Convulsive Status Epilepticus Research Articles

Development of a novel outcome prediction score (PEDSS) for pediatric convulsive status epilepticus: A longitudinal observational study.

The objectives of this study were to evaluate ENDIT score and develop a novel outcome prediction score for outcome of pediatric convulsive status epilepticus (CSE) at the hospital and 3months postdischarge. Children and adolescents aged 1month to 14years, presenting with CSE to a tertiary care teaching center in North India from January 2017 to March 2019, were screened for enrollment. In-hospital and 3-month postdischarge outcome were defined as poor if Pediatric Cerebral Performance Category Scale (PCPCS) score dropped by ≥2 levels. Overall, 61 patients were enrolled for final analysis after applying exclusion and inclusion criteria. The area under the receiver operating characteristic (ROC) curve for ENDIT score in predicting mortality and differentiating good from poor outcome at the hospital and at 3months postdischarge was 0.74 (95% confidence interval [CI] = 0.58-0.89), 0.7 (95% CI = 0.57-0.83), and 0.72 (95% CI = 0.6-0.82), respectively. Based on predictors in the present cohort that were significantly different between good and poor outcome cases at the hospital and 3months postdischarge, a new six-point score named PEDSS (pre-status epilepticus PCPCS, background electroencephalographic abnormalities, drug refractoriness, semiology, and critical sickness) was developed. The area under ROC curves for PEDSS score in predicting mortality and differentiating good from poor outcome at the hospital and at 3months postdischarge were 0.93 (95% CI = 0.87-0.99), 0.8 (95% CI = 0.7-0.9), and 0.89 (95% CI = 0.8-0.96), respectively. The best cutoff PEDSS scores for predicting mortality and poor outcome at the hospital and at 3months postdischarge were ≥4, ≥3, and ≥3, respectively. The PEDSS score has high predictive accuracy for mortality and differentiating good from poor outcome at the hospital and 3months postdischarge in pediatric CSE. Future studies should be planned to validate it in various geographical and health care settings and in adults.

Acute Provoked Seizures-Work-Up and Management in Adults.

Acute provoked seizures, also known as acute symptomatic seizures, occur secondary to a neurological or systemic precipitant, commonly presenting as a first-time seizure. In this article, we will discuss etiology, emergent protocols, medical work-up, initial treatment, and management of these seizures. The definitions, classifications, and management of convulsive status epilepticus and nonconvulsive status epilepticus in an acute setting will also be reviewed.

Preferential Antiseizure Medications in Pediatric Patients with Convulsive Status Epilepticus: A Systematic Review and Network Meta-Analysis

The optimal choice for first- and second-line antiseizure medications for pediatric patients with convulsive status epilepticus remains ambiguous. The present study aimed to estimate the comparative effect on the efficacy and safety of different antiseizure medications in pediatric patients with status epilepticus and provide evidence for clinical practice. We searched PubMed, EMBASE, and the Cochrane Library for eligible randomized controlled trials. Inclusion criteria included: (1) pediatric patients; (2) diagnosis of status epilepticus; and (3) randomized controlled trials. Exclusion criteria were: (1) mixed population without a pediatric subgroup analysis; (2) not status epilepticus; (3) received the study drug prior to admission; (4) sample size fewer than 30; and (5) not randomized controlled trials. Primary outcome was seizure cessation. Secondary outcomes were seizure recurrence within 24h, respiratory depression, and admission to an intensive care unit. The hierarchy of competing antiseizure medications was presented using the surface under the cumulative ranking curve. Eight first-line antiseizure medication studies involving 1686 participants and eight second-line antiseizure medication studies involving 1711 participants were eligible for analysis. Midazolam, diazepam, lorazepam, and paraldehyde were administered as first-line antiseizure medications. Valproate, phenobarbital, phenytoin, fosphenytoin, and levetiracetam were investigated as second-line antiseizure medications. No significant differences were observed across first- and second-line antiseizure medications. Midazolam ranked the best for primary and secondary outcomes among the first-line antiseizure medications. Phenobarbital ranked the best for seizure cessation and a lower risk of admission to the intensive care unit. Valproate had superiority in preventing recurrence within 24h. Levetiracetam had the lowest probability of developing respiratory depression. This study demonstrated the hierarchy of competing interventions. Midazolam could be a better option for first-line treatment. Phenobarbital, levetiracetam, and valproate had their respective superiority in the second-line intervention. This study may provide useful information for clinical decision making under different circumstances.

Posterior Reversible Encephalopathy Syndrome in infants and young children.

The aim of this study was to describe the characteristics of Posterior Reversible Encephalopathy Syndrome (PRES) in infants and young children (<6 years) and to compare them with the older pediatric population affected by PRES. we retrospectively reviewed records of 111 children (0-17 years) diagnosed with PRES from 2000 to 2018 in 6 referral pediatric hospitals in Italy. The clinical, radiological and EEG features, as well as intensive care unit (ICU) admission rate and outcome of children aged <6 years were compared to those of older children (6-17 years). Factors associated with ICU admission in the whole pediatric cohort with PRES were also evaluated. Twenty-nine patients younger than 6 years (26%) were enrolled with a median age at onset of PRES of 4 years (range: 6 months-5 years). Epileptic seizures were the most frequent presentation at the disease onset (27/29 patients). Status epilepticus (SE) was observed in 21/29 patients: in detail, 11 developed convulsive SE and 10 presented nonconvulsive SE (NCSE). SE was more frequent in children <6 years compared with older children (72% vs 45%) as well as NCSE (35% vs 10%). Seventeen children aged <6 years required ICU admission. Prevalence of ICU admissions was higher within younger population compared to older (59% vs 37%). In the whole study population SE was significantly associated with ICU admission (p=0.001). PRES in children<6 years differs from older children in clinical presentation suggesting a more severe presentation at younger age.

Decreased Cerebrospinal Fluid Orexin-A (Hypocretin-1) Concentrations in Patients after Generalized Convulsive Status Epilepticus.

The effects of status epilepticus on the orexin/hypocretin system have yet to be investigated. The present study aimed to assay orexin-A/hypocretin-1 in the cerebrospinal fluid (CSF) of patients after generalized convulsive status epilepticus (GCSE). The study groups included 20 GCSE patients, 24 patients diagnosed with epilepsy but remaining in remission (ER), and 25 normal controls (CTR). Diagnostic lumbar puncture was performed in GCSE patients within 3–10 days of seizure cessation, as well as in the ER and to CTR subjects. Among all GCSE patients, the outcome was graded according to the modified Rankin Scale (mRS) at 1-month follow-up. Orexin-A levels were measured in unextracted CSF samples, using a commercial radioimmunoassay. There was a significant overall difference in median CSF orexin-A concentrations between GCSE, RE, and CTR patients (p < 0.001). The lowest concentrations were noted in the GCSE group compared to ER (p < 0.001) or CTR (p < 0.001). CSF orexin-A levels in GCSE patients inversely correlated with clinical outcome as assessed on the mRS at 1-month follow-up (r = −0.55; p = 0.1). In conclusion, CSF orexin-A levels may serve as a biomarker of increased turn-over of the peptide or post-SE neuronal damage, and implicates the orexin system in the pathogenesis of SE.

Levetiracetam for convulsive status epilepticus in childhood: systematic review and meta-analysis

ImportanceProlonged seizures are life-threatening emergencies associated with significant morbidity.ObjectiveTo determine the efficacy and safety of levetiracetam in treating convulsive status epilepticus (CSE) in childhood.Data sources and study selectionsPubMed, Embase, the...

Does the accumulated antiepileptic drug load in chronic epilepsy reflect disease severity?

To ascertain factors that are related to the antiepileptic drug load in epilepsy. In this cross-sectional study, we analyzed a large cohort of conservatively treated patients with epilepsy (n=1135) and a smaller homogeneous group of presurgical patients with neuropathologically confirmed unilateral hippocampal sclerosis (n=91). Considered clinical variables comprised (1) presence of an underlying cerebral lesion, (2) onset and (3) duration of epilepsy, (4) seizure frequency, (5) generalized or focal to bilateral tonic-clonic seizures, (6) ictal impairment of awareness, and (7) a history of convulsive status epilepticus. In the presurgical sample, we additionally considered (8) the degree of pathology (hippocampal neuronal cell densities) instead of (1) presence of a cerebral lesion and (9) an overall rating of epilepsy severity (GASE scale). Drug load was quantified as (a) the number of concomitant antiepileptic drugs (AEDs) and (b) the total defined daily dose (DDD). Analyses disclosed only small correlations between clinical variables and drug load indices. In the conservatively treated cohort, the multiple regression analyses revealed that epilepsy onset, cerebral lesion, history of convulsive status epilepticus, and seizure frequency combined explained only 6%-10% of variance in drug load. Nearly the same variance (5%-8%) could be explained by duration of epilepsy alone. Degree of hippocampal pathology and the epilepsy severity ratings were not related to drug load indices. Clinical markers of epilepsy severity were only marginally associated with drug load. Findings rather indicate that patients seem to accumulate drugs due to the chronicity of epilepsy. Overall, the drug load remained largely unexplained. The findings nevertheless call for scrutinizing multidrug therapies in patients with long-lasting epilepsies.

Identification of Generalized Convulsive Status Epilepticus from Emergency Medical Service Records: A Validation Study of Diagnostic Coding

Background Generalized convulsive status epilepticus (GCSE) is a neurologic emergency demanding prehospital identification and treatment. Evaluating real-world practice requires accurately identifying the target population; however, it is unclear whether emergency medical services (EMS) documentation accurately identifies patients with GCSE. Objective To evaluate the validity of EMS diagnostic impressions for GCSE. Methods This was an analysis of electronic medical records of a California county EMS system from 2013 to 2018. We identified all cases with a primary diagnostic impression of “seizure-active,” “seizure-post,” or “seizure-not otherwise specified (NOS)” and within each diagnostic category, we randomly selected 75 adult and 25 pediatric records. Two authors reviewed the provider narrative of these 300 charts to determine a clinical seizure diagnosis according to prespecified definitions. We calculated a kappa for interrater reliability of the clinical diagnosis. We then calculated the positive predictive value (PPV), sensitivity, and specificity of an EMS diagnosis of “seizure-active” diagnosis for identifying GCSE. Sensitivity and specificity calculations were weighted according to the distribution of seizure cases in the overall population. We performed a descriptive analysis of records with an incorrect EMS diagnosis of GCSE or seizure. Results Of 38,995 total records for seizure, there were 3401 (8.7%) seizure-active cases, 12,478 (32.0%) seizure-NOS cases, and 23,116 (59.4%) seizure-post cases. An EMS diagnosis of “seizure-active” had a PPV of 65.0% (95% CI 54.8–74.3), sensitivity of 54.6% (95% confidence interval [CI] 39.3–69.0), and specificity of 96.6% (95% CI 95.1–97.6) for capturing GCSE. Limiting the case definition to patients who received an EMS diagnosis of “seizure-active” and were treated with a benzodiazepine increased the PPV (80.2%; 95% CI 69.9–88.2) and specificity (99.3%; 95% CI 98.7–99.6) while the sensitivity decreased (25.1%; 95% CI 17.0–35.3). Across the 300 records reviewed, there were 19 (6.3%) patients who had a non-seizure related diagnosis including non-epileptic spells (7 records), altered mental status (8 records), tremors (2 records), anxiety (1 record), and stroke (1 record). Conclusions EMS diagnostic impressions have reasonable PPV and specificity but low sensitivity for GCSE. Improved coding algorithms and training will allow for improved benchmarking, quality improvement, and research about this neurologic emergency.

Lorazepam timing for acute convulsive seizure control (LoTASC)

IntroductionGuidelines specify early administration of benzodiazepines (BZD) for the management of convulsive status epilepticus. The distinction between acute convulsive seizure and status epilepticus can be misconstrued resulting in BZD administration prior to a patient meeting criteria of status epilepticus. Early BZD administration may theoretically lead to systemic vital instability. Our study aims to assess if administering lorazepam, for convulsive seizures <5 min, causes vital instability. MethodsThis is a retrospective study analyzing patients who presented with a seizure lasting <5 min between 2011 and 2016. Continuous variables of lorazepam receivers versus non- receivers were analyzed using t-test for parametric and Mann-Whitney U test for nonparametric data. Categorical variables were analyzed using Chi-Square Test. Subsequently, subjects were analyzed through univariate and multivariate regression models to determine predictors of vital instability. ResultsOut of 1052 subjects initially screened, 165 were included. Of these, 91 (55 %) received lorazepam, and 74 (45 %) did not. Through univariate and multivariate analyses, there was a significantly higher incidence of vital instability (defined as receipt of a vasopressor or intubation) in patients who received lorazepam (OR = 6.76, 95 % CI = 1.48, 30.95) (p = 0.014). This was dose-dependent (p < 0.0001). It was responsible for 22.5 % of the vital instability. Lorazepam administration significantly prolonged the intensive care unit (ICU) length of stay (0 days [IQR 0 – 0] vs [IQR 0–2.3]; p = 0.038). ConclusionOur study suggests that lorazepam administration for acute convulsive seizures not meeting convulsive status epilepticus criteria may lead to iatrogenic vital instability and need for ICU admission.

The burden of decisional uncertainty in the treatment of status epilepticus.

Treatments for convulsive status epilepticus (SE) have a wide range of effectiveness. The estimated effectiveness of non-intravenous benzodiazepines (non-IV BZDs) ranges from approximately 70% to 90% and the estimated effectiveness of non-benzodiazepine antiseizure medications (non-BZD ASMs) ranges from approximately 50% to 80%. This study aimed to quantify the clinical and economic burden of decisional uncertainty in the treatment of SE. We performed a decision analysis that evaluates how decisional uncertainty on treatment choices for SE impacts hospital admissions, intensive care unit (ICU) admissions, and costs in the United States. We evaluated treatment effectiveness based on the available literature. Use of a non-IV BZD with high estimated effectiveness, like intranasal midazolam, rather than one with low estimated effectiveness, like rectal diazepam, would result in a median (p25 -p75 ) reduction in hospital admissions from 6 (3.9-8.8) to 1.1 (0.7-1.8) per 100 cases and associated cost reductions of $638 ($289-$1064) per pediatric patient and $1107 ($972-$1281) per adult patient. For BZD-resistant SE, use of a non-BZD ASM with high estimated effectiveness, like phenobarbital, rather than one with low estimated effectiveness, like phenytoin/fosphenytoin, would result in a reduction in ICU admissions from 9.1 (7.3-11.2) to 3.9 (2.6-5.5) per 100 cases and associated cost reduction of $1261 ($445-$2223) per pediatric patient and $319 ($-93-$806) per adult patient. Sensitivity analyses showed that relatively minor improvements in effectiveness may lead to substantial reductions in downstream hospital admissions, ICU admissions, and costs. Decreasing decisional uncertainty and using the most effective treatments for SE may substantially decrease hospital admissions, ICU admissions, and costs.

Electrocorticography in patients with severe traumatic brain injury

Introduction. The frequency of adverse outcomes in patients with severe traumatic brain injury (TBI) exceeds 25%. Epileptic seizures and vasospasm, in the absence of pathogenetic treatment, cause irreversible brain damage and thus complicate the course of severe TBI. Bedside electroencephalography (EEG) is traditionally used to diagnose these conditions. However, its low spatial resolution when recording from the scalp and a large number of artefacts that make it challenging to analyse the data. Materials and methods. Electrocorticography (ECoG) monitoring was performed using subdural electrodes implanted in the traumatic brain lesion during TBI surgery in 11 patients during the acute period of severe TBI. All patients were concurrently monitored using scalp EEG with subdermal needle electrodes. Results. Analysis of scalp recordings showed frequency disturbances and oscillation asymmetry in all patients, while sporadic epileptiform activity and rhythmic and periodic patterns were detected in 18% and 64% of subjects, respectively. Analysis of invasive EEG showed sporadic epileptiform activity in 27% of patients, while rhythmic and periodic patterns were present in 91%. Moreover, epileptiform activity was registered only by the subdural leads in 3 patients. The total percentage of subjects in whom we registered clinical and electrographic signs of convulsive and non-convulsive status epilepticus using EEG and ECoG was 55%. We found indirect EEG signs of slow-spreading cortical depolarization in one patient whose level of consciousness was coma, followed by an electrographic pattern of status epilepticus on ECoG. Conclusion. ECoG recording, while patients with severe TBI are in the intensive care unit, increases the diagnostic capabilities of this method, allowing electrographic seizures to be recorded more often and more accurately, but also to detect indirect signs of slow-spreading cortical depolarization using standard EEG amplifiers. Electrode implantation during TBI surgery is safe and does not significantly change the surgical approach.

Association of systemic secondary brain insults and outcome in patients with convulsive status epilepticus: A post hoc study of a randomized controlled trial.

To evaluate the association between systemic factors (mean arterial blood pressure, arterial partial pressures of carbon dioxide and oxygen, body temperature, natremia, and glycemia) on day 1 and neurologic outcomes 90 days after convulsive status epilepticus. This was a post hoc analysis of the Evaluation of Therapeutic Hypothermia in Convulsive Status Epilepticus in Adults in Intensive Care (HYBERNATUS) multicenter open-label controlled trial, which randomized 270 critically ill patients with convulsive status epilepticus requiring mechanical ventilation to therapeutic hypothermia (32°C-34°C for 24 hours) plus standard care or standard care alone between March 2011 and January 2015. The primary endpoint was a Glasgow Outcome Scale score of 5, defining a favorable outcome, 90 days after convulsive status epilepticus. The 172 men and 93 women had a median age of 57 years (45-68 years). Among them, 130 (49%) had a history of epilepsy, and 59 (29%) had a primary brain insult. Convulsive status epilepticus was refractory in 86 (32%) patients, and total seizure duration was 67 minutes (35-120 minutes). The 90-day outcome was unfavorable in 126 (48%) patients. In multivariate analysis, none of the systemic secondary brain insults were associated with outcome; achieving an unfavorable outcome was associated with age >65 years (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.20-3.85; p = 0.01), refractory convulsive status epilepticus (OR 2.00, 95% CI 1.04-3.85; p = 0.04), primary brain insult (OR 2.00, 95% CI 1.02-4.00; p = 0.047), and no bystander-witnessed seizure onset (OR 2.49, 95% CI 1.05-5.59; p = 0.04). In our population, systemic secondary brain insults were not associated with outcome in critically ill patients with convulsive status epilepticus. NCT01359332.

Feasibility of phenytoin as a paramedic-led second-line anti-epileptic drug

Background: Convulsive status epilepticus (CSE) is a medical emergency that is commonly encountered in the prehospital setting. In almost all prehospital settings, treatment is limited to benzodiazepines even though the standard of care in emergency departments includes second-line agents such as phenytoin. Methods: A literature search was conducted using PubMed and Google Scholar using the search terms ‘phenytoin’, ‘seizure’ or ‘convulsive’ and ‘prehospital’, ‘EMS’ or ‘ambulance’ or ‘emergency department’. Five articles were analysed and a narrative review formed. Results: Phenytoin is an effective and commonly used second-line anti-epileptic agent but there is a distinct lack of evidence on prehospital phenytoin. Phasing the introduction of phenytoin into practice while simultaneously running a well-designed research trial could provide data for prehospital providers and the wider health community. Conclusion: Management of CSE will continue to present challenges to prehospital providers. Promoting the introduction of phenytoin to select patients, administered by advanced clinicians, could be an excellent opportunity to generate much-needed clinical data and potentially reduce morbidity and mortality in CSE.

When and How to Treat Status Epilepticus: The Tortoise or the Hare?

Status epilepticus (SE) is a collective term that is used to describe a variety of subtypes. Forgetting this point can be perilous, even resulting in exposing patients to unnecessary harms. This review revisits the foundations of many of our current treatment guidelines, providing context to the ever-growing options in the treatment of SE. It aims to highlight the uncertainties that clinicians and EEGers face when treating SE. Several promising future approaches are raised. These bring hope of transitioning to therapies that are based on correcting maladaptive neuronal responses that are personally tailored using real time measures. All types of SE should be diagnosed as soon as possible, and treatment should be started expeditiously. For convulsive SE, treatment should be aggressive with full doses and cessation of seizures should be confirmed with EEG if patients are not returning to normal rapidly. For most other types of SE, the perennial debate about the tortoise or the hare continues: When should we be more measured and conservative and when should we rapidly escalate therapies to a combination of highly sedating agents?

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee.

Purpose:Established tonic–clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE.Methods:A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process.Results:No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study).Conclusions:Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.

P62 Cyclophosphamide and maintenance mycophenolate mofetil for the treatment of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in a paediatric patient

BackgroundAnti-NMDAR encephalitis is one of the commonest known types of autoimmune encephalitis with an increasing recognition in the paediatric population.1 2 It is characterised by abnormal behavioural and cognitive symptoms, seizures and movement disorders where treatment failure or failure to treat can result in long term disabilities or mortality.1A 4-year-old patient with a background of autism was admitted to the paediatric intensive care unit (PICU) due to encephalitis with convulsive status epilepticus where he remained intubated for 22 days and was later diagnosed with anti-NMDAR encephalitis. The patient had persistent abnormal choreoathetoid movements and intermittent seizures despite multiple anti-epileptics, two courses of corticosteroids, two courses of intravenous immunoglobulin, two cycles (10 sessions per cycle) of plasmapheresis and a course of weekly rituximab. Due to the lack of response from these initial pharmacological interventions, the use of cyclophosphamide and mycophenolate mofetil was considered. Cyclophosphamide and mycophenolate mofetil inhibits the proliferations of B- and T-lymphocytes3 4 which acts as the basis of its immunosuppressive actions. However, available evidence on the dosing and monitoring information in the paediatric population for this unlicensed indication is limited.Pharmacy ContributionsAfter discussion with the multi-disciplinary team (MDT) with extensive input from the paediatric neurologist, a literature search was conducted to determine an appropriate dosing regimen. As this was an off-label use, the paediatric neurologist and the attending consultant took clinical responsibility. Intravenous cyclophosphamide was started at 750 mg/m2 once a month for three cycles and oral mycophenolate mofetil was started at 600 mg/m2 twice a day as maintenance therapy a week after. The specialist pharmacist explained the individualised treatment plan for the patient to the MDT and ensured measures (hydration and mesna) for the prevention of cyclophosphamide-induced haemorrhagic cystitis were appropriately prescribed on the electronic prescribing system with the appropriate timings of administration. Monitoring parameters to determine adverse effects were closely observed. A local guideline was developed during the treatment cycles to ensure all members of the MDT were following the correct procedures.OutcomeThe patient responded to cyclophosphamide and clinically improved after the completion of three cycles of monthly treatment. Maintenance mycophenolate mofetil was subsequently stopped a month after the last cycle of cyclophosphamide due to neutropenia. A review of the patient one year after first presentation shows the patient is almost back to their baseline.Lessons LearnedAlthough there are potentially serious side effects, cyclophosphamide and mycophenolate mofetil has been successful in the treatment of anti-NMDAR encephalitis. The recovery of this patient required extensive support from the entire MDT.ReferencesNHS England. Clinical Commissioning Policy: Rituximab for second line treatment for anti-NMDAR autoimmune encephalitis (all ages). March 2018.Salvucci A, Devine IM, Hammond D, et al. Pediatric anti-NMDA (N-methyl D-Aspartate) receptor encephalitis. Pediatric Neurology 2014;50:507–510.Summary of Product Characteristics. Cyclophosphamide 1000 mg Powder for Solution for Injection or Infusion. Last updated on eMC on 27-Jun-2017. Available at https://www.medicines.org.uk/emc/product/3525/smpc# [Accessed 04 July 2019]Summary of Product Characteristics. CellCept 1 g/5 mL powder for oral suspension. Last updated on eMC on 16-Mar-2018. Available at https://www.medicines.org.uk/emc/product/1569/smpc [Accessed 04 July 2019]

Institutional Pediatric Convulsive Status Epilepticus Protocol Decreases Time to First and Second Line Anti-Seizure Medication Administration

PurposeConvulsive status epilepticus (CSE) is a medical emergency associated with high rates of morbidity and mortality. Although guidelines for CSE management recommend rapid treatment of seizures, prior studies show that compliance with these guidelines is low. In this study, we assessed if implementation of a paper-based clinical pathway for the treatment of CSE improves the timeliness and appropriate dosing of first and second line anti-seizure medications (ASM). MethodsA non-digital CSE treatment protocol was implemented as part of a quality improvement initiative in 2016. A retrospective analysis was subsequently conducted on cases of CSE originating in the pediatric emergency department (ED) from 2012-2019. Standard descriptive statistics were used to assess patient demographics as well as the timing and dosing of the first and second line ASMs used in our protocol (lorazepam [LZP] and fosphenytoin [FOS]). Statistical process control charts (XmR charts) were used to assess the variation in time to drug administration before and after implementation of the protocol. Results153 cases of CSE were identified (72 prior to and 81 after protocol implementation). Among patients who were actively having seizures on arrival to the ED (n = 44), the median time from arrival to ASM administration decreased from 15 to 11 minutes for the first LZP dose (p = 0.23), 23 to 10 minutes for the second LZP dose (p = 0.06), and 40 to 25 minutes for the PHE dose (p = 0.04). There was no improvement in time to LZP administration after seizure onset among those with seizure onset after hospital arrival (5 minutes before/after implementation for the first LZP dose and 15 to 14 minutes for second LZP dose); however, the time to FOS decreased from 42 to 22 minutes (p = 0.86). Statistical process control charts showed a universal decrease in variation for time to each drug administration after protocol implementation. Whereas FOS dosing was largely appropriate before and after protocol implementation, appropriate dosing of LZP did not improve, with only about half of patients receiving the recommended dose. ConclusionThe implementation of a paper-based treatment protocol for CSE was associated with a decreased time to ASM administration among patients who arrived to the ED, particularly for the second-line ASM. Approaches for improving appropriate benzodiazepine dosing are needed.

Brain networks involved in generalized periodic discharges (GPD) in post-anoxic-ischemic encephalopathy

AimGeneralized periodic discharge (GPD) is an EEG pattern of poor neurological outcome, frequently observed in comatose patients after cardiac arrest. The aim of our study was to identify the neuronal network generating ≤2.5 Hz GPD using EEG source localization and connectivity analysis. MethodsWe analyzed 40 comatose adult patients with anoxic-ischemic encephalopathy, who had 19 channel-EEG recording. We computed electric source analysis based on distributed inverse solution (LAURA) and we estimated cortical activity in 82 atlas-based cortical brain regions. We applied directed connectivity analysis (Partial Directed Coherence) on these sources to estimate the main drivers. ResultsSource analysis suggested that the GPD are generated in the cortex of the limbic system in the majority of patients (87.5%). Connectivity analysis revealed main drivers located in thalamus and hippocampus for the large majority of patients (80%), together with important activation also in amygdala (70%). ConclusionsWe hypothesize that the anoxic-ischemic dysfunction, leading to hyperactivity of the thalamo-cortical (limbic presumably) circuit, can result in an oscillatory thalamic activity capable of inducing periodic cortical (limbic, mostly medial-temporal and orbitofrontal) discharges, similarly to the case of generalized rhythmic spike-wave discharge in convulsive or non-convulsive status epilepticus.

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AbstractTranscranial photobiomodulation (tPBM) with wavelength at 808 nm was applied to a rat model of acute seizures. The tPBM successfully attenuated convulsive status epilepticus, and the tPBM was shown to reduce the apoptosis of parvalbumin‐positive interneurons (PV‐INs) and preserved the integrity of perisomatic inhibitory network of PV‐INs to principle cells in the hippocampus.Further details can be found in the article by Chung‐Min Tsai, Shwu‐Fen Chang, and Hsi Chang (e202000095). image

Prise en charge des états de mal épileptiques en préhospitalier, en structure d’urgence et en réanimation dans les 48 premières heures (à l’exclusion du nouveau‑né et du nourrisson)

La Société de réanimation de langue française et la Société française de médecine d’urgence ont décidé d’élaborer denouvelles recommandations sur la prise en charge de l’état de mal épileptique (EME) avec l’ambition de répondre leplus possible aux nombreuses questions pratiques que soulèvent les EME : diagnostic, enquête étiologique, traitementnon spécifique et spécifique. Vingt‑cinq experts ont analysé la littérature scientifique et formulé des recommandationsselon la méthodologie GRADE. Les experts se sont accordés sur 96 recommandations. Les recommandations avecle niveau de preuve le plus fort ne concernent que l’EME tonicoclonique généralisé (EMETCG) : l’usage des benzodia‑zépines en première ligne (clonazépam en intraveineux [IV] direct ou midazolam en intramusculaire) est recommandé,répété cinq minutes après la première injection (à l’exception du midazolam) en cas de persistance clinique. En casde persistance cinq minutes après cette seconde injection, il est proposé d’administrer la deuxième ligne thérapeu‑tique : valproate de sodium, (fos‑)phénytoïne, phénobarbital ou lévétiracétam. La persistance avérée de convulsions30 minutes après le début de l’administration du traitement de deuxième ligne signe l’EMETCG réfractaire. Il est alorsproposé de recourir à un coma thérapeutique au moyen d’un agent anesthésique intraveineux de type midazolam oupropofol. Des recommandations spécifiques à l’enfant et aux autres EME sont aussi énoncées.