Pediatric super‐refractory status epilepticus treated with allopregnanolone

Broomall, Eileen; Natale, JoAnne E.; Grimason, Michele; Goldstein, Joshua; Smith, Craig; Chang, Celia H.; Kanes, Stephen; Rogawski, Michael A.; Wainwright, Mark S.

doi:10.1002/ana.24295

Cited by 113 publications

(80 citation statements)

References 13 publications

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“…Allopregnanolone has limited systemic side effects,16 and is highly effective in terminating ongoing status epilepticus in animal models 9, 17. These cases provided critical translational evidence of the activity of allopregnanolone in patients with SRSE, that led directly to the treatment of additional patients, including two children 12. Cumulatively, these patient experiences guided the development of the first placebo‐controlled Phase III study of a novel drug for SRSE that is currently ongoing 18, 19…”

Section: Discussionmentioning

confidence: 99%

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

Vaitkevicius

Husain

Rosenthal

et al. 2017

Ann Clin Transl Neurol

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Super‐refractory status epilepticus (SRSE) is associated with high morbidity and mortality. Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization. Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a 120‐h continuous infusion of allopregnanolone. Both patients recovered from prolonged SRSE with good cognitive outcomes.

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Section: Discussionmentioning

confidence: 99%

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

Vaitkevicius

Husain

Rosenthal

et al. 2017

Ann Clin Transl Neurol

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“…After treatment with allopregnanolone, TLAs were tapered over the next 24 to 72 hours, and allopregnanolone was continued for 4 days and tapered on the fifth day. The patient remained free of seizures over the next 12 subsequent days and was eventually discharged 25. Another successful allopregnanolone treatment was reported in a 28‐year‐old adult male with SRSE 27.…”

Section: Discussionmentioning

confidence: 85%

“…Allopregnanolone infusion was subsequently reported in the successful treatment of other pediatric and adult SRSE cases25, 27 An 11‐year‐old female was treated with allopregnanolone after multiple days of treatment and unsuccessful TLA wean attempts. Treatment resulted in cessation of SE, cognitive improvement, and eventual discharge 25.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment resulted in cessation of SE, cognitive improvement, and eventual discharge 25. Another 2‐year‐old female received allopregnanolone after multiple trials of AEDs and numerous unsuccessful TLA wean attempts.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the preclinical evidence, three recent case studies report the successful treatment of SRSE with brexanolone (USAN; formerly SAGE‐547 Injection; Sage Therapeutics, Inc., Cambridge, MA), a proprietary formulation of allopregnanolone, in human patients 25, 26, 27. Given the evidence suggesting potential benefits of allopregnanolone in treating SRSE, the objectives of the present study were to evaluate the safety and tolerability, pharmacokinetics (PK), and response to brexanolone in a cohort of patients with SRSE.…”

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Brexanolone as adjunctive therapy in super‐refractory status epilepticus

Rosenthal

Claassen

Wainwright

et al. 2017

Annals of Neurology

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ObjectiveSuper‐refractory status epilepticus (SRSE) is a life‐threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of brexanolone (USAN; formerly SAGE‐547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open‐label evaluation of brexanolone response during and after anesthetic third‐line agent (TLA) weaning.MethodsPatients receiving TLAs for SRSE control were eligible for open‐label, 1‐hour brexanolone loading infusions, followed by maintenance infusion. After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance. After 4 days, the brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow‐up.ResultsTwenty‐five patients received open‐label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty‐two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24 hours.InterpretationIn an open‐label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342–352

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In the fast lane: Receptor trafficking during status epilepticus

Naylor

2023

Epilepsia Open

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Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first‐line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit‐selective receptor trafficking within minutes to an hour of SE involves GABA‐A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites. During the first hour of SE, synaptic GABA‐A receptors containing γ2 subunits move to the cell interior while extrasynaptic GABA‐A receptors with δ subunits are preserved. Conversely, NMDA receptors containing N2B subunits are increased at synaptic and extrasynaptic sites, and homomeric GluA1 (“GluA2‐lacking”) calcium permeant AMPA receptor surface expression also is increased. Molecular mechanisms, largely driven by NMDA receptor or calcium permeant AMPA receptor activation early during circuit hyperactivity, regulate subunit‐specific interactions with proteins involved with synaptic scaffolding, adaptin‐AP2/clathrin‐dependent endocytosis, endoplasmic reticulum (ER) retention, and endosomal recycling. Reviewed here is how SE‐induced shifts in receptor subunit composition and surface representation increase the excitatory to inhibitory imbalance that sustains seizures and fuels excitotoxicity contributing to chronic sequela such as “spontaneous recurrent seizures” (SRS). A role for early multimodal therapy is suggested both for treatment of SE and for prevention of long‐term comorbidities.

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Pediatric super‐refractory status epilepticus treated with allopregnanolone

Cited by 113 publications

References 13 publications

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

Brexanolone as adjunctive therapy in super‐refractory status epilepticus

In the fast lane: Receptor trafficking during status epilepticus

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