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 GABA A 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.

Management of Neurological Emergencies in Children: An Updated Overview

“…A recent review of 17 studies evidenced a remarkable nonadherence to recommended dosages, timing, and number of administrations in up to 61% of patients treated with benzodiazepines, even if they represent first-line treatments without further valid therapeutic alternatives. 19 Three recent trials (ConSEPT, EcLiPSE, and ESETT) demonstrated that levetiracetam and valproate have the same effectiveness and safety of phenytoin as second-line treatments. [20][21][22] Levetiracetam is preferred over phenytoin by a growing number of physicians because of advantages in terms of administration rapidity (5 vs. 20 minutes) and less serious side effects.…”

“…23 Ketamine avoided endotracheal intubation in a significant proportion of children with refractory status epilepticus in recently reported case series and case reports. 19,24 These positive results might result from the antagonist effect of ketamine on the overexpression of N-methyl-D-aspartate receptors during the late stages of status epilepticus. 23…”

Anticonvulsive Drug Use in Status Treatment in Children

“…10 mg) may repeat dose once aŌer ~10 min 5 mg (<15 kg), 10 mg (>15 kg) off-label alternaƟves: nasal or intramuscular midazolam, nasal or buccal lorazepam Early-phase treatment in hospital choose one of the following benzodiazepines if max dose not given yet*: Diazepam is lipophilic and, thus, rapidly penetrates the blood-brain barrier leading to rapid onset of action with a first effect after few minutes and a maximum effect expected after 10-20 min (half-life 20-100 h) (Singh et al 2020). Buccal midazolam is given at 0.2-0.5 mg/kg (maximum single dose 10 mg, maximum two doses; proposed doses: 3 months -< 1 year 2.5 mg, 1 -<5 years 5 mg, 5-<10 years 7.5 mg, >10 years 10 mg) with a maximum effect expected after approximately 10 min and a shorter half-life than diazepam of 3-4 h (Singh et al 2020). Which of these drugs is more superior remains a matter of debate.…”

“…Which of these drugs is more superior remains a matter of debate. In a recent Cochrane review on drug management of children with tonic-clonic seizures including convulsive SE, no sufficient evidence was found when comparing rectal diazepam to buccal midazolam for treatment of acute tonic-clonic seizures (Singh et al 2020). Buccal midazolam has been reported to be at least as effective in cessation of SE, equally safe, and also more socially acceptable than rectal diazepam (Scott et al 2012;Mpimbaza et al 2008;Brigo et al 2015;McTague et al 2018b;Capovilla et al 2013;McMullan et al 2010;McIntyre et al 2005).…”

Towards an evidence-based treatment of pediatric status epilepticus: still a mountain to climb

“…The relationship that was demonstrated between aetiologies of status epilepticus and prognosis represents an important stimulus for the realization of an adequate diagnostic work-up, but the prevention of mortal outcome or permanent neurological dysfunctions requires optimization of the available antiseizure medications [1,2,3,4,5]. The therapeutic approach that is described in the paper reflects national or single-centre protocols as well as the state of knowledge in the analysed temporal range (2013-2015) [1].…”