Treatment of Status Epilepticus

Summary: Status epilepticus, particularly the convulsive form, is a medical emergency, warranting prompt and aggressive treatment. To do this, one must have a thorough understanding of the pharmacology of the anticonvulsant agents. Therapy should be directed toward rapid termination of the status epilepticus, prevention of seizure recurrence, and treatment of any underlying cause. Most importantly, one should establish and adhere to a standard treatment protocol for best results.     

Treatment of the Nonconvulsive Epilepsies

Summary: Eliminating seizures should be the first goal of therapy for non-convulsive epilepsies, but preventing seizures, i.e., guarding against head injuries and immunizing against agents that attack the nervous system, is the second goal. An accurate diagnosis of seizure type helps ensure that the appropriate medication for that particular form of epilepsy will be prescribed. Drug decisions should also be based on the risk:benefit ratio to the individual patient, and drug interactions should be considered when more than one drug is required. Frequent monitoring of drug serum levels is necessary in the case of multiple drug therapy or until seizures are controlled. Ethosuximide is considered the drug of choice in absence seizures, but valproic acid is equally effective. Although effective in controlling absence seizures, clonazepam is not favored in this indication because of a high incidence of side effects and the development of tolerance. Atonic seizures are generally refractory to treatment, but valproate, clonazepam, and occasionally carbamazepine represent the drugs of choice in management. Phenytoin continues to be a very popular drug for most types of seizures, but carbamazepine, used adjunctively until recently, is effective as monotherapy for the control of partial seizures, particularly those of the complex partial variety.     

The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: A meta-analysis of published studies

PurposeSystematic evaluation of published evidence-base of the efficacy of five antiepileptic drugs – lacosamide, levetiracetam, valproate, phenytoin and phenobarbital – in convulsive benzodiazepine-resistant status epilepticus.MethodsData sources included electronic databases, personal communication, and back tracing of references in pertinent studies. These were prospective and retrospective human studies presenting original data for participants with convulsive benzodiazepine-resistant status epilepticus. Interventions were intravenous lacosamide, levetiracetam, phenobarbital, phenytoin and valproate. Outcome measured is clinically detectable cessation of seizure activity. Level-of-evidence was assessed according to Oxford Centre of Evidence-Based Medicine and The Cochrane Collaboration's Tool for Assessment of Risk. Twenty seven studies (798 cases of convulsive status epilepticus) were identified and 22 included in a meta-analysis. Random-effects analysis of dichotomous outcome of a single group estimate (proportion), with inverse variance weighting, was implemented. Several sources of clinical and methodological heterogeneity were identified.ResultsEfficacy of levetiracetam was 68.5% (95% CI: 56.2–78.7%), phenobarbital 73.6% (95% CI: 58.3–84.8%), phenytoin 50.2% (95% CI: 34.2–66.1%) and valproate 75.7% (95% CI: 63.7–84.8%). Lacosamide studies were excluded from the meta-analysis due to insufficient data.ConclusionValproate, levetiracetam and phenobarbital can all be used as first line therapy in benzodiazepine-resistant status epilepticus. The evidence does not support the first-line use of phenytoin. There is not enough evidence to support the routine use of lacosamide. Randomized controlled trials are urgently needed.     

Utility of Free Level Monitoring of Antiepileptic Drugs

Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) concentrations of antiepileptic drugs include extensive and variable binding to plasma proteins. Phenytoin and valproic acid belong to this category. It is shown that free drug concentration is independent of total drug concentration, whereas total drug concentration depends on free concentration and free fraction. Because antiepileptic drugs are predominantly bound to albumin, free fraction will increase in the presence of hypoalbuminemia (hepatic and renal disease, burns, and pregnancy). Free fraction also increases because of saturable binding (valproic acid) and competitive binding (valproic acid displacing phenytoin). There is suggestive evidence that side effects may be more closely related to the free, rather than to the total, plasma concentration of phenytoin. The clinical evidence that side effects or therapeutic effects are better correlated to the free, rather than the total, concentration of valproic acid or carbamazepine is not yet convincing. Knowledge of the free concentration improves our understanding of therapeutic and toxic effects of low total plasma concentrations. Further clinical trials are necessary for definitive assessment of the clinical relevance for free drug monitoring of valproic acid, carbamazepine, and phenytoin in the management of epileptic patients.     

Utility of monitoring the serum levetiracetam concentration for intraoperative seizure control during awake craniotomy

Awake craniotomy is an established procedure for resecting brain tumors in eloquent lesions, and intraoperative seizure is one of the most important complications. Phenytoin is normally used to control intraoperative seizures. Recently, phenytoin was replaced with levetiracetam at our institution because the latter has fewer side effects. While the phenytoin dose is calibrated in accordance with the serum concentration, there is currently no consensus on a method of monitoring the serum concentration of levetiracetam or the effective concentration range needed to control intraoperative seizures during awake craniotomy. The present study therefore aimed to determine whether monitoring the serum levetiracetam concentration is useful for controlling intraoperative seizures during awake craniotomy. The intraoperative serum concentration of levetiracetam during awake craniotomy was measured in 34 patients and compared with that of phenytoin in 33 patients undergoing the same procedure. The levetiracetam concentration inversely correlated with body surface area (BSA) and estimated glomerular filtration rate (eGFR). Levetiracetam was superior to phenytoin in terms of the correlation between the serum concentration and the dose adjusted for BSA and eGFR (correlation coefficient, 0.49 vs 0.21). Furthermore, the serum levetiracetam concentration in patients with intraoperative seizures was below the 95% confidence interval (CI) of the regression line whereas the serum phenytoin concentration of two patients with seizures was within the 95% CI, indicating that evaluating the serum levetiracetam concentration against the BSA and eGFR-adjusted dosage may be useful in preventing intraoperative seizures during awake craniotomy by allowing prediction of the seizure risk and enabling more accurate dosage calibration.     

Risk Factors Associated with Poor Outcomes in Patients with Brain Abscesses

Objective

The purpose of this study was to describe the clinical characteristics, treatment outcomes, and prognostic factors in patients with brain abscesses treated in a single institute during a recent 10-year period.

Methods

Fifty-one patients with brain abscesses who underwent navigation-assisted abscess aspiration with antibiotic treatment were included in this study. Variable parameters were collected from the patients'' medical records and radiological data. A comparison was made between patients with favorable [Glasgow Outcome Scale (GOS) ≥4] and unfavorable (GOS <4) outcomes at discharge. Additionally, we investigated the factors influencing the duration of antibiotic administration.

Results

The study included 41 male and 10 female patients with a mean age of 53 years. At admission, 42 patients (82%) showed either clear or mildly disturbed consciousness (GCS ≥13) and 24 patients (47%) had predisposing factors. The offending microorganisms were identified in 25 patients (49%), and Streptococcus species were the most commonly isolated bacteria (27%). The mean duration of antibiotic administration was 42 days. At discharge, 41 patients had a favorable outcome and 10 had an unfavorable outcome including 8 deaths. The decreased level of consciousness (GCS <13) on admission was likely associated with an unfavorable outcome (p=0.052), and initial hyperglycemia (≥140 mg/dL) was an independent risk factor for prolonged antibiotic therapy (p=0.032).

Conclusion

We found that the level of consciousness at admission was associated with treatment outcomes in patients with brain abscesses. Furthermore, initial hyperglycemia was closely related to the long-term use of antibiotic agents.     

Chronic subdural haematoma associated with disturbance of consciousness: significance of acute-on-chronic subdural haematoma

Abstract

Objective:

Detailed features of chronic subdural haematoma (cSDH) associated with disturbance of consciousness and acute-on-chronic subdural haematoma (a/cSDH), in which acute subdural haematoma overlaps cSDH, remain poorly understood. The object of this study was to clarify both characteristics of cSDH associated with disturbance of consciousness and the significance of a/cSDH.

Methods:

Clinical factors and computed tomography (CT) findings were retrospectively investigated in 349 consecutive patients admitted between 2006 and 2013 and diagnosed with cSDH.

Results:

Glasgow Coma Scale (GCS) was ≤?8 in 21 patients (6.0%) and 9–14 in 29 patients excluding aphasia and/or dementia (8.3%). Multiple logistic regression analysis indicated that a/cSDH, female sex and haemodialysis were significantly related to severe disturbance of consciousness (GCS?≤?8). Predictors for a/cSDH observed in 29 patients (8.3%) were trauma history within 7?days before admission, high prothrombin time–international rate, and use of anticoagulants and/or antiplatelets. Unfavourable outcomes were observed in 29 of 299 patients (9.7%) without consciousness disturbance, compared to 27 of 50 patients (54%) with consciousness disturbance. Predictors of unfavourable outcome were consciousness disturbance, increase in age, malignancy, trauma history within 7?days and haemodialysis.

Discussion:

Disturbance of consciousness associated with cSDH, often caused by either a/cSDH or concomitant disease, frequently resulted in unfavourable outcomes. As a result, in cSDH patients associated with disturbance of consciousness, underlying conditions, especially a/cSDH, which is often caused by haemostatic abnormality, should be clarified and managed.     

Levetiracetam,a new antiepileptic agent: lack of in vitro and in vivo pharmacokinetic interaction with valproic acid

PURPOSE: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited drug-interaction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions. METHODS: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, one-sequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. RESULTS: Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 microg/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadministered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 microg/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA. CONCLUSIONS: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during short-term administration, and suggest that dose adjustment is not required when these two drugs are given together.     

Comparison of the efficacy and safety of levetiracetam and phenytoin in the treatment of established status epilepticus: A systematic review and meta-analysis

Status epilepticus (SE) is the second most critical neurological illness after cerebrovascular disease. Phenytoin has traditionally been considered the second-line drug of first choice after failure of first-line treatment using benzodiazepines. In recent years, levetiracetam has been proposed as a potential substitute for phenytoin. To comprehensively evaluate the efficacy and safety of levetiracetam and phenytoin in the treatment of patients with established SE, we integrated the data from 11 eligible studies and conducted a systematic review and meta-analysis. The PubMed, Web of Science, Cochrane Library, and Embase databases were searched to identify eligible articles reporting outcomes including clinical seizure cessation within 60 min, clinical recurrence rate within 24 h, good final outcome at discharge, and adverse events (AEs) of treatment with levetiracetam and phenytoin. Our study included a total of 11 trials including a total of 1933 patients. The outcomes showed that the pooled Risk Raito (RR) of clinical seizure cessation within 60 min was 1.08 (95% CI = 1.02–1.14, P = 0.01). The pooled RR of clinical recurrence rate within 24 h was 1.03 (95% CI = 0.66–1.59, P = 0.91). The pooled RR of AEs was 0.83 (95% CI = 0.57–1.21, P = 0.34). The pooled RRs of life-threatening hypotension and acute respiratory depression were 0.29 (95% CI = 0.10–0.81, P = 0.02) and 0.63 (95% CI = 0.40–0.98, P = 0.04), respectively. Levetiracetam might be more effective than phenytoin for the treatment of established SE and is associated with a lower incidence of more serious AEs. Levetiracetam can be used as an alternative to phenytoin for the treatment of benzodiazepine-refractory SE.     

Comparison of the Anticonvulsant Efficacies and Neurotoxic Effects of Valproic Acid, Phenytoin, and the Ketogenic Diet

PURPOSE: The purpose of this study was to measure quantitatively the effectiveness of the ketogenic diet (KD) in comparison to two clinically important anticonvulsant drugs (AEDs), valproic acid (VPA) and phenytoin (PHT), and to evaluate possible associated neurotoxicity. METHODS: Rats were maintained on either a calorie-restricted, KD or calorie-restricted, rodent-chow diet for 3-5 weeks, after which neurobehavioral and seizure testing was completed. AEDs (either VPA or PHT) were injected acutely at the time to peak effect before neurotoxic and seizure assessment. Seizures were induced by timed infusion of pentylenetetrazole (PTZ) and maximal electroshock (MES). RESULTS: VPA protected from both MES- and PTZ-induced seizures, whereas the KD only elevated PTZ seizure threshold; PHT only attenuated MES-induced seizures. The KD was as effective as a high dose of VPA (i.e., 300 mg/kg) and combined treatment (i.e., KD + VPA) showed an additive increase in PTZ seizure threshold. No observed neurobehavioral deficits were associated with either diet treatment; however, drug-related side effects were noted with high doses of either VPA or PHT. CONCLUSIONS: These data suggest that the KD ranks among VPA and PHT as an effective treatment for seizures, without observed drug-associated neurobehavioral contraindications. In combination with AEDs, our results indicate that the KD plus VPA work synergistically to increase seizure threshold, whereas the KD plus PHT may be complementary, elevating seizure threshold (KD) and reducing seizure severity (PHT). These findings may provide insights into future directions for rational polytherapy; however, it is important to be aware that the KD has been shown to elevate VPA-induced hepatotoxicity.     

Stupor Following Administration of Valproic Acid to Patients Receiving Other Antiepileptic Drugs

Stupor is an unusual complication following the addition of valproic acid to other antiepileptic drugs. We report four such cases. Stupor occurred acutely in 3 patients and insidiously in the fourth. In the cases of acute toxicity, neither toxic levels of valproate nor significant elevations in blood levels of the other drugs occurred. In the fourth patient, stupor occurred concomitantly with a rise in the phenobarbital level. The electroencephalograms of all 4 patients revealed generalized high-amplitude rhythmic bisynchronous delta activity. Recovery occurred following discontinuation of valproic acid or other antiepileptic drugs. These observations suggest that stupor may occur as a result of drug interactions after the addition of valproic acid to other antiepileptic drugs.     

The prediction of long-term outcome after subarachnoid hemorrhage as measured by the Short Form-36 Health Survey

The Glasgow Outcome Scale (GOS) score is widely used to assess outcome after a subarachnoid hemorrhage (SAH). Patients who have recovered fully or with a mild disability (GOS scores 4 and 5) frequently complain about difficulties in conducting their daily activities. The Short Form-36 (SF-36) Health Survey is a questionnaire that assesses outcomes in multiple categories. This study was conducted to compare the quality of outcome assessment between the SF-36 Health Survey and GOS scores. A total of 128 patients with SAH (all data expressed as mean ± standard deviation) aged 53.1 ± 12.1 years, and a mean Hunt and Hess grade on admission of 2 ± 1, were retrospectively included in the study. Medical charts were reviewed to assess previous medical history, location of the aneurysm and the presence of vasospasm. The SF-36 and GOS scores were collected in structured interviews approximately 5 years (±2 years) after the SAH. The SF-36 data were compared to a historical healthy control cohort of 2,474 individuals. The results showed that 52% of patients experienced a favourable outcome after SAH (GOS scores 4 and 5). Vasospasm was recorded in 25% of patients. However, the average SF-36 results were lower in all tested categories for patients after SAH than the healthy normal controls. None of the SF-36 categories except physical function correlated significantly with the GOS score. Aneurysm location did not have an impact on SF-36 data. Patients after a SAH assessed as GOS score 5 are significantly impaired in social functioning and general health. We conclude that patients continue to suffer neuropsychological deficits years after a SAH. The GOS score is a rough outcome measure that primarily focuses on physical functioning. SF-36 is a useful tool to include in the neuropsychological outcome assessment of patients with SAH.     

Apolipoprotein E genotype and traumatic brain injury in children—association with neurological outcome

Objective To determine whether the presence of Apolipoprotein E ε4 genotype (ApoE ε4) is associated with outcomes of traumatic brain injury in children. Materials and methods The ApoE genotype was examined in the group of 70 pediatric patients who suffered from traumatic brain injury. The group consists of 48 boys and 22 girls, and the most frequent was the E3 isoform of ApoE. Polymerase chain reaction/restriction fragment length polymorphism method was used for the ApoE genotype assessment. The severity of trauma was assessed by Glasgow Coma Scale and graded into three categories. The presence of focal neurology signs, comparing the admission and dimission status, and duration of hospital care were observed. The neurological outcome after 1 year was assessed by Glasgow Outcome Scale. Trauma severity was compared with the neurological outcome, according to different ApoE genotypes. For statistical processing, t test, nonparametric Wilcoxon test, Fisher, and χ ² tests were used. Conclusion Our results suggest the association between the ApoE genotype and outcome of traumatic brain injury in children. Patients with ApoE ε4 genotype were more likely to have severe clinical symptomatology and unfavorable neurological outcome after traumatic brain injury compared to significantly better outcome with other ApoE genotype.     

Nonconvulsive Status Epilepticus in the Critically Ill Elderly

Summary: Purpose: To describe the electrographic and clinical features of nonconvulsive status epilepticus (NCSE) in the critically ill elderly and to identify potential predictors of outcome.
Methods: We prospectively identified 25 episodes of altered mentation and NCSE in 24 critically ill elderly patients associated with generalized, focal, or bihemispheric epileptiform EEG patterns. Patients with anoxic encephalopathy were excluded.
Results: Of 25 hospitalizations, 13 (52%) resulted in death, and 12 (48%) patients survived to discharge. Death was associated with the number of acute, life-threatening medical problems on presentation (survivors, 1.8; fatalities, 2.8; p = 0.013) and with generalized EEG pattern (p = 0.017). Higher doses or greater number of antiepileptic drugs (AEDs) did not improve outcome. Treatment with intravenous benzodiazepines was associated with increased risk of death (p = 0.033). Ten patients with advance directives were managed outside the intensive care unit (ICU). Mean hospitalization was 39 days in the ICU group and 22 for those with advance directives (p = 0.017).
Conclusions: Severity of illness correlates with mortality in critically ill elderly patients with NCSE. Treatment with intravenous benzodiazepines may increase their risk of death. Aggressive ICU management may prolong hospitalization at considerable cost, without improving outcome. It is unclear whether NCSE affects outcome in the critically ill elderly or is merely a marker for severity of disease in predisposed patients. The benefits of aggressive therapy are unclear. Carefully controlled, prospective trials will be necessary to determine the best therapies for NCSE in the critically ill elderly and the appropriate role of the ICU in their management.     

Treatment of Refractory Status Epilepticus in Childhood

Refractory status epilepticus (RSE) is characterized by a prolonged seizure that persists despite adequate initial management. RSE accounts for almost one quarter of all status epilepticus and carries significant risk for morbidity and mortality. Treatment varies widely between institutions regarding medication choice, dose, and monitoring. Several agents including nonanesthetic antiepileptic drugs (AEDs), anesthetic AEDs, enteral AEDs, and other therapies have been used in RSE. We review the current treatment strategies for RSE, focusing on patient selection, monitoring, optimal dosing and administration of medications, efficacy, adverse effects, and treatment duration.     

Neurosurgical Treatment of Refractory Status Epilepticus

Refractory status epilepticus (RSE) is defined as status epilepticus that continues despite aggressive treatment. A 9.8-year-old boy with a past history of daily left focal motor seizures was transferred to University of California at Los Angeles (UCLA) Hospital in pentobarbital coma after 4 days in RSE. The RSE was treated with very high doses of all appropriate antiepileptic drugs (AEDs), alone and in combination. The pentobarbital was titrated to burst suppression on EEG, but whenever pentobarbital was decreased, the seizures recurred. An ictal positron tomography scan of glucose metabolism demonstrated a right frontal area of hypermetabolism corresponding to an epileptic focus on EEG and magnetic resonance lesion. Eight days after the boy was admitted to UCLA, the right frontal focus was surgically removed, with immediate control of the status epilepticus. Whereas before onset of RSE, he had daily focal seizures, the boy has been seizure-free postoperatively for greater than 1 year. Operative treatment should be considered in patients with RSE in whom a focus of seizure onset can be demonstrated and who are reasonably considered surgical candidates.