Refractory Status Epilepticus In Children Research Articles

Lack of Association of First and Second-Line Medication Dosing and Progression to Refractory Status Epilepticus in Children

Purpose: Evaluate the relationship between first and second-line medication dosing and progression to refractory status epilepticus (RSE) in children. Methods: This is a retrospective analysis of prospectively collected data from September 2014 to February 2020 of children with status epilepticus (SE) who received at least two antiseizure medications (ASMs). We evaluated the risk of developing RSE after receiving a low total benzodiazepine dose (lower than 100% of the minimum recommended dose for each benzodiazepine dose administered within 10 minutes) and a low first non-benzodiazepine ASM dose (lower than 100% of the minimum recommended dose of non-benzodiazepine ASM given as the first single-dose) using a logistic regression model, adjusting for confounders such as time to ASMs. The proportion of patients receiving low first non-benzodiazepine ASM doses was calculated and a logistic regression model was used to evaluate risk factors for low dosing of the first non-benzodiazepine ASM. Results: Among 320 children, 170 (53.1%) developed RSE, and 150 (46.9%) responded to the first non-benzodiazepine ASM dose (non-RSE). One hundred thirty-seven (42.8%) received a low total benzodiazepine dose, and 128 (40%) received a low first non-benzodiazepine ASM dose. The odds of developing RSE were not higher after a low total benzodiazepine dose (OR=0.76, 95%CI 0.47-1.23, p=0.27) or low first non-benzodiazepine ASM dose (OR=0.85, 95%CI 0.42-1.71, p=0.65). Receiving a low first non-benzodiazepine ASM dose was independently associated with having received a low total benzodiazepine dose (OR=1.65, 95%CI 1.01-2.70, p=0.04). Conclusion: For most patients, dosing variability in first and second-line medications for SE was not the sole clinical feature predicting progression to RSE in this cohort of benzodiazepine-resistant patients. Identification of additional modifiable clinical biomarkers that predict progression to RSE is needed. Though lower ASM doses did not predict RSE in this model, the administration of ASMs at doses likely to prevent RSE remains crucial in SE treatment.

Natural Language Processing for Identification of Refractory Status Epilepticus in Children.

Pediatric status epilepticus is one of the most frequent pediatric emergencies, with high mortality and morbidity. Utilizing electronic health records (EHR) permits analysis of care approaches and disease outcomes at a lower cost than prospective research. However, reviewing EHR manually is time intensive. We aimed to compare refractory status epilepticus (rSE) cases identified by human EHR review with a Natural language processing (NLP)-assisted rSE screen followed by a manual review. We used the NLP screening tool, Document Review Tool (DrT), to generate regular expressions, trained a bag-of-words NLP classifier on EHR from 2017-2019, and then tested our algorithm on data from February to December 2012. We compared results from manual review to NLP-assisted search followed by manual review. Our algorithm identified 1528 notes in the test set. After removing notes pertaining to the same event by DrT, the user reviewed a total number of 400 notes to find patients with rSE. Within these 400 notes, we identified 31 rSE cases, including 12 new cases not found in manual review, and 19 of the 20 previously identified cases. The NLP-assisted model found 31/32 cases with a sensitivity of 96.88% (95% C.I. 82-99.84%), while manual review identified 20/32 cases, with a sensitivity of 62.5% (95% C.I. 43.75-78.34%). DrT provided a highly sensitive model compared to human review and an increase in patient identification through EHRs. The use of DrT is a suitable application of NLP for identifying patients with a history of recent rSE which ultimately contributes to the implementation of monitoring techniques and treatments in near real-time.

Ketamine for Management of Neonatal and Pediatric Refractory Status Epilepticus.

Few data are available regarding the use of anesthetic infusions for refractory status epilepticus (RSE) in children and neonates, and ketamine use is increasing despite limited data. We aimed to describe the impact of ketamine for RSE in children and neonates. Retrospective single-center cohort study of consecutive patients admitted to the intensive care units of a quaternary care children's hospital treated with ketamine infusion for RSE. Sixty-nine patients were treated with a ketamine infusion for RSE. The median age at onset of RSE was 0.7 years (interquartile range 0.15-7.2), and the cohort included 13 (19%) neonates. Three patients (4%) had adverse events requiring intervention during or within 12 hours of ketamine administration, including hypertension in 2 patients and delirium in 1 patient. Ketamine infusion was followed by seizure termination in 32 patients (46%), seizure reduction in 19 patients (28%), and no change in 18 patients (26%). Ketamine administration was associated with few adverse events, and seizures often terminated or improved after ketamine administration. Further data are needed comparing first-line and subsequent anesthetic medications for treatment of pediatric and neonatal RSE. This study provides Class IV evidence on the therapeutic utility of ketamine for treatment of RSE in children and neonates.

Specific characteristics and current diagnostic and treatment modalities performance of super refractory status epilepticus in children: A comparative study

Super-refractory status epilepticus (SRSE) is associated with significant morbidity and mortality in children. We explored the clinical spectrum, specific characteristics, and outcome in SRSE patients admitted in a pediatric intensive care unit (PICU) and investigated how well current diagnostic or treatment modalities perform compared to Status Epilepticus (SE) and Refractory SE (RSE) patients. Retrospective analysis of PICU patients admitted with convulsive SE during 2009-2019. Eighty-six patients were classified as SE, RSE, and SRSE. New-onset RSE (NORSE) and febrile infection-related epilepsy syndrome (FIRES) were also identified. Functional outcome was evaluated by the modified Rankin scale. Patients with SRSE (n=20) had longer weaning off anesthetics (p=0.014), length of stay, mechanical ventilation duration, higher illness severity scores, and poorer outcome compared to SE (n=13) or RSE (n=53) patients (all p<0.001). Diagnosis, mainly expressed by high prevalence of NORSE (n=13) and FIRES (n=9), was independently associated with SRSE (p=0.024). Abnormal MRI findings (p=0.005), and epilepsy-related pathogenic variants identified by whole-exome sequencing (WES) were mostly found in SRSE patients. Compared to intravenous immunoglobulins and steroid pulses, plasmapheresis and ketogenic diet, more often used in SRSE (p<0.01), contributed better to seizure control. Only SRSE (AUROC > 0.80, 95% CI=0.68-0.94, p<0.001) and diagnosis (AUROC > 0.70, 95% CI=0.55-0.83, p=0.02) could predict a poor outcome. The majority of SRSE patients are characterized by considerable functional decline and morbidity. WES analysis may reveal epilepsy-related pathogenic variants while early aggressive immunotherapy and/or ketogenic diet might prove beneficial. Multicenter studies for prediction models of outcome are needed.

Refractory status epilepticus in children: What Indian scenario needs now and future?

Refractory status epilepticus in children: What Indian scenario needs now and future?

Role of epilepsy surgery in refractory status epilepticus in children

IntroductionStatus epilepticus (SE) is one of the most common medical emergencies, requiring urgent treatment; nearly 30 % patients develop refractory SE. The role of epilepsy surgery (ES) for refractory SE however remains unclear with empirical evidence limited to single case reports and small case series. The aim of the present study was to determine the clinical presentation, imaging characteristics and outcome of children with refractory SE who underwent emergency ES for refractory SE. Material and methodPatients who had SE, failed to respond to escalating medical treatment of SE with/ without pharmacological suppression therapy, and eventually underwent ES were included. ResultsThere were ten children, 7 boys and 3 girls (range 6 months to 14 years). The age of onset of epilepsy varied from day 2 of life to 12.8 years. The duration of SE prior to surgery was 2–6 days (mean 3.7 days). Four patients had hemimegalencephaly, 3 had focal cortical dysplasia, 2 had Rasmussen’s encephalitis, and one had hemispheric porencephalic cyst. The time interval between onset of seizures and ES ranged from 2 months to 8 years (mean 3.1 year). Seven patients underwent hemispherotomy, resection of dysplasia in two and temporo-parieto-occipital disconnection in one. Nine had Engel I outcome and Engel IIIa in one, at follow up of 12–44 months (mean 31 months). ConclusionEmergency ES is an effective treatment option for termination of refractory SE in children with structural pathology, after failure of medical treatment. Patients with refractory SE with focal or hemispheric structural abnormality on MRI, and concordant semiology with/without concordant EEG can be surgical candidates with or without invasive monitoring.

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

ObjectiveWe aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE).MethodsPatients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks–24 h), and without fever.ResultsOf 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function.SignificanceAmong pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection‐related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

New-Onset Refractory Status Epilepticus in Children: Etiologies, Treatments, and Outcomes.

To elucidate etiologies, treatment, functional and neurocognitive outcomes of children with new-onset refractory status epilepticus. A single-center retrospective study. A tertiary care children's hospital. All patients between 1 month and 21 years old admitted with new-onset refractory status epilepticus between January 2004 and July 2017. None. Clinical presentation, laboratory data, imaging studies, and treatments were collected during hospitalization. Outcomes were assessed at hospital discharge and follow-up in the outpatient neurology clinic based on functional and neurocognitive outcomes as well as development of epilepsy. A total of 674 unique patients presented with status epilepticus of which 40 had new-onset refractory status epilepticus. Patients were classified into either refractory status epilepticus or super-refractory status epilepticus. The etiology of most children with new-onset refractory status epilepticus remained cryptogenic. The most common identified etiology was viral (20%). None of the patients had a contributory positive neuronal antibody test. Several treatments were tried including immunotherapy which was used in half of the patients. Five patients died (12.5%) during the acute phase of their disease, with four lost to follow-up. Twenty out of the remaining 31 patients (65%) developed epilepsy and 18 (58%) had persistent neurocognitive impairment. There was no statistical significant difference in various outcome measures and various etiologies, patients' characteristics, and treatments. In this single-center cohort, more than half of the children with new-onset refractory status epilepticus did not have an identifiable etiology. Unlike adult patients, the presence of positive neuronal antibody syndrome was rare. There was no difference in outcome between those with or without an identifiable etiology. As expected, patients with super-refractory status epilepticus had worse functional and neurocognitive outcomes. More standardized diagnostic and treatment algorithms are needed along with prospective multicenter studies.

Febrile Infection-Related Epilepsy Syndrome

AbstractFebrile infection-related epilepsy syndrome (FIRES) is a subset or variant of new-onset refractory status epilepticus in children. FIRES is characterized by the occurrence of a febrile episode between 24 hours and 2 weeks before the onset of refractory status epilepticus. A infectious cause is rarely identified in FIRES and an inflammatory or autoimmune etiology is implied. Seizures in FIRES are very difficult to control, and treatments include antiepileptic drugs, ketogenic diet, intravenous immunoglobulin, plasmapheresis, and corticosteroid therapy. The prognosis for patients with FIRES is poor, and most children are left with refractory epilepsy and cognitive impairment. The new consensus guidelines on the terminology of FIRES and recent interest in new treatment approaches have been welcome developments for clinicians who face the challenge of diagnosing and managing status epilepticus in a previously healthy child that occurs following a minor febrile episode. This review aims to provide clinicians with an update on the current hypotheses for the etiology, pathogenesis, clinical evaluation, management, and future directions in the diagnosis and treatment of FIRES.

Pathophysiology and management of refractory status epilepticus in children

Pathophysiology and management of refractory status epilepticus in children

Treatment of Refractory Status Epilepticus in Children: Current Practice and Opportunities to Improve Care*

Treatment of Refractory Status Epilepticus in Children: Current Practice and Opportunities to Improve Care*

Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital.

To describe pediatric patients with convulsive refractory status epilepticus in whom there is intention to use an IV anesthetic for seizure control. Two-year prospective observational study evaluating patients (age range, 1 mo to 21 yr) with refractory status epilepticus not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent. Nine pediatric hospitals in the United States. In a cohort of 111 patients with refractory status epilepticus (median age, 3.7 yr; 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment. The median (interquartile range) ICU length of stay was 10 (3-20) days. Up to four "cycles" of serial anesthetic therapy were used, and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9-34) hours for the first cycle and longer when a second cycle was required (30 [4-120] hr; p = 0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam nonresponders, transition to a second agent occurred after a median of 1 day. Most patients (94%) experienced seizure termination with these two therapies. Midazolam and pentobarbital remain the mainstay of continuous infusion therapy for refractory status epilepticus in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study.

Management of Status Epilepticus in Children.

Status epilepticus is a common pediatric neurological emergency. Management includes prompt administration of appropriately selected anti-seizure medications, identification and treatment of seizure precipitant(s), as well as identification and management of associated systemic complications. This review discusses the definitions, classification, epidemiology and management of status epilepticus and refractory status epilepticus in children.

Refractory Convulsive Status Epilepticus in Children: Etiology, Associated Risk Factors and Outcome.

Refractory status epilepticus (RSE) is a life-threatening disease in children wherein the patient's convulsive seizures do not respond to adequate initial anticonvulsants. RSE is associated with high rate of mortality and morbidity. This study was aimed to survey the risk factors leading status epilepticus (SE) to RSE in children, and their early outcome. Patients with SE hospitalized in Tabriz Children's Hospital, Iran were studied during the years 2007 and 2008 with regard to their clinical profile, etiology, the treatment methods available to them and their outcome upon release from the hospital. Among 132 patients with SE, 53 patients (40.15%) suffered from RSE. Acute symptomatic etiology was a risk factor responsible for developing RSE in the patient (P=0.004). Encephalitis was the most common etiology of acute symptomatic SE. There was no significant relationship observed between RSE and the patients' age, gender, date of initial drug intake and type of seizure. The mortality rate was 8.3% and a new neurological deficit occurred in 25.7% of cases. None of RSE with encephalitis returned to the baseline status. Mortality and morbidity rates were significantly higher in children with RSE than in those with SE (P=0.006). Etiology of SE significantly influenced prognosis of it with significant incidence of RSE in acute symptomatic group. Because acute neurological insult such as encephalitis and meningitis are common causes of RSE in children, properly management of them is necessary to avoid permanent brain damage.

Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies*.

A systematic literature search and review of the best evidence for intensive care treatment of refractory status epilepticus in children using continuous infusion of midazolam or anesthetic agents. MEDLINE and EMBASE search before December 2013 using key words and/or Medical Subject Headings identified English-language citations that were screened for eligibility and used if 1) the study was about high-dose benzodiazepine or anesthetic agent for children; 2) the treatment protocol was described and used for refractory status epilepticus; 3) the outcomes included seizure control; and 4) the series included at least five children. Sixteen studies (645 patients) were identified, including midazolam (nine studies), barbiturate (four studies), and other anesthetic approaches (three studies). When midazolam was used as the initial agent for refractory status epilepticus, the rate of clinical seizure control was 76%, which was achieved on average 41 minutes after starting the infusion. When midazolam was used in conjunction with continuous electroencephalography, the time to seizure control was much longer and the mean dose required for seizure control was 10.7 μg/kg/min compared with a lower dose (2.8 μg/kg/min) in the studies not using this form of monitoring, suggesting that continuous electroencephalography provided additional targets for treatment. Barbiturates were usually used after midazolam failed and treatment was started, on average, 66 hours after refractory status epilepticus onset with the goal of electroencephalography burst suppression, which was achieved, on average, 22.6 hours later. Among patients failing midazolam, barbiturate infusion was effective in 65%. Inhaled anesthetics, ketamine, and hypothermia were generally used after prior therapy with midazolam and barbiturates had failed, usually several days after seizure onset. The data on intensive care treatment of pediatric refractory status epilepticus are of poor quality, yet they show a hierarchy in strategies: early midazolam, then barbiturates, and then trial of other anesthetic strategies. In addition, using a solely clinical endpoint for seizure control may be missing significant seizure burden in pediatric refractory status epilepticus.

Surgical treatment of refractory status epilepticus in children

Refractory status epilepticus (RSE) is a life-threatening neurological emergency associated with high morbidity and mortality. Affected patients often require prolonged intensive care and can suffer multiple complications. Surgical intervention to control RSE is rarely used but can obviate the risks of prolonged seizures and intensive care treatment. Authors of the present study analyzed their experience with the surgical management of patients suffering from RSE. The Epilepsy Surgery Database at Miami Children's Hospital was reviewed for patients who had undergone surgery for RSE. Clinical presentation, electrophysiological profile, radiological data, surgical details, and postoperative course were evaluated. Between 1990 and 2012, 15 patients underwent surgery for uncontrolled seizures despite high-dose medical suppressive therapy. The mean preoperative duration of status epilepticus was 8 weeks. Ictal SPECT and FDG-PET imaging in conjunction with intraoperative electrophysiological studies helped to outline the extent of resection. Surgical intervention controlled seizures in all patients and facilitated the transition out of intensive care. Adverse events related to a prolonged intensive care unit stay included sepsis and respiratory complications. Four patients had worsened neurological function, developing hemiparesis and dysphasia. There was no operative mortality. Surgical intervention can successfully control refractory partial status epilepticus, prevent associated morbidity, and decrease intensive care unit stay. Ictal SPECT and PET are valuable in guiding resection.

Efficacy and safety of ketamine in refractory status epilepticus in children

To evaluate the efficacy and safety of ketamine (KE) in the management of refractory convulsive status epilepticus (RSE) in children. In November 2009, we started using KE for treating all children consecutively referred for RSE. Clinical and treatment data were analyzed. Between November 2009 and June 2011, 9 children with RSE received IV KE. In 8 patients, SE had persisted for more than 24 hours (super-refractory RSE), with a median of 6 days (mean 8.5 ± 7.5; range 2-26 days). Prior to KE administration, conventional anesthetics were used, including midazolam, thiopental, and propofol in 9, 5, and 4 patients each. Median dose of KE in continuous IV infusion was 40 gamma(μg)/kg/min (mean 36.5 ± 18.6 gamma[μg]/kg/min; range 10-60 gamma[μg]/kg/min). Midazolam was administered add-on to prevent emergence reactions. The use of KE was associated with resolution of RSE in 6 children. None of the patients experienced serious adverse events. Among the 3 individuals who did not respond to KE, 2 were cured by surgical removal of epileptogenic focal cortical dysplasia. In this small, open-label, unblinded series with no concurrent control group, KE appears effective and safe in treating RSE in children. Larger, randomized studies are needed to confirm data emerging from this preliminary observation. This study provides Class IV evidence that IV KE can be effective in treating children with RSE (no statistical analysis was done).

Therapeutic Hypothermia for Refractory Status Epilepticus in a Child with Malignant Migrating Partial Seizures of Infancy andSCN1AMutation: A Case Report

Status epilepticus (SE) is a common indication for neurocritical care and can be refractory to standard measures. Refractory SE (RSE) is associated with high morbidity and mortality. Unconventional therapies may be utilized in certain cases, including therapeutic hypothermia (TH), bumetanide, and the ketogenic diet. However, the literature describing the use of such therapies in RSE is limited. Details of a case of TH for RSE in an infant with malignant migrating partial seizures of infancy were obtained from the medical record. A 4-month-old child developed SE that was refractory to treatment with concurrent midazolam, phenobarbital, fosphenytoin, topiramate, levetiracetam, folinic acid, and pyridoxal-5-phosphate. This led to progressive implementation of three unconventional therapies: TH, bumetanide, and the ketogentic diet. Electrographic seizures ceased for the entirety of a 43-hour period of TH with a target rectal temperature of 33.0°C–34.0°C. No adverse effects of hypothermia were noted other than a single episode of asymptomatic hypokalemia. Seizures recurred 10 hours after rewarming was begun and did not abate with reinstitution of hypothermia. No effect was seen with administration of bumetanide. Seizures were controlled long-term within 48 hours of institution of the ketogenic diet. TH and the ketogenic diet may be effective for treating RSE in children.

Efficacy and Safety of Intravenous Sodium Valproate in Convulsive Status Epilepticus in Children in Shahid Sadoughi Hospital

Efficacy and Safety of Intravenous Sodium Valproate in Convulsive Status Epilepticus in Children in Shahid Sadoughi Hospital

EFFICACY OF CONTINUOUS HIGH DOSE MIDAZOLAM INFUSION IN CHILDHOOD REFRACTORY GENERALIZED CONVULSIVE STATUS EPILEPTICUS

Objecive Prolonged and uncontrolled refractory status epilepticus (SE) is a life-threatening medical emergency in children (1,2,3). There is no consensus on the optimal therapy for refractory status epilepticus (1). The aim of this study was to develop a new method for treating patients with refractory status epilepticus. Materials & Methods Ten children with refractory status epilepticus in Mofid Hospital, who did not respond to 10 μg/kg per min of intravenous midazolam, had their dose of midazolam increased to 30 μg/kg per min. All children were monitored for the development of side effects. Results Ten children with no response to low-dose midazolam were given a higher dose of midazolam, and 5 (50%) children had a good response. These patients had significantly different response to high-dose midazolam. One patient in the high-dose midazolam group was intubated and required mechanical ventilation. The duration of stay in the hospital and PICU and on mechanical ventilation in patients with no response to low-dose midazolam following with other drugs was longer than in the high-dose midazolam group. No death occurred in high dose midazolam group. Conclusion High-midazolam dose drip infusion is a safe and effective protocol for refractory status epilepticus in children. Keywords: Refractory status epilepticus; midazolam; mortality; childhood