Misdiagnosis of Lamotrigine (Lamictal®) Toxicity as Transient Ischemic Attack or Stroke

Abstract, published in Epilepsy & Behavior

Purpose: Lamotrigine (LTG) is one of the most used antiseizure medications (ASMs). Titration is indicated for incomplete seizure control, but toxicity with dizziness, impaired coordination, and double vision may ensue. Lamotrigine concentration would be the optimal diagnostic test. However, patients often receive a stroke evaluation when seen in the emergency department (ED), leading to unnecessary cost and delayed management. We investigated the frequency of stroke evaluation for symptoms associated with LTG toxicity and attempted to identify factors leading to this expensive evaluation.

Results: Thirteen patients with LTG toxicity had 16 negative stroke evaluations in the emergency room. Their average age was 62 years (range: 43-79) as compared with 47 years for all patients treated with LTG. The average daily LTG dose was 621 mg (range: 300-900 mg). A LTG serum concentration was requested on the day of evaluation in 7 instances, though the result was never available until at least the next day. In 4 instances, the LTG level was drawn 1-3 days after the patient had been seen. Five of the patients in this group were among 71 patients with clinical LTG toxicity and LTG concentration >20.

Conclusions: Emergency departments will frequently call a stroke alert for patients taking LTG and having symptoms consistent with LTG toxicity, particularly in seniors at greater risk of stroke. This adds not only expense but also radiation and contrast exposure from computed tomography (CT) studies. We recommend that a rapid LTG assay be made available and always ordered in patients receiving LTG, avoiding the considerable expense of an unnecessary stroke evaluation.

Dosing Recommendations for Delayed or Missed Doses of Valproic Acid (Depakote®) in Patients with Epilepsy

Abstract, published in Epilepsy & Behavior

Objective: Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the metabolism of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients.

Methods:. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed.

Results: The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas strategy C was recommended when the delayed dose was close to the next scheduled dose. strategy D was only suggested for delayed two doses.

One million Epilepsy Patients in China Missing Out on Beneficial Surgery

Press release, published by Monash University

In 2010, Professor Patrick Kwan from Monash University’s Department of Neuroscience, led an international team researching the causes and outcomes of epilepsy patients in rural China. A decade later the results indicate that at least one million Chinese people with epilepsy could be candidates for a standard operation that may leave them seizure-free.

The study, published in Neurology, incorporated 600 epilepsy patients from across four rural provinces in China from July 2010 and December 2012, with each participant undergoing an MRI and other tests looking for abnormalities in brain imaging. Of those, 108 were found to have lesions that could potentially be cured by surgery.

“In a best-case scenario, around 70-80% of them would be seizure-free – often after enduring seizures uncontrolled by medications for 20 years or more,” Professor Kwan said.

The participants were assessed by local primary care doctors trained by provincial neurologists in main hospitals to use a standardized questionnaire and take patient histories. The patients then traveled to provincial centers to have tests including MRIs and blood taken, for use in later research into genetic causes for epilepsy.

Professor Kwan said those patients identified as potential surgery candidates would need to undergo further tests including video-EEGs and neuropsychological assessments to ensure surgery would be effective, with the actual operation only taking three to four hours.

The same standard operation is carried out for suitable patients routinely around the world including Australia, UK and US.

“Extrapolating out the study results, potentially at least a million people could benefit from the operation – that’s a huge surgical treatment gap,” Professor Kwan said. “These findings are significant, highlighting the magnitude of the unmet needs for epilepsy surgery in China.

“Hopefully this information demonstrates a quantifiable need. By raising awareness we hope to influence policymakers to provide more resources in epilepsy care, including proper evaluation in specialist centers and proceeding to surgery if deemed appropriate.”

###

The multicenter study was conducted with international collaborators in London, Shanghai and Beijing, and was funded by the National Institutes of Health (US) and Chinese Ministry of Science and Technology.

The statistical analysis in the study was conducted by Dr Zhibin (Ben) Chen (joint first author) from Monash University’s Department of Neuroscience. Also instrumental in the study were; joint first author Dr Indran Davagnanam, Dr Chandrashekar Hoskote, Professor John Duncan and Professor Josemir (Ley) Sander from UCL, Dr Wenzhi Wang from Beijing Neurosurgical Institute, and Associate Professor Ding Ding from Shanghai’s Fudan University.

Professor Kwan is a medical specialist in neurology, an internationally recognized expert in epileptology and antiepileptic drug development, and is the head of the Comprehensive Epilepsy Program at the Alfred Hospital in Melbourne.

For Media Enquiries please contact:

E: media@monash.edu
T: +61 (0) 425 725 836

Brivaracetam (Briviact®) Substituting Other Antiepileptic Treatments: Results of a Study in German Epilepsy Centers

Summary, published in Epilepsy Open

Objective: To evaluate the success of initiation of “add-on” brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam.

Methods: In this retrospective non-interventional study conducted in specialized epilepsy centers across Germany, patients initiated “add-on” brivaracetam between 15 February and 31 August 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months and withdrew at least one AED either before/within 6 months after brivaracetam initiation.

Results: 506 patients had at least one brivaracetam dose and were included in the safety set (SS). 470 patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation and were included in the full analysis set (FAS) for effectiveness analyses. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (Keppra® [(49.4%)]. 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure-free. In the SS, 34.6% of patients reported treatment-emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug-related. Incidences of behavioral AEs before and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs).

Significance: Brivaracetam was effective and well-tolerated in patients who required a change in AED drug regimen and initiated “add-on” brivaracetam in German clinical practice.

FDA Approves New Therapy for Dravet Syndrome

FDA Press Release

On June 25, 2020, the U.S. Food and Drug Administration approved Fintepla® (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients age 2 and older.

“Dravet syndrome is a debilitating disease that takes a tremendous toll on both patients and their families,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome. The FDA will continue to work with companies on drug development for Dravet syndrome and other types of epilepsy.”

The effectiveness of Fintepla for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages 2 and 18. The studies measured the change from baseline in the frequency of convulsive seizures. In both studies, subjects treated with Fintepla had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment). These reductions were seen within 3-4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.

Fintepla labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Because of these risks, patients must have cardiac monitoring using echocardiograms performed before treatment, every six months during treatment, and once three to six months after treatment is discontinued. If the echocardiogram shows signs of VHD, PAH, or other cardiac abnormalities, health care professionals must consider the benefits and risks of continuing treatment with Fintepla for the patient.

Because of the risks of VHD and PAH, Fintepla is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS). The Fintepla REMS requires health care professionals who prescribe Fintepla and pharmacies that dispense Fintepla to be specially certified in the Fintepla REMS and that patients be enrolled in the REMS. As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive Fintepla.

The most common adverse reactions in clinical studies were decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.

The FDA granted this application Priority Review. Fintepla received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Fintepla to Zogenix, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Comparison of Phenytoin (Dilantin®) Versus Fosphenytoin (Cerebyx®) for Second-Line Treatment of Status Epilepticus

Abstract, published in Seizure

Purpose: For status epilepticus, the choice of antiepileptic drugs for second-line treatment after benzodiazepine remains controversial: although both phenytoin and fosphenytoin are recommended, it not unknown which is better. Using a nationwide inpatient database in Japan, we compared the efficacy and safety of these two drugs.

Method: An observational study identified adult patients who had been admitted for status epilepticus and who had received intravenous diazepam (Valium®) on the day of admission from January 1, 2011 through December 31, 2015.

Results: The analysis examined data from 5265 patients: 2969 patients received phenytoin; 2296 received fosphenytoin, on the day of admission. No significant difference was found for use of a vasopressor, which is a drug to treat low blood pressure, or for mechanical ventilation, on the day of admission; in-hospital mortality; length of hospital stay; or total hospitalization cost. Higher age, comorbidity of cardiac diseases and lower body mass index were associated significantly with increased vasopressor use, whereas the dose of phenytoin equivalents and the choice of fosphenytoin were not.

Conclusions: This nationwide observational study found no evidence that fosphenytoin provides higher efficacy or safety than phenytoin for treatment of status epilepticus in adults after diazepam. Age, cardiac disease, and low body mass index were identified as independent risk factors for vasopressor use in both phenytoin and fosphenytoin.

Relationship Between Saliva and Plasma Rufinamide (Banzel®) Concentrations in Patients with Epilepsy

Abstract, published in Epilepsia

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Also investigated were the relationships between plasma rufinamide concentrations and dose as well as the influence of “add-on” medications

Assay results in the two tested fluids correlated well, but concentrations in saliva were moderately lower than those in plasma. In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. However, patients receiving valproic acid (Depakote®) “add-on” medication had higher dose-normalized plasma rufinamide levels than patients taking “add-on” medications metabolized by a different enzyme than that for rufinamide.

Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Nevertheless, because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.

Changes in Cognition After Introduction or Withdrawal of Zonisamide (Zonegran®) Versus Topiramate (Topamax®) in Epilepsy Patients

Abstract, published in Epilepsia

Objective: This study aims to evaluate the impact of zonisamide (ZNS) compared to topiramate (TPM) on cognition in patients with epilepsy. Although the risk of cognitive side effects has been clearly demonstrated for TPM, comparable side effects in ZNS have been suggested but evidence from studies is inconclusive.

Methods: In this retrospective observational study, the team analyzed patients’ records from before and after introduction or withdrawal of ZNS vs TPM. Data were gathered during routine clinical care protocols. Standardized monitoring of executive functions verbal memory and subjective health was performed in 73 patients when TPM (n = 45) or ZNS (n = 28) was introduced and 62 patients when TPM (n = 29) or ZNS (n = 33) was withdrawn.

Results: There was decisive evidence for a negative effect of “add-on” antiseizure therapy with ZNS and TPM on executive function and a positive effect of their withdrawal. The ZNS effect seemed smaller, although the difference was inconclusive. Verbal memory and subjective quality of life were not significantly affected. Subjectively, ZNS was connected to lower anxiety and fewer headaches, whereas TPM had a perceived effect on weight, fluent speech and comprehension, headaches, and balance.

Significance: This is the first study to provide objective evidence for a considerable negative effect of ZNS treatment on executive function. Comparable to the well-known TPM effect, cognition worsens when ZNS is used as add-on therapy and recovers when it is withdrawn. However, most patients do not show a significant negative effect, suggesting disparate susceptibilities to adverse events. The findings emphasize the need for routine monitoring of cognitive side effects to identify early on those patients who are negatively affected by new AED.

Clinical Factors Associated with Suicide Risk Independent of Depression in Persons with Epilepsy

Summary, published on MDLinx

In individuals with epilepsy, researchers assessed if epilepsy-related factors are correlated with suicide risk independent of depression. Participants in the cross-sectional study were adults (n = 212; 52.4% men) with epilepsy. Study participants were divided into two age groups (under 40 vs over?40 years). The risk of suicide was reported in 31.6% of candidates, while risk of depression was reported in 22.2% of candidates. Independent of depression and a past or family history of psychiatric disorders, there was a significant link between an antiepileptic drug load greater than one and suicide risk. Independent of current depression, use of pregabalin (Lyrica®) in the younger group and frequent seizures in the older group were associated with a risk of suicide.

The risk of suicide in people with epilepsy may be linked to epilepsy-related factors such as high antiepileptic drug load, frequent seizures (over one per month), and pregabalin use, regardless of depression. Such risk factors can vary according to the patient’s age.

Cognitive Behavioral Therapy reduces the impact of Psychogenic Nonepileptic Seizures

Press Release from NIHR Maudsley Biomedical Research Centre 

Scientists have found that adding cognitive behavioral therapy (CBT) to standardized medical care gives patients with dissociative seizures longer periods of seizure freedom, less bothersome seizures and a greater quality of life, in a study published in Lancet Psychiatry today and by the Cognitive behavioral therapy for adults with dissociative seizures (CODES) study group funded by National Institute for Health Research (NIHR).

Psychogenic nonepileptic seizures, also called functional and dissociative seizures, look similar in appearance to epileptic seizures or fainting but are related to a different type of involuntary blackout that is typically distressing and disabling for patients and their carers. Up to 1 in 5 adults presenting in epilepsy clinics have this hidden condition which is one of several types of Functional Neurological Disorder (FND). Historically patients with dissociative seizures have often been ignored or disbelieved by doctors and research on treatment is limited. They are more likely to be found in women and usually have a poor outcome with a worse quality of life than people with epilepsy alone. People with dissociative seizures have a marked increase in health service use.

In the largest treatment trial to date for dissociative seizures, 368 patients from centers across England, Scotland, and Wales were followed up 6 months and 12 months after treatment courses began. Researchers found patients treated with dissociative seizure specific CBT alongside standardized medical care reported the highest number of consecutive dissociative seizure-free days in the previous 6 months, along with greater functional status, self-rated and doctor-rated change in global impression scores, and satisfaction with treatment when compared with standardized medical care alone.