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.

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.

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.

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.

Does adherence to epilepsy quality measures correlate with reduced epilepsy-related adverse hospitalizations? A retrospective experience.

In 2011, the American Academy of Neurology (AAN) established eight epilepsy quality measures (EQMs) for chronic epilepsy treatment to address deficits in quality of care. This study assesses the relationship between adherence to these EQMs and epilepsy-related adverse hospitalizations (ERAHs). A retrospective chart review of 475 new epilepsy clinic patients with an ICD-9 code 345.1-9 between 2010 and 2012 was conducted. Patient demographics, adherence to AAN guidelines, and annual number of ERAHs were assessed. Fisher's exact test was used to assess the relationship between adherence to guidelines (as well as socioeconomic variables) and the presence of one or more ERAH per year. Of the eight measures, only documentation of seizure frequency, but not seizure type, correlated with ERAH (relative risk [RR] 0.343, 95% confidence interval [CI] 0.176-0.673, p = 0.010). Among patients in the intellectually disabled population (n = 70), only review/request of neuroimaging correlated with ERAH (RR 0.128, 95% CI 0.016-1.009, p = 0.004). ERAHs were more likely in African American patients (RR 2.451, 95% CI 1.377-4.348, p = 0.008), Hispanic/Latino patients (RR 4.016, 95% CI 1.721-9.346, p = 0.016), Medicaid patients (RR 2.217, 95% CI 1.258-3.712, p = 0.009), and uninsured patients (RR 2.667, 95% CI 1.332-5.348, p = 0.013). In this retrospective series, adherence to the eight AAN quality measures did not strongly correlate with annual ERAH.

Tiagabine-induced stupor in patients with psychogenic nonepileptic seizures: nonconvulsive status epilepticus or encephalopathy?

BACKGROUND: Nonconvulsive status epilepticus has been rarely reported with tiagabine (TGB) use. METHODS: We report findings from continuous video-EEG monitoring and serial neurological examinations during prolonged episodes of stupor associated with TGB use in three patients who did not have epilepsy. RESULTS: All three patients had emergence of new type of events after starting TGB treatment. All three patients had gradual decline in responsiveness to verbal stimuli, intermittent twitching of the upper extremities, and urinary incontinence. The corresponding EEG showed gradual build-up of generalized bisynchronous delta-wave activity with subsequent intermingled sharp transients. Two patients did not respond to IV lorazepam, one of whom also did not respond to IV phenytoin. The EEG slowly normalized in conjunction with associated clinical improvement. Habitual seizures were found to be psychogenic, with no interictal evidence for epilepsy. CONCLUSION: Tiagabine-related stupor may represent a form of toxic encephalopathy in some cases rather than nonconvulsive status epilepticus.

New observations in primary and secondary reading epilepsy: excellent response to levetiracetam and early spontaneous remission.

The response of reading epilepsy to new antiepileptic drugs is not known. Due to the rarity of this condition little is known about its natural history. We evaluated and treated three patients with primary and secondary reading epilepsy. Seizures in all patients were characterized by twitching of the jaw or lips with secondarily generalized tonic-clonic seizures if reading continued. One patient with primary reading epilepsy became seizure-free with divalproex monotherapy and another with levetiracetam monotherapy after failure of lamotrigine. One other patient with secondary reading epilepsy became seizure-free with levetiracetam add-on therapy. The divalproex-treated patient stopped therapy less than 3 years after seizure onset and remained seizure-free with 6 years of follow-up. We propose levetiracetam as a first-line treatment for primary and secondary reading epilepsy. Spontaneous medication-free remission of primary reading epilepsy may occur within 3 years of seizure onset, much earlier than previously reported.

Update on Antiseizure Medications 2022.

EDITORS NOTE: The article "Update on Antiseizure Medications 2022" by Dr Abou-Khalil was first published in the February 2016 Epilepsy issue of Continuum: Lifelong Learning in Neurology as "Antiepileptic Drugs," and at the request of the Editor-in-Chief was updated by Dr Abou-Khalil for the 2019 issue and again for this issue.

This article is an update from the article on antiepileptic drug therapy (now referred to as antiseizure medication therapy ) published in the two previous Continuum issues on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with antiseizure medication monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual antiseizure medications is essential for optimal treatment for epilepsy. This article addresses antiseizure medications individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. Since the most recent version of this article was published, two new antiseizure medications, cenobamate and fenfluramine, have been approved by the US Food and Drug Administration (FDA), and the indications of some approved medications have been expanded. Older antiseizure medications are effective but have tolerability and pharmacokinetic disadvantages. Several newer antiseizure medications have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older antiseizure medications as first-line therapy for focal epilepsy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy for focal epilepsy. Other newer antiseizure medications with a variety of mechanisms of action are suitable for adjunctive therapy. Antiseizure medications marketed since 2016 have benefited from the FDA policy allowing a drug's efficacy as adjunctive therapy in adults to be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an antiseizure medication has equivalent pharmacokinetics between its original approved use and its extrapolated use. Rational antiseizure medication combinations should avoid antiseizure medications with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. Knowledge of antiseizure medication pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate antiseizure medication therapy for patients with epilepsy.

Determinants of postictal agitation and recovery after tonic-clonic seizures in generalized and focal epilepsy.

OBJECTIVE: The postictal state after bilateral tonic-clonic seizures is often prolonged and can have significant impact on a patient's quality of life. Considerable variability exists in the magnitude of postictal agitation and in the speed of recovery, the determinants of which are not well understood. We studied postictal behavior after tonic-clonic seizures in various epilepsy localizations, focusing on postictal agitation and time to responsiveness. METHODS: We retrospectively identified 15 adult patients each with idiopathic generalized, left temporal lobe, right temporal lobe and frontal lobe epilepsy. Localization in focal epilepsy was validated by good outcome after resective surgery at one-year of follow-up. The first tonic-clonic seizure with reliable video and EEG for each patient was analyzed by two reviewers, one of whom was blinded to clinical data. Clinical, ictal and postictal variables were collected for each patient and analyzed. Postictal agitation was classified as mild and marked. RESULTS: We reviewed 60 tonic-clonic seizures, 15 in each of four patient groups. Postictal agitation was observed in 14 patients (23.3%; marked in one and mild in 13). Postictal agitation was most common in patients with left temporal (seven patients) and least common in idiopathic generalized epilepsy (one patient) groups (p=0.035). Based on subgroup analysis (n=28), time to responsiveness was 6.6 minutes for frontal, 7.2 minutes for generalized, 10 minutes for right temporal and 15.7 minutes for the left temporal groups (p<0.05 for frontal vs. left temporal, generalized vs. left temporal). Time to responsiveness was longer in patients with agitation than without (13.9 minutes vs. 7.7 minutes; p=0.048). Patient ictal and postictal characteristics demonstrated no relationship to agitation or latency to postictal recovery. SIGNIFICANCE: To mitigate harm, patients must be monitored carefully after tonic-clonic seizures, especially patients with left temporal lobe epilepsy. Studies evaluating medical and behavioral interventions to promote postictal recovery are needed.

Temporal intermittent rhythmic theta activity (TIRTA): A marker of epileptogenicity?

Objective: To describe a novel EEG rhythm, temporal intermittent rhythmic theta activity (TIRTA), and its potential association with epilepsy. Methods: We report TIRTA on scalp EEG in a series of 12 patients, all of whom were found to have epilepsy. The clinical and electroencephalographic characteristics of each patient were reviewed. In addition, features that may distinguish TIRTA from benign EEG patterns, including rhythmic temporal theta bursts of drowsiness (RTTBD), were identified. Results: TIRTA was unilateral in all cases. For all patients, TIRTA was seen in the awake and drowsy states. Eight patients also had TIRTA observed during N2 sleep. The average frequency of TIRTA was 5.5 Hz and the average duration of a train of TIRTA was 5.25 s. In seven cases the morphology was notched in appearance. Temporal intermittent rhythmic delta activity (TIRDA) was seen in seven patients on the same side as TIRTA. Eleven patients also had ipsilateral temporal sharp waves. Abnormal MRI (6/12) and or PET (5/5) findings were ipsilateral to TIRTA. Conclusions: In this preliminary report we suggest that TIRTA may be a novel marker of potential epileptogenicity, possibly representing a higher frequency variant of TIRDA.

Predictors of a nondiagnostic epilepsy monitoring study and yield of repeat study.

OBJECTIVE: Failure to record typical events during long-term video/EEG monitoring (LTM) leaves the diagnosis uncertain. The purpose of this study was to analyze predictors of an initial nondiagnostic LTM study and to evaluate the yield of a repeat study. METHODS: We reviewed all adult LTM studies performed at Vanderbilt University from January 2004 to June 2008. We identified 150 patients with no typical events on LTM and matched them with consecutive controls with typical events. We compared patient demographics, epilepsy risk factors, history of antiepileptic use/failures, and prior EEG and MRI results. RESULTS: Of 2397 LTM studies, 380 (15.8%) failed to record typical events. Absence of epilepsy risk factors and normal outpatient EEG predicted this outcome. A repeat LTM study was successful in 18 of 45 patients (42%). CONCLUSION: The prediction of a nondiagnostic LTM can help to reduce the cost of investigating spells of unknown nature.

Transient improvement after brief antiepileptic drug withdrawal in the epilepsy monitoring unit--possible relationship to AED tolerance.

PURPOSE: A drug holiday seems to produce seizure interval prolongation (SIP) after reinstitution of antiepileptic drugs (AEDs). This effect was demonstrated mainly with carbamazepine. We evaluated SIP with newer AEDs and tested the relationship of SIP to history of AED tolerance. METHODS: We prospectively studied patients with refractory epilepsy admitted to the Vanderbilt epilepsy monitoring unit (EMU) over a period of 12 months. We included only patients on levetiracetam, lamotrigine, or oxcarbazepine who had their AEDs withdrawn on admission and reinstituted without change upon discharge. We defined SIP as the interval from EMU discharge to first seizure minus the interval between the last two seizures before EMU admission. RESULTS: A total of 43 patients completed the study; 15 were on monotherapy. SIP was greater than zero in this patient group (p < 0.0001), with a mean prolongation of 19.4 +/- 28.0 days. The average SIP was higher (p = 0.01) in patients on monotherapy (29.7 +/- 23.8 days) than patients on polytherapy (13.9 +/- 29.0 days). SIP tended to be greater in patients with a prior history of AED tolerance (25.7 +/- 36.8 days) compared to patient with no prior history of AED tolerance (14.0 +/- 16.3 days). DISCUSSION: SIP does occur after brief AED withdrawal. This effect is greater in patients on monotherapy and tends to be larger in patients with a history of AED tolerance. The SIP effect may be related to the phenomenon of tolerance, clinically seen as resistance to AED therapeutic effect.

A structured questionnaire predicts if convulsions are epileptic or nonepileptic.

OBJECTIVE: Therapy for convulsive seizures is usually initiated on the basis of clinical assessment, without video/EEG confirmation, but a nonepileptic origin may eventually be demonstrated. This study evaluates the diagnostic value of a witness-questionnaire in distinguishing between convulsive epileptic seizures (CES) and convulsive nonepileptic seizures (CNES). METHODS: We prospectively identified all adult patients admitted for video/EEG evaluation of convulsive attacks and interviewed the "best" witness using 12 questions on ictal and postictal features. RESULTS: Video/EEG diagnosed CES in 19 and CNES in 26 patients. The predictive accuracy of the questionnaire was 84.4%. Six features were strong predictors of CNES diagnosis: ictal eye closure, presence of side-to-side movements, prolonged seizure duration, and three postictal breathing features (not loud, shallow, no snoring). CONCLUSION: A structured witness questionnaire distinguishes CES and CNES and will help in selecting patients for early video/EEG evaluation and rapid initiation of appropriate therapy.

Development of a System for Postmarketing Population Pharmacokinetic and Pharmacodynamic Studies Using Real-World Data From Electronic Health Records.

Postmarketing population pharmacokinetic (PK) and pharmacodynamic (PD) studies can be useful to capture patient characteristics affecting PK or PD in real-world settings. These studies require longitudinally measured dose, outcomes, and covariates in large numbers of patients; however, prospective data collection is cost-prohibitive. Electronic health records (EHRs) can be an excellent source for such data, but there are challenges, including accurate ascertainment of drug dose. We developed a standardized system to prepare datasets from EHRs for population PK/PD studies. Our system handles a variety of tasks involving data extraction from clinical text using a natural language processing algorithm, data processing, and data building. Applying this system, we performed a fentanyl population PK analysis, resulting in comparable parameter estimates to a prior study. This new system makes the EHR data extraction and preparation process more efficient and accurate and provides a powerful tool to facilitate postmarketing population PK/PD studies using information available in EHRs.

Update on Antiepileptic Drugs 2019.

PURPOSE OF REVIEW: This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. RECENT FINDINGS: Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity.Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug's efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. SUMMARY: Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.

Avoiding anaesthetics after multiple failed drug-induced comas: an unorthodox approach to management of new-onset refractory status epilepticus (NORSE).

New-onset refractory status epilepticus (NORSE) is a rare, poorly understood and often catastrophic condition. There is little guidance available for management. Here, we describe the course of a 19-year-old man with NORSE who was treated successfully with a new approach. Our patient was initially treated with first-, second- and third-line agents including a total of seven failed drug-induced coma courses until the 30th day of hospitalization. When withdrawal of care was contemplated, management was then assumed by dedicated epileptologists and treatment course was changed. An unorthodox decision was made to avoid IV anaesthetics unless there were generalized bisynchronous tonic-clonic or generalized non-convulsive (electrographic) seizures. This approach allowed real-time assessment of treatment response to aggressive non-sedating AED therapy while the multifocal convulsive and non-convulsive seizures were ongoing. It also eliminated potentially fatal IV anaesthetic-induced complications and prevented anaesthetic withdrawal seizures. This was effective in achieving full recovery in our patient. The patient's awakening also changed the perspective of family members and care providers, avoiding premature withdrawal of care, which is often the cause of death in similar patients.

Temporal pattern of oxcarbazepine and phenytoin withdrawal seizures during epilepsy monitoring.

PURPOSE: To compare the temporal pattern of seizures after acute withdrawal of oxcarbazepine (OXC) and phenytoin (PHT) in the epilepsy monitoring unit (EMU). METHODS: We identified all epilepsy patients admitted to our EMU on OXC or PHT monotherapy, over a period of 5 years. The OXC taper usually occurred over 2 days while PHT was abruptly discontinued on admission day. For each patient, we recorded the number and type of seizures for each EMU day. We used Poisson regression models to estimate daily seizure frequency separately for complex partial seizures (CPSs) and generalized tonic-clonic seizures (GTCSs). RESULTS: Forty patients were admitted on OXC and 32 on PHT monotherapy. The temporal distribution of seizures varied between the two groups. The first GTCS was more likely to occur in the first 2 days of monitoring for the OXC group (p<0.046). There was a higher frequency of GTCS on day 2 of admission in the OXC group (p=0.011). The groups did not differ in the pattern of CPS. CONCLUSIONS: OXC is disproportionately associated with increased GTCS in the first 2 days after acute withdrawal. The early peak of GTCS favors a rebound phenomenon in addition to loss of therapeutic effect.

Lacosamide efficacy and tolerability in clinical practice - Post marketing analysis from a single dedicated epilepsy center.

OBJECTIVES: Post marketing analysis of anti-epileptic drug (AED) efficacy and tolerability is of great value to the clinician since it is more representative of clinical practice than clinical trial data. We analyzed our experience with lacosamide (LCM) in patients treated after marketing. PATIENTS AND METHODS: We identified all patients who were treated with LCM during the four year period after marketing, excluding patients who were in clinical trials. We recorded demographic data and analyzed efficacy and tolerability in patients who had at least one follow up visit or telephone call 3 months after the initiation of LCM. RESULTS: A total of 165 patients met our inclusion criteria. The mean age was 41 years. The majority of the cohort had focal epilepsy (146 patients) (88.4%). The mean duration of treatment was 31.2 months. Eighty one patients (49.1%) were continuing LCM at last follow up. Adverse effects (AEs) and discontinuation were significantly more common when LCM was added to one or more Na-channel blocking agents (NCB) (p = 0.0003 and 0.17). The 50% responder rate was 26% at 3 months and increased to 49% at 36 months. Patients were more likely to continue the drug and less likely to have AEs with slower titration over >4 weeks (p = 0.02 for each). Four or more previously failed AEDs predicted poorer response rate compared to three or less AEDs (p = 0.001). CONCLUSION: LCM use in clinical practice was associated with greater rate of seizure freedom than in clinical trials. Discontinuation and occurrence of AEs were significantly more likely with faster titration and adding LCM to NCB agents.