Pharmacotherapy for Pediatric Convulsive Status Epilepticus

Abstract

Convulsive status epilepticus (CSE) is one of the most common pediatric neurological emergencies. Ongoing seizure activity is a dynamic process and may be associated with progressive impairment of gamma-aminobutyric acid (GABA)-mediated inhibition due to rapid internalization of GABAA receptors. Further hyperexcitability may be caused by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors moving from subsynaptic sites to the synaptic membrane. Receptor trafficking during prolonged seizures may contribute to difficulties treating seizures of longer duration and may provide some of the pathophysiological underpinnings of established and refractory SE (RSE). Simultaneously, a practice change toward more rapid initiation of first-line benzodiazepine (BZD) treatment and faster escalation to second-line non-BZD treatment for established SE is in progress. Early administration of the recommended BZD dose is suggested. For second-line treatment, non-BZD anti-seizure medications (ASMs) include valproate, fosphenytoin, or levetiracetam, among others, and at this point there is no clear evidence that any one of these options is better than the others. If seizures continue after second-line ASMs, RSE is manifested. RSE treatment consists of bolus doses and titration of continuous infusions under continuous electro-encephalography (EEG) guidance until electrographic seizure cessation or burst-suppression. Ultimately, etiological workup and related treatment of CSE, including broad spectrum immunotherapies as clinically indicated, is crucial. A potential therapeutic approach for future studies may entail consideration of interventions that may accelerate diagnosis and treatment of SE, as well as rational and early polytherapy based on synergism between ASMs by utilizing medications targeting different mechanisms of epileptogenesis and epileptogenicity.

Conflict of interest statement

Avantika Singh and Coral Stredny have no conflicts of interest or disclosures to report. Tobias Loddenkemper serves on the Council of the American Clinical Neurophysiology Society, on the American Board of Clinical Neurophysiology, as founder and consortium PI of the pediatric status epilepticus research group (pSERG), as an Associate Editor for Wyllie’s Treatment of Epilepsy 6th and 7th editions, and as a member of the NORSE Institute, PACS1 Foundation, and CCEMRC. He is part of patent applications to detect and predict seizures and to diagnose epilepsy. Dr. Loddenkemper is co-inventor of the TriVox Health technology, and Dr. Loddenkemper and Boston Children’s Hospital might receive financial benefits from this technology in the form of compensation in the future. He received research support from the Epilepsy Research Fund, NIH, the Epilepsy Foundation of America, the Epilepsy Therapy Project, the Pediatric Epilepsy Research Foundation, and received research grants from Lundbeck, Eisai, Upsher-Smith, Mallinckrodt, Sunovion, Sage, Empatica, and Pfizer. He served as a consultant for Zogenix, Upsher Smith, UCB, Grand Rounds, Advance Medical, and Sunovion. He performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies at Boston Children’s Hospital and affiliated hospitals and bills for these procedures and he evaluates pediatric neurology patients and bills for clinical care. He has received speaker honorariums from national societies including the AAN, AES and ACNS, and for grand rounds at various academic centers. His wife, D. Karen Stannard, is a pediatric neurologist and she performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies and bills for these procedures and she evaluates pediatric neurology patients and bills for clinical care.

Figures

Fig. 1

Pediatric status epilepticus treatment algorithm combining current guidelines. This approach combines the timeline-based algorithm from current guidelines by Neurocritical Care Society [11], International League Against Epilepsy [14], the American Epilepsy Society [13], and information from institutional guidelines. See Tables 1 and 2 for further detailed dosing recommendations. Notably, the above are recommendations that should be customized for each patient based on individual case and seizure characteristics and institutional medication availability. ASM Anti-seizure medication, BZD benzodiazepine, EEG electro-encephalography, IM intramuscular, IN intranasal, IV intravenous, PE phenytoin-equivalent, POLG DNA polymerase gamma, SE status epilepticus