Patterns of antiseizure medication utilization in the Human Epilepsy Project.

OBJECTIVE: This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially started on monotherapy. METHODS: The data were derived from the Human Epilepsy Project. Differences between the durations of the most commonly first prescribed ASM monotherapies were assessed using a Cox proportional hazards model. Subjects were classified into three groups: monotherapy, sequential monotherapy, and polytherapy. RESULTS: A total of 443 patients were included in the analysis, with a median age of 32 years (interquartile range [IQR] = 20-44) and median follow-up time of 3.2 years (IQR = 2.4-4.2); 161 (36.3%) patients remained on monotherapy with their initially prescribed ASM at the time of their last follow-up. The mean (SEM) and median (IQR) duration that patients stayed on monotherapy with their initial ASM was 2.1 (2.0-2.2) and 1.9 (.3-3.5) years, respectively. The most commonly prescribed initial ASM was levetiracetam (254, 57.3%), followed by lamotrigine (77, 17.4%), oxcarbazepine (38, 8.6%), and carbamazepine (24, 5.4%). Among those who did not remain on the initial monotherapy, 167 (59.2%) transitioned to another ASM as monotherapy (sequential monotherapy) and 115 (40.8%) ended up on polytherapy. Patients remained significantly longer on lamotrigine (mean = 2.8 years, median = 3.1 years) compared to levetiracetam (mean = 2.0 years, median = 1.5 years) as a first prescribed medication (hazard ratio = 1.5, 95% confidence interval = 1.0-2.2). As the study progressed, the proportion of patients on lamotrigine, carbamazepine, and oxcarbazepine as well as other sodium channel agents increased from a little more than one third (154, 34.8%) of patients to more than two thirds (303, 68.4%) of patients. SIGNIFICANCE: Slightly more than one third of focal epilepsy patients remain on monotherapy with their first prescribed ASM. Approximately three in five patients transition to monotherapy with another ASM, whereas approximately two in five end up on polytherapy. Patients remain on lamotrigine for a longer duration compared to levetiracetam when it is prescribed as the initial monotherapy.

The cenobamate-clobazam interaction- evidence of synergy in addition to pharmacokinetic interaction.

OBJECTIVES: Report insights into the pharmacokinetic and pharmacodynamic interaction between cenobamate (CNB) and clobazam (CLB), derived from data in patients enrolled at our center in a global multicenter open-label safety study of CNB. MATERIALS & METHODS: Patients in this study either took CLB at baseline (n = 6) or had CLB added after CNB titration to maximal dose (n = 5) in addition to other antiseizure medications. Clobazam was always administered as a single bedtime dose. Random serum concentrations of CLB and N-desmethylclobazam (N-CLB) were obtained. RESULTS: Baseline daily CLB doses were 20-50 mg. Sedation began in the six baseline CLB patients at CNB doses of 25-100 mg. The N-CLB/ CLB ratio increased proportionally to the CNB dose. CLB was stopped in all six patients, five of whom were ≥50% responders. Seizure control deteriorated after stopping CLB, with only one remaining responder. Clobazam was restarted at 5 mg/d in five of the six patients. At the last follow-up, four of these patients were continuing CLB; two were seizure-free and 2 were ≥50% responders. Among the five patients that added 5 mg/d CLB de novo, three were responders. All patients were still on CNB at the end of the study. DISCUSSION: Data suggest starting CLB dose reduction at CNB doses of 25-100 mg/d. Due to possible synergy, the addition of low-dose CLB could be considered in patients with incomplete response to CNB.

Retrospective analysis of nurse-administered fall assessment scales in the Epilepsy Monitoring Unit.

INTRODUCTION: Inpatient falls within the Epilepsy Monitoring Unit (EMU) are a common, and potentially preventable adverse event contributing to morbidity for patients living with epilepsy. Accurate fall risk screening is important to identify and efficiently allocate proper safety measures to high-risk patients, especially in EMUs with limited resources. We sought to compare existing screening tools for the ability to predict falls in the EMU. METHODS: This is a retrospective, single-center, case-controlled, comparative analysis of 7 nurse-administered fall risk assessment tools (NAFRAT) of patients admitted to the Vanderbilt University Medical Center (VUMC) EMU. Analysis of categorical data was compared using chi-square analysis while quantitative distributions were compared using student's t-test. RESULTS: A total of 56 patient records (28 falls and 28 controls) were included in the analysis. Epilepsy Monitoring Unit falls were most common within the first 3 days of admission (p = .0094). Pre-admission documentation of falls was a strong predictor of falls within the EMU (p < .0001). Epilepsy Monitoring Unit falls were associated with documented falls after EMU discharge (p = .011). The John Hopkins fall risk assessment tool (JHFRAT) accurately stratified fall risk in the fall group compared to the control (p = .008), however, none of the 7 NAFRATs demonstrated significant categorical differences among the epilepsy subgroups. There was a significant difference in the distribution of quantitative scores, higher in the fall group according to the Morse Fall Scale (MFS) (p = 0.012), JHFRAT (p = 0.003), Schmid Fall Risk Assessment Scale (p = 0.029) and Hester-Davis Scale (p = 0.049). The modified Conley (p = 0.03) and Morse scale (p = 0.025) demonstrated differences in the distribution of quantitative scores in the epilepsy subgroups. CONCLUSION: The findings of this study demonstrate variable accuracy of NAFRATs in assessing fall risk among patients admitted to the EMU, particularly among patients with epilepsy. The findings underscore the need for a validated, EMU-specific, fall assessment tool that accurately stratifies fall risk and inform efficient use of patient-specific fall prevention resources and protocols.

Epilepsy with anterior temporal encephaloceles: Baseline characteristics, post-surgical outcomes, and comparison to mesial temporal sclerosis.

OBJECTIVE: To review clinical and neuropsychological characteristics and natural history of a series of patients with temporal lobe epilepsy (TLE) and anterior temporal encephaloceles (ATE) and compare them to a similar series of TLE patients with mesial temporal sclerosis (MTS) to identify characteristics suggestive of ATE-related epilepsy. METHODS: Patients with epilepsy and ATE were identified via clinic encounters and consensus epilepsy surgery conference at a Level 4 epilepsy center. The drug-resistant subset of these patients who underwent epilepsy surgery (twenty-two of thirty-five) were compared to age- and laterality-matched patients with MTS. Clinical, neuropsychological, electrophysiologic, and surgical data were abstracted through chart review. RESULTS: In comparison with MTS, ATE patients were more often female, had significantly later onset of epilepsy, and did not have prior febrile seizures. In addition, ATE patients were more likely to have chronic headaches and other historical features consistent with idiopathic intracranial hypertension (IIH). Failure to identify ATE on initial imaging was common. Most patients had limited temporal cortical resections sparing mesial structures. Of the twenty ATE patients who had a long-term postsurgical follow-up, seventeen (85%) had International League Against Epilepsy (ILAE) Class 1 or 2 outcomes. SIGNIFICANCE: A shorter duration of epilepsy, female gender, and lack of history of febrile seizures may suggest ATE as an etiology of refractory TLE in adults. Targeted encephalocele resections can result in seizure freedom, underscoring the importance of encephalocele identification.

Near SUDEP during bilateral stereo-EEG monitoring characterized by diffuse postictal EEG suppression.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. The pathophysiology of SUDEP is unknown. Postictal phenomena such as postconvulsive immobility (PI), postictal generalized electroencephalography (EEG) suppression (PGES), arousal deficits, cardiac arrhythmias, central apneas, and obstructive apneas due to laryngospasms have been suggested to contribute to SUDEP. We present, to our knowledge, the first case of a near-SUDEP event in a patient undergoing intracranial, stereotactic EEG (sEEG) monitoring. This case spotlights potential mediators of SUDEP, most notably the striking PGES and postictal apnea. The nature of the sEEG investigation illustrates the extent of cortical and subcortical postictal EEG suppression and showcases a transient return of cerebral activity likely to be missed on scalp-EEG recording. Critically, this case emphasizes the importance of continuous cardiorespiratory monitoring and underscores the importance of postictal arousal as a pathophysiological mechanism in SUDEP.

Post hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications.

OBJECTIVE: To report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long-term, open-label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention. METHODS: Patients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50 mg/day biweekly increments were allowed during maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until last visit, at data cut-off, on or after September 1, 2019. RESULTS: A total of 240 patients meeting eligibility criteria were assessed (median [max] exposure 30.2 [43.0] months), with 177 patients continuing cenobamate at data cut-off. Most common baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam. For most baseline concomitant ASMs, ~70% of patients taking that ASM were continuing cenobamate at data cut-off. Patients continuing cenobamate had greater mean ASM dose reductions and percent dose changes from baseline vs those who discontinued. Of patients continuing cenobamate, 24.6% discontinued one or more concomitant ASMs completely. Dose decreases for all concomitant ASMs generally occurred during titration or early maintenance phases and were mostly due to central nervous system (CNS)-related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Responder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of concomitant ASMs (of those most commonly taken), with ~81% being ≥50% responders and ~12% achieving 100% seizure reduction in the maintenance phase, which lasted up to 40.2 (median = 29.5) months. SIGNIFICANCE: Concomitant ASM dose reductions were associated with more patients remaining on cenobamate. This is likely due to efficacy and improved tolerability, with overall reduced concomitant drug burden in patients with uncontrolled seizures despite taking one to three baseline concomitant ASMs.

Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study.

OBJECTIVE: To report long-term post hoc efficacy and safety data from 10 US study sites from an open-label Phase 3 study of adjunctive cenobamate (NCT02535091). METHODS: Patients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019. RESULTS: Of 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1-4 (12.5-25 mg/day cenobamate) and 61.7% during Weeks 5-8 (50-100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12-month duration of 100% seizure reduction. Common treatment-emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%). SIGNIFICANCE: This post hoc analysis of a subset of patients from the long-term open-label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures.

Enhanced rates of detection and treatment of depression and anxiety disorders among adult patients with epilepsy using automated EMR-based screening.

OBJECTIVE: Depression and anxiety disorders are common among patients with epilepsy (PWE). These comorbidities have been shown to influence prognosis and may have a greater impact on quality of life than seizure control. Despite guideline recommendations and expert consensus to regularly screen for and treat both conditions, there is evidence that they are underdiagnosed and undertreated. Our goal was to test a novel screening method to determine if it would increase the rate of detecting and treating depression and anxiety disorders among PWE. METHOD: The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and the Brief Epilepsy Anxiety Survey Instrument (brEASI) were selected as validated screening instruments for depression and anxiety disorders, respectively. They were sent via an electronic medical record-linked patient portal to all patients of four epileptologists 48 h prior to their clinic appointment. We evaluated whether this increased the rate of detecting and treating depression and anxiety disorders relative to a historical control group. RESULTS: A total of 563 patients were included of whom 351 were sent the screening instruments. 62.7% of patients completed the screening instruments of whom 47.7% screened positive for either depression only (16.4%), anxiety disorders only (5.5%) or both (25.9%); a statistically significant increase relative to the control group. There was also a significantly increased proportion of patients for whom treatment was initiated for depression (p < 0.01), anxiety disorders (p < 0.01), or both (p < 0.01). CONCLUSIONS: We identified an easily applicable and efficient means of enhancing detection and treatment rates for depression and anxiety disorders among PWE in a busy clinic setting.

Baseline neuropsychological characteristics in patients with epilepsy with left temporal lobe encephaloceles compared with left mesial temporal sclerosis.

BACKGROUND: Temporal lobe encephaloceles (TE) are increasingly recognized as a cause of drug-resistant temporal lobe epilepsy. Improved recognition of these lesions offers an opportunity to treat them with a limited resection sparing the hippocampus. However, as they can be difficult to identify on imaging, additional clues pointing to the diagnosis can be helpful. We sought to understand the baseline cognitive/neuropsychological profile in patients with left temporal lobe epilepsy caused by encephaloceles compared with that caused by mesial temporal sclerosis (MTS), a common entity in the differential diagnosis. METHODS: Neuropsychological testing, including language (semantic and phonemic fluency and naming), verbal memory, intelligence quotient (IQ), and executive function measures were compared across two groups (five patients with left TE and five age- and gender-matched patients with left MTS). Other clinical variables related to cognition, including patient age, electroencephalographic characteristics, epilepsy duration, and factors related to antiseizure medication dosing, were also compared between groups. RESULTS: More patients with left MTS had atypical language lateralization (3/5 with right-sided language in the group with MTS compared with 0/5 in the group with TE). Patients with MTS had significantly worse scores on the Verbal Comprehension Index (VCI) subscore of the Wechsler Adult Intelligence Scale (WAIS; p = 0.026). General IQ was also worse in patients with MTS (p = 0.028). There was a trend towards worse executive function in patients with MTS as measured on Trails B (p = 0.096). Other measures related to language and verbal memory did not differ significantly between the groups nor did other relevant clinical variables, except epilepsy duration, which was significantly longer in patients with MTS (p = 0.0001). CONCLUSIONS: This pilot study demonstrates few significant differences between the groups with left MTS and TE surveyed. A higher rate of atypical language lateralization was noted in patients with left MTS. The higher baseline global IQ and VCI scores in patients with left TE compared with patients with MTS may be attributable to longer duration of epilepsy in patients with left MTS. Future work with a larger sample size will focus on establishing a unique neuropsychological profile related to epilepsy due to TE.

Misdiagnosis of lamotrigine toxicity as posterior circulation transient ischemic attack or stroke.

PURPOSE: Lamotrigine (LTG) is one of the most used antiseizure medications (ASMs). Titration is indicated for incomplete seizure control, but toxicity with vertigo, ataxia, and diplopia may ensue. Lamotrigine concentration would be the optimal diagnostic test. However, patients often receive a stroke evaluation when presenting to 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. METHODS: We identified adult patients treated with LTG who presented to an emergency room with dizziness, ataxia, or diplopia and received a negative stroke evaluation, between 2003 and 2018. They were among 972 patients treated with LTG for epilepsy. We collected age at time of occurrence, symptoms presented, imaging studies performed, LTG dose and serum concentration, and the time the result was available. As a denominator, we also identified patients who developed clinical LTG toxicity during the same time period. RESULTS: Thirteen patients with LTG toxicity had 16 negative stroke evaluations in the emergency room. Their mean age was 62 years (range: 43-79) as compared with 47 years for all patients treated with LTG (p < 0.0005). The mean 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 presentation. Five of the patients in this group were among 71 patients with clinical LTG toxicity and LTG concentration >20. CONCLUSION: Emergency departments will frequently call a stroke alert for patients taking LTG and presenting with 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.

Rhythmic ictal nonclonic hand (RINCH) motions in general EMU patients with focal epilepsy.

BACKGROUND: Automatisms are frequently encountered during video-monitoring of patients with focal epilepsy in the EMU and generally thought to have a low lateralizing value in isolation. Rhythmic ictal nonclonic hand (RINCH) motions have been described in small series as a potentially lateralizing semiologic sign. We aimed to expand on prior work and determine the prevalence, characteristics, and lateralizing value of RINCH motions in general epilepsy monitoring unit (EMU) population with focal epilepsy. METHODS: All patients with recorded seizures in the EMU were included in our database search. Search was performed to identify seizures with reported RINCH motions. Both electroencephalography (EEG) and video of identified seizures were reviewed. RESULTS: We identified RINCH motions in 131 seizures in 71 patients. Overall seizure localization was temporal in 57 patients, frontotemporal in 3 patients, and extratemporal in 7 patients. We estimated RINCH motions to occur in 8.5% of EMU patients with recorded seizures. The most common RINCH motions in descending order were as follows: hand opening and closing, finger rubbing, milking motions, finger flexion/extension, and pill rolling. The mean RINCH motion latency from seizure onset was 34.48 s in temporal lobe epilepsy and 10.31 s in frontal lobe epilepsy. The RINCH motions were contralateral to seizure onset in 61 of 65 (93.8%) with lateralized seizure onset. Dystonic posturing was present in 43% of seizures with RINCH motions. CONCLUSION: The RINCH motions are a common sign in focal seizures and should be distinguished from other types of manual automatism as they carry a strong lateralizing value.

De novo mutations in epileptic encephalopathies.

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

Functional connectivity disturbances of the ascending reticular activating system in temporal lobe epilepsy.

OBJECTIVE: Seizures in temporal lobe epilepsy (TLE) disturb brain networks and lead to connectivity disturbances. We previously hypothesised that recurrent seizures in TLE may lead to abnormal connections involving subcortical activating structures including the ascending reticular activating system (ARAS), contributing to neocortical dysfunction and neurocognitive impairments. However, no studies of ARAS connectivity have been previously reported in patients with epilepsy. METHODS: We used resting-state functional MRI recordings in 27 patients with TLE (67% right sided) and 27 matched controls to examine functional connectivity (partial correlation) between eight brainstem ARAS structures and 105 cortical/subcortical regions. ARAS nuclei included: cuneiform/subcuneiform, dorsal raphe, locus coeruleus, median raphe, parabrachial complex, pontine oralis, pedunculopontine and ventral tegmental area. Connectivity patterns were related to disease and neuropsychological parameters. RESULTS: In control subjects, regions showing highest connectivity to ARAS structures included limbic structures, thalamus and certain neocortical areas, which is consistent with prior studies of ARAS projections. Overall, ARAS connectivity was significantly lower in patients with TLE than controls (p<0.05, paired t-test), particularly to neocortical regions including insular, lateral frontal, posterior temporal and opercular cortex. Diminished ARAS connectivity to these regions was related to increased frequency of consciousness-impairing seizures (p<0.01, Pearson's correlation) and was associated with impairments in verbal IQ, attention, executive function, language and visuospatial memory on neuropsychological evaluation (p<0.05, Spearman's rho or Kendell's tau-b). CONCLUSIONS: Recurrent seizures in TLE are associated with disturbances in ARAS connectivity, which are part of the widespread network dysfunction that may be related to neurocognitive problems in this devastating disorder.

Magnetic resonance imaging connectivity for the prediction of seizure outcome in temporal lobe epilepsy.

OBJECTIVE: Currently, approximately 60-70% of patients with unilateral temporal lobe epilepsy (TLE) remain seizure-free 3 years after surgery. The goal of this work was to develop a presurgical connectivity-based biomarker to identify those patients who will have an unfavorable seizure outcome 1-year postsurgery. METHODS: Resting-state functional and diffusion-weighted 3T magnetic resonance imaging (MRI) was acquired from 22 unilateral (15 right, 7 left) patients with TLE and 35 healthy controls. A seizure propagation network was identified including ipsilateral (to seizure focus) and contralateral hippocampus, thalamus, and insula, with bilateral midcingulate and precuneus. Between each pair of regions, functional connectivity based on correlations of low frequency functional MRI signals, and structural connectivity based on streamline density of diffusion MRI data were computed and transformed to metrics related to healthy controls of the same age. RESULTS: A consistent connectivity pattern representing the network expected in patients with seizure-free outcome was identified using eight patients who were seizure-free at 1-year postsurgery. The hypothesis that increased similarity to the model would be associated with better seizure outcome was tested in 14 other patients (Engel class IA, seizure-free: n = 5; Engel class IB-II, favorable: n = 4; Engel class III-IV, unfavorable: n = 5) using two similarity metrics: Pearson correlation and Euclidean distance. The seizure-free connectivity model successfully separated all the patients with unfavorable outcome from the seizure-free and favorable outcome patients (p = 0.0005, two-tailed Fisher's exact test) through the combination of the two similarity metrics with 100% accuracy. No other clinical and demographic predictors were successful in this regard. SIGNIFICANCE: This work introduces a methodologic framework to assess individual patients, and demonstrates the ability to use network connectivity as a potential clinical tool for epilepsy surgery outcome prediction after more comprehensive validation.

Generalized paroxysmal fast activity in EEG: An unrecognized finding in genetic generalized epilepsy.

OBJECTIVE: To study generalized paroxysmal fast activity (GPFA) in patients with genetic generalized epilepsy (GGE). INTRODUCTION: GPFA is an electroencephalographic (EEG) finding in patients with symptomatic generalized epilepsy consisting of 15-25Hz bifrontally predominant generalized fast activity seen predominantly in sleep. Historically GPFA is linked to epileptic encephalopathy with drug resistant epilepsy and intellectual disability. However, GPFA has been rarely described as an atypical finding in patients with GGE without negative prognostic implication. We report cognitive profile and seizure characteristics in seven patients with GGE and GPFA. METHODS: The Vanderbilt EMU and EEG reports were searched for the keywords "idiopathic generalized epilepsy", "GPFA"and "generalized spike and wave discharges (GSWD)". We reviewed the EEG tracings and the electronic medical records of patients thus identified. The seizure type, frequency, neurological work-up, clinical profile and imaging data were recorded. RESULTS: Awake and sleep states were captured on EEGs of all patients. On EEG tracing review six patients were confirmed to have GSWD and GPFA; one patient had GPFA but no GSWD. All patients had normal cognitive function. Four had a normal brain MRI and one a normal head CT (two were never imaged). None of the patients had tonic seizures. The main seizure type was generalized tonic-clonic seizures (GTCS) in five patients, absence in two. Age at onset of epilepsy ranged from 4 to 24years. The mean GTC seizure frequency at the time of EEG was 3; two patients were seizure free on two antiepileptic drugs (AEDs). CONCLUSIONS: GPFA can be an unrecognized electrographic finding in patients with genetic generalized epilepsy. While GPFA remains an important diagnostic EEG feature for epileptic encephalopathy (Lennox-Gastaut syndrome) it is not specific for this diagnosis. Thus, GPFA may have a spectrum of variable phenotypic expression. The finding of GPFA is not necessarily indicative of unfavorable outcome.

Adjunctive eslicarbazepine acetate: A pooled analysis of three phase III trials.

OBJECTIVE: To assess the safety and efficacy of once-daily (QD) adjunctive eslicarbazepine acetate (ESL). METHODS: This post-hoc pooled analysis of three randomized, placebo-controlled trials (2093-301, -302, -304) involved adults with refractory partial-onset seizures (POS) receiving 1-3 antiepileptic drugs (AEDs). All studies included 8-week baseline, 2-week titration, and 12-week maintenance periods. Patients were randomized equally to placebo, ESL 400mg (studies 301, 302), 800mg, or 1200mg QD. The primary endpoint was standardized seizure frequency (SSF; per 4weeks); secondary endpoints included responder rates (maintenance period), and incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious AEs (SAEs), and deaths. RESULTS: The safety and efficacy analysis populations totaled 1447 and 1410 patients, respectively. SSF was significantly reduced versus placebo with ESL 800mg (p=0.0001) and 1200mg (p<0.0001) but not 400mg (p=0.81). There were no significant interactions between treatment effect and age, gender, race/ethnicity, geographic region, epilepsy duration, or concomitant AED use. Incidences of TEAEs and TEAEs leading to discontinuation increased with ESL dose. Incidences of the most frequent TEAEs were lower for patients who initiated dosing at 400 versus 800mg QD, regardless of titration regimen and maintenance dose. SAE incidence was <10%; there were 3 deaths (placebo, n=2; ESL 800mg, n=1). CONCLUSIONS: ESL (800 and 1200mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS.

Generalized onset seizures with focal evolution (GOFE) - A unique seizure type in the setting of generalized epilepsy.

PURPOSE: We report clinical and electrographic features of generalized onset seizures with focal evolution (GOFE) and present arguments for the inclusion of this seizure type in the seizure classification. METHODS: The adult and pediatric Epilepsy Monitoring Unit databases at Vanderbilt Medical Center and Children's Hospital were screened to identify generalized onset seizures with focal evolution. We reviewed medical records for epilepsy characteristics, epilepsy risk factors, MRI abnormalities, neurologic examination, antiepileptic medications before and after diagnosis, and response to medications. We also reviewed ictal and interictal EEG tracings, as well as video-recorded semiology. RESULTS: Ten patients were identified, 7 males and 3 females. All of the patients developed generalized epilepsy in childhood or adolescence (ages 3-15years). Generalized onset seizures with focal evolution developed years after onset in 9 patients, with a semiology concerning for focal seizures or nonepileptic events. Ictal discharges had a generalized onset on EEG, described as either generalized spike-and-wave and/or polyspike-and-wave discharges, or generalized fast activity. This electrographic activity then evolved to focal rhythmic activity most commonly localized to one temporal or frontal region; five patients had multiple seizures evolving to focal activity in different regions of both hemispheres. The predominant interictal epileptiform activity included generalized spike-and-wave and/or polyspike-and-wave discharges in all patients. Taking into consideration all clinical and EEG data, six patients were classified with genetic (idiopathic) generalized epilepsy, and four were classified with structural/metabolic (symptomatic) generalized epilepsy. All of the patients had modifications to their medications following discharge, with three becoming seizure-free and five responding with >50% reduction in seizure frequency. CONCLUSION: Generalized onset seizures may occasionally have focal evolution with semiology suggestive of focal seizures, leading to a misdiagnosis of focal onset. This unique seizure type may occur with genetic as well as structural/metabolic forms of epilepsy. The identification of this seizure type may help clinicians choose appropriate medications, avoiding narrow spectrum agents known to aggravate generalized onset seizures.

Video-EEG results and clinical characteristics in patients with psychogenic nonepileptic spells: The effect of a coexistent epilepsy.

RATIONALE: Epilepsy and psychogenic nonepileptic spells (PNES) can coexist, often posing diagnostic and therapeutic challenges. We sought to identify clinical and historical characteristics of two groups of patients, those with coexisting epilepsy and PNES and those with PNES alone, and determine the prevalence of coexisting epilepsy/PNES with strict diagnostic criteria in a large group of epilepsy monitoring unit (EMU) patients. METHODS: We reviewed the medical records of all consecutive patients admitted to the Vanderbilt University Medical Center Adult EMU between July 1, 2007 and June 30, 2012. We identified patients with recorded PNES and classified them as having coexisting epilepsy/PNES or PNES alone and then systematically compared the clinical characteristics of these two groups. RESULTS: A total of 1567 patient medical records were reviewed. The prevalence rate of coexisting epilepsy/PNES was 5.2% among all EMU admissions (12.3% of all patients with epilepsy and 14.8% of all patients with PNES). These rates were lower when patients with interictal epileptiform activity (IEA) alone and no recorded ictal discharges were not included in the group with epilepsy (2.6%, 6.2%, and 7.4%, respectively). The accuracy of pre-EMU clinical suspicion was significantly higher in the group with PNES-only. Patients with epilepsy/PNES were significantly more likely to require more than one EMU admission for definitive diagnosis. The first PNES event preceded an epileptic seizure (ES) in 94.4% of patients with epilepsy/PNES. The group with PNES-only had significantly higher suggestibility, and the group with epilepsy/PNES had a significantly higher presence of epilepsy risk factors. Abnormal neurological examination and abnormal brain MRI were also significantly more common in the group with epilepsy/PNES. CONCLUSIONS: Our study defined the prevalence of coexisting epilepsy/PNES in a large cohort with strict diagnostic criteria and outlined specific clinical and historical characteristics differentiating the two groups of patients with coexisting epilepsy/PNES and PNES-only. These findings should help guide clinicians to reach the correct diagnosis faster and provide appropriate treatment earlier.

Temporal lobe origin is common in patients who have undergone epilepsy surgery for hypermotor seizures.

RATIONALE: Hypermotor seizures are most often reported from the frontal lobe but may also have temporal, parietal, or insular origin. We noted a higher proportion of patients with temporal lobe epilepsy in our surgical cohort who had hypermotor seizures. We evaluated the anatomic localization and surgical outcome in patient with refractory hypermotor seizures who had epilepsy surgery in our center. METHODS: We identified twenty three patients with refractory hypermotor seizures from our epilepsy surgery database. We analyzed demographics, presurgical evaluation including semiology, MRI, PET scan, interictal/ictal scalp video-EEG, intracranial recording, and surgical outcomes. We evaluated preoperative variables as predictors of outcome. RESULTS: Most patients (65%) had normal brain MRI. Intracranial EEG was required in 20 patients (86.9%). Based on the presurgical evaluation, the resection was anterior temporal in fourteen patients, orbitofrontal in four patients, cingulate in four patients, and temporoparietal in one patient. The median duration of follow-up after surgery was 76.4months. Fourteen patients (60%) had been seizure free at the last follow up while 3 patients had rare disabling seizures. CONCLUSIONS: Hypermotor seizures often originated from the temporal lobe in this series of patients who had epilepsy surgery. This large proportion of temporal lobe epilepsy may be the result of a selection bias, due to easier localization and expected better outcome in temporal lobe epilepsy. With extensive presurgical evaluation, including intracranial EEG when needed, seizure freedom can be expected in the majority of patients.

Segmentation of the thalamus based on BOLD frequencies affected in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy is associated with functional changes throughout the brain, particularly including a putative seizure propagation network involving the hippocampus, insula, and thalamus. We identified a specified frequency range where functional connectivity in this network was related to duration of disease. Then, to identify specific thalamic nuclei involved in seizure propagation, we determined the subregions of the thalamus that have increased resting functional oscillations in this frequency range. METHODS: Resting-state functional magnetic resonance imaging (fMRI) was acquired from 20 patients with unilateral temporal lobe epilepsy (TLE; 14 right and 6 left) and 20 healthy controls who were each age and gender matched to a specific patient. Wavelet-based fMRI connectivity mapping across the network was computed at each frequency to determine those frequencies where connectivity significantly decreases with duration of disease consistent with impairment due to repeated seizures. The voxel-wise power of the spontaneous blood oxygenation fluctuations of this frequency band was computed in the thalamus of each subject. RESULTS: Functional connectivity was impaired in the proposed seizure propagation network over a specific range (0.0067-0.013 Hz and 0.024-0.032 Hz) of blood oxygenation oscillations. Increased power in this frequency band (<0.032 Hz) was detected bilaterally in the pulvinar and anterior nucleus of the thalamus of healthy controls, and was increased over the ipsilateral thalamus compared to the contralateral thalamus in TLE. SIGNIFICANCE: This study identified frequencies of impaired connectivity in a TLE seizure propagation network and used them to localize the anterior nucleus and pulvinar of the thalamus as subregions most susceptible to TLE seizures. Further examinations of these frequencies in healthy and TLE subjects may provide unique information relating to the mechanism of seizure propagation and potential treatment using electrical stimulation.