Management of Acute Seizure Episodes

Summary: Acute seizures may represent the initial manifestation of epilepsy or isolated events. Urgent treatment of these episodes is indicated to reduce the risk for permanent neurologic damage. Status epilepticus (SE), one form of acute seizure, has an estimated annual incidence of 100,000–150,000 cases per year in the United States. Management of SE focuses on terminating clinical and electrical seizure activity while providing supportive care and identifying the precipitating factors. Physician preference and patient-related factors may dictate the choice of pharmacologic treatment of SE. However, benzodiazepines, which enter the brain rapidly and offer the opportunity for most rapid seizure cessation, are the foundation for SE management. At our institution, first-line treatment consists of i.v. lorazepam followed by a long-acting antiepileptic drug (AED). When i.v. access cannot be attained, high AED blood levels can be rapidly achieved with rectally administered diazepam (DZP). For management of acute repetitive seizures, it is desirable to have an effective drug that can be safely administered by caregivers outside of the hospital setting. Clinical trial data indicate that rectal administration of a prepackaged viscous DZP solution fulfills these criteria. In these studies, rectal DZP gel reduced seizure frequency and recurrence compared to seizure control, improved patient and family quality of life, and was cost-effective because it reduced the need for emergency and inpatient treatment.     

Antiepileptic Drug Actions

Summary: Antiepileptic drugs (AEDs) vary in their efficacy against generalized tonic-clonic, myoclonic, and absence seizures, suggesting different mechanisms of action. Phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) reduced the ability of mouse central neurons to sustain high-frequency repetitive firing of action potentials (SRF) at therapeutic free serum concentrations. Phenobar-bital (PB) and the benzodiazepines (BZDs), diazepam (DZP), clonazepam (CZP), and lorazepam (LZP), also reduced SRF, but only at supratherapeutic free serum concentrations achieved in treatment of generalized tonic-clonic status epilepticus. These AEDs interact with sodium channels to slow the rate of recovery of the channels from inactivation. The BZDs and PB enhanced γ-aminobutyric acid (GABA) responses evoked on mouse central neurons by binding to two different sites on the GABA_A receptor channel. BZDs increased the frequency of GABA receptor channel openings. In contrast, barbiturates increased the open duration of these channels. VPA enhanced brain GABA concentration and may enhance release of GABA from nerve terminals. Ethosuximide (ESM) reduced a small transient calcium current which has been shown to be involved in slow rhythmic firing of certain neurons. Reduction of SRF, enhancement of GABA-ergic inhibition, and reduction of calcium current may be, in part, the bases for A ED action against generalized tonic-clonic, myoclonic, and absence seizures, respectively.     

Inadequate benzodiazepine dosing may result in progression to refractory and non‐convulsive status epilepticus

Aims. Status epilepticus (SE) is defined as ongoing seizures lasting longer than five minutes or multiple seizures without recovery. Benzodiazepines (BZDs) are first‐line agents for the management of SE. Our objective was to evaluate BZD dosing in SE patients and its effects on clinical/electrographic outcomes. Methods. A retrospective analysis was conducted from a prospective database of SE patients admitted to a university‐based neurocritical care unit. The initial presentation and progression to refractory SE (RSE) and non‐convulsive SE (NCSE) with coma was evaluated. Outcome measures included length of stay (LOS), rates of intubation, ventilator‐dependent days, and Glasgow outcome scale (GOS). The lorazepam equivalent (LE) dosage of BZDs administered was calculated and we analysed variations in progression if 4 mg or more of LE (adequate BZDs) was administered. Results. Among 100 patients, the median dose of LE was 3 mg (IQR: 2–5 mg). Only 31% of patients received adequate BZDs. Only 18.9% of patients with NCSE without coma received adequate BZDs (p=0.04). Among patients progressing to RSE, 75.4% had not received adequate BZDs (p=0.04) and among patients developing NCSE with coma, 80.6% did not receive adequate BZDs (p=0.07). Escalating doses of BZDs were associated with a decrease in cumulative incidences of RSE (correlation coefficient r=‐0.6; p=0.04) and NCSE with coma (correlation coefficient r=‐0.7; p=0.003). Outcome measures were not influenced by BZD dosing. Conclusion. The majority of our patients were not adequately dosed with BZDs. Inadequate BZD dosing progressed to RSE and had a tendency to lead to NCSE with coma. Our study demonstrates the need to develop a hospital‐wide protocol to guide first responders in the management of SE.     

Aborted and refractory status epilepticus in children: a comparative analysis

PURPOSE: The aims of this retrospective study were: (1) to compare the demographics, clinical characteristics, etiology, and EEG findings of status epilepticus aborted with medication (ASE) and refractory status epilepticus (RSE), (2) to describe the treatment response of status epilepticus (SE), and (3) to determine predictors of long-term outcome in children with SE. METHODS: Medical records and EEG lab logs with ICD-9 diagnostic codes related to SE were reviewed. Patients younger than 18 years of age, hospitalized in 1994-2004 at the Mayo Clinic, Rochester, were included. RESULTS: One hundred fifty-four children had SE; 94 (61%) had ASE, and 60 (39.0%) had RSE. Family history of seizures, higher seizure frequency score, higher number of maintenance antiepileptic drugs (AEDs), nonconvulsive SE, and focal or electrographic seizures on initial EEG were associated with RSE by univariate analysis. In-hospital mortality was significantly higher in RSE (13.3%) than in ASE (2.1%). In the long term, survivors with RSE developed more new neurological deficits (p < 0.001) and more epilepsy (p < 0.004) than children with ASE. Children treated in a more aggressive fashion appeared to have better treatment responses (p < 0.001) and outcomes (p = 0.03). Predictors of poor outcome were long seizure duration (p < 0.001), acute symptomatic etiology (p = 0.04), nonconvulsive SE (NCSE) (p = 0.01), and age at admission <5 years (p = 0.05). DISCUSSION: Several patient and clinical characteristics are associated with development of RSE and poor outcome. Prospective, randomized trials that assess different treatment protocols in children with SE are needed to determine the optimal sequence and timing of medications.     

Administration of diazepam during status epilepticus reduces development and severity of epilepsy in rat

Prevention of epileptogenesis after brain insults, such as status epilepticus (SE), head trauma, or stroke, remains a challenge. Even if epilepsy cannot be prevented, it would be beneficial if the pathologic process could be modified to result in a less severe disease. We examined whether early discontinuation of SE reduces the risk of epilepsy or results in milder disease. Epileptogenesis was triggered with SE induced by electrical stimulation of the amygdala. Animals (n = 72) were treated with vehicle or diazepam (DZP, 20 mg/kg) 2 h or 3 h after the beginning of SE. Electrode-implanted non-stimulated rats served as controls for histology. All animals underwent continuous long-term video-electroencephalography monitoring 7-9 weeks and 11-15 weeks later to detect the occurrence and severity of spontaneous seizures. As another outcome measure, the severity of hippocampal damage was assessed in histologic sections. In the vehicle group, 94% of animals developed epilepsy. DZP treatment reduced the percentage of epileptic animals to 42% in the 2-h DZP group and to 71% in the 3-h DZP group (p < 0.001 and p < 0.05 compared to the vehicle group, respectively). If epilepsy developed, the seizures were less frequent in DZP-treated animals compared to the vehicle group (median 16.4 seizures/day), particularly in the 2-h DZP group (median 0.4 seizures/day). Finally, if DZP treatment was started 2 h, but not 3 h after SE, the severity of hippocampal cell loss was milder and the density of mossy-fiber sprouting was lower than in the vehicle group. These data indicate that treatment of SE with DZP within 2 h reduces the risk of epilepsy later in life, and if epilepsy develops, it is milder.     

Epilepsia partialis continua and neuronal migration anomalies.

Neuronal migration anomalies commonly cause seizures that are partial in type and generally refractory to medical treatment. Epilepsia partialis continua (EPC), an unusual form of epilepsy commonly related to acute damage of the cerebral cortex or to a chronic lesion, has never been described in a patient with neuronal migration anomalies. In 50 children with epilepsy due to neuronal migration anomalies, we observed two cases of EPC. These two children had unilateral neuronal migration abnormalities with partial seizures other than EPC and contralateral hemiparesis. Epilepsia partialis continua appeared two to three years after the onset of partial attacks and was accompanied by a worsening of the children's previous hemiparesis. Although a rare seizure manifestation in children with neuronal migration anomalies, when it does appear, EPC can aggravate the clinical neurological condition and should always be investigated for in these cases. Because its clinical appearance is often subtle, as in these two children, EPC may easily remain undiagnosed.     

Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure

The occurrence of status epilepticus (SE) is considered the main cause of brain lesions and morphological alterations, such as hippocampal neuron loss, that result in chronic epilepsy. Previous work demonstrated the convulsive and widespread neuropathological effects of soman, an organophosphorus compound that causes SE and severe recurrent seizures as a result of exposure. Seizures begin rapidly after exposure, can continue for hours, and contribute to prolonged physical incapacitation of the victim. This study attempts to identify anticonvulsive and neuroprotective drugs against soman exposure. Male Sprague-Dawley rats were exposed to 1.0 LD(50) soman. EEGraphical and neuropathological (Fluoro-Jade B staining) effects were analyzed at 72 h post-exposure to soman and subsequent treatments with diazepam (DZP) alone or in combination with histone deacetylase inhibitors, suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). The extent of brain damage was dependent on the length of SE and not on the number of recurrent seizures. DZP treatment alone decreased SE time and damage in hippocampus, amygdala, thalamus and cortex, but not in piriform nuclei. The combination of DZP and VPA 100 mg/kg showed more anticonvulsive effects, decreased SE time, and afforded more neuroprotection in the hippocampus, mainly the ventral portion. The combination DZP and SAHA 25 mg/kg was more neuroprotective, but not more anticonvulsant than DZP alone. The DZP combination with VPA HDAC inhibitor proved to be a good treatment for SE and neuronal damage caused by soman exposure.     

Refractory status epilepticus: frequency, risk factors, and impact on outcome

BACKGROUND: Refractory status epilepticus (RSE) is a life-threatening condition in which seizures do not respond to first- and second-line anticonvulsant drug therapy. How often RSE occurs, risk factors that predispose to this condition, and the effect of failure to control seizures on clinical outcome are poorly defined. OBJECTIVE: To determine the frequency, risk factors, and impact on outcome of RSE. DESIGN: Retrospective cohort study. SETTING: Large academic teaching hospital. PATIENTS: Consecutive sample of 83 episodes of status epilepticus in 74 patients (mean age, 63 years). MAIN OUTCOME MEASURES: Refractory status epilepticus was defined as seizures lasting longer than 60 minutes despite treatment with a benzodiazepine and an adequate loading dose of a standard intravenous anticonvulsant drug. Factors associated with RSE were identified using univariate and backward stepwiselogistic regression analyses. RESULTS: In 57 episodes (69%), seizures occurred after treatment with a benzodiazepine, and in 26 (31%), seizures occurred after treatment with a second-line anticonvulsant drug (usually phenytoin), fulfilling our criteria for RSE. Nonconvulsive SE (P=.03) and focal motor seizures at onset (P=.04) were identified as independent risk factors for RSE. Eleven (42%) of 26 patients with RSE had seizures after receiving a third-line agent (usually phenobarbital). Although mortality was not increased (17% overall), RSE was associated with prolonged hospital length of stay (P<.001) and more frequent functional deterioration at discharge (P=.02). CONCLUSIONS: Refractory status epilepticus occurs in approximately 30% of patients with SE and is associated with increased hospital length of stay and functional disability. Nonconvulsive SE and focal motor seizures at onset are risk factors for RSE. Randomized controlled trials are needed to define the optimal treatment of RSE.     

Status epilepticus in the course of epilepsy in children and adolescents

Status epilepticus (SP) is defined as a single seizure or recurrent seizures of over 30 min. duration, without regaining full consciousness. In approximately 50% of cases SE is related to epilepsy. The International League Against Epilepsy has recently proposed a new SE classification (2001). The purpose of this prospective study is to evaluate SE incidence in children and adolescents in relation to their age and type of epilepsy, as well as to determine usefulness of the new classification of SE. A group of 600 children and adolescents with epilepsy was observed prospectively. The inclusion criteria were: recently diagnosed epilepsy in children aged under 15 years, and long-term treatment and observations (mean = 5 years, SD = 3.2). Out of the 600 children and adolescents with epilepsy 39 (6.1%) had one or more episodes during the observation period. Two factors were correlated with SE: age at the onset of epilepsy (under 5 years), and the type of epileptic syndrome (the Lennox-Gastaut syndrome, myoclonic-astatic epilepsy, symptomatic and cryptogenic partial epilepsy, progressive myoclonic epilepsy, and the Kojevnikov syndrome). Only in a fourth of the patients the cause of SP was related to a known factor, such as e.g. infection or sudden discontinuation of anti-epileptic medication. The currently used classification of SP (by Appelton and Gibbs) was found to be more useful than the one newly proposed by ILAE, because the former is better suited to the evaluation of SE in children.