Non-intravenous high-dose phenobarbital therapy for status epilepticus refractory to continuous infusion of midazolam or pentobarbital: report of three cases]

The management of refractory status epilepticus (RSE) is crucial in preventing neurologic impairment. Although a variety of treatments for RSE including continuous infusion of midazolam (MDL) or pentobarbital (PTB) have been carried out, they are not always effective. Intravenous very-high-dose phenobarbital (PB) has been recommended as having many advantages in the United States, but is not available in Japan. We treated 3 patients suffering from long term RSE with non-intravenous high-dose PB (NIHDPB). Their seizures were not controlled by continuous infusion of MDL and/or PTB. PB was initially given intramuscularly or rectally and then orally. Within a few or ten days, seizures were completely controlled, and consciousness level gradually improved in all cases. The serum levels of PB at seizure control ranged from 50 to 58 micrograms/ml. The epileptiform activities on EEG nearly disappeared in the absence of the burst suppression pattern. Hypotention and respiratory depression did not develop during NIHDPB. Elevated gamma-GTP levels with normal hepatic transaminases were seen in all cases, but it was not necessary to discontinue NIHDPB. NIHDPB may be one of the most effective and safe treatments in Japan for status epileptics refractory to continuous infusion of MDL or PTB.     

Corpus callosotomy for treatment of pediatric refractory status epilepticus

Medically refractory status epilepticus (RSE) causes high morbidity and mortality in children. There are no evidence-based guidelines for treatment. Epilepsy surgery is a treatment option for RSE. We describe a 9-year-old boy treated successfully for RSE with complete corpus callosotomy (CC). Epilepsy surgery should be considered for prolonged RSE. In the absence of evidence of focal epileptogenesis, complete corpus callosotomy may be effective in select cases.     

Valproic acid treatment of experimental status epilepticus.

The efficacy of valproic acid (VPA) in control of generalized convulsive status epilepticus was tested in a rat model. Rats with cortical cobalt lesions were injected with homocysteine thiolactone to induce secondarily generalized tonic-clonic seizures (GTCS). The median effective dose (ED50) for control of GTCS was 211.9 mg/kg (270 micrograms/ml in serum 30 min post dose) when treatment was given intraperitoneally after the second GTCS. VPA entered both serum and brain very rapidly after injection, with little change in concentration from 5 to 30 min post dose. In earlier experiments with phenytoin, phenobarbital, diazepam and lorazepam in this model, we found that the serum concentrations produced by the ED50s versus GTCS were very similar to those which have been reported to be effective in treating human status epilepticus. If this same relationship holds true for VPA, we would predict that a serum concentration of around 270 micrograms/ml VPA would be required for control of generalized convulsive status epilepticus in human patients. The safety of this high a concentration of VPA has not been tested.     

Topiramate loading for refractory status epilepticus in children

PURPOSE: To describe three cases of refractory status epilepticus (RSE) in children responsive to topiramate (TPM). METHODS: Patients with SE refractory to therapeutic doses of at least two antiepileptic medications were given TPM, 10 mg/kg/d, for 2 consecutive days, followed by maintenance doses of 5 mg/kg/d. RESULTS: This protocol has been used in three cases of RSE at our institution. In each case, SE was aborted within 21 h of the initial dose of TPM. Two patients avoided pharmacologic coma, and one was rapidly weaned from continuous benzodiazepine infusion. CONCLUSIONS: Our experience indicates that TPM loading can be effective in the treatment of RSE in children.     

Treatment of Refractory Status Epilepticus with Propofol: Clinical and Pharmacokinetic Findings

Summary: Purpose: We compared propofol with high-dose barbiturates in the treatment of refractory status epilepticus (RSE) and propose a protocol for the administration of propofol in RSE in adults, correlating propofol's effect with plasma levels.
Methods: Sixteen patients with RSE were included; 8 were treated primarily with high-dose barbiturates and 8 were treated primarily with propofol.
Results: Both groups of patients had multiple medical problems and a subsequent high mortality. A smaller but not statistically significant fraction of patients had their seizures controlled with propofol (63%) than with high-dose barbiturate therapy (82%). The time from initiation of high-dose barbiturate therapy to attainment of control of RSE was longer (123 min) than the time to attainment of seizure control in the group receiving propofol (2.6 min, p = 0.002). Plasma concentrations of propofol associated with control of SE were 14 μM ± 4 (2.5 μg/ml). Recurrent seizures were common when propofol infusions were suddenly discontinued but not when the infusions were gradually tapered.
Conclusions: If used appropriately, propofol infusions can effectively and quickly terminate many but not all episodes of RSE. Propofol is a promising agent for use in treating RSE, but more studies are required to determine its true value in comparison with other agents.     

Vagus nerve stimulation in refractory and super-refractory status epilepticus – A systematic review

RationaleRefractory status epilepticus (RSE) is the persistence of status epilepticus despite second-line treatment. Super-refractory SE (SRSE) is characterized by ongoing status despite 48 h of anaesthetic treatment. Due to the high case fatality in RSE of 16–39%, off label treatments without strong evidence of efficacy in RSE are often administered. In single case-reports and small case series totalling 28 patients, acute implantation of VNS in RSE was associated with 76% and 26% success rate in generalized and focal RSE respectively. We performed an updated systematic review of the literature on efficacy of VNS in RSE/SRSE by including all reported patients.MethodsWe systematically searched EMBASE, CENTRAL, Opengre.eu, and ClinicalTrials.gov, and PubMed databases to identify studies reporting the use of VNS for RSE and/or SRSE. We also searched conference abstracts from AES and ILAE meetings.Results45 patients were identified in total of which 38 were acute implantations of VNS in RSE/SRSE. Five cases had VNS implantation for epilepsia partialis continua, one for refractory electrical status epilepticus in sleep and one for acute encephalitis with refractory repetitive focal seizures. Acute VNS implantation was associated with cessation of RSE/SRSE in 74% (28/38) of acute cases. Cessation did not occur in 18% (7/38) of cases and four deaths were reported (11%); all of them due to the underlying disease and unlikely related to VNS implantation. Median duration of the RSE/SRSE episode pre and post VNS implantation was 18 days (range: 3–1680 days) and 8 days (range: 3–84 days) respectively. Positive outcomes occurred in 82% (31/38) of cases.ConclusionVNS can interrupt RSE and SRSE in 74% of patients; data originate from reported studies classified as level IV and the risk for reporting bias is high. Further prospective studies are warranted to investigate acute VNS in RSE and SRSE.     

Three cases of delivery under sodium valproate--placental transfer, milk transfer and probable teratogenicity of sodium valproate

Here is a report of three cases of delivery from women who have taken sodium valproate (VPA). One neonate was born with polydactylism, and we reviewed the congenital malformations in children of mothers who have taken VPA. In the other two cases, we also examined the levels of VPA in the cord serum and breast milk. The levels of VPA in the cord serum were 50 micrograms/ml at 12 hours after the last maternal dose and 75 micrograms/ml at 14 hours after the last maternal dose. The blood levels of VPA in the two mothers were 48-59 micrograms/ml and 55-85 micrograms/ml in their late pregnancy, respectively. The levels of VPA in the breast milk were 2.0-3.5 micrograms/ml and the ratio of VPA in the breast milk to blood was 2-3%. These results suggest the high rate of placental transfer and the low rate of milk transfer of VPA.     

The use of topiramate in refractory status epilepticus

In cases of refractory status epilepticus (RSE) unresponsive to sequential trials of multiple agents, a suspension of topiramate administered via nasogastric tube was effective in aborting RSE, including one patient in a prolonged pentobarbital coma. Effective dosages ranged from 300 to 1,600 mg/d. Except for lethargy, no adverse events were reported.     

Refractory status epilepticus: A prospective observational study

Purpose: Status epilepticus (SE) that is resistant to two antiepileptic compounds is defined as refractory status epilepticus (RSE). In the few available retrospective studies, estimated RSE frequency is between 31% and 43% of patients presenting an SE episode; almost all seem to require a coma induction for treatment. We prospectively assessed RSE frequency, clinical predictors, and outcome in a tertiary clinical setting. Methods: Over 2 years we collected 128 consecutives SE episodes (118 patients) in adults. Clinical data and their relationship to outcome (mortality and return to baseline clinical conditions) were analyzed. Results: Twenty‐nine of 128 SE episodes (22.6%) were refractory to first‐ and second‐line antiepileptic treatments. Severity of consciousness impairment and de novo episodes were independent predictors of RSE. RSE showed a worse outcome than non‐RSE (39% vs. 11% for mortality; 21% vs. 63% for return to baseline clinical conditions). Only 12 patients with RSE (41%) required coma induction for treatment. Discussion: This prospective study identifies clinical factors predicting the onset of SE refractoriness. RSE appears to be less frequent than previously reported in retrospective studies; furthermore, most RSE episodes were treated outside the intensive care unit (ICU). Nonetheless, we confirm that RSE is characterized by high mortality and morbidity.     

Phenobarbital treatment of status epilepticus in a rodent model

Although phenobarbital is frequently used in the treatment of status epilepticus, little has been published concerning the dose or serum concentration which effectively control adult status. We studied the efficacy of phenobarbital in controlling status in a rat model which induces generalized tonic-clonic seizures (GTCS) which respond to other drugs at serum concentrations similar to those reported to be effective in human status. We found that phenobarbital is rapidly absorbed following intraperitoneal injection, but entry into brain is delayed. Brain entry was facilitated during uncontrolled status epilepticus. The ED50 values for control of seizures in this model rose in a dose-dependent manner for increasing levels of seizure control, from 14.2 mg/kg for control of GTCS to 76.6 mg/kg for control of all motor and electrographic ictal activity. Raising serum concentrations above the 20 micrograms/ml required to control GTCS produced increasingly better control of the various types of ictal activity seen in this model.     

Etiologies and characteristics of refractory status epilepticus cases in different areas of the world: Results from a global audit

To describe the demographics, etiologies, types of status epilepticus (SE), and outcomes in people with refractory and super‐refractory SE from around the world, we prospectively collected cases of refractory SE (RSE) treated with continuous intravenous anesthetic drugs in an intensive care unit setting through online questionnaires using “active surveillance.” We collected information about 776 cases of RSE in 50 countries over 4 years. Control of SE was achieved in 74% of the cases. Neurologic outcomes were poor in 41% of patients, and 24% died. Good outcome was associated with younger age and a history of epilepsy. Etiology strongly influenced the outcome. Patients from Asia were younger, more frequently presented with convulsive SE, and were more frequently affected by infectious etiologies when compared with patients from Europe and the Americas. Despite these differences, outcomes were similar in all countries. Demographics of patients with RSE in a global audit are similar to those in prior single center series, providing evidence of generalizability of those studies. Important differences exist among patients with RSE from different regions of the world, but these do not seem to significantly influence patient outcomes.     

Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit

OBJECTIVE: To assess risk factors and prognosis in patients with refractory status epilepticus (RSE). METHODS: We retrospectively analysed all episodes of status epilepticus (SE) treated between 1993 and 2002 on the neurological intensive care unit (NICU) of the Charite-Universitatsmedizin Berlin. The predictive and prognostic features of RSE were compared with non-RSE (NRSE). All patients with "de novo" SE were followed up to identify the possible development of post-SE symptomatic epilepsy. RESULTS: A total of 83 episodes fulfilled our criteria of SE. Of these 43% were refractory to first line anticonvulsants. The mean age of patients with SE was 53.3 (SD 19) years, with only two patients younger than 18 years. Encephalitis was significantly more often the primary cause in RSE (p<0.05), whereas low levels of antiepileptic drugs were significantly more often associated with NRSE (p<0.001). Hyponatraemia within the first 24 hours after onset of status activity was significantly more often associated with RSE (p<0.05). In RSE, compared with NRSE, significantly longer duration of seizure activity (p<0.001), more frequent recurrence of epileptic activity within the first 24 hours after the end of seizure activity (p<0.001), longer stay in the NICU and in hospital (p<0.001 and p<0.01, respectively), and more frequent development of symptomatic epilepsy (p<0.05) were seen. CONCLUSIONS: SE treated in the NICU is frequently refractory to first line anticonvulsant drugs. Encephalitis is a predictor for RSE, which is associated with markedly poor outcome, in particular, the development of post-SE symptomatic epilepsy. Thus prevention of this most severe form of SE should be the primary target of treatment of SE.     

Ketamine controls prolonged status epilepticus

New treatments are needed to control prolonged status epilepticus given the high failure rate of current therapies. In an animal model of status epilepticus based on electrical stimulation of the hippocampus, rats demonstrate at least 5 five-hours of seizure activity following stimulation. Phenobarbital (70 mg/kg) administered 15 min after stimulation effectively controlled seizures in 66% of animals (n=6). When phenobarbital (70 mg/kg) was administered 60 min after stimulation, seizures were controlled in 25% of animals (n=4). Ketamine (100 mg/kg) administered 15 min after stimulation did not control seizures in any animal (n=4). But when ketamine was administered one hour after stimulation it effectively controlled seizures in all animals (n=4). Increasing doses of ketamine were administered 60 min after stimulation to generate a dose-response curve. The ketamine dose response (fraction of seizure free rats) data were fit to a sigmoid curve to derive an ED(50) of 58 mg/kg. These findings suggest that prolonged status epilepticus becomes refractory to phenobarbital but can be effectively controlled by ketamine. For patients experiencing prolonged status epilepticus that is refractory to phenobarbital, ketamine may be an alternative to general anesthesia.     

Phenacemide therapy of complex partial epilepsy in children: determination of plasma drug concentrations

We used monotherapy with phenacemide to treat complex partial seizures in 13 children who were refractory to conventional antiepileptic drug therapy. Twelve patients responded with a reduction in seizure frequency, and 5 have been totally seizure free since the start of therapy. Phenacemide therapy was well tolerated with a minimum of untoward side effects and no evidence of irreversible drug toxicity. We developed a rapid and sensitive assay for the determination of plasma phenacemide concentrations by high performance liquid chromatography to monitor drug levels during therapy. Seizure control was achieved at plasma drug levels that ranged from 16 to 75 micrograms/ml. The median effective dose in our series was 52 micrograms/ml. The recurrence of seizures in three patients was, in each case, associated with trough plasma phenacemide levels below 50 micrograms/dl.     

The role of ketogenic diet in the treatment of refractory status epilepticus

Ketogenic diet (KD) is known to be effective in intractable epilepsy. However, the role of KD in refractory status epilepticus (RSE) has not been well described. The aim of this study is to explore the role of KD in patients with RSE. We retrospectively reviewed the medical records of four children and one adult with RSE between October 2006 and August 2010. All presented with status epilepticus (SE) that was presumed to be associated with viral encephalitis. After we failed to control the seizures with standard measures for SE, we tried KD. The overall seizure frequency decreased to <50% of baseline in median eight (1-19) days. At one month of KD, two patients were seizure-free, one patient showed >90% seizure reduction, and the others had >75% decrease without generalized seizures. With improvement in the RSE, we were able to taper the antiepileptic drugs (AEDs) and wean patients from prolonged mechanical ventilation. The adverse events of KD in RSE included aspiration pneumonia, gastroesophageal reflux, constipation, and hypertriglyceridemia. Those results demonstrate that KD can be a valuable therapeutic option for patients with RSE.     

Lidocaine in refractory status epilepticus: confirmation of efficacy with continuous EEG monitoring.

Lidocaine was efficacious in 2 patients with refractory status epilepticus (RSE) unresponsive to several antiepileptic drugs (AEDs), including high-dose barbiturates. We confirmed the efficacy of lidocaine with, for the first time in adults, continuous EEG monitoring. Lidocaine, when properly used, may be a treatment option in RSE.     

Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children

High-dose suppressive therapy (HDST) is used to treat refractory status epilepticus (RSE). Prolonged therapy is required in some cases, and prognosis is important in making therapeutic decisions. The authors therefore studied the long-term outcome in previously normal children who survived prolonged HDST for acute symptomatic RSE. All have intractable epilepsy, and none returned to baseline.     

Propofol and barbiturates for the anesthesia of refractory convulsive status epilepticus: pros and cons

OBJECTIVE: To discuss mainly the use of propofol and barbiturates in the anesthesia of refractory status epilepticus (RSE). METHODS: Review of literature. RESULTS: There are no prospective, randomized works comparing the effects of anesthetics in the treatment of RSE. Recently, the use of propofol has increased in the treatment of RSE. Propofol terminates both clinical and electric seizures quickly, but the maintenance of burst-suppression EEG pattern requires repetitive titration of doses. Relapses of seizures have occurred in 19-33% of patients, especially when tapering of dose. The advantages of barbiturates are lower frequency of short-term treatment failures, breakthrough seizures and changes to a different anesthetic agent. On the other hand, prolonged recovery leads to prolonged duration of mechanical ventilation, intensive care and hospital stay. DISCUSSION: The use of propofol, barbiturates or midazolam in the anesthesia of RSE can be justified. When using propofol, the duration of high doses should be limited to 48 hours and the risk of propofol infusion syndrome should be kept in mind. High doses of barbiturates terminate effectively seizures but recovery from anesthesia prolongs ventilator treatment and intensive care.     

Levetiracetam in children with refractory status epilepticus

The objective of this study was to investigate the utility of levetiracetam (LEV) in children with refractory status epilepticus (RSE). Records of children with RSE who received LEV as adjunctive therapy were reviewed. Over a 7-year period, 11 children had received LEV for RSE. Age ranged from 2 days to 9 years (median = 2.5 months). Prior to administration of LEV, the number of anticonvulsants used to treat RSE ranged from 2 to 7 (median = 3). Starting doses of LEV ranged from 15 to 70 mg/kg (median = 30 mg/kg). LEV was felt to be of benefit in 45% (5/11) of cases, resulting in either resolution of RSE or successful weaning of patients off continuous infusions of other anticonvulsants. In 27% (3/11), response to LEV was unclear as other medications were either added or increased concomitantly with LEV use. The median latency to cessation of RSE following LEV initiation was 1.5 days (range = 1-8 days). All responding patients were on LEV doses >or= 30 mg/kg/day (median 40 mg/kg/day). No significant adverse effects of LEV were reported. LEV may be an effective and safe adjuvant therapy in children with RSE.     

Utilisation du midazolam dans l’état de mal épileptique réfractaire de l’enfant

Morbidity and mortality are high in children with refractory status epilepticus (RSE). Here, we assess the efficacy of midazolam for RSE in children.MethodsThis was a retrospective analysis of 29 children admitted to the Lille University Hospital pediatric intensive care unit (PICU) for RSE between May 2006 and July 2008. The onset of the study corresponded with a new therapeutic protocol applied in the PICU for RSE where midazolam was proposed as the first-line treatment (bolus ten continuous infusion until control) to be replaced by thiopenthal in case of failure.ResultsWe recorded 29 patients with RSE during the study period: 26 were treated with midazolam, including two where midazolam replaced thiopenthal because of hypotension. Midazolam successfully controlled RSE in 58% of patients. Mean delay to cessation of RSE was 48 ± 65 minutes. Hypotension was observed in 8% of midazolam-treated patients and 71% of thiopenthal-treated patients. Overall mortality was 15% (4/26). Two deaths occurred long after the cessation of RSE. None of the deaths occurred in midazolam-treated patients.ConclusionMidazolam is an efficient treatment for RSE in children. Morbidity and mortality appear to be lower with midazolam compared with other antiepileptic drugs used for the treatment of RSE.