Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Closing the Major Gap in PNES Research: Finding a Home for a Borderland Disorder.

Psychogenic nonepileptic seizures (PNES) are events commonly encountered by primary care physicians, neurologists, pediatricians, and emergency medicine physicians in their practices, yet there continues to be significant variability in the way they are evaluated, diagnosed, and treated. Lack of understanding this condition and limited data on long-term outcome from current treatment paradigms have resulted in an environment with iatrogenic injury, morbidity, and significant costs to the patient and healthcare system. This article will review the current state of research addressing PNES treatment both in the adult and pediatric populations.

Analysis of scalp EEG and quantitative MRI in cases of temporal lobe epilepsy requiring intracranial electrographic monitoring.

Abstract Purpose. Contradictory scalp electroencephalographic (sEEG) and discordant imaging features are common in temporal lobe epilepsy (TLE). We assessed the relative importance of sEEG features and their relation to quantitative magnetic resonance (MR) imaging measures in regard to surgical outcome. Methods and materials. Patients with a putative TLE underwent extraoperative electrocorticography (eECoG) with bitemporal subdural electrodes for clarification of the ictogenic source. Patients were categorized by sEEG ictal patterns (IPs) as showing unilateral or bilateral onset. Concordance with the side of resection, as determined by eECoG, to that suggested by the predominant sEEG IP was further analysed as: (a) entirely ipsilateral eECoG IPs with discordant nonelectrographic data; (b) ipsilateral preponderant (> 80%) eECoG IPs; and c) contralateral preponderant (> 80%) eECoG IPs. Quantitative hippocampal volumes and signal characteristics were applied for comparison. Results. Of 26 patients, eECoG confirmed a unilateral IP on sEEG in 19 (73%). Of these 19, exclusively ipsilateral sEEG interical epileptiform discharges (IEDs) were identified in 9 (47%). When bilateral, generalized, absent or contralateral IEDs were found, 6 cases (60%) still showed a preponderantly ipsilateral IP identifying the epileptogenic side. In patients with sEEG bilateral IPs, 5 (71%) also had bilateral IEDs. Of the 16 patients who underwent resection, 14 (87.5%) achieved favourable outcomes and 9 (56%), seizure cessation. Hippocampal volumetry in 23 patients correctly lateralized 7 (30%) whereas fluid-attenuated inversion recovery (FLAIR) signal measures applied in 23 patients lateralized 9 (39%). Conclusions. Favourable surgical outcomes are attainable following eECoG in cases where ambiguity exists regarding the laterality of TLE on sEEG, even for those in whom bilateral IPs and either bilateral or no IEDs are demonstrated on sEEG. Neither volumetric nor FLAIR signal ratios were sufficiently reliable for lateralizing TLE in the majority of cases.

Diagnosis, costs, and utilization for psychogenic non-epileptic seizures in a US health care setting.

BACKGROUND: Psychogenic non-epileptic seizures (PNES) pose a substantial burden to patients and the health care system, due to long diagnostic and treatment delays. METHODS: This study used medical chart notes from 103 patients to shed light on the diagnostic process. Electronic medical records and cost data from a US health system were also used to investigate costs and utilization for the 12-months before and after PNES diagnosis. RESULTS: The results show that accurate diagnosis was typically achieved via the use of multiple medical tests, including vEEG, magnetic resonance imaging (MRI), and computed tomography (CT) scans, as well as historical diagnostic and clinical information. In the year following PNES diagnosis, a decline in average visits (-1.45) and costs (-$1784) were observed. The largest cost savings were seen in neurology care and inpatient stays. CONCLUSIONS: This study has implications for timely and accurate diagnosis of PNES, which may decrease the overall health care burden for individuals and the health care system.

Ictal barking as a manifestation of temporal lobe epilepsy.

Ictal nonspeech vocalizations have been described as manifestations of either frontal or temporal epileptogenicity originating mainly from the dominant hemisphere. Ictal barking, particularly, has been considered a manifestation of mesial frontal epilepsy. A 42-year-old right-handed male with posttraumatic drug-resistant complex partial epilepsy manifested ictal barking near electrographic onset. Extraoperative electrocorticography with subdural electrode coverage of the right frontoparietal and temporal and left frontal surfaces provided surveillance of ictal origin and propagation. Ictal origin was identified in the right mesial temporal lobe with barking vocalization manifesting within 3s of electrographic onset. No subsequent spread of activity was noted beyond the temporal lobe. Resection of the mesial temporal structure resulted in seizure freedom. Pathology identified hippocampal sclerosis. This case supports the notion that an intrinsic, intralobar epileptogenic neural network in either hemisphere can act as a conduit into the limbic and memory circuits without a laterality bias to manifest as barking.

Management of epilepsy in drug-resistant patients.

Epilepsy affects > 2 million people in the United States, making it one of the most common neurobiological conditions. Typically, epilepsy is treated with one of several available antiepileptic drugs and patients are able to experience freedom from seizures with minimal side effects. However, there are some patients who do not respond to treatment and require the use of multiple drug combinations or surgical intervention. Although there are few studies supporting its use, multi-drug regimens have been known to be helpful for patients, although clinicians should monitor patients for adverse side effects. Vagus nerve stimulation is the only US Food and Drug Administration-approved surgical neurostimulation therapy for epilepsy, and patients' conditions often progress for many years before epilepsy surgery options are considered. Lastly, due to the chronic nature of epilepsy, clinicians should be aware of the presence of comorbid psychiatric conditions as well. This supplement is Part One in the "Case in Point: Evidence-Based Insights for Epilepsy Management" series. In this Expert Review Supplement, Andrew J. Cole, MD, FRCPC, outlines a case of a patient with drug resistant epilepsy, and Brien J. Smith, MD, outlines the best practices for the case patient including discussion on defining drug resistance in patients as well as the benefits and risks of available and emerging drug and surgical treatments.

The burden of epilepsy to patients and payers.

The extraordinary burden of epilepsy on quality of life (QOL) is well known, as is the very high economic burden associated with the disease. Epilepsy is associated not only with seizures, but also a variety of serious comorbidities, including respiratory, cardiovascular, and neurologic dysfunctions. Psychiatric conditions are very prevalent in the epilepsy population, and may have pathological mechanisms in common with epilepsy. Compared with healthy controls, patients with untreated epilepsy have scored significantly worse across a spectrum of neurocognitive tests. Patients with epilepsy and comorbidities-neurocognitive or otherwise-engage in higher rates of healthcare utilization than those without comorbidities. This, in part, explains why approximately 80% of overall medical costs for patients with epilepsy are for non-epilepsy-related care. The key driver of direct costs in epilepsy is medical service expenditures. For uncontrolled seizure disorders, this becomes even more problematic as medical service use increases. At the same time, the proportional cost of antiepileptic medications decreases as other costs escalate. Although the direct costs of epilepsy are substantial, the overwhelming majority of total costs, as much as 86%, are attributable to indirect costs such as job absenteeism. Ultimately, the burden of epilepsy for patients, in terms of severely reduced QOL, and for payers, in terms of both direct and indirect costs, would be best addressed and reduced by achieving optimal control of seizures.

Concerns with AED conversion: comparison of patient and physician perspectives.

When discussing AED conversion in the clinic, both the patient and physician perspectives on the goals and risks of this change are important to consider. To identify patient-reported and clinician-perceived concerns, a panel of epilepsy specialists was questioned about the topics discussed with patients and the clinician's perspective of patient concerns. Findings of a literature review of articles that report patient-expressed concerns regarding their epilepsy and treatment were also reviewed. Results showed that the specialist panel appropriately identified patient-reported concerns of driving ability, medication cost, seizure control, and medication side effects. Additionally, patient-reported concerns of independence, employment issues, social stigma, medication dependence, and undesirable cognitive effects are important to address when considering and initiating AED conversion.

Direct medical costs for patients seeking emergency care for losses of epilepsy control in a U.S. managed care setting.

The objective of this retrospective claims database study was to compare the costs of care from a U.S. payer perspective before and after epilepsy treatment in emergent care settings and, secondarily, to describe the frequency of toxic effects and physical injuries occurring on the date of the emergent care. Nine and four-tenths percent of patients receiving emergent care for epilepsy (114/1213) had an injury or adverse antiepileptic drug effect on the same date. The majority of incidents were superficial injuries and contusions (28%), fractures (21%), open wounds or injury to blood vessels (19%), intracranial injury (10%), and/or medication toxicity (10%). Both non-epilepsy-related (US$12,745.56) and epilepsy-related (US$2013.62) direct medical costs of care pre-index were significantly different from those post-index (US$15,274.95 and US$7087.53, respectively). The cost of care for possible reestablishment of epilepsy control and treatment of co-occurring injuries is significant when compared with that for the period prior to seizure.

Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes.

PURPOSE: Although antiepileptic drugs (AEDs) with multisource generic alternatives are becoming more prevalent, no case-control studies have been published examining multisource medication use and epilepsy-related outcomes. This study evaluated the association between inpatient/emergency epilepsy care and the occurrence of a recent switch in AED formulation. METHODS: A case-control analysis was conducted utilizing the Ingenix LabRx Database. Eligible patients were 12-64 years of age, received >or=145 days of AEDs in the preindex period, had continuous eligibility for 6 months preindex, and no prior inpatient/emergency care. Cases received care between 7/1/2006 and 12/31/2006 in an ambulance, emergency room, or inpatient hospital with a primary epilepsy diagnosis. Controls had a primary epilepsy diagnosis in a physician's office during the same period. The index date was the earliest occurrence of care in each respective setting. Cases and controls were matched 1:3 by epilepsy diagnosis and age. Odds of a switch between "A-rated" AEDs within 6 months prior to index were calculated. RESULTS: Cases (n = 416) had 81% greater odds of having had an A-rated AED formulation switch [odds ratio (OR) = 1.81; 95% confidence interval (CI) = 1.25 to 2.63] relative to controls (n = 1248). There were no significant differences between groups regarding demographics or diagnosis. Significant differences were found with regard to medical coverage type (case Medicaid = 4.6%, control Medicaid = 1.8%, p = 0.002). Post hoc analysis results excluding Medicaid recipients remained significant and concordant with the original analysis. DISCUSSION: This analysis found an association between patients receiving epilepsy care in an emergency or inpatient setting and the recent occurrence of AED formulation switching involving A-rated generics.

A survey of neurologists' views on epilepsy surgery and medically refractory epilepsy.

There is a 20-year delay between the diagnosis of epilepsy and surgical treatment. The aim of this study was to describe the different views held by neurologists regarding refractory epilepsy that may contribute to the delay in referring patients for epilepsy surgery. Neurologists in Michigan were mailed a 10-item survey inquiring about their definition of medically refractory epilepsy and their decision-making process in referring patients for epilepsy surgery. Eighty-four neurologists responded (20%). The majority defined medically refractory epilepsy as failure of three monotherapy antiepileptic drug (AEDs) trials and at least two polytherapy trials. Nineteen percent responded that all approved AEDs had to fail before a patient could be defined as medically refractory. Eighty-two percent of the respondents had referred patients for epilepsy surgery. Almost 50% were not satisfied with the level of communication from epilepsy centers. One-third reported serious complications resulting from surgery. These findings suggest that further education and improved communication from comprehensive epilepsy centers may shorten the time to referral and ultimately improve the lives of patients with epilepsy.

Conversions between monotherapies in epilepsy: expert consensus.

To develop expert consensus for conversion between antiepileptic drug (AED) monotherapies, an 11-member panel used the Delphi Technique over three rounds to: (1) identify relevant issues, (2) vote on the issues, and (3) develop consensus. The panel agreed on the basic principle to taper the existing AED only after a presumably efficacious dose of the planned AED was reached. Application is modified by adverse effects possibly attributable to the existing drug, in which case earlier or more rapid tapering of the existing drug should be considered. Patients with uncontrolled seizures, as well as seizure-free patients for whom driving privileges are a consideration, may benefit from slower tapering by smaller dosage decrements of the existing AED. For 10 of the 12 AEDs considered, the panel made titration recommendations concerning initial and target doses for the planned AED, supplementing limited data in the prescribing information. This expert guidance will aid in the period of transitional polytherapy with AEDs from monotherapy to monotherapy.

Vasovagal syncope misdiagnosed as epilepsy for 17 years: prime importance of clinical history.

Distinguishing epilepsy from syncope often can be challenging. We report a case of a 20-year-old patient with presumed refractory epilepsy since the age of 3 years. Although the clinical suspicion of syncope was raised at the age of 9 years, key historic features were not identified, cardiac work-up was not pursued and despite lack of electrographic evidence of epilepsy, he received anticonvulsant treatment. During his presurgical evaluation for "refractory epilepsy", one typical event was captured that was associated with asystole and normal electroencephalogram. The diagnosis of vasodepressor syncope was made and anticonvulsant medication was discontinued. With this case report, we would like to emphasize the importance of a meticulous history and the need to perform continuous video electroencephalographic with simultaneous electrocardiographic recordings in the evaluation of paroxysmal events with atypical presentation. [Published with video sequences].

Magnetoencephalographic localization of the basal temporal language area.

Magnetoencephalography (MEG) recordings were made on 25 native English-speaking patients with localization-related epilepsy during a semantic language task (verb generation). Eighteen right-handed subjects with normal reading ability had MEG scans performed during the same language task. MEG data was analyzed by MR-FOCUSS, a current density imaging technique. Detectable MEG signals arising from activation in the left fusiform gyrus, also known as the basal temporal language area (BTLA), occurred at 167 +/- 18 ms (n = 43) in all subjects. The BTLA has been associated with a variety of language production and comprehension tasks involving processing of semantic, orthographic, and phonologic information. MEG may become an important tool in efforts to further define the linguistic operations of specific regions within this language area.

Language laterality determined by MEG mapping with MR-FOCUSS.

Magnetoencephalography recordings were made on 27 patients with localization related epilepsy during two different language tasks involving semantic and phonological processing (verb generation and picture naming). These patients underwent the semi-invasive intracarotid amobarbital procedure (IAP), also referred to as the Wada test, to determine the language-dominant hemisphere. Magnetoencephalography (MEG) data were analyzed by MR-FOCUSS, a current density imaging technique. A laterality index (LI) was calculated from this solution to determine which hemisphere had more neural activation during these language tasks. The LIs for three separate latencies, within each language task, were calculated to determine the latency that correlated best with each patient's IAP result. The LI for all language processing was calculated for the interval 150-550 ms, the second LI was calculated for the interval 230-290 ms (Wernicke's activation), and the third LI was calculated for the interval 396-460 ms (Broca's activation). In 23 of 24 epilepsy patients with a successful IAP, the LIs for Broca's activation, during the picture naming task, were in agreement with the results of the IAP (96% agreement). One of three patients who had an undetermined or bilateral IAP had an LI calculated for Broca's activation (396-460 ms) that agreed with intracranial mapping and clinical testing. These results indicate an 89% agreement rate (24 of 27) for magnetoencephalographic LI determination of the hemisphere of language dominance.