Episode 37- Status Epilepticus & Anti-Seizure Medications

Welcome to Med Pods, the audio podcast from the Department of Medicine at AFMC. In our last conversation on the topics on urology, we spoke to Manish Bhaktia, specialist in urology in the Command Hospital in Pune on approach to seizure. Taking on from there, today we shall be discussing the emergency in this subject which is status epilepticus and also the use of anti-seizure medications. So, welcome back Manish. Thank you sir. So, our last conversation on seizure was very well appreciated and it has sort of opened up the discussion on this very important issue and as we understand status epilepticus happens to be a life-threatening emergency in which effective recognition and management is so important. So, let us talk about it. So, I want you to start by explaining to our students what is status epilepticus and why is it an emergency? So, status epilepticus is one of the most common neurological emergencies worldwide. There have been various definitions for status epilepticus. Most of them are time-bound in the sense that we have got a certain time period beyond which if the seizures persist, then it is considered as status epilepticus. So, the latest definition that is being used currently states it as a condition which results from failure of mechanisms responsible for seizure termination or initiation of mechanisms that lead to abnormally prolonged seizures beyond a particular time. So, let us call this time as T1 and if the seizures persist beyond a specific time, then there is a great likelihood of neuronal death, neuronal injury or alteration of neuronal networks leading to morbidity and mortality. So, let us call this time as time T2. So, basically the present definition has got two operational time dimensions, E1, E1 is the time beyond which the treatment should be initiated. So, this is considered as five minutes in cases of typical generalized ketonic-clonic seizures. This is a time till when the seizures are still benzodiazepine responsive, they respond very well to the treatment. Now, T2 is the time period beyond which if the seizures continue, then there is a likelihood that there would be some amount of neuronal damage. So, this is generally considered as around 30 minutes for convulsive status epilepticus and 60 minutes for non-convulsive status epilepticus. Now, status epilepticus can further be classified into, broadly into two categories. One is the convulsive status epilepticus, which is characterized by continuous motor activity and non-convulsive status epilepticus in which you may not find any overt convulsive activity, but there we are electrophysiological evidence of continuous seizures that is there. It is a neurological emergency with a mortality of almost 9 to 21 percent in best of the centers. If not treated in time, it is associated with increased morbidity, increased hospital stay, thereby leading to complications of increased duration of hospital stay. And it has got both long-term as well as short-term effects on the patient. Right. So, it is very interesting like when we were discussing stroke, we were talking about time is brain and there it is because of the lack of blood supply and the neuronal damage. Here if the damage is likely due to the excessive electrical activity that can happen and if it goes unchecked. So, when a patient comes with status, what is the initial approach in managing these patients? And like you already mentioned that time is crucial, so I would like to know more about that. The initial approach and management would consist of first is ABC, so airway, breathing, circulation and I would like to add to it is a vascular access. So, you assess the airway, you assess the breathing, you assess the circulation and as in other standard emergencies, you augment them if any one of them is requires a life support. Second thing, the fourth thing I would like to add is a vascular access. It is very important to establish an early vascular access in these patients because most of the drugs would be given through this room. Alternately, we investigate all the patients to rule out any causes of symptomatic status epileptica. In the sense that we have to rule out hypoglycemia, electrolyte disturbances or any other mimics of seizures and do a toxicology panel if indicated. If a patient qualifies as a case of status epileptica, we should terminate the seizures as early as possible. The preferred drugs are short acting benzodiazepines which include lorazepam, mirazolam and diazepam. All these drugs have got almost equal efficacy in various clinical trials. The routes can be either in most communities intravenous, in case there is a delay in finding an intravenous access, it can be given intramuscular, they can be given per rectal or they can be given through a nasal route also. The dose of lorazepam is 0.1 milligram per kg IV bolus, standard dose is around 4 milligrams. Diazepam, the dose is 0.15 milligram per kg IV bolus or 0.2 milligram per kg per rectal. The advantage of lorazepam over diazepam is that it has got slightly longer duration of action. So, after the initial termination of caesars, it prevents the recurrence of caesars to say around one and a half hours. Now, coming on to mirazolam, it is short acting benzodiazepine. The main advantage is that it can be given through any of the routes. It can be given IV, it can be given intramuscular, it can be given per rectal and it can be given through nasal sprays also. The dose is for IV is 0.1 milligram per kg body weight and IM is 0.2 milligram per kg body weight. In fact, in the pre-hospital management of caesars or stator suplepticus, it is emerging as the drug of choice. You give 10 milligram IM bolus, it has got the same efficacy as IV lorazepam or diazepam terminating the caesars. Now, after giving a short acting benzodiazepine, almost 40 to 50 percent of the people will have a termination of the caesars. This is we are assuming that we ruled out causes such as hyperglycemia or any other metabolic derangement which can be corrected. Simultaneously, to prevent the further recurrence of the caesars, we have to give them one more non-silating intravenous anti-caesare drug. So, the most commonly used drugs are phenytoin, phosphenytoin, sodium valproate, leptoracetam and nowadays there is increasing evidence that even lacosamide upfront can be used. The doses are, phenytoin is given in a dose of 20 milligram per kg stat dose which is given generally over 30 minutes of phosphenytoin which is a pro drug of phenytoin. It is given in the dose of 20 milligram phosphoid phenytoin equivalents. The advantage with phosphenytoin is that it can be given faster in the sense up to 150 milligram per hour. It can be given. So, the total dose goes in say 5 to 10 minutes and the other advantage is that it causes less hypotension and less arrhythmia as compared to phenytoin. Sodium valproate is a broad spectrum anti-caesare medication which can be used in almost any kind of statosyplepticus. The maximum dose that we use is 40 milligram per kg ib bolus and the rate limiting is 10 milligram per minute. Placidam again a very safe drug. The maximum dose of around 60 milligram per kg ib can be used which has to be infused over 10 to 15 minutes. The dose of lacosamide is 400 milligram ib stat followed by the maintenance doses. Now, all these drugs in different trials have been found to be equally effective in controlling the seizures. Right. So, one challenging aspect of statosyplepticus is when it turns refractory. So, as per the practice and definitions, at what point do you call seizure as refractory? So, refractory statosyplepticus almost around 15 to 20 patients of statosyplepticus will turn into refractory statosyplepticus in the best of the centers. Now, it is defined as clinical or electrographic seizures that continue after the initial treatment of statosyplepticus, that is, it includes a short-acting benzodiazepine and one other non-siliting anti-seizure medication in appropriate doses. Normally, the time cutoff is 60 minutes. Now, how do we go about treating it? So, the management is slightly different as compared to statosyplepticus. We have to remember that whatever management we were giving for statosyplepticus that continues hand in hand. You got two options. One is we add one more anti-seizure medication. The trials have shown that it may not be very effective. Second is we straightaway go to IV anesthetic agents. Now, the IV anesthetic agents, the moment we decide to give IV anesthetic agents, the patient has to be mechanically ventilated. Then there has to be continuous EEG monitoring facility which has to be available and a neurologist should be involved in the care. The aim is to achieve burst suppression on EEG. So, I will not be going into the details of burst suppression. It is a very specialized field and it should be done under the care of a neurologist preferably. Now, the IV anesthetic agents that we are available are Medazolam, Popofol or Phenobarbonyl. So, Medazolam is given in the loop as a continuous infusion with a bolus of initial 0.2 milligram per kg bolus followed by a continuous IV infusion rate of 1 to 3 milligram per kg per hour. Popofol is given as a bolus initially of 1 to 2 milligram per kg loading dose followed by maximum dose of 20 micrograms per kg per minute infusion. Phenobarbonyl or the bar, or the barbonyl coma that is called commonly called as the initial IV bolus is 5 milligram per kg at a maximum rate of 50 milligram per minute. The infusion rate is 1 milligram per hour. Now, we can choose either of these three drugs practically most of the times we will be using Medazolam as it is number one short acting and it has got less metabolic complications as compared to the other two drugs. The aim is to achieve the burst suppression and seizure free interval of at least 24 hours after that we start slowly tapering off the drugs. Now, there are two scenarios possible after this either the seizures would be controlled or the seizures would not be controlled. In case the seizures are still recurring or there is an electrocardic electro graphic evidence of seizures on continuous EEG monitoring, we can interchange or we can shift over to the another anesthetic agent. So, and also what I understand is that the longer you take initiating treatment force it is epilepticus it is more likely to get refractory is that right? Yes sir. Okay. So, now there is another terminology called super refractory status epilepticus. So, how is it different from the garden variety of refractory status? Super refractory status epilepticus is a condition which is defined by continuous seizure activity beyond 24 hours of anesthetic treatment or recurrence of seizures within 24 hours of withdrawal of an anesthetic agent. So, it means that actually it is a continuum the status epilepticus refractory status epilepticus and the super refractory status epilepticus. The moment we find that beyond 24 hours of treatment of standard refractory status epilepticus the seizures are not being controlled or they have recurred once we have given a trial of weaning off from the anesthetic agent, we classify the condition as super refractory status epilepticus. Almost 10 to 15 percent of the patients of refractory status epilepticus will be ultimately going into the condition of super refractory status epilepticus. Now, how is it different from garden variety status epilepticus or refractory status epilepticus? First of all, the etiology is slightly different. Most of the times it is due to an acute severe brain injury or the second set of the individuals is other individuals what we call as nowadays NARS. So, NARS stands for new onset refractory status epilepticus. These patients they do not have any previous history of epilepsy. They may have a prodromal illness, may not have a prodromal illness and they suddenly go into a refractory status epilepticus. Most of the times it is caused by infections or encephalitis and one more important cause nowadays is an autoimmune encephalitis. In the best of the centers still 30 to 40 percent of them will not have any etiolus. So, we will not be able to classify them as either infectious or autoimmune. The prognosis is very bad almost 40 percent mortality is seen in such kind of cases. So, almost 30 to 40 percent of the cases of super refractory status epilepticus will not be able to find any etiology and add to it the prolonged hospital stay, the prolonged complications of hospital stay and high mortality. Right. So, how is the management of these super refractory cases different or do we have any newer options for them? One thing that we have to keep in mind is that as we are treating the patient, simultaneously we are also trying to find out the etiology of the stator septicus underlying etiology. So, in case we are able to find out an underlying etiology then we target the underlying etiology that is likely to control the seizures. In addition to the standard management of refractory stator septicus that is an IV anesthetic agent we add ketamine. So, ketamine has got a dual action it is known to have an additive effect along with propofol or metazole in preventing seizures. In addition to that we if the patient is of Norse and we are able to rule out with confidence that there is no underlying infection which is causing it, then we go in for immune therapy. Immune therapy in the form of pulse, high dose pulse steroids or we can consider them for plasma exchange or we can consider for them for intravenous immunoglobulin. In case we are able to find out any other treatable cause it is treat that cause or if on brain imaging we are able to find out a lesion which is likely to be seizureogenic or the focus of the seizures then we can take up them for receptive surgery as an emergent basis. In addition to that nowadays IV magnesium is also being used, the target is to maintain serum magnesium levels around 3.5 millimoles per liter but of course we have to monitor for magnesium toxicity. We can try induced hypothermia or sometimes electroclerosis therapy is also used. In addition to this nowadays paramphenyl it is an mpericeptor antagonist that is also being used in very high doses to treat the patients of course. If still we are not able to control these seizures we can go in for ketogenic diet also. Ketogenic diet is a high fat, low carbohydrate diet which induces ketosis which is known to suppress the seizures. The exact mechanism, the detailed mechanism is out of preview of this talk but these are a few things that we can try in case we are having a patient of super refractive status septicus and we should remember that we keep on continuing the anti-seizure medications that were there. We continue the general anesthesia agents that we are using and we do an add-on therapy to all this. So now with these kind of seizures which go on and are to control the landing into refractory or super refractory states what are the potential complications which are associated with them. So as I already said that there is a high morbidity and mortality associated with the super refractory or refractive status septicus. So these can be divided into two, one are the early systemic complications that occur because of the seizures per se. Then the complications which are related to the treatment because all this does that we are using none of them is completely safe they have got their own set of side effects or adverse effects and the third category would be complications of prolonged ICU care. So the early systemic complications include massive catecholamine release. So whenever there is a status septicus there is it is a hyperadrenergic state there are lots of catecholamines which are released which can lead to neurocardiogenic pulmonary manifestations or even renal injury in the form of myoglobinuria or nebdomylicis due to excessive muscle activity. The most common neurocardiogenic manifestation is tachosubocardium apathy which can occur due to myocardial stunning and occult arrhythmias which are occurring and they can go into renal shutdown due to rebdomylicis. Complications related to treatment with anesthetic agents they are specific to anesthetic agents and anticesial medicines as I said that arrhythmias and hypotension can occur with phenytoin and phosphenytoin, propofol can lead to propofol infusion syndrome. Mirazolam infusion can lead to respiratory diffusion it can lead to hypotension and phenobarbital has got its own complications it has got a prolonged duration of action so even if you stop it today the effect might be there for almost 24 hours because of its prolonged half life. In relation to this these patients they develop metabolic acidosis which may be severe metabolic acidosis depending on the seizure activity and complications of prolonged ICU care such as ventilator associated demonias then bed sores then infections due to central line access the CLABSI the catheteral lateral infections so the incidence is more in these patients. So we've covered status epilepticus and the refractory one super refractory status and understand that there is an emergency which needs to be managed effectively however as a chronic disease epilepsy management itself is a challenge and this is one field where we've had so many drugs from historically and then with newer drugs coming in and it's so important to understand these drugs because we often have to switch from one to another or probably add so to get into that aspect of this topic I just want you to tell us how do you decide the choice of the drug to be used as far as anti seizure medication is concerned and thereafter what do you go about continuing that. So epilepsy is one of the best neurological diseases to treat provided you know how to treat so first of all who all should be offered anti seizure medicine so it should be offered to every patient who has had more than one unprovoked or reflex seizure more than 24 hours apart or if he if he or she fits into a definitive epilepsy syndrome or the risk of subsequent seizures after the first episode is more than 60 percent when there is only one episode of seizure then during the initiation of anti seizure medicines we have to take in consideration the patient factors the risk the patient has and we also have to find out the type of seizures that the patient is having so what anti-epileptic to start so if we have once decided that say patient A has to be given anti seizure medicines then the next step is to actually identify the type of seizure that the patient is having whether the seizure is a focal seizure it is a generalized seizure or whether they are myoclonic seizures the reason being that the initial drug therapy for all the three is different and there are certain drugs which may be contraindicated in one particular kind of seizures so the patient factors that decide what anti seizure medicine has to be started are one is the seizure type or the epilepsy syndromes whether they are focal or generalized age of the patient gender of the patient any co-morbidities of the patient and if the patient is on any other medicines which may interact with the anti seizure medicines so the second thing is that we always start as a monotherapy so once we have decided that we have to give the patient has got say focal seizures then we always start as a monotherapy we escalate the dose slowly we reach the appropriate target and we maintain the dose and we explain the patient to cut down the variables which might be there in the sense that we should they should not switch over the brands or different manufacturers because the availability of the drug might be different in different preparations ideally we should be monitoring the drug levels if a patient is on anti seizure medicines if they are not available then we should at least ensure that the patient is consul for number one compliance to medicines and the other non pharmacological advices that have been given to him or her now there are a host number of there are a vast number of anti seizure medicines which are available earlier they were called as anti epileptic drugs so they can be divided broadly into two categories one are the older generation anti seizure medicines and the other ones are newer generation anti seizure medicines so the older generation anti seizure medicines included medicines such as phenobarbitone sodium dylantin sodium valproate carbonsapine and the newer generation anti seizure medicines they started with libiterazetam and now there are a host of lots of them such as Brevarazetam then acylcarbonsapine is there then lecosamide is there lemotrigine is there so there are certain advantages and disadvantages of both of this the main advantages of the newer generation are that they have got lesser drug to drug interactions they have got a better profile of adverse events and they have got possibly better compliance long term compliance the main disadvantages availability in the poor countries and affordability by the patients because they are actually cost one more aspect that we have to take into consideration is that there are certain drugs which are contraindicated in certain epilepsies such as sodium channel inhibitors they are contraindicated in myoclonic jerks or myoclonic seizures in fact they may precipitate them so drugs such as phenotone carmas being oxanose being they should be avoided in myoclonic epilepsies for focal epilepsies or focal seizures the first line drugs are carmasapine ox carmasapine phenotone then the second line would be say sodium valproate on the libiterazetam in cases of generalized seizures libiterazetam works very well sodium valproate works very well and their congeners they work very well so in nutshell sodium valproate is the broadest spectrum anti-epileptic anti-seizure medicine it can be used in almost any kind of epilepsy barring a few such as mitochondrial disorders phenotone is again a very commonly used drugs but we should remember that it should not be used in myoclonic epilepsy right so like we have the refractory status we also have situations in chronic epilepsy management that the patient is not responding to the treatment or continues to have breakthrough seizures so in such drug resistant states what are the alternatives that you have so if the patient is on monotherapy we generally go in for one more addition or one more drug but before that we have to ensure that the adequate compliance and adequate drug levels of the previous or the baseline drug should have been achieved then we add the drugs with multiple mechanisms for action so there are certain drugs that such as libiterazetam which have got multiple mechanism of actions and second thing that we have to take care that we should not act the drugs from the same class I mean you cannot act add past karma has been to karma has been because they are not going to have any synergistic action thus but we are trying to achieve is a super additive action or synergistic action of two different drugs one more thing that we should take care is that we should be aware of the drug drug interactions now anti-seizure medicines they also interact amongst themselves so if suppose if a patient is on sodium valcroate and you add sodium or phenytoin to it so phenytoin will cause displacement of sodium valcroate from the protein bound state and it will cause its increased levels so we have to be aware of these interactions also in case we are able to achieve drug free or seizure free state then we continue with whatever combination we have achieved the best or after that we can consider adding third agent also again we follow the same principles once the patient is refractory or the patient continues to have the recurrent breakthrough seizures on the on three first line anti-epileptic drugs then it is termed as refractory epilepsy or refractory seizures now the management is slightly different in these patients we try to find out the focus of seizures if we are able to find out the focus of seizures so these are the patients who need evaluation for epilepsy surgery now epilepsy surgery is best described for classical mesial temporal lobe epilepsy in this what we are trying to do is we are trying to do a resection of the focus of the seizures in the cortex so how do we look how do we localize the what area of the brain is causing the seizures to come so we need concordance we need and concordance on the EEG then the neuro imaging such as MRI brain or even we may have to do pet spec or sometimes we may have to do even an invasive invasive EEG monitoring to find out the exact focus of the seizures from which part of the cortex the seizures are originating once we have got the concordance of at least two factors then the patients may be taken up for reception or epilepsy surgery but it is a highly specialized field which should be done is generally done at centers of excellence and you need a highly dedicated team for that okay so now coming towards the end of this discussion a few things like when you manage patients in the outpatient for epilepsy what are the usual challenges that you face and I think one thing is of course patient adherence that you need to ensure the other thing that I want you to tell us also is what do you do when you are dealing with patients who are in the reproductive age group say when it comes to pregnancy which are the drugs which are safe so as we all know that adherence to medicine medications in any chronic illness it goes down as the you know the time from onset of the disease progresses especially in a disease like epilepsy which is an episodic disease it may occur today you may they may not have any seizure for next three to four months so the maintaining compliance especially in the adolescent age group is very different and most of these agents they have got functionally limiting side effects also so it is very important to educate the patient to educate the parents and I should also say that we have to educate their peers or even our society that epilepsy is a disease which is potentially treatable and maybe curable also there are lots of social stigma which are associated with the epilepsy I think we need to create an awareness regarding all those misconceptions which are there regarding epilepsy now the second thing is about the patients in the reproductive age group so as we discussed earlier that there are lots of patient factors which decide what kind of anti-seizure medicines have to be given to a particular patient age and the sex of the patient to these two important things now in the reproductive age group anti-seizure medicines which should not be given are sodium balkyrate phenytoin or even the phenobalkytoin the medicines which can be safely continued are left restatum in fact left restatum is probably the best drug which can be given to pregnant ladies more important than this is you know preconception counseling which should be there so whenever a patient who is newly married or they are planning or if he or she is under your follow-up especially she if she is under your follow-up and she is getting married then you should counsel them they should always come back to you if they are planning to start a family in case the patient is on a drug like say phenytoin or a sodium balkyrate they have to be stopped and they have to be changed over to a safer drug maybe left restatum in case they have already conceived then they have to be told about the risk factors associated with these medicines so heterogenicity is maximum during the first you know during the first time ester when the organogenesis takes place sodium balkyrate has the got the highest incidence of around 5 to 10 percent left restatum and certain newer anti-seizure medicines are probably safer but they are not completely safe also so regular monitoring of the fetus is required then you have to adjust the dose of the anti-seizure medicines also because in pregnancy the lot of pharmacokinetic changes might occur there is weight gain there is increase in plasma volume so the best thing best practice is to titrate the dose of anti-seizure medicines as per the serum levels but if they are not available as a guideline in the second trimester we generally increase the dose by 25 percent in the final trimester around 40 to 45 percent and we can come back to the baseline dose that around after one week of postpartum. Right that is very interesting and very informative thank you very much Manish I think this topic has been very comprehensively covered there is something that will be of academic relevance but also to the young specialists who keep seeing such patients in their output then they can make a difference. So thank you for your time and we will come back to you from the feedback that we received from our audience. Thank you sir. [Music]