaborated with European and American researchers in this neurogenetic study of early infantile epileptic encephalopathy, published online Feb. 21, 2018 in Annals of Neurology.

The study focused on mutations in the gene SCN3A. Scientists already knew that the gene had a pattern of high expression in the brain, before and shortly after birth. Variants in SCN3A had also been previously linked to less severe forms of epilepsy, but the current research solidified this link and was the first to establish that SCN3A mutations cause the severe infantile form.

Translating these findings into potential clinical treatments, Goldberg stressed, will require considerable further research — both in nerve cells and in future animal models, in which neurologists can test possible precision-medicine treatments for safety and efficacy before they can be investigated in patients. In addition, the current research allowed the SCN3A gene to be added to an existing diagnostic test, CHOP’s Epilepsy Panel, which uses next-generation sequencing to rapidly test for over 100 genetic causes of childhood epilepsy.

Precise, early diagnosis, added Goldberg, will be crucial, because of the highly regulated timetable of early-life neurological events. “The mutation’s activity in the Nav1.3 sodium ion channel occurs during a short period in newborns, but if we can intervene during that window, we may be able to help prevent long-term neurological injury and benefit patients,” he said.

First Patient Enrolled in Cavion Multi-Center Phase 2 Clinical Trial in Epilepsy

Cavion, Inc. announced March 20th that the first patient has been enrolled in its innovative T-WAVE Phase 2a proof-of-concept clinical trial (NCT03406702). T-WAVE will assess the safety, tolerability and efficacy of the T-type calcium channel modulator CX-8998 in drug-resistant absence seizures in adolescents and young adults with generalized epileptic syndromes.

Generalized epileptic syndromes are associated with abnormal activity of selected neural networks. T-type calcium channels, called Cav3, control neuronal firing and signaling. Cav3 is a strong genetic target as gain-of-function Cav3 mutations have been identified in patients with generalized seizures. CX-8998 is a first-in-class oral therapeutic drug that was designed to selectively and potently inhibit Cav3 channels, repairing aberrant neuronal activity. Data from genetic preclinical models of generalized epilepsy suggest that CX-8998 suppresses epileptiform discharges and prevents the development of seizures, including absence seizures.

Cavion has deep expertise advancing the science of Cav3 modulation in white-space central nervous system indications with high unmet need. T-WAVE leverages Cavion’s unique clinical development engine that delivers insightful data using cutting edge digital biomarkers and artificial intelligence while collaborating with advocacy groups to put patients and their families at the forefront, said Spyros Papapetropoulos, Cavion’s Executive Vice President, Head of Research & Development and Chief Medical Officer.

New treatment options to control generalized seizures and maintain quality of life for patients and their families are particularly needed, as there are limited options currently available. New treatments for generalized epilepsy would provide a significant opportunity to help adolescents and young adults, said Dr. Jacqueline French, Chief Scientific Officer at the Epilepsy Foundation and Professor of Neurology at NYU School of Medicine.