The key to treating encephalitis is early detection and treatment. A child with encephalitis requires immediate hospitalization and close monitoring. Sometimes, depending on what doctors think the specific cause of the encephalitis is, certain medications can be used to fight infections that may cause it.
In this podcast, Dr. Stuart Tomko, MD, Washington University pediatric neurologist at St. Louis Children's Hospital, discusses Autoimmune Encephalitis and when to refer to a specialist.
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Autoimmune Encephalitis
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Learn more about Stuart Tomko, MD
Stuart Tomko, MD
Stuart Tomko, MD, is a Washington University pediatric neurologist at St. Louis Children’s Hospital.Learn more about Stuart Tomko, MD
Transcription:
Autoimmune Encephalitis
Melanie Cole (Host): Our topic today is autoimmune encephalitis. My guest is Dr. Stuart Tomko. He’s Washington University Pediatric Neurologist at St. Louis Children’s Hospital. Welcome to the show Dr. Tomko. So, let’s start with what is autoimmune encephalitis and how common is it?
Dr. Stuart Tomko, MD (Guest): Sure, thanks for having me. It’s great to have an opportunity to talk about this. So, autoimmune encephalitis is a condition similar to other autoimmune conditions in the body where the immune system essentially gets confused and instead of doing its normal job of fighting off infections, it instead turns and attacks the brain. So, in the most prototypical example of autoimmune encephalitis, anti-NMDA encephalitis, your body gets confused and your B-cells start producing antibodies and those antibodies bind to the NMDA receptors which are expressed on the surface of nerve cells and in so doing, those receptors are actually internalized into the nerve cell and so the brain kind of loses it’s ability to communicate normally between the different nerve cells and that gives rise to a whole host of problems. So, that’s one form of autoimmune encephalitis where it is actually the antibodies binding to the surface of the cells, binding to receptors that cause problems.
There is another related but slightly different form of autoimmune encephalitis that tends to be more associated with tumors and we see more in adults a paraneoplastic syndrome and so that’s an autoimmune encephalitis often associated with cancers like lung cancer or breast cancer and in that case, the antibodies are actually targeting proteins within the cell and it’s other parts of the immune system that cause problems so T-cells come in and damage the brain. And so those are the two kinds of most typical related but somewhat different kinds and in kids again, we more frequently see the type where it is the antibodies causing problems so like anti-NMDA.
It’s actually surprisingly common, so there was a study out of California a few years ago that looked at patients that presented with all different types of encephalitis, not specifically looking for any one type and they found that anti-NMDA encephalitis was up to four times more common than HSV encephalitis, West Nile Virus, VCV, so it’s more common in kids than some of these viruses that jump to our mind when we think of encephalitis. So, it is quite common.
Melanie: Wow, is this considered a new disease? Has it been around a while?
Dr. Tomko: It’s not new per se but we are learning more about it. So, the disease itself has been around for quite a while. It has gone by different names in the past. So, we didn’t always know it was an autoimmune condition so, it was described as a constellation of symptoms. We have learned more recently as we have discovered more antibodies, we found it is anti-NMDA, or anti-AMPA or these other targets of the antibodies. So, in the past, patients would come in with movement disorders and encephalitis and we would give them steroids and get better but not really understand why and now we are really trying to understand what’s causing the encephalitis and we have gotten a better understanding and so I think that’s why it’s getting better understood recently.
Melanie: So, what kind of doctors treat autoimmune encephalitis?
Dr. Tomko: It usually takes a team to treat autoimmune encephalitis and we have a great team here at Washington University and St. Louis Children’s Hospital. So, very frequently there is a neurologist involved. We are fortunate enough to have neuroimmunology team, so that is myself and another doctor here Soe Mar. So, we are neurologists that specialize in the immune system and specifically the interaction between the immune system and the brain. Very often our rheumatology colleagues get involved as well because they have such familiarity with autoimmune conditions and with some of the medications that we use to treat autoimmune encephalitis. We will frequently involve our neuropsychiatric team to help us understand how these conditions are impacting children’s ability to learn and function and kind of as they are improving; reintegrate into school and that sort of thing. A lot of these conditions are associated with seizures and epilepsy so, I actually also manage epilepsy and seizures but sometimes it will be bad enough that we will be starting to think about surgical interventions and that sort of thing, so we will have our epilepsy team involved occasionally as well.
Melanie: Well, it is a very multidisciplinary disease so, what’s the clinical presentation of autoimmune encephalitis?
Dr. Tomko: Sure, so I’m going to talk about the presentation of anti-NMDA encephalitis because that’s the most common type of autoimmune encephalitis and that’s what we have the best literature on. So, that’s what I will talk about here as an example of how autoimmune encephalitis can present.
So, most patients will have we call it prodrome, so they will have some headache, fever, nausea, vomiting, leading up to the more acute onset. Often that is diagnosed as a nonspecific viral illness or something like that. Frequently, within two weeks, some psychiatric or behavioral symptoms develop. So, in adults that can be things like delusions, mania, paranoia, anxiety. But in children of course, they can’t tell us that they are feeling manic or paranoid necessarily, so they will present with irritability, hyperactivity, temper tantrums, and then often have trouble with language, so difficulty speaking or repeating what people around them are saying. And then that can progress to alternating periods of agitation, decreased responsiveness and that is often when these patients will really come to medical attention because they look very altered at that time. Frequently a movement disorder or abnormal movements are part of this, so that can involve the face with bizarre facial movements or arm, leg movements and that sort of thing. And then it can progress to autonomic symptoms, so they can have really fast heart rate, slow heart rate, high blood pressure, problems maintaining their body temperature and that can be so severe that we will end up placing children in the ICU. Sometimes they will need to be intubated. Those symptoms can be quite severe.
The presentation is generally similar but differs a little bit across age groups. So, in the younger children, less than 12 years old; it’s the seizures, and the behavior symptoms that really predominate. That and movement disorders are kind of a triad that if you are seeing new onset seizures, new onset behavioral or psychiatric symptoms and a new movement disorder; really makes me think of anti-NMDA encephalitis. As patients get older, it’s more the behavioral and cognitive symptoms that start to predominate. So, those new onset psychiatric symptoms, or cognitive problems and often they will also have seizures, but it is more the behavioral and cognitive things. There are other conditions that present slightly differently than anti-NMDA, but generally one thing that really ties them together it is a subacute presentation. So, it’s a normal or relatively normal patient that presents over the course of a few weeks or maybe a month with this deterioration. So, it is not a patient that has had this going on for several years, usually it is something that has happened more in the acute or subacute time period.
Melanie: How important is the early diagnosis as being crucial to improve your outcome prediction? Tell us about some of your diagnostic tools and are there any complications if it is left untreated?
Dr. Tomko: So, early diagnosis is very important. There is a paper that came out a few years ago, that’s a pretty large paper looking at prognostic factors and outcome in anti-NMDA patients. And one of the factors that they found was that early diagnosis and treatment seemed to improve outcome. There is some indirect evidence that early more aggressive immunotherapy with things like Rituximab and other more specialized medications might also improve outcome. So, it is very important to have a high index of suspicion because the initial symptoms can be very nonspecific and to get the multidisciplinary team we discussed earlier involved so that you can get a neuroimmunologist and or rheumatologist thinking about doing some of these other medications.
Our workup’s pretty broad so things that almost all our patients will get is an MRI scan of the brain to look for any structural changes and in specifically anti-NMDA encephalitis about half of them have abnormalities on their MRI scan, so it doesn’t make or break the diagnosis either way. But it is helpful to rule out other causes. We will almost always do a lumbar puncture to look for signs of inflammation. So, we will send the stuff that we are used to sending like protein and glucose and cell count but also more specialized things like looking for oligoclonal bands and neopterin which is a nonspecific marker of inflammation. Another crucial aspect of the workup are panels. So, I send it to the Mayo laboratory and they have an autoimmune encephalopathy panel that has many antibodies on it and I will send that from the serum and from the spinal fluid.
Thinking of anti-NMDA, the serum is actually about 85% sensitive and the spinal fluid is thought to be 100%. It is the gold standard. So, I will usually send it from both. But if you are really concerned we would want to do a lumbar puncture. We will usually get an EEG. A lot of these patients will have seizures and the vast majority will have some abnormality on their EEG, so that can help us with the diagnosis and make sure we are not missing seizures or something else treatable. And then we will frequently do an infectious workup with it because in the acute presentation; as a sick kid coming in with seizures and encephalopathy; it’s not always clear if that’s due to an autoimmune process or an infectious process. So, we will send antibodies for infections like mycoplasma, we will send PCRs, viral PCRs from the CSF and that sort of thing to rule out infections which becomes very important as we are thinking about giving immunotherapy. Because we wouldn’t want to give a patient immunotherapy if there is an active infection.
Melanie: So, what else would a referring pediatrician want to know about this condition? What would you like people to know about treatment and long-term treatment and in looking forward to the next ten years in this field?
Dr. Tomko: So, I think one thing as we kind of mentioned earlier is that high index of suspicion. So, if you have a patient that is presenting with new onset seizures, and new psychiatric symptoms and maybe some movements or anything like that; it’s important to get them to somewhere that can do the full evaluation and consider the lumbar puncture and the EEG and MRI and that sort of thing and has familiarity with these conditions because as we said, the early treatment is important for outcome.
In anti-NMDA specifically, most patients do get better. So, up to 81% of patients will improve over the first two years of therapy. That’s because once we get rid of the antibodies the NMDA receptors repopulate the surface of the neuronal cells and the brain starts to talk normally to itself again. That Is not the case for some other conditions so the ones like the associated with cancer, the paraneoplastic encephalidities. Those often have T-cell mediated damage to the brain. So, even once we get rid of the antibody, those kids might not improve as much. But the antibodies against the surface antigens, those patients do tend to improve.
So, up to 12% might have a relapse and the rate of relapse is actually higher if you do not have a tumor. The thinking there being that if you have a tumor and remove it, then you remove the inciting agent where if it is just idiopathic occurring without a tumor; it is more likely to happen again. That’s been called into question recently if the tumor is really that important in relapse, but that is out there in the literature. Once you have a relapse; you are increased risk of having further relapses.
So practically how that looks is when a patient comes in we will treat them very aggressively up front. So, we will often do IV steroids, IVIG, Rituximab which is a engineered antibody that binds to and kills all the B-cells in the body. So, we give it and then all the B-cells are dead for usually around six months. So, that kind of gives the immune system a chance to reset itself. If those don’t work, we move on to more aggressive immunotherapy things like Cytoxan which was actually developed as a chemotherapy agent. We will give that because that’s very good at aggressively shutting down the immune system and then the role of long-term immunotherapy is actually still being figured out a little bit. So, some providers out there will re-dose Rituximab and make sure al the B-cells are killed for a year or so. Some providers will give the Rituximab, give the IV steroids and watch the B-cells come back over time and assess the patient for a relapse or for worsening as the B-cells repopulate and may decide for further treatment based on the clinical course. Other things that people have done is use oral immunotherapy, so given medications like CellCept for a year or two to try to give the immune system time to recover.
And so, the shot-term treatment has been fairly standardized, but the long-term treatment; there is still ongoing research and ongoing debate about what the best way to do long-term treatment is. We often see as kids are getting better that they have as one might expect, issues returning to school and with academic functioning and that sort of thing. Sometimes seizures remain a problem and we have to keep treating them with anti-seizure medications. Some patients will continue to have movement problems or that something along those lines after they improve so, there are long-term issues that these patients face but again, the nice thing is these patients can look very, very, very sick, intubated in the ICU and people are very concerned about their long-term prognosis but in anti-NMDA; most patients actually do fairly well over time.
Melanie: Thank you so much. What an interesting topic Dr. Tomko. Thanks for being with us today. A physician can refer a patient by calling Children’s Direct Physician Access Line at 1-800-678-HELP. That’s 1-800-678-4357. You’re listening to Radio Rounds with St. Louis Children’s Hospital. For more information on resources available at St. Louis Children’s Hospital you can go to www.stlouischildrens.org , that’s www.stlouischildrens.org. This is Melanie Cole. Thanks so much for tuning in.
Autoimmune Encephalitis
Melanie Cole (Host): Our topic today is autoimmune encephalitis. My guest is Dr. Stuart Tomko. He’s Washington University Pediatric Neurologist at St. Louis Children’s Hospital. Welcome to the show Dr. Tomko. So, let’s start with what is autoimmune encephalitis and how common is it?
Dr. Stuart Tomko, MD (Guest): Sure, thanks for having me. It’s great to have an opportunity to talk about this. So, autoimmune encephalitis is a condition similar to other autoimmune conditions in the body where the immune system essentially gets confused and instead of doing its normal job of fighting off infections, it instead turns and attacks the brain. So, in the most prototypical example of autoimmune encephalitis, anti-NMDA encephalitis, your body gets confused and your B-cells start producing antibodies and those antibodies bind to the NMDA receptors which are expressed on the surface of nerve cells and in so doing, those receptors are actually internalized into the nerve cell and so the brain kind of loses it’s ability to communicate normally between the different nerve cells and that gives rise to a whole host of problems. So, that’s one form of autoimmune encephalitis where it is actually the antibodies binding to the surface of the cells, binding to receptors that cause problems.
There is another related but slightly different form of autoimmune encephalitis that tends to be more associated with tumors and we see more in adults a paraneoplastic syndrome and so that’s an autoimmune encephalitis often associated with cancers like lung cancer or breast cancer and in that case, the antibodies are actually targeting proteins within the cell and it’s other parts of the immune system that cause problems so T-cells come in and damage the brain. And so those are the two kinds of most typical related but somewhat different kinds and in kids again, we more frequently see the type where it is the antibodies causing problems so like anti-NMDA.
It’s actually surprisingly common, so there was a study out of California a few years ago that looked at patients that presented with all different types of encephalitis, not specifically looking for any one type and they found that anti-NMDA encephalitis was up to four times more common than HSV encephalitis, West Nile Virus, VCV, so it’s more common in kids than some of these viruses that jump to our mind when we think of encephalitis. So, it is quite common.
Melanie: Wow, is this considered a new disease? Has it been around a while?
Dr. Tomko: It’s not new per se but we are learning more about it. So, the disease itself has been around for quite a while. It has gone by different names in the past. So, we didn’t always know it was an autoimmune condition so, it was described as a constellation of symptoms. We have learned more recently as we have discovered more antibodies, we found it is anti-NMDA, or anti-AMPA or these other targets of the antibodies. So, in the past, patients would come in with movement disorders and encephalitis and we would give them steroids and get better but not really understand why and now we are really trying to understand what’s causing the encephalitis and we have gotten a better understanding and so I think that’s why it’s getting better understood recently.
Melanie: So, what kind of doctors treat autoimmune encephalitis?
Dr. Tomko: It usually takes a team to treat autoimmune encephalitis and we have a great team here at Washington University and St. Louis Children’s Hospital. So, very frequently there is a neurologist involved. We are fortunate enough to have neuroimmunology team, so that is myself and another doctor here Soe Mar. So, we are neurologists that specialize in the immune system and specifically the interaction between the immune system and the brain. Very often our rheumatology colleagues get involved as well because they have such familiarity with autoimmune conditions and with some of the medications that we use to treat autoimmune encephalitis. We will frequently involve our neuropsychiatric team to help us understand how these conditions are impacting children’s ability to learn and function and kind of as they are improving; reintegrate into school and that sort of thing. A lot of these conditions are associated with seizures and epilepsy so, I actually also manage epilepsy and seizures but sometimes it will be bad enough that we will be starting to think about surgical interventions and that sort of thing, so we will have our epilepsy team involved occasionally as well.
Melanie: Well, it is a very multidisciplinary disease so, what’s the clinical presentation of autoimmune encephalitis?
Dr. Tomko: Sure, so I’m going to talk about the presentation of anti-NMDA encephalitis because that’s the most common type of autoimmune encephalitis and that’s what we have the best literature on. So, that’s what I will talk about here as an example of how autoimmune encephalitis can present.
So, most patients will have we call it prodrome, so they will have some headache, fever, nausea, vomiting, leading up to the more acute onset. Often that is diagnosed as a nonspecific viral illness or something like that. Frequently, within two weeks, some psychiatric or behavioral symptoms develop. So, in adults that can be things like delusions, mania, paranoia, anxiety. But in children of course, they can’t tell us that they are feeling manic or paranoid necessarily, so they will present with irritability, hyperactivity, temper tantrums, and then often have trouble with language, so difficulty speaking or repeating what people around them are saying. And then that can progress to alternating periods of agitation, decreased responsiveness and that is often when these patients will really come to medical attention because they look very altered at that time. Frequently a movement disorder or abnormal movements are part of this, so that can involve the face with bizarre facial movements or arm, leg movements and that sort of thing. And then it can progress to autonomic symptoms, so they can have really fast heart rate, slow heart rate, high blood pressure, problems maintaining their body temperature and that can be so severe that we will end up placing children in the ICU. Sometimes they will need to be intubated. Those symptoms can be quite severe.
The presentation is generally similar but differs a little bit across age groups. So, in the younger children, less than 12 years old; it’s the seizures, and the behavior symptoms that really predominate. That and movement disorders are kind of a triad that if you are seeing new onset seizures, new onset behavioral or psychiatric symptoms and a new movement disorder; really makes me think of anti-NMDA encephalitis. As patients get older, it’s more the behavioral and cognitive symptoms that start to predominate. So, those new onset psychiatric symptoms, or cognitive problems and often they will also have seizures, but it is more the behavioral and cognitive things. There are other conditions that present slightly differently than anti-NMDA, but generally one thing that really ties them together it is a subacute presentation. So, it’s a normal or relatively normal patient that presents over the course of a few weeks or maybe a month with this deterioration. So, it is not a patient that has had this going on for several years, usually it is something that has happened more in the acute or subacute time period.
Melanie: How important is the early diagnosis as being crucial to improve your outcome prediction? Tell us about some of your diagnostic tools and are there any complications if it is left untreated?
Dr. Tomko: So, early diagnosis is very important. There is a paper that came out a few years ago, that’s a pretty large paper looking at prognostic factors and outcome in anti-NMDA patients. And one of the factors that they found was that early diagnosis and treatment seemed to improve outcome. There is some indirect evidence that early more aggressive immunotherapy with things like Rituximab and other more specialized medications might also improve outcome. So, it is very important to have a high index of suspicion because the initial symptoms can be very nonspecific and to get the multidisciplinary team we discussed earlier involved so that you can get a neuroimmunologist and or rheumatologist thinking about doing some of these other medications.
Our workup’s pretty broad so things that almost all our patients will get is an MRI scan of the brain to look for any structural changes and in specifically anti-NMDA encephalitis about half of them have abnormalities on their MRI scan, so it doesn’t make or break the diagnosis either way. But it is helpful to rule out other causes. We will almost always do a lumbar puncture to look for signs of inflammation. So, we will send the stuff that we are used to sending like protein and glucose and cell count but also more specialized things like looking for oligoclonal bands and neopterin which is a nonspecific marker of inflammation. Another crucial aspect of the workup are panels. So, I send it to the Mayo laboratory and they have an autoimmune encephalopathy panel that has many antibodies on it and I will send that from the serum and from the spinal fluid.
Thinking of anti-NMDA, the serum is actually about 85% sensitive and the spinal fluid is thought to be 100%. It is the gold standard. So, I will usually send it from both. But if you are really concerned we would want to do a lumbar puncture. We will usually get an EEG. A lot of these patients will have seizures and the vast majority will have some abnormality on their EEG, so that can help us with the diagnosis and make sure we are not missing seizures or something else treatable. And then we will frequently do an infectious workup with it because in the acute presentation; as a sick kid coming in with seizures and encephalopathy; it’s not always clear if that’s due to an autoimmune process or an infectious process. So, we will send antibodies for infections like mycoplasma, we will send PCRs, viral PCRs from the CSF and that sort of thing to rule out infections which becomes very important as we are thinking about giving immunotherapy. Because we wouldn’t want to give a patient immunotherapy if there is an active infection.
Melanie: So, what else would a referring pediatrician want to know about this condition? What would you like people to know about treatment and long-term treatment and in looking forward to the next ten years in this field?
Dr. Tomko: So, I think one thing as we kind of mentioned earlier is that high index of suspicion. So, if you have a patient that is presenting with new onset seizures, and new psychiatric symptoms and maybe some movements or anything like that; it’s important to get them to somewhere that can do the full evaluation and consider the lumbar puncture and the EEG and MRI and that sort of thing and has familiarity with these conditions because as we said, the early treatment is important for outcome.
In anti-NMDA specifically, most patients do get better. So, up to 81% of patients will improve over the first two years of therapy. That’s because once we get rid of the antibodies the NMDA receptors repopulate the surface of the neuronal cells and the brain starts to talk normally to itself again. That Is not the case for some other conditions so the ones like the associated with cancer, the paraneoplastic encephalidities. Those often have T-cell mediated damage to the brain. So, even once we get rid of the antibody, those kids might not improve as much. But the antibodies against the surface antigens, those patients do tend to improve.
So, up to 12% might have a relapse and the rate of relapse is actually higher if you do not have a tumor. The thinking there being that if you have a tumor and remove it, then you remove the inciting agent where if it is just idiopathic occurring without a tumor; it is more likely to happen again. That’s been called into question recently if the tumor is really that important in relapse, but that is out there in the literature. Once you have a relapse; you are increased risk of having further relapses.
So practically how that looks is when a patient comes in we will treat them very aggressively up front. So, we will often do IV steroids, IVIG, Rituximab which is a engineered antibody that binds to and kills all the B-cells in the body. So, we give it and then all the B-cells are dead for usually around six months. So, that kind of gives the immune system a chance to reset itself. If those don’t work, we move on to more aggressive immunotherapy things like Cytoxan which was actually developed as a chemotherapy agent. We will give that because that’s very good at aggressively shutting down the immune system and then the role of long-term immunotherapy is actually still being figured out a little bit. So, some providers out there will re-dose Rituximab and make sure al the B-cells are killed for a year or so. Some providers will give the Rituximab, give the IV steroids and watch the B-cells come back over time and assess the patient for a relapse or for worsening as the B-cells repopulate and may decide for further treatment based on the clinical course. Other things that people have done is use oral immunotherapy, so given medications like CellCept for a year or two to try to give the immune system time to recover.
And so, the shot-term treatment has been fairly standardized, but the long-term treatment; there is still ongoing research and ongoing debate about what the best way to do long-term treatment is. We often see as kids are getting better that they have as one might expect, issues returning to school and with academic functioning and that sort of thing. Sometimes seizures remain a problem and we have to keep treating them with anti-seizure medications. Some patients will continue to have movement problems or that something along those lines after they improve so, there are long-term issues that these patients face but again, the nice thing is these patients can look very, very, very sick, intubated in the ICU and people are very concerned about their long-term prognosis but in anti-NMDA; most patients actually do fairly well over time.
Melanie: Thank you so much. What an interesting topic Dr. Tomko. Thanks for being with us today. A physician can refer a patient by calling Children’s Direct Physician Access Line at 1-800-678-HELP. That’s 1-800-678-4357. You’re listening to Radio Rounds with St. Louis Children’s Hospital. For more information on resources available at St. Louis Children’s Hospital you can go to www.stlouischildrens.org , that’s www.stlouischildrens.org. This is Melanie Cole. Thanks so much for tuning in.