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Navigating Status Epilepticus: Breakthroughs in Management · VJNeurology Podcast

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Challenging conditions because they are imposing a more refractory stage of
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status epileptical, which have failed the initial medications.
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And the challenge that is imposed is that these stages of status epilepticals
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require high dose of anesthetics that can be associated with long-term ICU complications,
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more time in the mechanical ventilations, and also complications with the hospital.
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New data has shown that the use of anesthetics has not been associated with
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mortality, which which I think is something really good for us to know,
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because there's some fear into starting these medications and giving adequate
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dose of this medication for the management of status epilepticos.
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The underlying etiology of the disease is the one that's going to lead to mortality.
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Challenges that we have in terms of evidence is that we don't know which of
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the anesthetics is the best to initiate for the management of super refractory
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status epilepticos or refractory status epilepticos.
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And we need more data to collect in order to see which one is the best agent
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to start immediately upon being in these stages.
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In general, for status epilepticals, we have really good data that benzodiazepines really work.
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However, the majority of the patients tend to be underdosed for benzodiazepines.
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One of the biggest trials that was recently published in 2019,
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the ESSE trial, in post hoc analysis showed that 70% of these patients were
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underdosed with benzodiazepine.
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So I just encourage all my colleagues to please give an adequate dose of benzodiazepine
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medications early on because it's going to prevent the progression of the disease,
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and it's not being really associated with increased number of intubations.
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Other thing that is challenging in the early stages of status epilepticus is
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that once they have failed benzodiazepine, we have three well-studied drugs,
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levotiracetam, barbroacetam, and fosfenidone, and all those are 50% efficacious.
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So we need any other drugs or any other interventions in these early on stages
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stages to stop the progression of the disease.
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Now, there is studies going on that it can be used in patients that have failed these two medications.
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One of these drugs is attacking the GABA-A receptors that are outside the synaptic clip.
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And I'm hoping to see the results for this study because it is very promising
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in the management of our patients to prevent the use of anesthetics and intubations,
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as well because it's preventing the progression of the disease.
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There is limited data for neuro-simulation techniques and those have been used
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most in the late stages of status epilepticos.
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One of the new interventions that I am passionate about and I'm looking into
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is the replacement of pyridoxine which is vitamin B6.
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Vitamin B6 is vitamin that once it gets phosphorylated in your body,
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it transforms to an agent called PLP that is a critical co-factor for the development
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or the production of GABA neurotransmitters.
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And my group, my team show two years ago that about 80% of our patients that
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have established status epilepticos have deficiency of vitamin B6.
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So there's an association between deficiency of vitamin B6.
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And this is after correcting for other critical illness scores and also when
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we compare to other groups. groups, patients that were also admitted to the
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ICU, patients that were admitted to the hospital, and outpatients.
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So there's some promising data into possible replacements of V6.
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It's something I'm very passionate about.
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But in terms of neurostimulations, we have very limited data into how it's working
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in the latest stages to really extrapolate the efficacy for earlier stages.
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So I think we're early on.
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Is gaining a lot of popularity for superrefractory status epilepticus and refractory
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status epilepticus is the early use of ketamine.
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Going back into the pathophysiology, our brain lives in a harmonious state between
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GABA and glutamate, inhibition and excitation.
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But we have animal data that within 20 minutes of having status epilepticus,
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there's a downregulation of the GABA receptors in the synaptic left and abregulation
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of that excitatory receptors such as NMDA and AMPA.
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Ketamine is one of the drugs, a drip, that has NMDA antagonism properties.
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So early on use of ketamine in these patients might be beneficial for seizure cessation.
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There are case reports, there are case theories that upon starting ketamine,
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seizures can reduce to a stop up to like 68% and can reduce in terms of seizure
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burden up to 80% of the the patients.
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However, this case series normally have a wide timing on when they start ketamine
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within 12, 24 hours to like 27 days.
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So early on in the stages, you know, within minutes or hours of the presentation
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to our hospital, because if we think about it, the patient takes about like
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20 to 30 minutes to come to us. And this balance is already occurring.
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If the patient has failed that first and second line, and we're thinking about
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using anesthetics, ketamine might be also a.
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Neonates, they have, so the neonatal brain responds with seizure to many insults.
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It's very hyper excitable.
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And although seizures are short, babies go very fast into status epilepticos.
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The difference between adults and
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older children is that we don't have any history, any previous history.
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So our baby comes to the neonatal intensive care unit without any,
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so we need to find out the diagnosis as fast as we can and as precise as we can.
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Seizures in neonates are only focal. So neonates, because their myelination is not complete,
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so all the structure of the brain are not complete, they do not do the generalized
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tonic-clonic seizures that are common in status epilepticus in adults.
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They have focal seizures.
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Neonates may have status epilepticus because of, as an acute provoked status
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epilepticus due to hypoxic ischemic encephalopathy, stroke, infection,
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but a significant minority has status epilepticus because there's an onset of a neonatal epilepsy.
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So there are two different situations and it's very important to differentiate
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between them because there is different treatment and different management. Dr.
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Cilio also discusses etiology-specific treatment of seizures in neonates with SE.
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Patients with different etiologies respond differently to treatments.
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Stratification of patients with seizures based on etiology is important in developing
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evidence-based treatment methods.
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She also highlights the importance of early diagnosis beyond treatment.
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So what I was presenting today and what I believe on is a novel approach to
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seizures and status epilepticus in neonates. which goes a little bit,
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beyond the all one size fits all model that we had, how do we treat neonatal seizure?
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And then I say, how do we treat neonates with seizure? Meaning that we need
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to stratify those patients.
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Patients with hypoxic ischemic encephalopathy tend to respond very well to phenobarbital first line,
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but infants with stroke might respond better to sodium channel blockers and
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neonates with channelopathies, so genetic neonatal onset epilepsy,
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tend to respond even to oral medication like carbamazepine.
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So I think stratification is very important and will help us to gather more
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evidence-based data and move toward a precision medicine as we do in older children and adults,
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but I think something that neonates deserve as well.
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Well, this is also an important part.
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We have genetics, we have neuroimaging, and early diagnosis,
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first of all, means some disorders can be treated, and we want to diagnose them as soon as possible.
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Disorders like channelopathy might need a different treatment than hypoxic ischemic
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encephalopathy, and we want to differentiate them earlier.
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But even for diseases with short lifespan,
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giving a diagnosis to parents and caregivers allow us to consider moving into
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comfort care and avoiding,
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you know, unhelpful and maybe painful treatments.
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And at the very end, giving a name to a disease allows family that lives very
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far apart to get in contact and helping each other,
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even when separated by long distance.
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We started both at the Yale University School of Medicine and in the Paris hospital,
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the PTSL Petri Hospital in Paris.
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And this project we conducted on biospecimens that have been collected since
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several years now to better understand the pathophysiological mechanisms underlying
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the development of neon-set refractory stylus epilepticus.
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So neon-set refractory stylus epilepticus is the full name of NORS,
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which is one of the most severe neurological conditions in which patients will
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experience very refractory seizures, like continuous seizures,
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as they do not respond to anticonvulsant medication.
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Most of the time, these patients have to be managed in intensive care units
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and require prolonged anesthesia with coma-inducing drugs to get the seizure under control.
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And since like the past maybe five years, there was severe evidence suggesting
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that this pathology may be due to disorder of immunity, leading to exacerbated
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cerebral inflammation.
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But until we started the study, we just had a few case reports published with
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a maximum of like 10 cases,
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suggesting that some inflammation biomarker may be used either to diagnose NERSC
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or to better understand what happens in those patients.
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But like with only a few patients, it was hard to really define what was going on.
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So that's why we would like to conduct a study on a much larger cohort of patients.
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So in this study, we investigate the inflammation by measuring cytokines in
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both serum and CSF from patients with NORS.
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And we compare the cytokine profile to patients with other form of refractory status epilepticus.
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So 37 of those patients compared to 61 north.
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And patients without status epilepticus.
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And so we noticed that overall patients with status epilepticus had a significant
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increase of several pro-inflammatory cytokines when compared to patients without status epilepticus.
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And that concerned mostly interleukin-6, interleukin-8, CCL2, or MIP1-alpha.
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And in a second time, we study more specifically the north population,
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and we compare the cytokine profile to the other patient with refractory status
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epilepticus, but not north.
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So the differences between these two groups of patients are mostly the etiology,
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because to be defined as a north patient, you should not have any history of
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epilepsy and any acute acute or active toxic structural or metabolic cause found in the first 72 hours.
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So if you have a cause like a brain trauma or a tumor, you will not be defined as a NARS patient.
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And so when we compare the profile of this NARS patient to the other status
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epilepticus patients, we found that patients with NARS had a significant increase
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of serum pro-inflammatory cytokines.
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So it was the case for interleukin-8, MIP1-alpha, and CCL2.
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And in the CSF, they also have an increase of interleukin-1-beta.
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So this study seems to let us know that North patients share some pathophysiological
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mechanisms not found in other status epilepticus patients.
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And the last part of our project for comparison was to investigate the patients
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for whom no etiology has been found at the end of the hospitalization,
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despite a very extensive workup with biological tests,
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EEG, MRI, clinical evaluation,
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two patients for whom we found an etiology.
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And we noticed that the cytokine, interleukin A, CCL2, and MIP1-alpha were still
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much higher in the serum of SUS patients compared to SUS with an etiology.
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So we conclude on SUS the result that the serum innate immunity cytokine may
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be important to explain why status epinepticus occurred in these patients.
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So it was the most important part of our project.
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And our second part, thanks to the large cohort of patients we analyzed,
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was to investigate if the patient who had the most important dysregulation of
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this immunity may also have the worst outcomes.
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And so for the first time, we use like a heat map correlation,
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and we look at the correlation between serum or CSF cytokine level and patient's outcome.
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And we observe that patients who have the most important concentration of this
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pro-inflammatory cytokine have the worst outcomes, both at ICU discharge,
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but also several months after status epileptic is onset. set.
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And so based on that, we made the hypothesis that if you target this immune
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dysregulation, you may prevent and improve patients' outcomes at short and long term.
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So we have two main perspectives on this project.
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So the first one is to continue measuring the cytokine profile in other patients with NOS and FIERS.
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So now we are able to receive biospecimens from all over the world,
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from patients with NORTH.
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And for that, we just need to enroll the patient in an open biorepository named
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the NORTH and FIERS biorepository at Yale.
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So when physicians have some patients and would like to get some cytokine results,
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they can just contact us.
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We have a generic email address, it's north at yale.edu.
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And based on this, we can enroll the patient in the biorepository, receive biospecimens.
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We perform from the cytokine measurement, and we send back the result to the centers.
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And by increasing the number of patients, we are also interested to investigate
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the impact of specific immune therapies on the cytokine level.
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To know if, for example, when a patient has been started with a cytokine targeting
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interleukin-6, is that will be followed
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by a decrease of the interleukin-6 level in the blood and the CSF.
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So it's the first perspective we have. So continue measuring samples and try
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to figure out the impact of immunotherapies on this cytokine level.
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And our second part is more for therapeutic purposes. So now we demonstrated
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that immunotherapies could really be efficient for those patients according
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to their cytokine profile.
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We would like to be able to guide as a treatment strategy for patients who are
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refractory to first-line immunotherapies like steroids, plasma exchange,
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intravenous immunoglobulins.
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So currently, we know that for these patients, it's recommended within one week
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to start the second line immunotherapy that can target interleukin 1 beta with
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anakinra, interleukin 6 with tocilizumab or other stuff.
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But currently we don't know for which patient we have to use anakinra and for
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which we have to use tocilizumab, for example.
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So we aim to be able to define some guidelines according to cytokine profile
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to be able to know which patients have to be treated by which therapy.
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And I think currently a randomized clinical trial will be the best idea just
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to evaluate also the efficacy of these therapeutics in those patients.