Challenges in the treatment of convulsive status epilepticus

Zaccara, Gaetano; Giannasi, Gianfranco; Oggioni, R; Rosati, Eleonora; Tramacere, Luciana; Palumbo, Pasquale

doi:10.1016/j.seizure.2017.02.015

Cited by 46 publications

(39 citation statements)

References 89 publications

(128 reference statements)

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“…An alternative approach is to prevent the emergence of the epileptic state [ 8 ]. However, breakthrough seizures, treatment resistance [ 8 ], increased epilepsy-related morbidity and mortality [ 9 ] are fairly common, highlighting the fact that the efficacy of our current antiepileptogenic medications remains suboptimal [ 10 ]. This major public health concern calls for novel therapeutic targets for epilepsy [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70

et al. 2018

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l-Carnitine is a unique nutritional supplement for athletes that has been recently studied as a potential treatment for certain neuropsychiatric disorders. However, its efficacy in seizure control has not been investigated. Sprague Dawley rats were randomly assigned to receive either saline (Sal) (negative control) or pentylenetetrazole (PTZ) 40 mg/kg i.p. × 3 times/week × 3 weeks. The PTZ group was further subdivided into two groups, the first received oral l-carnitine (l-Car) (100 mg/kg/day × 4 weeks) (PTZ + l-Car), while the second group received saline (PTZ + Sal). Daily identification and quantification of seizure scores, time to the first seizure and the duration of seizures were performed in each animal. Molecular oxidative markers were examined in the animal brains. l-Car treatment was associated with marked reduction in seizure score (p = 0.0002) that was indicated as early as Day 2 of treatment and continued throughout treatment duration. Furthermore, l-Car significantly prolonged the time to the first seizure (p < 0.0001) and shortened seizure duration (p = 0.028). In addition, l-Car administration for four weeks attenuated PTZ-induced increase in the level of oxidative stress marker malondialdehyde (MDA) (p < 0.0001) and reduced the activity of catalase enzyme (p = 0.0006) and increased antioxidant GSH activity (p < 0.0001). Moreover, l-Car significantly reduced PTZ-induced elevation in protein expression of caspase-3 (p < 0.0001) and β-catenin (p < 0.0001). Overall, our results suggest a potential therapeutic role of l-Car in seizure control and call for testing these preclinical results in a proof of concept pilot clinical study.

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Section: Introductionmentioning

confidence: 99%

l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70

et al. 2018

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“…Irrespective of initial BZD dose, respiratory depression after more than two doses of BZD was reported in the North London CSE in Childhood Surveillance Study [34]. In a retrospective cohort study that analyzed 126 SE events, guideline deviation was associated with more than Table 1 First-and second-line anti-seizure medications (ASMs) Medication Dose [11,49] Pharmacokinetics and other considerations [11,38,49,111] Mechanism of action [49,111] Serious adverse effects [11,49] (continued)…”

Section: Initial Benzodiazepine Dosingmentioning

confidence: 99%

“…Medication Dose [11,49] Pharmacokinetics and other considerations [11,38,49,111] Mechanism of action [49,111] Serious adverse effects [11,49] [32]. Patients who received higher than suggested BZD doses had increased respiratory compromise [15].…”

Section: Initial Benzodiazepine Dosingmentioning

confidence: 99%

“…When patients continue to have persistent seizure activity after second-line treatment, SE is often considered refractory, with reported mortality of 16-43.5% [45][46][47], though some recent case series also report lower mortality of 17% [48] in pediatric patients. Refractory SE (RSE) is seen in 23-44% of patients with CSE and there is no clear evidence to direct therapy in this phase [13,49]. Pharmacotherapy includes additional boluses of second-line medications (e.g., fosphenytoin, levetiracetam, valproate, and phenobarbital, among others) and consideration of medically induced coma with IV continuous infusions of anesthetic agents (e.g., midazolam, propofol, barbiturates) with critical care treatment and EEG monitoring [50] (see Table 2 and Fig.…”

Section: Third-line Therapy Phase (40-60 Min Refractory and Super-rementioning

confidence: 99%

“…Once a steroid trial is initiated and it is ineffective within 2-3 days, IVIg or plasma exchange may be considered. If there is cessation of SE, ongoing immunotherapy may be considered depending on the clinical scenario and underlying etiology [49,51,[72][73][74][75]. While steroids and immunotherapy may be considered a last resort treatment option, we usually reserve this approach for patients with suggestions of an underlying inflammatory or autoimmune etiology.…”

Section: Immunomodulatory Therapiesmentioning

confidence: 99%

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Pharmacotherapy for Pediatric Convulsive Status Epilepticus

2019

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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.

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New and Emerging Antiepileptic Drugs

Witkin

Golani

Smith

2021

Burger's Medicinal Chemistry and Drug Discovery

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This article provides the biologist, chemist, and clinician with an overview into currently existing epilepsy medicines, an appreciation of those currently in development, and a glimpse at future possibilities. The discovery and development of antiepileptic drugs with improved efficacy and side‐effect dimensions are urgently needed. We discuss various strategies for discovering new antiepileptic drugs. We then provide summary data on the mechanisms of action, efficacy, and tolerability of some of the newer third‐generation antiepileptic drugs – eslicarbazepine, brivaracetam, retigabine, lacosamide, and perampanel. Additional compounds that are currently in development for epilepsy are also reviewed. These include the novel α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonists CERC‐611 and JNJ‐55511118 that are first‐in‐class drugs blocking only those AMPA receptors associated with the auxiliary protein TAPP γ‐8. The GABA A (α2/3)‐selective compounds, KRM‐II‐81, MP‐III‐080, and PF‐06372865 hold additional promise and potential advantage over nonselective GABA A receptor modulators. The developmental status of another positive allosteric modulator of GABA A receptors, the neuroactive steroid ganaxolone, is also summarized. In addition, two mGlu2 receptor modulators, JNJ‐40411813 and LY2812223 are discussed. Finally, initial data on cannabidiol, anakinra, and padsevonil are reviewed. Literature data derived from studies on both human epileptic tissue and rodent seizure modeling were utilized to glean several compelling novel drug targets for consideration in future antiepileptic drug discovery programs. Thus, in the past decade, key advances have been made that are benefiting the epileptic patient community. The current compounds in development and new drug targets give additional promise of improved antiepileptic drugs.

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Challenges in the treatment of convulsive status epilepticus

Cited by 46 publications

References 89 publications

l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70

l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

New and Emerging Antiepileptic Drugs

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