What's new in status epilepticus: Dr. Eugen Trinka

This episode covers a wide scope of issues, including treatment options, treatment response, prognosis and the role of seizures versus the underlying etiology, most common etiologies for different age groups, new-onset refractory status (NORSE), and the prevalence and special considerations of non-convulsive status epilepticus.

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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Transcript

Dr. Eugen Trinka: Hello, my name is Eugen Trinka and I'm chair of the Department of Neurology, Neurointensive Care and Neuro Rehabilitation in Salzburg at the Paracelsus Medical University’s Christian Doppler University Hospital.

And I'm currently involved in the International League Against Epilepsy as strategic advisor to our president and the executive committee. And I was chair of the ILAE Europe board for many years and also involved in several guideline and classification committees. 

Nancy Volkers: Thank you so much for joining me. We're going to be discussing status epilepticus. So I think to start, it would be great if you could define the term. What is status epilepticus and has the definition changed over time?

Dr. Eugen Trinka: Yes, status epilepticus is a quite a unique condition.

You can say it's the most extreme expression of a seizure, and it has been traditionally defined when a seizure is above a certain time period. But there was no clear definition of what the time period is, and first attempts to specify that were that half an hour of seizure activity, that is status epilepticus.

But if you think on half an hour of seizure activity, you come too late with the treatment. And that started the process of discussion, and many people were involved in that research to renew the definition about 10 years ago. The observation that usually, generalized tonic-clonic seizures or bilateral tonic-clonic seizures don't last longer than two to three minutes made up a new window to define what status epilepticus might be clinically, and there was an agreement that seizure activity, tonic-clonic activity for more than five minutes is status epilepticus. That's a time point, which we call T-1, when a seizure or a status is unlikely to stop spontaneously and you have to start treatment.

And the whole thing is about brain damage which is associated with status epilepticus when status has a certain duration, and that is called time point T-2. That is when status epilepticus leads to neuronal damage or alteration of neuronal networks.

So this time point T-2 is what we want to prevent, because that means brain damage. We had only previously animal experiments to show that, but now we have quite good human data in terms of T-1, five minutes for tonic-clonic seizures and time point T-2, around half an hour where brain damage occurs.

What I say is related to tonic-clonic status epilepticus, it is a form of status epilepticus with prominent motor activity, prominent motor phenomena. And in our classification also from 2015, the group of status with prominent motor phenomena encompassed tonic-clonic status, but also other motor status activity.

For instance, hypermotor status activity or hyperkinetic status epilepticus or focal motor status epilepticus with or without impaired consciousness. So those with prominent motor phenomena are a certain group where you can observe motor phenomena with your eyes and you know that this is epileptic and you know that this is status epilepticus once it’s longer than five minutes.

And we have another group, which is also a broad clinical group, called non convulsive status epilepticus. That's the one with only minor motor phenomena. The non convulsive forms, they're more difficult to diagnose and you can only assess that properly by using additional investigations, most likely EEG.

Nancy Volkers: Okay, great. Thank you. That's an excellent overview. So I feel like the tonic-clonic status epilepticus is sort of the one that's most, maybe most commonly known. Is that also the most common? And what are some of the etiologies of tonic-clonic status epilepticus?

Dr. Eugen Trinka: Tonic-clonic status is definitely the most well-known, and it's known since antiquity, but it's not the most common. More common are nonconvulsive forms, and they have been under recognized for many years. And if they are recognized, they have been overtreated in some cases. So these two clinical conditions have different phases. One phase is the one which you see clearly. That's a convulsive tonic-clonic associated with a certain mortality.

And the most common causes are number one, cerebrovascular in the older age, and tumors and brain trauma. This is the most common. In the middle age, it's intoxication, alcohol and drug related, and in childhood, most commonly epilepsy syndromes are the cause of status epilepticus, maybe the first symptom of developmental epileptic encephalopathy, for instance, Dravet syndrome, which is characterized by exceedingly abnormally long seizure duration. Many of the seizures in Dravet qualify for status epilepticus. 

On the other hand, the non-convulsive forms, they have been increasingly recognized after the introduction of validated EEG criteria. That's the so-called Salzburg EEG criteria for non-convulsive status epilepticus. But what we know now is that in the older ages, quite a lot of persons come with minor phenomena. They come with altered mental status, only mild motor phenomena, such as twitching in the face or minor jerking in the extremities, which you don't see if you don't investigate the person carefully.

And this is a sign of non-convulsive status epilepticus, which you then can prove with EEG. What is new in the development is that, lesson number one, status epilepticus with tonic-clonic activity only does not have a high mortality and is very often treated early and vigorously and leads to a good outcome. Non convulsive status epilepticus with impaired consciousness, clouding of consciousness, somnolence, stupor, or coma, is the one associated with the highest mortality: 40%, up to 60% of those people don't survive the status episode. 

If you look at nonconvulsive status in coma, we thought that those with the most prominent symptoms have the highest mortality. No, it's not true. The ones in coma, these are the most problematic. And if you look at the course, imagine 5 minutes, 10 minutes, you have motor activity. After 15 minutes, you lose the motor activity. But the brain is still ongoing in seizure activity, so you don't see it anymore, and the brain is still in status, which is called electromechanical dissociation. This phenomenon leads to the nonconvulsive forms, which is a whole variety. 

On the other hand, there are nonconvulsive status forms, such as absent status in childhood or in adolescence, which probably don't harm the brain irrespective how long they last. We don't see any brain damage when investigating these people with MRI, even after a certain duration in status. In between those two groups, non-convulsive in coma and absence status without coma with impairment of awareness, is the intermediate group, which was previously called psychomotor status in the ‘70s, and then it was complex partial status epilepticus, and now it's focal status with impaired consciousness. It's all the same name. In terms of T-1 they have after 10 minutes, it's unusually long, and T-2 occurs around one hour and then we see local brain damage. If we treat successfully, we see an atrophy afterwards. Again, the most prominent etiologies, the most common etiologies are remote brain trauma, remote cerebrovascular, accident, or inflammation. In some areas of the world, inflammation or infection are the most common causes for this group.

Nancy Volkers: For nonconvulsive status with coma, I believe you said 40% to 60% of people die. So what's driving the outcome? Is it the seizures or is it the etiology underneath? 

Dr. Eugen Trinka: So the drivers for the outcome, I believe, are at least two factors. One is the underlying etiology and the second is the duration of status. And we have evidence for both of these.

So the nonconvulsive and also the convulsive forms of status, they cluster into distinct groups. One of the clusters is acute symptomatic etiology, plus an EEG which shows periodic, generalized periodic discharges, lateralized periodic discharges, or burst suppression. And they are associated with a poor outcome and low responsiveness to antiseizure medicines. Whereas others with tonic-clonic phase only, with only acute EEG changes but no ongoing periodic changes, they tend to have a good outcome. 

So these electroclinical clusters have been described, but what comes into the equation is the etiology, and you absolutely correctly identified this problem. These status types, they do not have all the same etiology. They look the same. But if the status is caused due to intoxication, it may be tonic-clonic with impaired consciousness and following that non convulsive status. But the cause is completely reversible and the outcome is good. If the same status type is associated with cerebrovascular accident or an encephalitis, the outcome is worse. So it's a combination of both. 

And studies from Finland clearly show that earlier treatment does better. We did a comparative study looking at status epileptics in Salzburg in time to treatment, which is short, as compared to Indonesia, where time to treatment is much longer. They have different causes too. But if you control for causes, the outcome there is worse if you treat later. So early identification, early treatment and treatment of seizures of status and the underlying cause is probably the golden rule.

Nancy Volkers: Excellent, thank you. So in terms of tonic-clonic status epilepticus, there have been quite a few studies showing that first-line treatment is often underdosed or not given at all. Despite the fact that, as you said, it's fairly easy to recognize. So this would be generally pre-hospital treatment. It's either at home with a family, if it's a child or an adult, or a first responder. Could you talk about that issue, the underdosing? 

Dr. Eugen Trinka: We all agree that time is brain and early treatment is better in these emergency situations, especially tonic-clonic status epilepticus. There are good randomized clinical trials, all of them come from us showing that benzodiazepines are the drug of choice in the early phases and depending on which type of benzodiazepine you use, intravenous lorazepam and intravenous clonazepam and intravenous diazepam are the three probably the best, which you have for the early phases.

But that's intravenous and that's, you can do it out of hospital with paramedics or emergency doctors, or you do it in hospital. But think about the time you need to bring a needle into a vein and give the appropriate dose. So these are two challenging things in the emergency settings. Alternative routes would be ideal to give it earlier on. And you have a buccal route, you have an intranasal route, and you have an intramuscular route which you can apply, but you give the same substances. You give benzodiazepines and for the intranasal and buccal route, there is midazolam, which is of course excellent because it's water soluble. It's very acidic if you spray it into the nose. But it's water soluble and it acts quickly.

Having said that, these benzodiazepines have a negative effect, which is sedation and respiratory depression. So doctors may fear, I don't want to overdose, I just give the half dose, and I want to avoid respiratory depression. Every one of us working in hospitals, when you do your training and you give an elderly person a full dose of benzodiazepines, you sometimes see how he or she stops breathing and you have to give him oxygen or help the ventilation.

So this is something doctors fear. That may be one reason why benzodiazepines are underdosed. The second reason is that in randomized clinical trials, you use generally high doses because you want to see an effect and to stick to these high doses for all the other people outside of a clinical trial sometimes makes problems because you want to avoid adverse effects.

And the third reason is that the danger of status epilepticus in the acute setting is very often underestimated. So therefore, I think our definition, the ILAE definition, that status epilepticus harms the brain after a certain time period, really can improve treatment because you have it in your mind that you have to treat early, otherwise you will have the brain damage.

So these three reasons could be an answer. I'm not sure, because studies from Europe, we did an old study with more than 1,000 patients, studies from the US and also other countries showed that 50 to 70% of patients are underdosed. What is the hope? If the treatment is not given by the doctors, but by the parents or caregivers of a child or a young person, they follow the rules and they give the appropriate dose. Underdosing in this setting is less common than in the hospital setting when doctors are in charge of treatment.

Our wish would be to have a non-sedating medication for first line, which enters the brain rapidly but does not make you sleep, or does not depress your respiration.

But at the moment we don't have it, and that's a clear unmet need.

Nancy Volkers: Excellent. Thank you. And then after first line treatment is given, how long do the guidelines say to wait before proceeding to second line if the person is still having seizures? 

Dr. Eugen Trinka: Yeah, so the guidelines are not always what is happening in real life.

So the guidelines say you have to wait for a certain time period, at 10 minutes. But if you, if you look at that, why should you wait for 10? You give benzos, they have an immediate effect within one or two minutes. If you don't see anything and it still goes on and there is no improvement, immediately go for the next drug.

And that is either intravenous levetiracetam, intravenous valproic acid, or in the US also intravenous fosphenytoin. Fosphenytoin is not available in many countries of the world but this is also an option. But the main, I think most globally use levetiracetam or valproic acid and a few people still use phenytoin and not fosphenytoin. It's a cost issue, also. 

The second-line treatment is underdosed in most of the instances. The full dose for an adult person would be 3,000 milligram or 2,500 milligram of levetiracetam intravenously given in around five minutes. So rapid infusion of the full loading dose, which is usually calculated by 50 to 60 milligram per kilogram body weight. And what I say to young doctors in the emergency settings, if you start to calculate, you lose time. So give the dose, and it doesn't matter whether it's a little bit higher because it's not sedating in the same way as benzos are.

Pediatricians are a different category or a different species because they always think in milligrams per kilogram and they have it in their genes. But adult neurologists don't do that usually. 

But what the emergency doctors and adult neurologists have to know is related to pharmacokinetics and pharmacodynamics. As I said, the highest incidences going up to 80 per 100,000 per year is in the elderly population and not in the young children or in the adult population. It's in the elderly population, and they are characterized by increased sensitivity to central sedating effects. Even levetiracetam in the elderly can be sedating.

So this is one of the things which you forget. The renal elimination goes down, the hepatic metabolism slows also down, and some of these patients are simply intoxicated. When you try to stop status and you use two high doses, the result is intoxication. So that's one caveat. And the other caveat is the use of valproic acid. You know, valproic acid is still one of the best antiseizure medicines with some of the most severe problems in epilepsy. That's number one, teratogenicity and delay in neurodevelopmental outcomes. So if you have a woman of childbearing potential, you don't know her status related to pregnancy and you don't have the test within five minutes, I'd rather avoid this a drug unless I know pregnancy is excluded or unless I know she doesn't respond to any other thing. 

And if the cause is unknown and there is a slight suspicion that this might be due to mitochondrial disorders, especially in the younger population, valproic acid can be problematic. It can cause and also worsen mitochondrial diseases. So that's an important caveat, which you have to keep in mind. This is why levetiracetam has some advantages. There are other intravenous anti-seizure medicines at the moment. We have intravenous brivaracetam and we have intravenous lacosamide, which are excellent drugs for status epilepticus if levetiracetam does not work.

And we have a global organization with a global audience. And in many parts of the world phenobarbital is an available drug. It's cheap. It is highly efficacious. It has side effects, which is also CNS depression, respiratory depression, but it's highly effective. So that is also an option which you have.

So I repeat, levetiracetam, valproic acid, fosphenytoin, lacosamide, brivaracetam, and phenobarbital. Six drugs. 

Nancy Volkers: So after second-line treatment, is it possible to give a percentage of how many cases of status epilepticus resolve, and then what happens after second-line treatment? When the person is still having seizures, they enter refractory status epilepticus. How common is that? And what happens then? 

Dr. Eugen Trinka: Yeah, so if we look at the incidence of status epilepticus, it's around 30 to 50 per 100,000 per year. So that's the incidence globally. Some areas it's higher, some areas it's lower, or some studies report higher and some report lower figures.

But that's the average with the first line treatment. And if you're early, you can control around 60%, 50% to 60%. So half of the patients are controlled. If they're not controlled and they enter the established status epilepticus definition, and you treat them with intravenous antiseizure medicines, about half of them are controlled, and then status becomes refractory. That's what we say when it doesn't respond to benzos plus antiseizure medicines. Then it becomes difficult. With each treatment step, the response becomes lower, lower, lower. But you should never give up because even in refractory and super refractory status epilepticus, after weeks, a reasonably good outcome can be achieved.

I heard this story at the last conference, which was here in Salzburg, where an anesthesiologist said, “So we have a standard operating procedure where we say after five days in status epilepticus, we withdraw treatment.” And I said, “Oh my God, that's completely wrong, because there is good evidence that good outcome can be achieved.”

We did a global survey on more than 700 patients of super-refractory status epilepticus and 70% survived. And that's something where you should not give up.

So that's one of the key messages when we go to this refractory, super-refractory status types. This is more or less an evidence-free zone. When we say evidence is randomized clinical trials, we don't have one. We only have clinical reasoning. We have case series. We have reported outcomes. We have good registries now, and we know that in terms of response rate, not a big difference between high-dose benzodiazepines, namely midazolam high-dose infusion, thiopental or pentobarbital, and propofol, which are the three classic intravenous anesthetic drugs.

Well, having said that, thiopental, pentobarbital, they have more side effects than midazolam. Propofol is somehow well tolerated and it's very popular because it has a short half-life. If you have high-dose propofol and you get out within a few hours, it's gone. Right? With midazolam, it only goes out of the body in the early phases, but if you have a high-dose infusion with midazolam, the half-life extends to 50 hours. So after 50 hours, you still have half of the midazolam in your body and you have a delayed wake up. That's also something which is sometimes forgotten.

Propofol has also a side effect that is propofol infusion syndrome. It can cause metabolic acidosis and severe organ failure if you have high-dose long-term treatment. And it's more common in children than in adults. So we need other anesthesia drugs in the refractory setting. 

So all the others which I mentioned previously, midazolam, propofol and the barbiturates, they act on the GABA receptors. So the GABA receptors tend to lose their efficacy. The synaptic GABA receptors are internalized, the extra synaptic are still there. And the three intravenous anesthetics, they act on the extra synaptic receptors and have also some other effects.

But we need other drugs. And ketamine acts on the glutamate receptors, which is the main excitatory transmitter. Very good drug. I also mention topiramate here because it also acts on the glutamate receptors. So to have an intravenous topiramate infusion would be extremely helpful in these instances. Perampanel acts also on the glutamate receptors and we can only give it through nasogastric tube.

And what we also have to say that these patients are severely ill, and you have to look on the systemic factors which influence that. So keep the blood pressure up, look for the electrolyte balance, prevent infections, et cetera. That's in neurointensive care management in these patients. 

Nancy Volkers: So are people who advance to this category—are there certain etiologies associated with that? So someone who is undergoing alcohol withdrawal, are they ever going to be in super-refractory status epilepticus, or is it specific etiologies where the person is already very ill from something else, or injured?

Dr. Eugen Trinka: Yeah. So your point is absolutely important. It's the etiology causing this refractory status epilepticus. So you can say those etiologies which don't make structural damage, which is intoxication, which is alcohol withdrawal, which is antiseizure medicine withdrawal, which is metabolic derangement. They are rarely in this stage, but they still can be refractory. So it's not zero, but it's around 5, 10, 15% which enter these phases. But they have a very good outcome if you correct the metabolic derangement. Or if you control for the intoxication and the substances are out of the body.

Antiseizure medicine withdrawal sometimes can be refractory, especially in developmental epileptic encephalopathies or in severe drug-resistant epilepsies, and therefore correction of the antiseizure medicines, but also additional measures, for instance, implantation of a vagal nerve stimulator.

The etiologies which are most, which are refractory, are different ones. Cerebrovascular trauma, tumor, which is especially problematic, or bleeding when it comes to that. But there's a group where you don't find an immediate cause -  that's so-called new onset refractory status epilepticus. The term NORSE. These NORSE, they often affect adults or young adults, adolescents, that have been previously healthy and they go into terrible refractory status epilepticus and only in half of them you can identify a cause. 

And these causes are the so-called uncommon causes, which is autoimmune encephalitis, now increasingly recognized, you have good tests available for the antibody causing it. The second is mitochondrial diseases or other genetic diseases which can occur also later in life. So the oldest patient with mitochondrial status epilepticus we had was 60 years. Imagine that you don't think about this. But mitochondrial diseases, rare infections can cause status epilepticus and then paraneoplastic syndromes can cause refractory status. And then in around half of them, the cause is unknown. And that's a very intriguing condition because here, when people die with NORSE there's of course a huge emotional impact. Imagine a person who was full of life, completely normal, and from one day to the other, there is something happening.

And these patients are most often treated with immunomodulation. Steroids, intravenous immunoglobulins, plasma exchange, which is I think very helpful because you have it quite early, followed by immunomodulatory drugs such as rituximab. It's depleting the CD20 cells. Or interleukin-1 receptor inhibitors, anakinra or tocilizumab. Or interleukin-6 receptor blockers and many others. 

So all these drugs, which we know from oncology or immunology can be used in these cases, but you have to be sure, or you have to have good evidence, clinical evidence, and good suspicion that this is immune mediated.

Nancy Volkers: Excellent. Thank you.  If you don't have that suspicion, if the person does have a history of epilepsy you mentioned VNS, vagal nerve stimulation. Are there other non-pharmacologic treatments for refractory status, like surgery or the ketogenic diet? And are those being used? 

Dr. Eugen Trinka: Yeah they are used and you have to also have a clear concept as far as what you do and not out of the blue. So ketogenic diet tends to show better results in in children. There also results in adults, but they're less convincing. Why is it the case? I don't know. Some of the epilepsy syndromes are especially responsive to ketogenic diet, some developmental epileptic and encephalopathies, GLUT-1 deficiency, et cetera.

So if that is in the early stage, highly recommended you have to have experience in your center because getting a patient into the ketogenic state and applying the ketogenic diet, you need a dietician, et cetera. So the team has to know what they’re doing. That’s number one. 

Number two is neurostimulation. And I mentioned already vagal nerve stimulation, which is the most commonly applied neurostimulation. And I can only say from my own experience, I was not convinced. I was not a believer. I said, “There is a reporting bias.” It's interesting. And then we did it twice. The first was not successful, but the second was clearly convincing that this implantation in the acute phase was changing the game. So there is something which I personally want to explore further, but there are other forms of neurostimulation. For instance, deep brain stimulation. There have been some small case reports there. We did some electroconvulsive treatment which is according to the protocol which we use in psychiatry for severe depression. And the reports are of course biased. It's a publication bias and they report around 50% to 60% success rate also for TMS, transcranial magnetic stimulation.

And sometimes also emergent epilepsy surgery. So if you have a patient with a lesion, with a structural lesion, for instance, focal cortical dysplasia, in a region which is amenable to surgery, the acute decision for surgery may be taken. But this can only be done in a center with good epilepsy surgery experience and not outside that. 

Nancy Volkers: So we've talked a lot about mostly tonic-clonic status epilepticus. I'd like to go back a little bit to non-convulsive status.

Dr. Eugen Trinka: So for non-convulsive status epilepticus, the same therapeutic regimen applies. Benzodiazepines go first, followed by anti-seizure medicines.

Broadly, two categories have to be distinguished in the non-convulsive status. In this classification, we have one taxonomic criterion, whether there are prominent motor phenomena, yes or no? And it is non-convulsive if it's clearly no. But then we have the second taxonomic criterion, which is impairment of consciousness.

And that's not an all or nothing, it's a gradual process. So when your consciousness is impaired, you first are disoriented, then you get somnolent and you’re soporous, and then you are comatose, and then you are deeply comatose, right? And this development really comes out of the blue. Very often it's a convulsive status epilepticus, which then moves to a non-convulsive and coma. Very often you don't see the first convulsive phase because you find the patient in coma with some eye twitching or with some other twitching. So that is the case. So to distinguish in the non-convulsive group between those with impairment of consciousness, especially with coma, and those without impairment of consciousness, is important.

So I give you an example. A patient coming in with repetitive jerks in the upper extremity, slightly confused, going on for let's say half an hour. That's clearly not comatose. It has some minor motor phenomena. And you may say, well, it's prominent motor phenomena. But you also may say, well that's myoclonic status epilepticus without coma, right? This has a good prognosis. Or absence status. The patient comes in blinking and slightly unresponsive, but not coma. Good prognosis. 

The patient who is deeply comatose (and) does not respond to external stimuli - that is a poor prognosis. Dangerous is the one in coma. This is the one where you have to concentrate your treatment.

And also the time is brain principle applies to these patients. Don't lose time, start treatment vigorously, high dose to control the seizures. If you have an EEG, that's the time to order the EEG and to see whether you can control status because you don't have any clinical parameters anymore in the comatose.

Nancy Volkers: Is there anything else you wanted to mention as far as gray areas of treatment or controversies or debates or research that you find particularly intriguing? Anything that you think would be of interest to people listening? 

Dr. Eugen Trinka: Yeah, it's a purely subjective assessment what I personally find interesting or intriguing or important.

So number one is early treatment, time is brain. And for the early treatment we need a setting which is out of the hospital, which is, you know, in myocardial infarction we have, all over, we have defibrillators because we see it's important that everyone can use it. So we need to have some mindset which is similar. Status epilepticus is a dangerous condition and it harms the brain. Early treatment as early as possible is important, and ideally we need drugs which enter the brain fast, which are non-sedating, and which can interrupt status at early stages. If this does not work, we have to get better treatment options in our armamentarium. 

We still don't have randomized controlled trials in refractory status epilepticus, and I think that's very important to be better there. And in terms of research, we have nice criteria for the EEG. It's depending on the frequency of the EEG discharges and the location, but the definition of non-convulsive is, depending on the frequency of EEG, we have some additional criteria.

But who tells us that these discharges are correct? We may say that faster discharges are worse, or we may even say that lower discharges, lower frequency discharges not at 2.5 hertz, but that maybe at 1 hertz are even more dangerous. And there are some new data which we see with MRI that some patients very early have MRI changes, diffusion-weighted imaging changes which indicate neuronal damage.

So frequency is important to have the yes or no status epilepticus, but how dangerous is the frequency? We don't know. That's ongoing research, which would change our paradigm to really take it seriously. That's especially important when you have a patient in the intensive care unit and you do continuous EEG monitoring, like many centers do on many patients. Do you chase each spike or do you look at the overall picture? What harms the brain? What can be tolerated? This is a controversy between now we can diagnose at least spike activity, but we are not sure whether we should treat every spike—to be hyperactive in treatment can also be damaging the patient.

So the concept which we proposed some time ago is the impact of burden model, right? So the treatment is a burden on the patient. Status epilepticus is a burden on the patient and it can worsen the prognosis on top of the underlying cause. But if you reverse status epilepticus, you don't improve the cause. So the treatment effect can only reverse status but not the cause. And if the treatment itself is toxic, you worsen it. So we need better tolerated treatments, which is important, early treatment and later treatment. 

So the third point is the causes and there is still an enigma around NORSE and why patients are not responding, why you don't find any cause. These were healthy persons. This is something which you cannot explain. If you find something, of course that's good that you can explain and treat with immune modulatory treatment, et cetera. But if you don't find anything, what should you do? And this is quite emotionally demanding and the only way to tackle that is international collaboration. Across the Atlantic Ocean, across the Pacific, globally. We need to make bio databases and put all the facts together to help these patients. There are fantastic initiatives, in the US it’s the NORSE Foundation, if I may say. And there is EpiCARE, which is a reference network for rare diseases in Europe. And I think we have to collaborate there and everyone who is of good will is cordially invited.

Nancy Volkers: Well, thank you so much for joining me. Very enlightening discussion and a lot of information, so I really appreciate your time. 

Dr. Eugen Trinka: It was a great pleasure. Thank you for listening and enjoy the podcast.