The treatment of status epilepticus

Status epilepticus (SE) is a life-threatening emergency that requires prompt treatment, including basic neuroresuscitation principles (the ABCs), antiepileptic drugs to stop the seizure, and identification of etiology. Symptomatic SE is more common in younger children. Treating the precipitating cause may prevent ongoing neurologic injury and facilitates seizure control. A systematic treatment regimen, planned in advance, is needed, including one for refractory status epilepticus (RSE). Here we emphasize definitions, clinical and electroencephalography stages, early treatment, special circumstances that may require immediate seizure control, and treatment of RSE. Because much clinical research in SE has been done in adults, we indicate the patient population studied.     

Pentobarbital treatment of refractory status epilepticus

We studied nine patients with status epilepticus refractory to standard therapy. In all patients so treated, IV pentobarbital terminated seizure activity. Mortality was high (77%) in those treated, but was attributed to underlying pathology and possibly to duration of status epilepticus. Pentobarbital therapy should be initiated within 0 to 2 hours after onset of seizures, with continuous EEG monitoring in an intensive care unit.     

Place of neurosteroids in the treatment of status epilepticus

The treatment of refractory or super‐refractory status epilepticus (SE) currently relies on low‐evidence strategies, including general anesthetics to induce pharmacologic coma, ketogenic diet, immunosuppression, and other physical measures. Besides the formal uncertainty regarding efficacy, concerns have been about tolerability. In this situation, identification of alternative, higher evidence treatments is urgently needed. Allopregnanolone is an endogenous neurosteroid exerting a positive allosteric modulation on γ‐aminobutyric acid (GABA)_A receptors. In animal experiments it has been demonstrated that this neurosteroid displays relevant antiseizure properties in a variety of SE models, and that the tolerance to benzodiazepines, relying on receptor internalization, does not affect its action. An experimental clinical use in patients with SE older than 2 years was initated more than 5 years ago. Being a naturally occurring compound, no relevant adverse events are expected, and until now its safety profile appears reassuring. Preliminary results of a phase I/II trial seemed promising, but a recent well‐designed randomized, placebo‐controlled trial could not find any difference in terms of efficacy; tolerability seemed nevertheless good. Patients with refractory and super‐refractory SE still deserve further well‐designed studies to improve current treatment options.     

Isoflurane anaesthesia in the treatment of convulsive status epilepticus

Summary Status epilepticus may be resistant to intravenous anticonvulsive drugs. In these cases treatment with the inhalation anaesthetic agent isoflurane may be helpful in the further management. We describe a 35-year-old female patient who suffered from status epilepticus with partial seizures. In spite of therapy with benzodiazepine and phenytoin the status evolved into tonic clonic seizures. Treatment with thiopentone sodium did not stop seizure activity. Anaesthesia with isoflurane (dosage up to 1.5 vol.%) carried out twice within 72 h finally led to a termination of status epilepticus. From our own experience and reports in the literature we conclude that general anaesthesia with isoflurane can and should be used in the treatment of severe status epilepticus that does not respond to intravenous anticonvulsive agents.     

Therapeutic coma for the treatment of status epilepticus

Background

There are scarce data available on the treatment of refractory status epilepticus (SE) where general anesthetics are recommended. However, these may be related to increased morbidity (and possibly mortality).

Question

When and how should therapeutic coma be used in this clinical setting?

Methods

Critical review of available international literature in the past 50 years as well as of personal experience.

Results

Patients with generalized convulsive or nonconvulsive SE in coma not responding to benzodiazepines and an antiepileptic drug should be treated under electroencephalographic (EEG) monitoring with coma induction and general anesthetics. Initially, midazolam/propofol seem to represent the safest options. A progressive weaning attempt should be made after 24?h without EEG seizures. Patients with absence SE should never be treated with coma, and in those with focal SE with preserved consciousness coma should be deferred after the trial of other nonsedating compounds. In cases of super-refractory SE, ketamine and/or a ketogenic diet may be considered.

Conclusion

In view of the limited current evidence, it seems reasonable to avoid indiscriminate use of general anesthetics in SE.

     

Anesthetic drugs for the treatment of status epilepticus

Worsening pharmacoresistance to antiseizure drugs is common with ongoing excitotoxic neuronal and systemic injury. Early initiation of anesthetic drugs in refractory status epilepticus (RSE) may halt these processes while allowing time for treatment targeting the cause of the seizures. Current guidelines support the use of anesthetic drugs as the third line pharmacologic therapy in generalized convulsive status epilepticus but do not clearly define the indications for these drugs in other types of status epilepticus. There is wide practice variation in choice of third line therapy for RSE, but there is overall consensus that anesthetics should be initiated earlier in generalized convulsive status epilepticus than in nonconvulsive forms. More recently, doubt has been cast on the appropriateness of anesthetic treatment of RSE following a series of studies associating their use with higher mortality and morbidity. This suggests that efforts should focus on determination of who benefits most, optimal use, and prevention of refractoriness. The risk‐benefit ratio of anesthetic use is discussed, with specific indications proposed. In addition, anesthetic dosing, supportive neurocritical care, electroencephalogram suppression target, and weaning of anesthesia are reviewed.     

Eslicarbazepine acetate for the treatment of status epilepticus

Objective

Due to the high mortality of patients with refractory status epilepticus (SE), new antiseizure medications (ASMs) are needed to improve long-term outcomes. In this study, we evaluated the efficacy and safety of eslicarbazepine acetate (ESL), a new sodium channel blocker, based on the data from a large epilepsy register.

Methods

Data on the efficacy and safety of ESL for the treatment of refractory SE were gathered from the Mainz Epilepsy Registry (MAINZ-EPIREG). Logistic regression was applied to identify predictors of status interruption.

Results

In total, 64 patients with remote symptomatic refractory SE were treated with ESL. No cases of idiopathic generalized epilepsy were included. The average age was 61.4 ± 11.0 years. The median number of administered ASMs before the start of ESL was three. On average, 2 days had elapsed since the onset of SE before the administration of ESL. The initial dose of 800 mg/day was increased up to a maximum daily dose of 1600 mg in case of nonresponse. In 29 of 64 patients (45.3%), the SE could be interrupted within 48 h of ESL therapy. In patients with poststroke epilepsy, the control of SE was achieved in 62% of patients (15/23). The earlier initiation of ESL therapy was an independent predictor of control of SE. Hyponatraemia occurred in five patients (7.8%). Other side effects were not observed.

Significance

Based on these data, ESL may be used as an adjunct therapy for the treatment of refractory SE. The best response was found in patients with poststroke epilepsy. In addition, early initiation of ESL therapy appears to result in better control of SE. Besides a few cases of hyponatraemia, no other adverse events were detected.     

Neurosurgical treatment of medically intractable status epilepticus

Medically intractable status epilepticus can be defined as status epilepticus (SE) that persists or recurs despite medical treatment with intravenous agents that suppress cortical activity. We describe the successful neurosurgical treatment of three patients with medically intractable status epilepticus who responded either to focal resection, multiple subpial transection, or callosal section. The duration of medically intractable status epilepticus before surgery ranged between 23 and 42 days, and multiple medical complications occurred during the failed medical therapy. We suggest that patients with medically intractable status epilepticus who fail to respond to three courses of cerebral suppressant therapy for approximately 2 weeks be considered for surgical treatment in the absence of any known remitting etiology. Focal resection and/or subpial transection is preferred for intractable partial SE with focal electrographic changes or a focal lesion demonstrated by structural or functional neuroimaging. Corpus callosotomy may be used for patients with generalized or non-localizable intractable status epilepticus.     

Surgical treatment of experimental limbic status epilepticus

Limbic status epilepticus was induced by means of a KA microinjection into unilateral amygdala, and the focus extirpation (amygdalotomy) was made in order to examine whether the status was suppressed or not. The amygdalotomy was effective when the status was mild and the focus was circumscribed to the amygdala. However, the surgery was no more effective when a severe limbic status was induced and a secondary epileptogenic focus was established. Within 8 hours after induction of the limbic status, neuronal cell damage was observed in the pyramidal cell layer of the hippocampus.     

Midazolam treatment for status epilepticus of children

We investigated the efficacy and safety of midazolam given intravenously for the treatment of status epilepticus in children. Patients received one to three bolus injections of midazolam (0.15 to 0.40 mg/kg) until seizures disappeared completely. In other patients, continuous infusion of midazolam (0.06 to 0.48 mg/kg/hr) followed a bolus of midazolam or other anti-epileptic agents. The dose was increased every 15 minutes until the seizures were brought under control. The etiology of 62 episodes of status epilepticus was epilepsy in 43, acute encephalopathy/encephalitis in 11, febrile seizures in 7 and hypoxic encephalopathy in 1. The age of the patients ranged from 0.2 to 18.4 years (average: 3.7 years). Bolus injections were administered in 53 episodes. The average loading dose was 0.35 +/- 0.22 mg/kg (range 0.15 to 0.90 mg/kg). Of the 42 episodes in which seizures disappeared, 13 required no further continuous infusions. Of the remaining 29 in which continuous infusion was done at the rate of 0.06 to 0.60 mg/kg/hr (mean 0.30 mg/kg/hr), 21 ended in cessation of the seizures. The duration of continuous infusions ranged from 4 to 288 hours (average 49.0 hours). In 6 episodes there were adverse effects:transient hypoxemia (5) and agitation during withdrawal (1). No intervention was needed except oxygenation by mask for less than 72 hours. Midazolam is effective and safe, and can be used as the first line drug in the treatment of status epilepticus in children.     

Intravenous lacosamide for treatment of status epilepticus

Kellinghaus C, Berning S, Immisch I, Larch J, Rosenow F, Rossetti AO, Tilz C, Trinka E. Intravenous lacosamide for treatment of status epilepticus.
Acta Neurol Scand: 2011: 123: 137–141.
© 2010 John Wiley & Sons A/S. Objectives – Treatment of established status epilepticus (SE) requires immediate intravenous anticonvulsant therapy. Currently used first‐line drugs may cause potentially hazardous side effects. We aimed to assess the efficacy and safety of intravenous lacosamide (LCM) in SE after failure of standard treatment. Methods – We retrospectively analyzed 39 patients (21 women, 18 men, median age 62 years) from the hospital databases of five neurological departments in Germany, Austria and Switzerland between September 2008 and January 2010 who were admitted in SE and received at least one dose of intravenous LCM. Results – Types of SE were generalized convulsive (n = 6), complex partial (n = 17) and simple partial (n = 16). LCM was administered after failure of benzodiazepins or other standard drugs in all but one case. Median bolus dose of LCM was 400 mg (range 200–400 mg), which was administered at 40–80 mg/min in those patients where infusion rate was documented. SE stopped after LCM in 17 patients, while 22 patients needed further anticonvulsant treatment. The success rate in patients receiving LCM as first or second drug was 3/5, as third drug 11/19, and as fourth or later drug 3/15. In five subjects, SE could not be terminated at all. No serious adverse events attributed to LCM were documented. Conclusions – Intravenous LCM may be an alternative treatment for established SE after failure of standard therapy, or when standard agents are considered unsuitable.     

Recent developments in the diagnosis and treatment of status epilepticus

Despite increased understanding of its potential complications, status epilepticus (SE) frequently remains difficult to diagnose and treat. Advances in continuous electroencephalogram (EEG) monitoring facilitate more rapid identification of SE, even without visible clinical signs of seizures. EEG monitoring assists in modifying SE treatment and in making a prognosis. Despite the improved recognition of SE, some patients continue to seize after treatment with intravenous benzodiazepines and other medications. There are new uses for valproic acid, levetiracetam, and topiramate, and they have evidence of efficacy in treating different forms of SE. If medical treatments do not terminate SE, other interventions, such as surgery and stimulation procedures, may promote seizure cessation. This article reviews recent studies evaluating the use of continuous EEG monitoring in the setting of SE, new uses of anticonvulsants, and nonpharmacologic interventions for SE.     

Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus

In 2006, levetiracetam was approved as the first of the newer anticonvulsive drugs as an intravenous formulation (ivLEV) for patients with epileptic seizures who are unable to take oral medication. We report our experience with the use of ivLEV for the treatment of 18 episodes of benzodiazepine refractory focal status epilepticus (SE) in 16 patients, including four patients with secondary generalised SE. SE was controlled in all patients by the given combination of drugs; application of further antiepileptic medications after ivLEV was necessary in two episodes. No severe side effects occurred. Our data suggest that ivLEV may be an alternative for the treatment of SE in the future, even in patients that did not respond to benzodiazepines. A large prospective, randomised, controlled study is warranted to investigate the efficacy and safety of ivLEV for the treatment of SE.     

利多卡因在难治性癫痫持续状态中的应用

目的 认识利多卡因在难治性癫痫持续状态中的作用。方法 对10例难治性强直阵挛发作癫痫持续状态患者持续静脉注射利多卡因，观察其疗效及副作用。结果 9例患者在给药24小时内终止发作，1例在36小时内终止发作。1例出现房性早搏，1例出现窦性心律不齐。结论 利多卡因静脉注射能有效控制难治性癫痫持续状态。     

Lorazepam versus diazepam for the treatment of status epilepticus

A retrospective study was performed to compare intravenous lorazepam and intravenous diazepam in the treatment of status epilepticus. Forty-five episodes of status epilepticus in children between the ages of 2 weeks and 18 years were reviewed. Lorazepam and diazepam proved similar in efficacy of seizure control and incidence of adverse effects. The dose of lorazepam required to control status epilepticus ranged from 0.03 to 0.22 mg/kg with a mean of 0.11 mg/kg (S.D. = 0.05 mg/kg). Among children treated with lorazepam, only children younger than 2 years of age had respiratory depression which required intubation.