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Pediatric Super-Refractory Status Epilepticus Treated With Allopregnanolone, Eileen Broomall, Joanne Natale, Michele Grimason, Joshua Goldstein, Craig Smith, Celia Chang, Stephen Kanes, Michael Rogawski, Mark Wainwright
Pediatric Super-Refractory Status Epilepticus Treated With Allopregnanolone, Eileen Broomall, Joanne Natale, Michele Grimason, Joshua Goldstein, Craig Smith, Celia Chang, Stephen Kanes, Michael Rogawski, Mark Wainwright
Michael A. Rogawski
Super-refractory status epilepticus is a life-threatening condition. Resistance to benzodiazepine and barbiturate treatment for this disorder is thought to be due to internalization of synaptic GABA-A receptors, and withdrawal of benzodiazepines and barbiturates during treatment often triggers seizure recurrence. The neurosteroid allopregnanolone acts as a positive allosteric modulator of synaptic and extrasynaptic GABA-A receptors. Here we describe the use of allopregnanolone in two pediatric patients with super-refractory status epilepticus. This treatment allowed the general anesthetic infusions to be weaned with resolution of status epilepticus. This is the first report of allopregnanolone use to treat status epilepticus in children.
Neuroactive Steroids For The Treatment Of Status Epilepticus, Michael Rogawski, Carlos Loya, Kiran Reddy, Dorota Zolkowski, Christoph Lossin
Neuroactive Steroids For The Treatment Of Status Epilepticus, Michael Rogawski, Carlos Loya, Kiran Reddy, Dorota Zolkowski, Christoph Lossin
Michael A. Rogawski
Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one third of cases. Synaptic GABA-A receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring benzodiazepine resistance, which is believed to be a major cause of treatment failure. GABA-A receptor positive allosteric modulator neuroactive steroids, such as allopregnanolone, also potentiate synaptic GABA-A receptors, but in addition they enhance extrasynaptic GABA-A receptors that mediate tonic inhibition. Extrasynaptic GABA-A receptors are not internalized, and desensitization of these …
Neurosteroids—Endogenous Regulators Of Seizure Susceptibility And Role In The Treatment Of Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Neurosteroids—Endogenous Regulators Of Seizure Susceptibility And Role In The Treatment Of Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Michael A. Rogawski
Certain steroid hormone metabolites that have activity as modulators of GABA-A receptors but lack conventional hormonal effects—including allopregnanolone and allotetrahydrodeoxycorticosterone—are synthesized within the brain, predominantly in principle (excitatory) neurons, and also in peripheral tissues. At low concentrations, such neurosteroids potentiate GABA-A receptor currents, whereas at higher concentrations they directly activate the receptor; large magnitude effects occur on nonsynaptic delta subunit-containing GABA-A receptors that mediate tonic currents. GABA-A receptor modulatory neurosteroids confer seizure protection in diverse animal models, without tolerance during chronic administration. Endogenous neurosteroids may play a role in catamenial epilepsy, stress-induced changes in seizure susceptibility, temporal lobe epilepsy, and …