Showing papers in "Epilepsy Currents in 2016"

Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society

Abstract: CONTEXT: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. OBJECTIVE: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. DATA SOURCES: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. STUDY SELECTION: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. DATA EXTRACTION: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. RESULTS: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to hav...

AES Position Statement on Generic Substitution of Antiepileptic Drugs

Abstract: Among the older antiepileptic drugs (AEDs), generic substitutes have been available for many years. Phenobarbital, synthesized in 1912, has long been available in generic form, and brand-name Luminal was discontinued in the United States decades ago. Phenytoin, developed in 1938, was prescribed for decades as extended-release Dilantin Kapseals (Pfizer, Inc., New York), but it has largely been replaced by generic extended-release products. After approval in the United States of carbamazepine in 1974 and valproic acid in 1978, the branded forms had many years of patent exclusivity, but generic alternatives later became available. Beginning in 1993 with felbamate, a series of approximately 20 new brand-name AEDs were approved by the U.S. Food and Drug Administration (FDA). Patent duration after FDA approval of these newer AEDs varied, but all approved before 2005 are now available as generics. Typically, generic drugs are less expensive than the branded original, which encourages, or may mandate, the substitution of generics for the brand product to reduce pharmaceutical costs. For any drug, bioavailability is defined as the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action (1). In order for a generic AED to be approved by the FDA, manufacturers are required to show pharmaceutical equivalence and to demonstrate bioequivalence of the generic form to the original brand-name product. Pharmaceutical equivalence requires that the drug product contains the same active ingredient, dosage form and strength, and route of administration. However, it may differ in inactive ingredients (e.g., binders, excipients), manufacturing process, and physical appearance (1). Bioequivalence (BE) is achieved if the product exhibits no substantial difference in the rate and extent of drug absorption. BE is tested in single-dose pharmacokinetic generally involving 24 to 36 healthy subjects under both fed and fasting conditions (1). Statistically, the BE standard requires that the entire 90% confidence interval (CI) of the log-transformed ratios of the test/reference for the maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) fall within the bounds of 80% to 125%. This is based on the judgment that a difference <20% between products would not result in a clinically-significant problem. Therefore, the test product is not significantly less than reference (T/R = 80%) and a reference product is not significantly less than test (T/R = 80%). As all data are expressed as T/R, this becomes 100/80 or 125%. In a recent analysis of 258 BE studies of AEDs the 80% to 125% BE rule resulted in <15% variability in AUC and Cmax in 99% and 89%, respectively (2).

2014 Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequence of Seizures and Their Treatment Across The Lifespan.

Abstract: Epilepsy represents a complex spectrum disorder, with patients sharing seizures as a common symptom and manifesting a broad array of additional clinical phenotypes. To understand this disorder and treat individuals who live with epilepsy, it is important not only to identify pathogenic mechanisms underlying epilepsy but also to understand their relationships with other health-related factors. Benchmarks Area IV focuses on the impact of seizures and their treatment on quality of life, development, cognitive function, and other aspects and comorbidities that often affect individuals with epilepsy. Included in this review is a discussion on sudden unexpected death in epilepsy and other causes of mortality, a major area of research focus with still many unanswered questions. We also draw attention to special populations, such as individuals with nonepileptic seizures and pregnant women and their offspring. In this study, we review the progress made in these areas since the 2016 review of the Benchmarks Area IV and discuss challenges and opportunities for future study.

Epileptogenesis: More Than Just the Latent Period.

Abstract: Commentary Epileptogenesis is the process through which neuronal networks are altered resulting in the generation of spontaneous, chronic seizures. Epileptogenesis is thought to involve three stages: 1) the initial insult or precipitating event, 2) the latent period, and 3) the chronic epilepsy phase. It has been suggested that during the latent phase, the process of acquired epileptogenesis is completed and culminates in seizure generation (Figure 1) (1). However, the current study suggests that epileptogenesis may be progressive with continuing changes in the neuronal network extending into the chronic epilepsy period (Figure 1). In support of the idea that epileptogenesis continues into the period of chronic epilepsy is evidence for the progression of epilepsy. Over 100 years ago, British neurologist, Sir William Gowers, coined the phrase “seizures beget seizures,” which is still widely used today to indicate the progressive nature of epilepsy. The observation that seizures beget seizures was largely based on untreated patients. Today, the progression of epilepsy is more difficult to measure given the introduction of more effective anticonvulsant medications and, thus, the inability to monitor the natural progression of epilepsy in the absence of treatment. In addition, we also now appreciate the heterogeneity of the epilepsies in which there are many different types of epilepsies with differences in the underlying etiology and types of seizure presentation. While it is apparent that in some patients epilepsy is not a self-perpetuating disorder, given that seizure frequency and severity remain stable and can even regress or remit (for review, see Blume [2]); it is also clear that some patients exhibit epilepsy progression, evident by increasing seizure frequency, progressive hippocampal damage, and the development of pharmacoresistance. Several theories have been proposed regarding the mechanisms contributing to epilepsy progression, including progressive primary etiologies, such as expanding lesions and progressive neurodegeneration, development of pharmacologic resistance, and seizure-induced plasticity/ kindling (for review, see Sutula [3]). However, we still know very little about the mechanisms underlying epilepsy progression. Understanding the mechanisms contributing to the progression of epilepsy will likely require studies into the emergent properties leading to seizure activity, including circuit-level investigation into network synchronization. The use of voltage-sensitive dyes and calcium imaging enables the activity of large populations of neurons within a network to be studied. These methods have been employed to examine changes in network dynamics associated with simultaneously recorded epileptiform activity (4, 5) (for review, see Goldberg and Coulter [1] and Coulter et al. [6]). The development of in vivo imaging techniques coupled with calcium imaging allows for the activity of neurons to be measured in an intact network during abnormal spontaneous electrographic activity associated with epilepsy (7). However, these studies are typically limited to acute seizure activity rather than the evolution of epileptogenesis. Studies investigating the evolution of epileptiform activity have largely relied on in vivo cortical and depth electrode recordings or acute and chronic in vitro field potential recordings. The limitations of these types of studies are that the Evolution of Network Synchronization During Early Epileptogenesis Parallels Synaptic Circuit Alterations.

2014 Epilepsy Benchmarks Area III: Improve Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects.

Abstract: The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy-one-third of patients-emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.

2014 Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression.

Abstract: Area II of the 2014 Epilepsy Research Benchmarks aims to establish goals for preventing the development and progression of epilepsy. In this review, we will highlight key advances in Area II since the last summary of research progress and opportunities was published in 2016. We also highlight areas of investigation that began to develop before 2016 and in which additional progress has been made more recently.

2014 Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions.

Abstract: The 2014 NINDS Benchmarks for Epilepsy Research included area I: Understand the causes of the epilepsies and epilepsy-related neurologic, psychiatric, and somatic conditions. In preparation for the 2020 Curing Epilepsies Conference, where the Benchmarks will be revised, this review will cover scientific progress toward that Benchmark, with emphasize on studies since 2016.

Epileptic Encephalopathy in Infants and Children.

Abstract: Epileptic encephalopathies, defined as syndromes in which seizures or epileptiform activity contribute to or exacerbate underlying brain dysfunction, represent one of the most daunting challenges in pediatric neurology. Although individually rare, the epileptic encephalopathies collectively exact an immense personal, medical, and financial toll on affected children and their families, healthcare providers, and the healthcare system. Yet, our understanding of the basic mechanisms, clinical consequences, and therapeutic options is limited. The Neurobiology of Diseases in Children symposium at the 2015 annual meeting of the Child Neurology Society aimed to further understand the clinical aspects, neurobiology, and pathogenesis, and therapeutic opportunities for treating epileptic encephalopathies in infants and children. This article summarizes some major points discussed at the symposium, with a focus on new findings and concepts that have translational relevance. Speakers discussed both individual syndromes and common features across syndromes, with the goal of establishing research priorities to improve the care and prognosis of affected children.

Neurogenesis in Epilepsy: Better to Burn Out or Fade Away?

Abstract: Commentary The generation of hippocampal dentate granule cells continues throughout life in almost all mammalian species. The function of these new neurons remains a topic of intense scientific scrutiny; however, the general consensus from studies in rodents indicates that these neurons have roles in both spatial memory and affective behavior, with dorsal hippocampus mediating the former and ventral the latter (1). During the development of epilepsy, generation of these new neurons is profoundly disrupted. Animal models reveal a complex temporal dynamic: increased neurogenesis occurs during the days and weeks after an epileptogenic insult, but decreased neurogenesis manifests during chronic phases (2). Disrupted neurogenesis may produce both lossand gain-offunction defects (1). Loss-of-function deficits could result from reduced neurogenesis during chronic epilepsy and might contribute to epilepsy comorbidities such as cognitive impairment or depression (1, 3). Gain-of-function deficits, however, can be mediated by new neurons generated during epileptogenesis. These neurons contribute to the aberrant rewiring of the hippocampus and are hypothesized to promote epileptogenesis. Indeed, genetically ablating adult-generated neurons before an epileptogenic injury in rodents has been shown to mitigate epileptogenesis (4). The work by Sierra and colleagues provides new insights into the complex dynamics of disrupted neurogenesis in epilepsy. They developed a clever approach using different doses of kainic acid to generate either chronic epileptiform activity without overt seizures, or full-blown status epilepticus followed by the development of recurrent seizures. Proliferative activity was tracked using a transgenic mouse line that expresses green fluorescent protein in granule cell progenitors and all of their daughter cells. Both epileptiform activity and status epilepticus increased neurogenesis acutely, followed by chronic reductions in proliferation. The treatments differed, however, both quantitatively and qualitatively. While epileptiform activity decreased the number of progenitor cells by 40% within 50 days of kainic acid treatment, status epilepticus decreased the progenitor pool by greater than 90% over the same period. Exacerbating the decline, cell proliferation in mice that underwent status epilepticus switched from neuron generation to reactive astrocyte generation. Paradoxically, the transient increase in neuron production induced by epileptiform activity and seizures may drive the chronic reductions. While increased neurogenesis in itself is not necessarily harmful, granule cell progenitors are not a limitless resource. Although they are capable of self-renewal, they eventually terminally differentiate, leading to reductions in new neuron generation with age (1). Increasing neurogenesis in the short term, therefore, appears to accelerate the eventual depletion of progenitors, either slowly with modest epileptiform activity, or rapidly with a severe insult. Both treatments also have the potential to produce gainof-function deficits by promoting the production of aberrant neurons; although whether kainic acid–induced epileptiform activity is sufficient to promote aberrant integration has yet to be assessed. The rapid elimination of neurogenesis with more severe insults might have the beneficial effect of limiting the accumulation of abnormal granule cells; however, the switch from neuron production to reactive astrocyte production likely produces its own damaging effects on hippocampal function and excitability (5). Neuronal Hyperactivity Accelerates Depletion of Neural Stem Cells and Impairs Hippocampal Neurogenesis.

Epilepsy and the Sensory Systems.

Abstract: The relations of epilepsy and the sensory systems are bidirectional. Epilepsy may act on sensory systems by producing sensory seizure symptoms, by altering sensory performance, and by epilepsy treatment causing sensory side effects. Sensory system activity may have an important role in both generation and inhibition of seizures.

Cognitive Rehabilitation for Epilepsy: What Do We Really Know?:

Abstract: Commentary Cognitive impairment is a prevalent and important feature of epilepsy. It is known that more than half of the patients with epilepsy report subjective disturbances of cognition and memory, with a comparable number demonstrating impairment on objective neuropsychological tests (1). Many patients report cognitive impairment to be one of the most serious and disabling consequences of epilepsy, with significant effects on perceived disability and quality of life (2). Clinicians caring for patients with epilepsy face a number of challenges when attempting to balance the issue of cognitive impairment in relation to treatment. It is well known that there is a potential worsening of cognition with the use of many standard antiepileptic drugs (AEDs), countered by the possibility of greater levels of decline observed in those with poorly controlled seizures (3). The challenges are compounded even further when one considers the possible negative effects of surgery, which is considered the best option for treatment in those patients who remain refractory to treatment with AEDs. Results from a systematic review of epilepsy surgery literature indicate a rate of memory decline in 44% of individuals undergoing resection of the dominant left hemisphere, with rate of decline reaching 20% in those undergoing right-side resection (4). The need for effective interventions for cognitive impairment in epilepsy has been recognized for many years. Results from studies evaluating the effects of pharmacological interventions for cognitive impairment in patients with epilepsy have been disappointing, with continuing hope that some effective form of cognitive rehabilitation or another type of intervention would be developed over time to meet this important clinical need for patients receiving treatment with either AEDs or surgery (5). In terms of the latter, it is often assumed by clinicians that sending a patient for cognitive rehabilitation is an appropriate referral for patients reporting memory deficits after temporal lobe resection. This is the appropriate time to determine whether there is any empirical evidence to support that practice. Before turning to the topic of interventions for cognitive impairment following epilepsy surgery, it is instructive to turn to more general literature on cognitive rehabilitation. What Effectiveness of Cognitive Rehabilitation Following Epilepsy Surgery: Current State of Knowledge.

Attitudes Toward Epilepsy Genetics Testing Among Adult and Pediatric Epileptologists-Results of a Q-PULSE Survey.

Abstract: Epilepsy genetics is complex and involves a multitude of different candidate genes with diverse mechanisms, varying modes of inheritance, and often a broad range of phenotypes for single genes (1). Patients and families frequently request genetic testing to better understand the basis of their disease, obtain a better understanding of potential risks to future offspring, and often with the hope to personalize treatment based on the genetic finding (2). Although a genetic diagnosis has a direct treatment implication only in a small number of cases, identifying a genetic cause may help avoid unnecessary testing and offer an explanation to patients and families (3, 4). There are also risks of testing including incurring substantial patient cost, patient fear of discrimination, and obtaining variants of uncertain significance that may be confusing for physicians and families (2, 5, 6). Given these complexities and the accelerating pace of discovery in epilepsy genetics, it has become increasing challenging to understand the proper application of genetic testing in epilepsy. Although there are reviews and proposed algorithms detailing genetic testing options in epilepsy, no formalized guidelines exist to date (5, 7–9). An understanding of the current perceptions and experiences with genetic testing in epilepsy among neurologists may be instrumental in identifying knowledge gaps and barriers to testing—ultimately improving epilepsy care. This Quantitative Practical Use-Driven Learning Survey in epilepsy (Q-PULSE) of the medical directors of leading U.S. epilepsy centers was conducted to investigate the varying practices and beliefs among pediatric and adult neurologists in the utilization of epilepsy genetic testing. Survey Results

Sending Mixed Signals: The Expanding Role of Molecular Cascade Mutations in Malformations of Cortical Development and Epilepsy

Abstract: Advances in gene sequencing techniques have led to a dramatic increase in the number of signaling cascade and cytoskeletal assembly mutations associated with malformations of cortical development and epilepsy. At the forefront of this research are novel mutations found in regulators of the PI3K/AKT/mTOR cascade and tubulin-associated malformations of cortical development. However, there is limited understanding of the consequences of these newly discovered germline and somatic mutations on cellular function or how these changes in cell biology may lead to areas-large or small-of malformed cortex and recurrent spontaneous seizures. We summarize and discuss what is currently known in this field in an effort to shine light on vast gaps in our knowledge of relatively common causes of cortical malformations.

Epilepsy and Suicidality: What's the Relationship?

Abstract: Commentary Suicidal thoughts and behaviors are known to be increased among persons with epilepsy (1). Reasons for this association remain unclear, and different explanations have been proposed. One school of thought is that epilepsy itself increases the risk; this view is supported by studies finding that incident epilepsy is associated with an increased risk for a first-ever suicide attempt (2, 3). A meta-analysis of clinical trial data of 11 antiepileptic drugs (AEDs), however, led the FDA to conclude that AEDs are associated with an increased risk of suicidality relative to placebo in randomized placebo-controlled trials (4). These randomized controlled trials were not originally designed to investigate suicidality, and no information was provided about patients’ prior suicidal thoughts or behaviors or psychiatric history. This relationship is not consistently found as seen in the results of an observational study comparing the incidence rate of suicide-related events among 1) patients without epilepsy, depression, bipolar disorder, or AED treatment; 2) patients with epilepsy who did not receive AED treatment; and 3) patients with epilepsy who received AEDs (5). Adjusted analyses found that AED therapy was not associated with an increased risk of suicide-related events among patients with epilepsy. Other studies reveal yet another possible relationship in that a history of attempted suicide was associated with an increased risk of developing epilepsy (2, 3, 6). An important confounding factor or mediator is comorbid psychiatric disorders. The epilepsy community is increasingly aware of the high percentages of psychiatric disorders among persons with epilepsy. Some studies find that psychiatric disorders are associated with an increased risk of suicide completion among persons with epilepsy compared with controls Occurrence and Recurrence of Attempted Suicide Among People With Epilepsy.

STXBP1-Related EOEE - Early Onset Epilepsy AND Encephalopathy, or is it Early Onset Epileptic Encephalopathy?

Abstract: Commentary Early onset epileptic encephalopathy is an electroclinical concept that embodies the notion that the epileptic activity itself may contribute to the severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone, and this can worsen over time. In other words, even for the same pathology (etiology), a child with early onset intractable epilepsy and interictal-ictal continuum of epileptiform abnormalities is likely to show more severe and likely progressive intellectual disability (ID) (1). However, some etiologies such as the syntaxin-binding protein 1 gene (STXBP1)-related neurological disease may per se directly lead to severe epilepsy and profound ID as two independent dimensions of a severe phenotype and the notion that epileptic activity is a predominant driver of ID may not apply. Early onset epilepsy and encephalopathy (EOEE) may be a more appropriate term, and is an argument made in Stamberger et al.’s report. Authors studied genotype-phenotype spectrum of a large cohort of 147 (includes 45 previously known but unreported) patients with STXBP1 epilepsy-encephalopathy (STXBP1-EE) using a network of collaborating clinicians and geneticists. Authors also reviewed published reports. STXBP1-EE is caused by mutations in the STXBP1 gene, a membrane-trafficking protein predominantly expressed in the brain and plays an important role in the vesicular docking and fusion, a necessary mechanism for neurotransmitter secretion. STXBP1 knockout mice showed neurodegeneration after an initially normal synaptic assembly indicating that functional STXBP1 is crucial to synaptic maintenance and function (2). In the case of STXBP1 happloinsufficiency, reduced STXBP1 was shown to increase synaptic depression at both GABAergic and STXBP1 Encephalopathy: A Neurodevelopmental Disorder Including Epilepsy.

Antiepileptic drug management in the epilepsy monitoring unit: Any standards?

Abstract: No single test is more critical than video-electro-encephalography (VEEG) for the current practice of epileptology. Diagnosing nonepileptic seizures and localizing drug-resistant epilepsy are only possible when the patient’s typical spells are captured on VEEG in the epilepsy monitoring unit (EMU) (1). With a condition like epilepsy where the “typical spells” are sporadic by definition, and in an era of cautious healthcare-resource allocation favoring efficient hospitalizations, epileptologists are motivated to provoke seizures as quickly as possible during the EMU stay without compromising patient safety. The QPULSE survey highlighted in this commentary polls epileptologists about antiepileptic drug (AED) withdrawal, the main tool allowing some control over the timing of seizures in the EMU. The survey mostly assessed adult EMUs (monitoring adults exclusively in 39% of the respondents, or primarily in 38%). The results and their implications are worth considering. First, most responder EMUs don’t have a written policy for AED withdrawal: Only 38% of those that mainly monitor adults and 27% of pediatric EMUs have a written protocol for their AED tapers. One might expect then a significant variability in how and when AEDs are stopped in this context. Some of the Q-PULSE findings support this variation in practice. Around half of the survey responders said they have no consistent pattern to the sequence of AED reduction (i.e., stopping all medications at the same time vs one at a time, etc.), suggesting that these decisions are mainly made on a case-by-case basis. Another area of variability relates to allowing a preadmission taper of AEDs. Forty-seven percent of adult patients expecting an admission to an EMU that exclusively monitors adults are never allowed a pre-admission AED taper, while only 24% of them face this rule if expecting an admission to an EMU that monitors both adults and children. A pre-admission AED withdrawal is favored by some as a tool to expedite the occurrence of seizures in the EMU, thus shortening the patient’s length-of-stay, yet it is feared by others as it may carry risks of acutely worsening seizure control and causing injury before the patient is actually safely monitored in the hospital. For the same patient population (adults with uncontrolled spells), it is difficult to imagine a scientific reason that this risk–benefit calculation should vary across epilepsy centers. Given the significant value on either side of the argument and the seemingly discrepant practices across epilepsy centers, the safety and appropriateness of pre-admission AED taper should be studied further. Second, despite the lack of a written AED withdrawal policy, it is interesting to note that there are more similarities than differences in the way epilepsy centers currently handle this issue. Across centers, the rate of AED withdrawal seems to be faster for adults than children (69% reduce AED dosing by more than 33% per day for adults as opposed to 53% doing so in children). Similarly, across centers and across age groups, seizure activation maneuvers are the same, and the factors taken into account when deciding how to taper AEDs mainly revolve around risk perception (prior status or clusters, expected psychogenic nonepileptic diagnosis) and need to capture spells (seizure frequency, prior nondiagnostic VEEGs). This prevalent “homogeneity in practice,” however, should not be equated with “correctness”: One would hope that medical practice is driven by what works rather than what we have been accustomed to. The challenge here is that very few of the decisions at hand in this Q-PULSE survey are actually supported by objective data. Let’s consider the issue of how fast to reduce AEDs as an example. Recently, Rizvi et al. (2) stated that in patients with no prior history of status epilepticus, a fast taper with reduction of all AEDs (except phenobarbital) to half-dose on admission and discontinuation at 24 hours provided a close to 90% diagnostic yield with minimal risk of injury (an overall complication rate of 5%). In cases where there was a history of status epilepticus or in patients taking phenobarbital or high doses of benzodiazepines, similar results were achieved when AEDs were tapered by 25% of the initial dose and ultimately Antiepileptic Drug Management in the Epilepsy Monitoring Unit: Any Standards?

Locus Heterogeneity in Epilepsy of Infancy with Migrating Focal Seizures.

Abstract: Commentary Epilepsy of infancy with migrating focal seizures (EIMFS) is characterized by onset before 6 months of age of nearly continuous electrographic seizures with multiple areas of onset in both hemispheres (1). Migration of ictal focal discharges is the hallmark of EIMFS. In addition to seizures, there is severe psychomotor deterioration, and outcomes are generally poor. The syndrome progresses through three distinct phases: In the first phase, seizures are often sporadic and begin as focal but often evolve to generalized. In the second phase, seizures become very frequent, occurring in clusters or being almost continuous. The third phase is relatively seizure-free, although seizure clusters or status epilepticus may be precipitated by illness. Mutations in SLC12A5 in Epilepsy of Infancy With Migrating Focal Seizures.

Meaningful Results in a Jiffy - A PERC of Multicenter Collaborations.

Abstract: Wirrell EC, Shellhaas RA, Joshi C, Keator C, Kumar S, Mitchell WG; Pediatric Epilepsy Research Consortium. Collaborators: Berg A, Brooks-Kayal A, Coryell J, Dlugos D, Gaillard WD, Goodkin H, Grinspan Z, Jansen L, Knupp K, Kossoff E, Hartman AL, Joshi S, Loddenkemper T, Millichap JJ, Mytinger J, Nickels K, Nordli D, Childrens L, Ryan N, Sanchez-Fernandez I, Sullivan J, Valencia I, Wong-Kisiel L, Wusthoff C, Yozawitz E. Epilepsia 2015;56:617–625.

The Burden of Normality in the Epilepsy Postsurgery Setting: Out With the Old and in With the New (…Roles).

Abstract: Commentary Over the past few decades, there have been unrelenting clinical and research efforts aimed at the eradication of intractable seizures. Through steady advances in pharmacologic sciences, neurosurgical intervention, and device interventions, exciting improvements in epilepsy care and outcomes are occurring. In that vein, numerous studies have documented an upward trend of people being “cured” (i.e., becoming seizurefree) following surgical intervention even in situations of life-long seizures and multiple anti-epileptic drug (AED) attempts (1). More recently, newer approaches (i.e., responsive neurostimulation) are beginning to make their mark in the intervention arena of epilepsy treatment, with the potential for significant seizure reduction/freedom, as well as potentially lower cognitive morbidity (2). In particular, surgery has historically been offered in the context of a medical team presenting, in certain clinical cases, an offer of a potential “cure,” and then a patient subsequently receives that intervention “cure.” The next step is that the patient who attains that seizure-freedom begins a journey that includes living with the “cure.” Within this setting of growing surgery and device-assisted populations of people (formerly having chronic epilepsy but now having achieved seizure-freedom), there is a large group of studies assessing how this new-found seizure-freedom has affected their quality of life (QOL) across aspects of social, emotional, vocational, and recreational functioning. In general, QOL improvements are found across most studies (3, 4). However, this has not always been the outcome when examined on a case-by-case basis. It has been shown that some people experience little to no QOL change, or even decline. Within this paradoxic context of medical “cure” but psychosocial/psychiatric “non-cure,” researchers have introduced and explored the concept of “burden of normality” for postoperative epilepsy populations. Originally introduced in 1992 by Bladin (5) and later expanded upon, (6, 7) it was shown that a sizable number of people rendered seizure-free were displaying continued preoperative adjustment problems or even developing de novo postoperative adjustment difficulties (i.e., sick role behaviors, family dysfunction, occupational disability). This group’s work via in-depth, structured, patient and family interviews describes heterogeneous individual trajectories of adjustment change following epilepsy surgery, which evolved to both positive and negative outcomes across various psychosocial dimensions (8). These findings reveal that often people with longstanding epilepsy who achieved seizure-freePredicting the Psychosocial Outcome of Epilepsy Surgery: A Longitudinal Perspective on the ‘Burden of Normality.’

Responsive Neurostimulation and Cognition.

Abstract: Commentary Cognition can suffer collateral damage in the battle against seizures. This is unsurprising because antiseizure therapy, directed against aberrant neuronal activity, may affect normal neuronal function. Although simplistic, an analogy can be made with antibiotic therapy for infection or chemotherapy for cancer: treatment exploits differences between host and bacterium or tumor cells, but shared characteristics of host and target may result in toxicity. Similarly, antiseizure therapy imperfectly targets rapidly firing neurons and may have spillover effects on normal neuronal function. Adverse cognitive effects of antiepileptic drug (AED) therapy are common, can be substantial, and have been well demonstrated in people with epilepsy and in healthy individuals who are assessed while on therapy (1, 2). Other treatments for epilepsy are also known to have a potential cognitive cost. Surgical treatment of epilepsy involves resection of an epileptogenic zone that may often include functional tissue. For example, a decline in verbal memory is often noted following dominant temporal lobe surgery, particularly when markers of preserved function such as normal hippocampal size and high preoperative verbal memory scores are present. Still, successful epilepsy surgery can have positive cognitive benefits. Seizure freedom may arrest the accelerated decline in cognition seen with chronic refractory epilepsy. Observed improvements in some cognitive domains following surgery may be a consequence of the release of relatively normal connected networks from the influence of the resected nociferous cortex. Neurostimulation, working by modulating rather than ablating epileptogenic tissue, would seem to have neurocognitive advantages over resection. Yet there have been mixed signals with regard to the cognitive effects of neurostimulation. Approximately 15 to 20 percent of Parkinson disease patients treated with deep brain stimulation (DBS) of the subthalamic nucleus experience negative neuropsychological or neurobehavioral sequelae (3, 4). In the pivotal trial of DBS of the anterior nucleus of the thalamus for treatment of epilepsy, there were significantly more reports of memory impairment and depression in the active stimulation than sham stimulation group (5). However, objective neuropsychological assessment of cognition and mood did not differ between the groups at the end of the blinded phase. Recent work has suggested that disruption of sleep by thalamic stimulationinduced arousals might explain the possible negative effects Differential Neuropsychological Outcomes Following Targeted Responsive Neurostimulation for Partial-Onset Epilepsy.

Temporal plus Epilepsy: Epileptic Territory beyond the Temporal Lobes:

Abstract: Commentary Temporal lobe resections have been performed for drugresistant epilepsy for more than half a century (1). Despite many advances in clinical description of syndromes, imaging, and neurophysiology, a significant percentage of patients do not become seizure free after surgery. On average, only about 65% of patients are seizure free long term (1). The reasons why surgery fails remain speculative. Possible explanations include the following:

Not Necessarily Benign: Rolandic Epilepsy.

Abstract: Commentary Appreciating the cognitive outcome of benign rolandic epilepsy (BRE) is an important endeavor, not only because it is the most common form of childhood epilepsy, but because BRE may provide a window from which to view the broader developmental consequences of epileptic activity in childhood or the presumed, yet unknown, consequences of interictal epileptic discharges (IEDs). Given typical early development and onset of seizures at approximately ages 5 to 7 years along with few clinical seizures, no structural abnormalities, few medications prescribed, and abundant focal IEDs, the study of children with BRE provides an opportunity to understand the concept of epileptic encephalopathy in a relatively mild form. This meta-analysis of literacy and language in children with rolandic epilepsy is illuminating and also consistent with the experiences of those of us who work clinically with children with BRE and conduct research with this population. Aggregating multiple small sample studies of BRE patients, it is clear that reading difficulties, along with phonological processing weaknesses, are present in children with BRE as a group, relative to healthy controls. Moreover, expressive and receptive language function are vulnerable in the population relative to healthy controls, and interestingly, this effect appears to be greater in older children than younger despite the fact that children with BRE are known to outgrow the syndrome in early to midadolescence (1). There is debate in this field about how benign BRE really is in terms of cognitive morbidity and to what degree this group of patients “out-grows” deficits over time. It is quite unlikely that seizures themselves contribute to cognitive limitations given the few clinical seizures observed in the typical BRE syndrome relative to reported learning and cognitive processing symptoms. Associations between cognitive function and IEDs have been variable across studies, as noted in the background section of the meta-analysis that is the target of this commentary. While the specific role of IEDs may not be elucidated as of yet, it is plausible that abnormal electrical activity is a signal of neurological dysfunction that has the potential to disrupt neural network function and development. With this in mind, the laterality, frequency, and age of onset of this abnormal pattern, theoretically, would all have the potential to contribute to cognitive dysfunction both during the active phase of the syndrome and over time due to developmental disruption by IEDs. Should evidence eventually identify a developmental cost associated with IEDs, such as verbal learning limitations as discussed here, then clear implications for treatment paradigms to suppress IEDs and support developmental progression would warrant a call for placebo controlled antiepileptic drug trials for BRE with cognitive outcome and IED suppression as the primary outcomes. However, the potential cost of negative neurodevelopmental effects of long-term AED use during the developmental period would need to be weighed against the potential benefit of IED suppression. Considering the developmental timing of the onset of the BRE syndrome is important. In this meta-analysis the average A Meta-Analysis Of Literacy And Language In Children With Rolandic Epilepsy.

Imaging Brain Inflammation: If We Can See It, Maybe We Can Treat It.

Abstract: Commentary Recently, neuroinflammation has been big news and a target of intense investigation for many diseases of the central nervous system, including Alzheimer’s disease, multiple sclerosis, and stroke. In each case, neuroinflammation is thought to contribute to the pathology; therefore, anti-inflammatory therapy has been contemplated as a potential intervention. The same has been true in epilepsy. Several studies have suggested that seizures initiate an inflammatory cascade, leading to upregulation of reactive astrocytes, and microglial cells, and production of cytokines such as Interleukin-1β Interleukin-6, and tumor necrosis factor (TNF)-α (1). This type of inflammation is called “innate” inflammation, to differentiate it from inflammation that can be present as part of the underlying etiology of some epilepsies, such as autoimmune diseases and brain infections. In contrast, innate inflammation is thought to be triggered by any etiology that can produce seizures and results, in part, from the seizures themselves. As noted by Theodore and colleagues in this article, this inflammatory cascade could then lead to brain hyperexcitability through a number of pathways, triggering more seizures and leading to a perpetuating cycle of excitation, seizures, and inflammation. Drugs that block this cycle Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein.

Generic Substitution of AEDs: Is it Time to Put This Issue to Rest?

Abstract: Commentary Few issues in the clinical management of epilepsy have resulted in as much controversy, confusion, and angst as the issue of generic substitution of antiepileptic drugs (AEDs) (1, 2). Surveys of both clinicians and patients have suggested an increasing level of concern over the introduction of multiple generic formulations of virtually all of our commonly used medications (3). Fueling these concerns are reports, including anecdotal reports, and retrospective database analyses that suggest both worsening of seizure control and increased healthcare costs, coincident with the generic substitution of AEDs (4–6). Data analyses by Krauss et al. further raise the questions regarding generic-to-generic substitution of approved AEDs (7). These concerns have prompted several professional societies, including the American Epilepsy Society and the American Academy of Neurology, to oppose generic substitution in patients with epilepsy without prior authorization by both physician and patient. These concerns are well placed given that many of our patients are “brittle,” meaning that minor variations in AED plasma concentrations appear to be associated with either breakthrough seizures or adverse effects. Despite these concerns, generic substitution in all areas of medicine is here to stay. Between 2003 and 2012, use of generics resulted in over $1.2 trillion in savings to the U.S. healthcare system.(8). The dilemma becomes how to reconcile the obvious economic benefits of generic drugs with the clinical perceptions of risk in our patients with epilepsy? The keyword here is perceptions. Until recently, much of our evidence was comprised of either personal experience, or retrospective pharmacy claims analyses utilizing surrogate indicators. There was a paucity of prospective, controlled pharmacokinetic (PK) Generic Lamotrigine Versus Brand-Name Lamictal Bioequivalence in Patients With Epilepsy: A Field Test of the FDA Bioequivalence Standard.

Cannabidiol Mellows Out Resurgent Sodium Current.

Abstract: Commentary Mutations in voltage-gated sodium channel genes are responsible for several epilepsy syndromes with a wide spectrum of clinical severity. For example, genetic epilepsy with febrile seizures plus (GEFS+) is relatively mild and has been associated with SCN1A missense mutations that encode NaV1.1 channels with subtle biophysical defects (1–4). At the other end of the spectrum, Dravet syndrome is a severe epileptic encephalopathy with multiple seizure types and impairment of psychomotor and cognitive development, most often caused by de novo SCN1A mutations resulting in loss of NaV1.1 function (4, 5). SCN8A epileptic encephalopathy is an emerging syndrome with multiple seizure types and cognitive impairment caused by de novo gain-of-function mutations in the SCN8A gene that encodes the NaV1.6 voltage-gated sodium channel (6, 7). The gain-of-function effects include increased resurgent sodium current that is predicted to increase neuronal excitability. Cannabidiol has received abundant media attention as a potential therapy for intractable epilepsy, based mainly on anecdotal evidence. Although it has shown some promise in an open-label trial of severe childhood-onset intractable epilepsy (8), the results of a randomized double-blind placebo-controlled trial are yet to be published. Another point of uncertainty surrounding cannabidiol is the mechanism underlying the potential anticonvulsant effect. Interestingly, other cannabinoids have been shown to inhibit voltage-gated sodium channels and, in some cases, preferentially inhibit resurgent current over peak transient current (9,10). In the current study, Patel and colleagues perform a detailed neurophysiological characterization of epilepsy-associated NaV1.1 and NaV1.6 mutations to determine if they result in aberrant resurgent current using heterologous expression of wild-type and mutant sodium channels. Additionally, they examined whether cannabidiol preferentially inhibits resurgent sodium current of both wild-type and mutant sodium channels. Finally, they probed the effect of cannabidiol on intrinsic firing properties of cultured striatal neurons, a neuronal population with significant resurgent current. A major question of this study is whether epilepsy syndromes resulting from mutations in NaV1.1 or NaV1.6 arise via Aberrant Epilepsy-Associated Mutant Nav1.6 Sodium Channel Activity Can Be Targeted With Cannabidiol.

How and Why Study Posttraumatic Epileptogenesis in Animal Models

Abstract: Traumatic brain injury (TBI) greatly increases the risk of medically intractable epilepsy. Several models of TBI have been developed to investigate the relationship between TBI and posttraumatic epileptogenesis. Because the incident that precipitates development of epilepsy is known, studying mechanisms of epileptogenesis, identifying biomarkers to predict PTE, and developing treatments to prevent epilepsy after TBI are attainable research goals.

Microglial TLR9: Guardians of Homeostatic Hippocampal Neurogenesis

Abstract: Commentary Epileptogenesis is a multifaceted process in which various cellular components contribute to the development of epilepsy. Among them, aberrant hippocampal neurogenesis induced by acute seizures is thought to be among the crucial players in the generation of spontaneous recurrent seizures and memory impairment (1, 2). However, the cellular and molecular mechanisms that regulate seizure-induced aberrant neurogenesis in the hippocampus remain largely unknown. In this study, Matsuda et al. elegantly showed that microglial activation after kainic acid (KA)-induced seizures could affect chronic seizure susceptibility and memory function by modulating the proliferation of hippocampal neural progenitors. With genetic and pharmacological manipulation of microglial activation, in addition to a conditioned medium-based cell culture system, the authors demonstrated microglial mechanisms controlling seizure-induced aberrant hippocampal neurogenesis. In their study, self-DNAs—possibly derived from nearby dead or degenerating neurons—could stimulate microglial Toll-like receptor 9 (TLR9), which triggered TNF-α production via the NF-κB signaling pathway, resulting in the reduced proliferation of neural progenitor cells in the epileptic dentate gyrus. Microglia (resident immune cells in the brain) have long been considered to play deleterious roles in epileptogenesis (3). Activated by various brain insults, microglia produce and secrete proinflammatory cytokines such as interleukin-1 (IL-1) and TNF-α. This cytokine surge turns on downstream signaling cascades, leading to histopathological outcomes and functional impairment. However, other studies have suggested that microglia have positive roles in epilepsy by secreting antiinflammatory cytokines, including IL-4, IL-10, and TGF-β. The paper discussed here supports the beneficial side of microglia. For example, both inhibition of microglial activation using minocycline or suppression of TNF-α by thalidomide aggravated seizure-induced enhanced proliferation in the dentate gyrus. Interestingly, considering that minocycline is an inhibitor of proinflammatory cytokine-producing microglia, the authors suggest a novel mechanism of proinflammatory microglia affecting epileptogenesis and a new positive effect of microglia in epilepsy. Since microglia can display proand anti-inflammatory functional states—depending on the different combinations of inducing factors, which largely fluctuates during the course of epileptogenesis—it will be interesting to further investigate the temporal pattern of alternating microglial states and their specific roles in aberrant hippocampal neurogenesis. TLRs are pattern-recognition receptors that respond to pathogen-associated molecular patterns (PAMPs) or damageassociated molecular patterns (DAMPs). Ever since the first human TLR was identified (4), many additional TLRs have been extensively studied in the brain. In adult hippocampus, TLR4 deficiency was shown to induce the proliferation of hippocampal progenitor cells (5). Moreover, TLRs are involved in cell fate choice. For example, TLR2 deletion promotes astrocyte differentiation at the expense of neurogenesis, while TLR4 deficiency promotes neuronal differentiation without affecting astrocyte differentiation (5). As expected, TLRs can also affect the survival of newborn granule cells, given that TLR3-deficient mice showed an increased number of adult-generated mature neurons (6). As for TLR9, the authors found no difference in the TLR9 Signalling in Microglia Attenuates Seizure-Induced Aberrant Neurogenesis in the Adult Hippocampus.

A MAP of Seizure-Freedom in Patients with a Normal MRI Scan.

Abstract: 4. Because of #3, new techniques are often first tested in the only well-characterized form of focal epilepsy we have, which is medial temporal lobe epilepsy. Of course, this is precisely the type for which we already have good tests, which is why it is better characterized. Furthermore, it is the form of epilepsy for which we have less need of such new techniques, since surgical outcomes are quite good. In this setting, generalizability to more challenging cases becomes much less certain.