Acute Antiepileptic Drug Research Articles

Acute antiepileptic drug use in intensive care units.

In intensive care units (ICUs), antiepileptic drugs (AEDs) are used for manifold indications. This is the first study to assess the prevalence of acute AED use in ICUs and to identify associated clinical variables. All patients in seven adult ICUs of a German university hospital in 2016 were retrospectively evaluated. Data were extracted from the computerized critical care information system and manually reviewed. Acute AED treatments were defined as initiated during ICU treatment or ≤ 6h before ICU admission, excluding benzodiazepines and sedatives. Among 2335 patients evaluated, 8.8% received acutely started AEDs: 5.1% due to epileptic seizures, mostly acute symptomatic, and 3.7% for other indications like pain, post-hypoxic myoclonus, and singultus. Following multivariable analyses, acute AED use was independently associated with intracranial reasons for ICU admission and long durations of ICU stay, but not with increased disease severity scores or mortality. Levetiracetam was the substance most frequently used to treat epileptic seizures (88%) as was pregabalin for other conditions (49%). Among surviving patients, acute AEDs were continued beyond ICU discharge in 86% if seizure-related and in 78% if not seizure-related, even if there was no evident need for long-term AED treatment. One out of eleven ICU patients receives acute AEDs, in almost half of cases for non-seizure indications. Acute AED use is a marker for intracranial ICU indications and prolonged ICU treatments. Usually, newer-generation AEDs are employed with favourable pharmacokinetic and safety profiles. However, whenever possible, acutely started AED should be discontinued before discharge from ICU.

A Review of Withdraw Strategies for Discontinuing Antiepileptic Therapy in Epilepsy and Pain Management

Purpose: Pain management is complicated by unacceptable levels of opioid abuse with few safe alternatives. The need exists for therapies of limited abuse potential and established pathways for their safe use. Antiepileptic drugs (AED) have been used as adjuncts to pain management since the 1960’s. By virtue of their pharmacokinetic and adverse event (ADR) risk profiles, antiepileptic drugs require more prescriber surveillance compared to other medications. However, there is no published standard approach for discontinuing these drugs. The objectives of this review were to summarize the risk profile associated with tapering antiepileptic drugs used for epilepsy vs. AED use in pain management and to identify best practices for safe tapering. Methods: A retrospective review of the literature was performed, addressing discontinuation of antiepileptic drugs. Articles were collected from PubMed and Ovid using keywords: anticonvulsant, antiepileptic, withholding treatment, taper and withdrawal. The limitations included English language only publications, regardless of country of origin, and publication between 1990 and 2013. Results: A search of the literature revealed 25 published randomized controlled trials, reviews, case reports and editorials. While no taper guideline was found, many studies used a gradual taper protocol ranging from one month to more than four years for discontinuation; however there was no consistency between protocols. Adverse events for continuation and inappropriate discontinuation of antiepileptic therapy were aggregated from FDA labeled information and published case reports constituting the risk profile. The risk profile in acute AED discontinuation when used for epilepsy versus use in pain management, are very different. In epilepsy, documentation of acute discontinuation of AEDs reported recurrence of epileptic episodes. Tapering therapy to discontinuation in epilepsy resulted in a higher risk of seizure recurrence within the first six months of discontinuation compared to patients continuing therapy. When used as adjuncts to pain management, acute discontinuation of AEDs was reported as a benzodiazepine-like withdrawal syndrome with symptoms such as diaphoresis, agitation and altered mental status. However unlike true benzodiazepine withdrawal, acute discontinuation of AEDs in pain management was unresolved by benzodiazepine administration. Conclusion: Tapering antiepileptic drugs when discontinuing therapy in epilepsy is common practice though there is no consistency amongst taper protocols documented in the literature. Tapering strategies for antiepileptic therapy when used in pain management are not well documented. This review identifies gaps in the literature concerning safe discontinuation of antiepileptic drugs when used in epilepsy as well as pain management. Further research is needed to establish safe tapering recommendations for AEDs which are specific to the applied use of the antiepileptic drug.

Nonconvulsive Status Epilepticus: Value of a Benzodiazepine Trial for Predicting Outcomes (S06.006)

Objective: We assess the value of clinical and electroencephalographic (EEG) responses to an acute antiepileptic drug (AED) trial for predicting outcomes in nonconvulsive status epilepticus (NCSE). Background NCSE is an increasingly indentified form for of status epilepticus. However the only well established predictor for outcome is seizure etiology. Managing NCSE poses many challenges that would benefit from additional reliable, early measures to predict patient outcomes. Design/Methods: We analyzed all patients referred to our Neurology Service with suspected NCSE assessed by a standard acute intravenous (IV) benzodiazepine (BDZ) protocol. We correlated patients9 clinical and EEG responses to the BDZ trial with their subsequent outcomes, including survival, recovery of consciousness, and functional status at hospital discharge. Results: From 1990 to 2001, we identified 62 patients with NCSE who were initially evaluated with an acute IV BDZ protocol trial. A favorable clinical response with improvement in consciousness was observed in 22 patients (35%), while 40 (65%) were clinical non-responders. All of the positive clinical responders (100%) survived, recovered consciousness, and exhibited good functional outcomes. In contrast, outcomes were significantly poorer (p Conclusions: This study demonstrates that in addition to the know predictor of etiology, a clinical and, to a lesser degree, EEG response to an acute trial of IV BDZs are predictive of subsequent outcome in patients with NCSE, and warrant further consideration and investigation for assessing and managing such patients. Disclosure: Dr. Krumholz has nothing to disclose. Dr. Hopp has nothing to disclose. Dr. Sanchez has nothing to disclose. Dr. Barry has nothing to disclose. Dr. Hart has nothing to disclose.

Nonconvulsive Status Epilepticus

Managing nonconvulsive status epilepticus (NCSE) poses many challenges that would benefit from additional early measures to predict patient outcomes. Here, we evaluate clinical and electroencephalographic responses to an acute antiepileptic drug trial as an added measure for predicting outcomes in patients presenting with suspected NCSE. We analyzed all patients referred to our Neurology Service with suspected NCSE assessed by a standard acute intravenous (IV) benzodiazepine (BDZ) protocol. We correlated patients' clinical and electrographic (EEG) responses to the BDZ trial with their subsequent outcomes, including survival, recovery of consciousness, and functional status at hospital discharge. From 1990 to 2001, we identified 62 patients with NCSE who were initially evaluated with an acute IV BDZ protocol trial. A favorable clinical response with improvement in consciousness was observed in 22 patients (35%), whereas 40 (65%) were clinical nonresponders. All of the positive clinical responders (100%) survived, recovered consciousness, and exhibited good functional outcomes. In contrast, outcomes were significantly poorer (P<0.001) for the clinical nonresponders; only 14 (35%) recovered consciousness and 22 (55%) survived, with 59% of those survivors demonstrating poor functional outcomes. EEG improvement with BDZs also predicted better outcome, but it was less robust than the clinical response, with better subsequent recovery of consciousness (P<0.05), but not functional outcome or survival. This study demonstrates that a clinical and, to a lesser degree, EEG response to an acute trial of IV BDZs are predictive of subsequent outcome in patients with suspected NCSE, and warrant further consideration and investigation for assessing and managing patients.

High-dose midazolam therapy for refractory status epilepticus in children

To assess the efficacy of high-dose midazolam in the treatment of refractory status epilepticus in children. Paediatric intensive care unit (PICU). Audit of clinical experience. Seventeen consecutive patients treated for episodes of refractory status epilepticus. Algorithm-driven administration of intravenous midazolam to control RSE. Regular, mandatory, patient evaluation to avoid delay in the appropriate escalation of therapy. Our target was the abolition of clinical seizures within 30 min of initiating treatment and early confirmation of cessation of all seizure activity using EEG. The algorithm had failed if clinical seizures persisted beyond 30 min despite the administration of midazolam at 24 microg/kg/min or if administration of a further acute anti-epileptic drug was required to achieve seizure control. The midazolam infusion rate, cumulative midazolam dose and duration of midazolam therapy at time of clinical seizure control were recorded. Haemodynamic parameters were recorded continuously. Episodes of algorithm failure, breakthrough seizures and seizure relapses were identified. Patient outcome was measured in terms of survival to PICU discharge. In 13 patients (76%) midazolam achieved clinical seizure control within 30 min of treatment initiation. Midazolam was eventually successful in treating 15 seizure episodes (88%). Breakthrough seizures occurred in 8 patients (47%). Relapse after discontinuation of therapy occurred in 1 patient (6%). No significant adverse effects attributable to the use of midazolam occurred. There were 3 deaths (18%) related to underlying CNS pathology. Midazolam can offer control of refractory status epilepticus without significant morbidity.

Cortical excitability during prolonged antiepileptic drug treatment and drug withdrawal

Objective Previous reports characterized the effects of administration of single oral doses of antiepileptic drugs (AED) on cortical excitability. However, AED effects on cortical excitability, and their relationship to plasma blood levels, during chronic drug administration at therapeutic doses are not known. The objective of the study was to determine whether plasma blood levels during chronic administration at therapeutic doses would accurately predict changes in corticomotor excitability. Methods We used transcranial magnetic stimulation (TMS) to measure cortical excitability during 5 weeks administration of carbamazepine (CBZ) and lamotrigine (LTG), and subsequent AED withdrawal in 20 healthy volunteers. Data were analyzed using ANOVA RM and regression analysis. Results Resting motor thresholds (r-MT) increased with increasing total and free CBZ and LTG levels during drug administration, but not drug withdrawal. After acute AED withdrawal, r-MT elevation persisted in most individuals with CBZ despite undetectable plasma levels, compared to a rapid normalization with LTG. In contrast, acute drug withdrawal resulted in a transient decrease in r-MT in 3/10 individuals with CBZ and 2/10 with LTG. Conclusions Plasma levels provide information on motor cortical function during active treatment phases but not during AED withdrawal. Significance The transient decrease in r-MT associated with acute AED withdrawal could represent a physiological substrate contributing to AED withdrawal seizures.

Antiepileptic drug withdrawal in patients with temporal lobe epilepsy undergoing presurgical video-EEG monitoring.

To investigate antiepileptic drug (AED) withdrawal during video-EEG monitoring in adult patients with temporal lobe epilepsy (TLE). Between 1995 and 1997, 102 consecutive patients with refractory TLE were admitted to the epilepsy monitoring unit for presurgical evaluation. Patients were monitored with ongoing AEDs being rapidly decreased and discontinued in 4-6 days. The monitoring was continued until sufficient numbers of seizures were recorded. Serum AED levels were checked at admission and after the first complex partial seizure (CPS). In all, 89 patients had 429 CPSs (mean, 4.8 per patient), including 156 (36.4%) secondarily generalized. A mean of 153.8 h (16-451 h) was required for completing the monitoring in each patient. Forty-three (48.3%) patients experienced seizure clusters, and eight (9.0%) had generalized seizures that had never occurred or had been absent for years. However, none evolved to status epilepticus. Carbamazepine was the most commonly used AED in 71.9% of patients, followed by valproate and phenytoin. When the first CPS occurred, mean 77.2 h since the beginning of the monitoring, serum levels of these three AEDs were mostly subtherapeutic rather than minimal. Acute AED withdrawal effectively provoked seizures in TLE patients undergoing presurgical video-EEG monitoring. However, nearly 50% of patients had seizure clusters or secondarily generalized seizures. Serum AED levels were mostly subtherapeutic when the first CPS occurred.

Antiepileptic Drug Withdrawal in Patients with Temporal Lobe Epilepsy Undergoing Presurgical Video‐EEG Monitoring

Summary Purpose: To investigate antiepileptic drug (AED) withdrawal during video‐EEG monitoring in adult patients with temporal lobe epilepsy (TLE). Methods: Between 1995 and 1997, 102 consecutive patients with refractory TLE were admitted to the epilepsy monitoring unit for presurgical evaluation. Patients were monitored with ongoing AEDs being rapidly decreased and discontinued in 4–6 days. The monitoring was continued until sufficient numbers of seizures were recorded. Serum AED levels were checked at admission and after the first complex partial seizure (CPS). Results: In all, 89 patients had 429 CPSs (mean, 4.8 per patient), including 156 (36.4%) secondarily generalized. A mean of 153.8 h (16–451 h) was required for completing the monitoring in each patient. Forty‐three (48.3%) patients experienced seizure clusters, and eight (9.0%) had generalized seizures that had never occurred or had been absent for years. However, none evolved to status epilepticus. Carbamazepine was the most commonly used AED in 71.9% of patients, followed by valproate and phenytoin. When the first CPS occurred, mean 77.2 h since the beginning of the monitoring, serum levels of these three AEDs were mostly subtherapeutic rather than minimal. Conclusions: Acute AED withdrawal effectively provoked seizures in TLE patients undergoing presurgical video‐EEG monitoring. However, nearly 50% of patients had seizure clusters or secondarily generalized seizures. Serum AED levels were mostly subtherapeutic when the first CPS occurred.

Clinical and electrographic effects of acute anticonvulsant withdrawal in epileptic patients

We retrospectively investigated the effects of acute antiepileptic drug (AED) withdrawal on seizure symptomatology--including frequency, clinical features, and electrical onset--by studying 35 patients during evaluation for epilepsy surgery. The highest risk for both partial and secondary generalized seizures occurred during absent or subtherapeutic, and not during rapidly falling, AED levels. AED withdrawal had minimal effect on clinical symptomatology or electrographic onset.

Photosensitivity as a model for acute antiepileptic drug studies

A technique is described for assessing the efficacy and time course of effects of antiepileptic drugs, after a single acute dose, by means of their action on the human photo-convulsive response. The range of frequencies of intermittent photic stimulation to which the patient is sensitive (photosensitivity range) is determined in a standardized manner at hourly intervals over the course of a waking day. 82 controlled studies have established that, with the rare exceptions of patients whowing a consistent circadian rhythm of photosensitivity, the photosensitivity range is stable over this time scale. A total of 72 studies have shown that representatives of all the major groups of established antiepileptic drugs, together with some experimental drugs, suppress photosensitivity following a single acute adminstration. By contrast barbiturates without antiepileptic action (methohexitone and quinalbarbitone) do not affect photosensitivity even in doses producing marked drowsiness. These findings suggest the technique to be a potentially useful tool for preliminary investigation of efficacy and duration of action of new potential antiepileptic drugs.

Photosensitivity as a model for acute anti-epileptic drug studies

Photosensitivity as a model for acute anti-epileptic drug studies