Prediction of Seizure Recurrence Risk Following Discontinuation of Antiepileptic Drugs

Abstract, published in Epilepsia

Objective: Discontinuation of antiepileptic drugs (AEDs) in seizure-free patients is an important goal because of possible long-term side effects and the social stigma burden of epilepsy. The purpose of this work was to assess seizure recurrence risk after suspension of AEDs, to evaluate predictors for recurrence, and to investigate the recovery of seizure control after relapse. In addition, the accuracy of a previously published prediction model of seizure recurrence risk was estimated.

Methods: Seizure-free patients with epilepsy who had discontinued AEDs were retrospectively enrolled. The frequency of seizure relapses after AED withdrawal as well as prognosis after recurrence were assessed and the predictive role of baseline clinical-demographic variables was evaluated. The aforementioned prediction model was also validated and its accuracy assessed at different seizure-relapse probability levels.

Results: The enrolled patients (n = 133) had been followed for a median of 3 years (range 0.8–33 years) after AED discontinuation; 60 (45%) of them relapsed. Previous febrile seizures in childhood (hazard ratio [HR] 3.927; 95% confidence interval [CI] 1.403–10.988), a seizure-free period on therapy of less than 2 years (HR 2.313; 95% CI 1.193–4.486), and persistent motor deficits (HR 4.568; 95% CI 1.412–14.772) were the clinical features associated with relapse risk in univariate analysis. Among these variables, only a seizure-free period on therapy of less than 2 years was associated with seizure recurrence in multivariate analysis (HR 2.365; 95% CI 1.178–4.7444). Pharmacological control of epilepsy was restored in 82.4% of the patients who relapsed. In this population, the aforementioned prediction model showed an unsatisfactory accuracy.

Significance: A period of freedom from seizure on therapy of less than 2 years was the main predictor of seizure recurrence. The accuracy of the previously described prediction tool was low in this cohort, thus suggesting its cautious use in real-world clinical practice.

Factors Associated with Patients Not Proceeding with Proposed Resective Epilepsy Surgery

Study, published in Seizure

This study was intended to explore the relationship between eligible patients not proceeding with resective epilepsy surgery and various demographic, disease-specific, and epilepsy-evaluation variables. Researchers designed a retrospective case-control study including patients identified as candidates for resective epilepsy surgery at the Montefiore Medical Center between January 1, 2009, and June 30, 2017. They used Chi-squared, two-tailed, independent sample t-test and logistic regression to distinguish variables associated with patients not proceeding with surgery. Only 53 ultimately proceeded with surgery (33%), among the 159 potential surgical candidates reviewed over the 8.5-year study period. There is a relationship between employment status and whether the patient had epilepsy surgery: employed patients were 4.2 times more likely to not proceed with surgery compared to unemployed patients. It has been reported that patients with a temporal lobe lesion on MRI, temporal lobe EEG ictal onsets, and/or a temporal epileptogenic zone were more likely to proceed with surgery. There is a need for future study to assess these findings prospectively, determine if they generalize to other patient populations, explore the decision whether or not to proceed with epilepsy surgery from a patient-centered perspective, and imply strategies to reduce barriers to this underutilized treatment.

Perception of Memory Performance After First Seizure in Patients With and Without an Epilepsy Diagnosis

Abstract, published in Epilepsy & Behavior

Objectives: Memory complaints in patients with epilepsy have been well-studied. Although memory complaints are commonly reported by patients with chronic epilepsy, to date, few studies exist on memory complaints at the onset of epilepsy. The present study investigated the presence of memory complaints and their relation to mood and memory performance in patients after their first seizure. Thereby, we examined differences between individuals who received a diagnosis of epilepsy immediately with the occurrence of their first seizure and those who were diagnosed as having the first epileptic seizure, without fulfilling the ILAE criteria for the diagnosis of epilepsy.

Methods: Sixty-one patients participated in the study and completed, among others, a memory task and questionnaires on memory complaints and depression after their first epileptic seizure. We investigated the level of memory complaints and their correlation and accuracy in classification with a memory measure. We compared patients who received an epilepsy diagnosis after the first seizure with those who did not.

Results: Memory complaints did not correlate with objective memory performance. Classification into impaired/unimpaired showed low concordance between memory complaints and neuropsychological memory measures. After their first epileptic seizure, patients reported few memory complaints overall (10%), and there were no differences in memory complaints between patients with and without an epilepsy diagnosis.

Conclusion: At epilepsy onset, in contrast to established epilepsies, memory complaints are rare. Although influences of anticonvulsant drugs and seizures are not present at the beginning of epilepsy, this substantial absence of memory complaints at epilepsy onset emphasizes the need for comprehensive neurological and psychological treatment early with the given diagnosis. Treatment should focus on anticonvulsant drug regimens, patients’ concerns and convey realistic expectations.

How Much Can Medical Management Alone Improve the Outcome of Adult Drug-resistant Epilepsy? An Exploratory Study on Possibilities and Limitations of Combining Multiple Therapeutic Actions

Abstract, published in Epilepsy & Behavior

Purpose: Failure to control epileptic seizures with two medications, adequately chosen and dosed, indicates drug-resistant epilepsy (DRE). The chance of pharmacologically controlling seizures is low for patients with DRE and uncontrolled seizures who are not candidates for surgery, who have already undergone surgery, or who already had a vagus nerve stimulator (VNS) placed. Patients experiencing these conditions must instead rely on medical management of their seizures, and there is no breakthrough solution on the horizon. Medical care of DRE might be optimized by systematically considering factors that promote and inhibit breakthrough seizures. For example, seizure control could be enhanced through measures such as increasing the frequency of follow-up visits, tracking treatment plan compliance, treating sleep disorders, rational polypharmacy, adjusting drug administration to achieve higher levels when seizures are more likely and educating patients on seizure triggers. A systematic and simultaneous implementation of all of these measures is likely to yield a sizable, clinically relevant, improvement. This paper presents an exploratory study on the effects of implementing such an approach, specifically evaluating this method’s impact on seizure frequency.

Methods: I performed a retrospective chart review of 659 consecutive adult patients with epilepsy followed up at the University of Utah and at the Salt Lake City VA Medical center using the multimodal approach described above. I identified 27 patients who had DRE and uncontrolled seizures and in whom a medical management optimization protocol was implemented. I measured these patients’ seizure frequency at the beginning and the end of the study period and compared the results with those of a matching control group of 48 patients.

Results: The optimization protocol did not increase the number of seizure-free patients with DRE; however, it was effective in minimizing seizure frequency in patients whose seizures remained uncontrolled. Among these patients, the median seizure frequency dropped by 64% in the optimization group but did not change in the control group.

Conclusions: Despite the high occurrence of drug-resistant epilepsy, there is no accepted protocol for the related medical management. This paper describes an effective approach that can be implemented in a clinically relevant and readily achievable manner.

Opportunities and Challenges For MicroRNA-targeting Therapeutics For Epilepsy

Abstract, published in Trends in Pharmacological Sciences

Epilepsy is a common and serious neurological disorder characterized by recurrent spontaneous seizures. Frontline pharmacotherapy includes small-molecule anti-seizure drugs that typically target ion channels and neurotransmitter systems, but these fail in 30% of patients and do not prevent either the development or progression of epilepsy. An emerging therapeutic target is microRNA (miRNA), small noncoding RNAs that negatively regulate sets of proteins. Their multitargeting action offers unique advantages for certain forms of epilepsy with complex underlying pathophysiology, such as temporal lobe epilepsy (TLE). miRNA can be inhibited by designed antisense oligonucleotides (ASOs; e.g., anti-miRs). Here, we outline the prospects for miRNA-based therapies. We review design considerations for nucleic acid-based approaches and the challenges and next steps in developing therapeutic miRNA-targeting molecules for epilepsy.

U.Va. Researchers Develop a New Imaging Approach to Target Epilepsy Seizures

Article, published in The Cavalier Daily


An improved form of positron-emission tomography detects glucose in the brain in an effort to prevent seizures.

U.Va. Health neurologist Mark Quigg, radiology and medical imaging Assist. Prof. Bijoy Kundu and Class of 2020 alumnus Vikram Seshadri launched a small pilot study using seven participants to test out a new technique to improve how diagnoses are made. Their goal was to refine the method of glucose mapping for more accuracy and better resolution.

“Normally in a PET scan when we’re taking a picture of glucose use in the brain we use a radioactive tracer,” Quigg said. “What [Kundu] has invented is a process of a dynamic PET.”

In the dynamic PET scan, a tracer is injected into the bloodstream while the patient is already in the scanner. The scanner then takes pictures like a stop motion animation movie. The result is a time map of glucose uptake and glucose use in relation to brain region. The time map is used to identify points in time that yield the most difference among the functional places in the brain, or areas with most glucose uptake, and the nonfunctional places in the brain, or areas with least uptake.

The key difference between the former way of imaging and the dynamic method lies in the way the images are taken.  Instead of producing a single snapshot of the brain, the dynamic PET captures a series of snapshots that then require mathematical modeling for image analysis.

This new technique poses a huge advantage because the results are more quantitative and rigid, which allows for clearer data and less subjectivity compared to the previous PET scan method.

Quigg believes that the findings from this research are very promising for new treatment plans. The new diagnostic approach is completely non-invasive and enables more accurate diagnoses.

Dietary Medium Chain Triglycerides for Management of Epilepsy: New Data from Human, Dog, and Rodent Studies

Abstract, published in Epilepsia

Many studies show that glucose metabolism in epileptic brain areas can be impaired. Energy is crucial to maintain normal brain function, including ion and neurotransmitter balances. Energy deficits can lead to disruption of ion gradients, which can trigger neuronal depolarization and generation of seizures. Thus, perturbed metabolic processing of glucose in epileptogenic brain areas indicates a specific nutritional need for people and animals with epilepsy, as they are likely to benefit from auxiliary brain fuels other than glucose. Ketogenic diets provide the ketone bodies acetoacetate and ?-hydroxybutyrate, which can be used as auxiliary fuel by the brain. In approximately 50% children and adults with certain types of epilepsy, who can tolerate and maintain these dietary regimens, seizure frequency can be effectively reduced. More recent data demonstrate that addition of medium chain triglycerides (MCTs), which provide the medium chain fatty acids octanoic and decanoic acid, as well as ketone bodies as auxiliary brain energy, can be beneficial in rodent seizure models, and dogs and humans with epilepsy. Here, this evidence is reviewed, including tolerance in 65% of humans, efficacy studies in dogs, possible anticonvulsant mechanisms of actions of MCTs, and specifically decanoic acid as well as metabolic and antioxidant mechanisms. In conclusion, medium chain triglycerides are a promising adjunct to standard pharmacological treatment for both humans and dogs with epilepsy, as they lack central nervous system side effects found with current antiepileptic drugs. There is now a need for larger clinical trials in children, adults, and dogs to find the ideal composition and doses of MCTs and the types of epilepsy that respond best.

Selection of Anti-seizure Medications for First Add-on Use: A Consensus Paper

Abstract, published in Epilepsy & Behavior

Introduction: When monotherapy used alone or sequentially fails to achieve seizure control, a trial of combination therapy may be considered.

Objective: To define optimal criteria to guide choice of an anti-seizure medication (ASM) for use as first add-on.

Methods: A standardized Delphi procedure was applied to produce a list of consensus statements. First, an Expert Board consisting of 5 epileptologists agreed on a set of 46 statements relevant to the objective. The statements were then finalized through an iterative process by a Delphi Panel of 84 Italian pediatric and adult neurologists with expertise in the management of epilepsy. Panel members provided anonymous ratings of their level of agreement with each statement on a 9-point Likert scale.

Results: Consensus, defined as agreement by at least 80% of Panel members, was reached for 36 statements. Medication-related factors considered to be important for drug selection included efficacy, tolerability and safety, interaction potential, mechanism of action, and ease of use. The need to optimize adherence and to tailor drug selection to individual characteristics was emphasized.

Conclusions: Choice of an anti-seizure medication for first add-on requires consideration of many factors, many of which also apply to choose initial treatment. Factors more specifically relevant to add-on use include drug interaction potential and the preference for an anti-seizure medication with a different mechanism of action.

Network of Depression and Anxiety Symptoms in Patients with Epilepsy

Abstract, published in Epilepsy Research

Purpose: Depression and anxiety are often comorbid in people with epilepsy. Network models consider this comorbidity as an interacting system of depressive and anxiety symptoms. The present study investigates the network structure of depressive and anxiety symptoms in people with epilepsy and aims to identify the central and bridge symptoms to provide suggestions for the prevention of and intervention for depression-anxiety comorbidity in patients with epilepsy.

Methods: A total of 313 patients with epilepsy were enrolled in our study. Anxiety symptoms were evaluated with the Generalized Anxiety Disorder 7-Item questionnaire. Depressive symptoms were evaluated with the Patient Health Questionnaire-9. Network analyses were used for the statistical analysis.

Results: The findings indicated that ten edges with the strongest regularized partial correlations existed in the network. Six were among depressive symptoms, such as “sleep difficulties” with “fatigue” and ” feeling of worthlessness” with “thoughts of death”. Four were among anxiety symptoms, such as “nervousness or anxiety” with “uncontrollable worry” and “uncontrollable worry” with “worry too much”. Those strongest edges had no connection linking anxiety and depressive symptoms. The symptoms “depressed or sad mood”, “trouble relaxing” and “uncontrollable worry” had the highest strength centrality in the network. The results revealed three bridge symptoms: “psychomotor agitation/retardation”, “irritable”, and “depressed mood”.

Conclusion: “Feeling of worthlessness” was identified as a key priority due to associations with suicidal ideation. The current study highlighted the critical central symptoms “depressed or sad mood”, “trouble relaxing” and “uncontrollable worry” and the critical bridge symptoms “psychomotor agitation/retardation”, “irritable”, and “depressed or sad mood”. Implications for clinical prevention and intervention based on these symptoms are discussed.

The ‘Mozart Effect’ Shown to Reduce Epileptic Brain Activity, New Research Reveals

Article, published in EurekAlert!

Music by Mozart has been shown to have an anti-epileptic effect on the brain and may be a possible treatment to prevent epileptic seizures, according to new research presented today at the 7th Congress of the European Academy of Neurology (EAN).

Researchers believe that the acoustic (physical) properties within the music are responsible for this effect.

Listening to the famous 18th century composer’s Sonata for Two Pianos K448 led to a 32% reduction in epileptiform discharges (EDs). These are electrical brain waves associated with epilepsy and can cause seizures or bursts of electrical activity that temporarily affect how the brain works.