AAN 2024 | The management of refractory and super-refractory status epilepticus
Clio Rubinos, MD, University of North Carolina at Chapel Hill, Chapel Hill, NC, discusses the challenges associated with managing refractory and super refractory status epilepticus. There is a body of data supporting the use of benzodiazepines in order to prevent disease progression; however, a recent post-hoc analysis identified that 70% of patients receiving these agents are under-dosed. Following treatment failure on benzodiazepines, three well-studied drugs are available to treat patients – levetiracetam, valproic acid, and fosphenytoin – but Dr Rubinos highlights that the efficacy of these agents is ~50%. Late stages of the disease require treatment with high-dose anesthetics, which are associated with long-term complications, and there is a lack of evidence on the best anesthetics to deploy in this setting. Therefore, the development of novel strategies is necessary, and a drug targeting the GABAA receptor outside of the synaptic cleft is showing promise in an ongoing trial. Dr Rubinos also expresses her excitement at the potential for vitamin B6 (pyridoxine) supplementation, highlighting that, in her clinic, 80% of patients with status epilepticus were deficient in this compound. This interview took place at the American Academy of Neurology (AAN) Annual Meeting 2024 in Denver, CO.
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Transcript
These are really challenging conditions because they are imposing a more refractory stage of status epilepticus, which have failed the initial medications. The challenge that is imposed is that these stages of status epilepticus require a high dose of anesthetics that can be associated with long-term ICU complications, more time in the mechanical ventilation, and also complications with hospitals...
These are really challenging conditions because they are imposing a more refractory stage of status epilepticus, which have failed the initial medications. The challenge that is imposed is that these stages of status epilepticus require a high dose of anesthetics that can be associated with long-term ICU complications, more time in the mechanical ventilation, and also complications with hospitals. New data has shown that the use of anesthetics has not been associated with mortality, which I think is something really good for us to know, because there’s some fear into starting these medications and giving an adequate dose of these medications for the management of status epilepticus. The underlying etiology of the disease is the one that’s going to lead to the mortality. Challenges that we have in terms of evidence, is that we don’t know which of the anesthetics is the best to initiate for the management of super refractory status epilepticus or refractory status epilepticus, and we need to collect more data in order to see which one is the best agent to start immediately upon being in these stages.
In general, for status epilepticus, we have really good data that benzodiazepines really work. However, the majority of the patients tend to be underdosed for benzodiazepines. One of the biggest trials that was recently published in 2019, the ESETT trial, showed in post hoc analysis that 70% of these patients were underdosed with benzodiazepines. So, I encourage all my colleagues to please give an adequate dose of benzodiazepine medications early on, because that’s going to prevent the progression of the disease, and it’s not been really associated with increased number of intubations. Another thing that is challenging in the early stages of a status epilepticus is that once they have failed benzodiazepine, we have three well-studied drugs; levetiracetam, valproic acid, and fosphenytoin. However, all of those are only 50% efficacious. So, we need any other drugs or any other interventions in these early stages to stop the progression of the disease. Now, there are studies going on that it can be used in patients that have failed these two medications. One of these drugs is attacking the GABAA receptors that are outside the synaptic cleft. I’m hoping to see the results for this study, because it is very promising in the management of our patients to prevent the use of anesthetics and intubations. As well, it is promising for preventing the progression of the disease.
There’s limited data for neurostimulation techniques, and those have been used most in the late stages of status epilepticus. One of the new interventions that I am passionate about and I’m looking into is the replacement of pyridoxine, which is vitamin B6. Vitamin B6 is a vitamin that once it gets phosphorylated in your body, transforms to an agent called PLP, which is a critical cofactor for the development and the production of GABA neurotransmitters. My team showed two years ago that about 80% of our patients that have established status epilepticus have deficiency of vitamin B6. So, there’s an association between deficiency of vitamin B6. This is after correcting for other critical illness scores, and also when we compare to other groups: patients that were also admitted to the ICU, patients who were admitted to the hospital, and outpatients. So, there’s some promising data into possible replacements of B6, and it is something that I’m very passionate about. But, in terms of neurostimulation, we have very limited data into how it is working in the latest stages to really extrapolate their efficacy for earlier stages. I think we’re early on in that in that term of management.
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Disclosures
Dr Rubinos reports the following disclosures: Consulting for Qualtrics Inc. Scientific Advisory or Data Safety Monitoring board for Azurity Pharmaceuticals. Speakers Bureau for American Epilepsy Society & Marinus Pharmaceutical. The institution of Dr Rubinos has received research support from University of North Carolina.
