Vigabatrin and High-Dose Prednisolone Therapy for Patients with West Syndrome

CONCLUSION: Using a treatment protocol involving vigabatrin and prednisolone for West syndrome (WS), 72.7% of patients showed resolution of spasms and a BASED score of ?2. This study also found that this drug administration protocol was safe. However, further studies are warranted as this study describes results from observational study with limited sample size.

OBJECTIVE: Hormonal therapy and vigabatrin are now accepted as the first-line or standard therapies for WS. However, the superiority of these drugs in terms of monotherapy or combination therapy is still in question. In this study, we designed a treatment protocol for WS and prospectively assessed the efficacy of these therapies in controlling spasms, stabilizing electroencephalography (EEG), and allowing for developmental catch-up.

METHODS: In patients diagnosed with WS, vigabatrin was first administered alone for 2 weeks, and then prednisolone was administered in combination with vigabatrin if patients did not respond to vigabatrin. The detailed drug administration protocol was as follows: vigabatrin 50?mg/kg/day for 1 day, followed by vigabatrin 100?mg/kg/day for 3 days, vigabatrin 150?mg/kg/day if spasms were still present or the burden of amplitudes and epileptiform discharges (BASED) score on EEG was ?3 on day 5; 40?mg/day of prednisolone was added if spasms were still present or the BASED score was ?3 on day 14. The prednisolone dose was increased to 60?mg/day if spasms were still present or the BASED score was ?3 on day 21.

RESULTS: Sixty-six patients newly diagnosed with WS (median seizure onset age: 5.7 [IQR, 4.1-7.1] months, median age at diagnosis: 6.6 [IQR, 5.4-8.1] months, n?=?40 [60.6%] boys) were subjected to the vigabatrin and prednisolone therapy protocol. Of the 66 patients, 22 (33.3%) patients showed resolution of spasms and a BASED score of ?2 after vigabatrin alone, and 26 (39.4%) patients showed resolution of spasms and a BASED score of ?2 after a combination of vigabatrin and prednisolone, for a total of 48 (72.7%) patients who were responsive to the protocol without relapse for at least 7 months after WS diagnosis. The mental and psychomotor age quotients were higher at the time of diagnosis and remained significantly higher 6 months after the diagnosis in responsive patients (p?<? 0.001). No serious adverse reactions leading to discontinuation or reduction of drug doses were observed.

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.

Effects of Valproate on Reproductive Endocrine Function in Male Patients with Epilepsy: A Systematic Review and Meta-Analysis

CONCLUSIONS: This meta-analysis indicates that VPA may lead to a significant decrease in the levels of FSH and testosterone and alter the concentrations of LH, DHEAS, SHBG, and ADION to some extent, which might contribute to the reproductive endocrine dysfunction in male patients with epilepsy. It is important for clinical neurologists to be cautious when prescribing VPA to reproductive-aged male patients with epilepsy.

BACKGROUND: Valproate (VPA) is a broad spectrum antiepileptic drug (AED) that is generally used as a first line agent for most idiopathic and symptomatic generalized epilepsies. Many studies have indicated that AEDs cause reproductive endocrine disorders in males, but the exact etiology underpinning these dysfunctions is not clear. This meta-analysis and systematic review was intended to evaluate the effect of VPA on reproductive endocrine function in male patients with epilepsy.

METHODS: A literature search was performed using electronic databases up to December 2017 for eligible studies. The differences in the levels of the reproductive factors, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG), testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione (ADION) in the male patients with epilepsy treated with VPA (treatment group) were compared with the those of the healthy controls (control group) by the use of the Standardized mean difference (SMD) with 95% confidence intervals (CIs).

RESULTS: Six publications with a total of 316 subjects were identified. The result revealed that the levels of FSH (SMD?=?-1.33, 95% CI: -2.60 to -0.07, P?=?0.039) and testosterone (SMD?=?-0.45, 95% CI: -0.87 to -0.03, P?=?0.038) of the treatment group were decreased significantly compared with the healthy controls. There was an increase in the levels of SHBG (SMD?=?0.41, 95% CI: -0.21 to 1.03, P?=?0.197), DHEAS (SMD?=?0.20, 95% CI: -0.06 to 0.45, P?=?0.126) and ADION (SMD?=?0.73, 95% CI: -0.10 to 1.57, P?=?0.086), and a decrease in that of LH(SMD?=?-0.71, 95% CI: -1.49 to 0.07, P?=?0.075) in the male patients with epilepsy treated with VPA, but the differences did not reach statistical significance (P?>?0.05).

Clinical Trial to Investigate the Efficacy and Clinical Usability of Staccato Alprazolam (STAP-001) in Those with Epilepsy with a Predictable Seizure Pattern

The StATES trial (Inpatient, Dose-Ranging Study of Staccato Alprazolam in Epilepsy With Predictable Seizure Pattern) is a study to investigate the efficacy, safety and clinical usability of Staccato Alprazolam (STAP-001) in adult subjects (18 years and older) with epilepsy with a predictable seizure pattern.

Adult subjects that have an established diagnosis of focal or generalized epilepsy with a documented history of predictable seizure episodes are eligible for this trial.

This is a multi-center, double-blind, randomized, in-patient study. Subjects will be admitted to a Clinical Research Unit (CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the in-patient unit will be 2-8 days.

What are the possible outcomes of this study?

Once the subject enters the CRU or EMU and has a seizure, they will be treated with STAP-001. One seizure per subject will be treated. STAP-001 is delivered orally to the deep lung for systemic delivery. The Staccato delivery system is user-friendly and easy to use and accomplished with a single, normal breath by the subject.

The duration and timing of the seizure event and occurrence of subsequent seizures will be assessed by the Staff Caregiver(s) through clinical observation and confirmed with video electroencephalogram (EEG).

The following measures will be assessed:

  • If the seizure stopped within two minutes of administering STAP-001
  • If seizures recurred within 2 to 12 hours after giving STAP-001
  • Seizure duration
  • Seizure severity
  • The use of rescue medication to stop a seizure that doesn’t respond to the study drug 5 minutes post-drug and for up to 2 hours post-drug

 

Who is eligible to participate in this study?

Subjects may be eligible to participate in this study if they meet certain inclusion criteria, including:

  • Subject is able to provide, personally signed and dated informed consent to participate in the study or will have a legally authorized representative (LAR) sign the informed consent on his or her behalf before completing any study related procedures
  • Male or female adult (18 years or older)
  • Subject has an established diagnosis of focal or generalized epilepsy with a documented history of predictable seizure episodes that includes at least one of the following:
    • Generalized seizure episodes starting with a flurry of absence seizures or myoclonic seizures with a minimum duration of 5 minutes
    • Episodes of a prolonged focal seizure with a minimum duration of 3 minutes
    • Multiple (?2) focal seizures within a 2-hour time period
    • Prior to randomization, has experienced ?4 seizure episodes with predictable pattern during the last 4 weeks (qualification period) and no more than one week without a predictable seizure episode before the Screening Visit
  • Female participants (if of child-bearing potential and sexually active) and male participants (if sexually active with a partner of child-bearing potential) who agree to use a medically acceptable and effective birth control method throughout the study and for 1 week following the end of the study. Medically acceptable methods of contraception that may be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide,intrauterine device (IUD), surgical sterilization, and progestin implant or injection. Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone
  • Subject is able to comply by the requirements of the protocol, particularly the requirements and specific Institution policies during the in-clinic stay

 

Who is not eligible to participate in the study: 

Potential participants will be excluded from the study if they meet the following exclusion criteria:

  • History or diagnosis of non-epileptic seizures (e.g. metabolic or pseudo-seizures)
  • History of status epilepticus in the 6 months prior to Screening
  • Has a progressive neurological disorder such as brain tumor, demyelinating disease, or degenerative central nervous system (CNS) disease that is likely to progress in the next 3 months
  • Receiving chronic benzodiazepine treatment (defined as an average of ? 4 administrations per week) prior to admission to the in-patient unit
  • Use of strong CYP 3A4 inhibitors; including azole antifungal agents (e.g., etoconazole, itraconazole), nefazodone, fluvoxamine, cimetidine, HIV protease inhibitors (e.g., ritonavir)
  • Has severe chronic cardio-respiratory disease
  • History of HIV-positivity
  • Pregnant or breast-feeding
  • Clinically significant renal or hepatic insufficiency (hepatic transaminases >2 times the upper limit of normal (ULN) or creatinine ? 1.5 x ULN)
  • History of acute narrow angle glaucoma, Parkinson’s disease, hydrocephalus, or history of significant head trauma
  • Subjects who use medications to treat airways disease, such as asthma or COPD or have any acute respiratory signs/symptoms (e.g., wheezing)
  • Use of any investigational drug within 30 days or 5 half-lives of the investigational drug prior to administration of study medication, whichever is longer
  • A history within the past 1 year of drug or alcohol dependence or abuse
  •  Positive urine screen for drugs of abuse at Screening (positive Cannabis/Cannabinol results are acceptable if there is a documented history of stable use for medical purposes)

 

Are there any risks to participating in this study? 

In a prior study of the effects of STAP-001 in individuals with epilepsy, dose-related sedation was the most common adverse event. Overall, STAP-001 was well-tolerated and no serious adverse events were reported. Vital signs, heart rhythm, and brain activity will be monitored throughout the inpatient period of the study to monitor for sedation.

What is required of me? 

StATES is an in-patient study. The subjects will be admitted to a Clinical Research Unit (CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the in-patient unit will be 2-8 days. The total StATES trial will be about 8 to 12 weeks long, including the screening and follow-up periods.

After an initial screening in an outpatient visit, you will be followed for 4 weeks to make sure you are eligible for the study. During this period, you will record your seizure activity in a daily seizure diary. If your seizure pattern qualifies, you will be randomly assigned to either the study drug or a placebo. Neither you nor the study administrator will know which medicine you are getting.

The treatment phase of the study will occur next. You will be admitted to a CRU or EMU in anticipation of a seizure. After you have a seizure, you will be given one dose of STAP-001 or placebo. You will be followed for at least 12 hours after the medicine is given.

Following discharge from the CRU or EMU, your last study visit will be done by a phone call with a study coordinator 12-16 days after you received the study drug (STAP-001).

What is the total time involved?

The StATES study will take a total of 8 to 12 weeks.

What are the study time frames?

Actual study start date: March 16, 2018
Estimated Primary Completion Date: May 2019
Estimated Study Completion Date: May 2019

How do I find out more information about this study?

If you would like to see if you are eligible to participate please visit www.epilepsyhealthstudy.com. You may also contact the program director at: studydirector@engagetherapeutics.com.

New Technique Fine-Tunes Treatment for Severe Epilepsy Cases

One of three epilepsy patients experience no relief from drugs and are candidates for surgery. An advance by researchers at Yale and the Cleveland Clinic will enable surgeons to more precisely target areas of the brain causing debilitating symptoms in a subset of these patients.

The technology called magnetoencephalography or MEG measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and the researchers have developed a novel way to employ it.

Recording of seizures during routine MEG in some surgical candidates can help precisely identify affected areas of the brain and, in a few cases, even negate the need to conduct invasive intracranial EEG evaluations prior to surgery, the authors say. Lead author of the study published June 11 in the journal JAMA Neurology is Dr. Rafeed Alkawadri, assistant professor of neurology at Yale and director of Yale Human Brain Mapping Program. Dr. Andreas Alexopoulos of the Cleveland Clinic is senior author of the paper.

Transcutaneous Vagal Nerve Stimulation (t-VNS): An Adjunctive Treatment Option for Refractory Epilepsy

PURPOSE: The aim of this trial was to investigate the efficacy and safety of transcutaneous vagal nerve stimulation (t-VNS) in the palliative treatment of drug resistant epileptic patients ineligible for surgery.

METHODS: Twenty adult patients received four hours of t-VNS per day for six months (T1), followed by a two-month washout period (T2). The frequency and type of seizures recorded at T1 and T2 were compared with those occurring in the three months preceding study entry (T0). Responders (>30% reduction in the total number of seizures) subsequently received two hours of t-VNS per day for further six months (T3). All patients underwent electroencephalography (EEG) and completed the Quality of Life in Epilepsy questionnaire at baseline and T1.

RESULTS: At T1 six patients were considered responders. In these patients, at T3 the average reduction in seizure frequency was 60% compared to T0 (p?=?0.043), and 51% compared to T2 (p?=?0.043). Responders had more often seizures with falls (5 of 6; 83.3%) compared with non-responders (3 of 14; 21.4%) (p?=?0,010) and t-VNS reduced their frequency by a percentage ranging from 47.5 to 100%. There was no change in responders’ EEG findings after stimulation. At the end of the trial, three responders continued t-VNS, one implanted VNS.

CONCLUSIONS: t-VNS had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients. Further studies should be planned to assess whether t-VNS is a suitable tool to predict the efficacy of implanted VNS.

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

Generic antiepileptic drugs (AED) are significantly cheaper than brand name drugs, and may reduce overall health care expenditures. Regulatory bodies in Europe and North America require bioequivalence between generic and innovator drugs with regard to area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax); strict cutoff values have been defined. The main issue is if bioequivalence ensures therapeutic equivalence. Are switches from brand to generic, or between generic AEDs entirely safe or potentially harmful in patients with epilepsy?

We summarized and evaluated the available evidence from bioequivalence, health care utilization, and clinical studies on safety of generic AEDs. In most cases, variations in AUC and Cmax were negligible when comparing innovator and generic AEDs. Due to interindividual pharmacokinetic and pharmacodynamic variability, measured differences between innovator and generic drugs may be the same as differences between different lots of the same brand. Studies from several countries based on insurance data have reported an increase in health care usage after switch from brand to generic AEDs; switchback rates are significantly higher for AEDs compared to other compounds. Patients may be confused, and nonadherence may increase, when AEDs are switched between manufacturers, perhaps due to changes in medication shape and color. But clinical studies do not report changes in seizure frequency and tolerability attributable to generics.

Sufficient evidence indicates that most generics 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. We recommend 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.

NeuroPace Launches Next Generation RNS System, the World’s Only Brain-Computer Interface for the Treatment of Refractory Epilepsy

NeuroPace, Inc. announced on June 1 the launch of its Next Gen RNS® System for the treatment of refractory epilepsy, which affects an estimated 1 million people in the United States alone. The RNS System is a type of brain-computer interface that treats seizures by continuously monitoring brain waves, recognizing each patient’s unique “seizure onset fingerprint,” and automatically responding with imperceptible electrical pulses before seizures occur.

Epilepsy is a chronic disorder originating in the brain, characterized by unpredictable seizures. Approximately 50 million people worldwide have epilepsy, making it one of the most common neurological diseases globally. In the United States, more people live with epilepsy than autism spectrum disorder, Parkinson’s disease, multiple sclerosis and cerebral palsy combined. About one-third of individuals living with epilepsy are refractory to medications.

“NeuroPace revolutionized epilepsy therapy in 2013 with the introduction of the world’s first closed-loop, brain-responsive neuromodulation system—the only device that applies brain-computer interface technology to successfully treat refractory focal onset epilepsy,” said NeuroPace CEO Frank Fischer. “We have maintained our relentless focus on product innovation, and are excited to make the Next Gen RNS System—with twice the longevity and twice the memory in the same size device—available to our physician customers and their patients.”

The Next Gen RNS System is a major advance over the existing system. The battery life of the RNS Neurostimulator has more than doubled from 3.9 to 8.4 years at medium stimulation settings, which will allow patients to live their lives with fewer interruptions. The amount of available memory has also doubled, which will allow physicians to review a wider set of brain activity data.

UCB Receives CHMP Positive Opinion for Adjunctive Use of BRIVIACT as Paediatric Treatment for Epilepsy Patients

UCB announced on June 1 that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for BRIVIACT(R) (brivaracetam) to extend the therapeutic indication to include adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in patients with epilepsy from 4 years of age.

The European Commission is expected to make a decision based on this CHMP positive opinion over the coming weeks. When approved, BRIVIACT’s paediatric indication will represent an important new treatment option for children with epilepsy, their family and care-givers, as well as European healthcare professionals.

BRIVIACT is the newest medicine in the family of the synaptic vesicle protein 2A (SV2A) anti-epileptic drugs (AED) – a class of medicines discovered and developed by UCB. BRIVIACT demonstrates a high and selective affinity for SV2A in the brain which may contribute to its anticonvulsant effects.

“We’re very proud to be at the forefront of global epilepsy management, and to be able to provide healthcare professionals, their patients and their family members with new and additional choices to support them in their individual epilepsy journeys.” said Jeff Wren, Executive Vice-President, Head of UCB’s Neurology Patient Value Unit. “Today’s positive CHMP opinion for BRIVIACT(R) is another important step forwards in our efforts to realize true patient value and to further improve the lives of this highly impacted patient population by providing additional treatment options.”

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

Objective: To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy.

Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations.

Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n?=?117) were older at the time of the first seizure than those treated with phenobarbital (n?=?38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P?<?.001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P?=?.01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]).

Conclusions and Relevance: 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.