Good afternoon, and welcome to Part 2 of Infections, Inflammatory CNS Conditions. My name is Casey Ulm-Shipman, and I am at the University of North Carolina where I am a neurointensivist. I also take care of children with neurocritical care disease conditions, and I'm excited to be here with you today. I have no financial disclosures. The learning objectives for today's presentation are that we're going to describe the criteria and the differential for autoimmune encephalitis. We'll also be reviewing the lab and radiographic features of some of the more common autoimmune encephalitis syndromes. And then finally, we're going to be going over the diagnostic criteria and spectrum of presentation of fulminant demyelinating diseases. So autoimmune encephalitis is a large category of disease conditions, and the most common cause of autoimmune encephalitis is due to an infectious etiology. And in today's talk, we're actually going to be focusing on the noninfectious or parainfectious causes of encephalitis. So those include encephalitis that are antibody-mediated, systemic autoimmune, ADEM, NMO, multiple sclerosis, and some of the other fulminant demyelinating disease conditions. When you are working up a patient who may have autoimmune encephalitis, some of the differential diagnoses that are important to consider include seizures that may have been prolonged and refractory and cause vasogenic edema, gliomas, and then vasculitis. And there is perhaps more overlap between vasculitis and autoimmune encephalitis as some of the vasculitides are autoimmune-mediated. And so those are just important to keep in mind and have on the differential, especially if vascular imaging is concerning. And just a few of those are listed here for your reference. Criteria for possible autoimmune encephalitis has been proposed by Grouse and Dalmo in their 2016 Lancet Neurology paper, and they proposed three main criteria that need to be met in order to consider something a possible autoimmune encephalitis. And those are, number one, it should be a subacute onset, so rapid progression, less than three months, oftentimes accompanied by short-term memory loss or psychiatric symptoms. And then at least one of the following, having new focal CNS symptoms, seizures that aren't previously known, CSF, pleocytosis, and if there are abnormalities on the MRI that would suggest an encephalitis. And then of course, excluding other alternative causes, and as we know, anyone who has taken care of these patients, sometimes the workup can be quite expansive for these patients. So we'll start out by talking about some of the core features of antibody-mediated encephalitis. So in these disorders, antibodies are attacking neuronal cell surface proteins, ion channels or receptors, and neurological symptoms predominate. Oftentimes these disorders are preceded by a prodromal syndrome. So patients or family members will describe an ill-defined viral syndrome that preceded some of the neurological symptoms. Notably, these antibody-mediated encephalitis can occur at any age, ranging from very young children to the elderly. And finally, the etiology is varied. Some of these are associated with tumors, but not all. They can occur as a post-viral autoimmune infectious syndrome, and then the majority of causes are idiopathic. Neuropsychiatric symptoms are a hallmark of antibody-mediated encephalitis, and these may include behavioral disturbances, psychosis, seizures, abnormal movements, cognitive impairment, or declines in level of consciousness. Many of the antibody-mediated encephalitis may be accompanied by dysautonomia. One example of this where it's quite commonly seen is an NMDA, receptor autoimmune encephalitis. Some of the typical dysautonomia symptoms include hypersalivation, hyperthermia, wide labile swings in blood pressure or heart rate, and respiratory patterns. So what you will see on this slide and the following is a table delineating the different types of antibody-mediated encephalitis and some of their clinical features by antibody. I will say that things are organized here in order of how common these are. So the most common encephalitis are NMDA receptor encephalitis and LGI-1. What you will see is that there's a wide range of ages that can be affected. Some of these are more commonly seen in children or young adults. That's very notable for NMDA receptor encephalitis. And then the MRI findings can range quite a bit. Some of the disease conditions, they typically tend to have normal findings or nonspecific findings on MRI. And then some of them, if there are going to be abnormal findings, oftentimes follow a pattern of what you would see with a limbic encephalitis, so hyperintensities of either the bilateral or unilateral medial temporal lobes. And then as far as the cancer associations, again, antibody-mediated encephalitis are sometimes associated with cancer, but sometimes it's actually quite rare or not associated at all. And this slide is a continuation of that table. I would point out on this table that the main clinical features are certainly not unique to any one particular condition, meaning that there can be quite a bit of overlap in some of the symptoms that you might see in a patient presenting with an antibody-mediated encephalitis. But these are some of the more common symptoms that are associated with that particular antibody. So let's take a moment to discuss the difference between classical perineoplastic disorders versus antibody-mediated encephalitis. So first, it's important to recognize that there is some overlap here where antibody-mediated encephalitis can be associated with tumors and hence would be considered a perineoplastic syndrome, but not all of them are, and many of them aren't. So perineoplastic disorders almost always occur in adults, and more specifically, older adults, whereas antibody-mediated encephalitis can occur in children and adults. So there's a very wide age range with the autoimmune antibody-mediated encephalitis. Also, perineoplastic disorders usually are involving a T-cell immune response to intracellular proteins that are in the central nervous system and peripheral nervous system, whereas for autoimmune antibody-mediated encephalitis, it is an antibody targeting neuronal cell surface proteins, ion channels, or receptors that are on the surface. And then finally, of course, perineoplastic disorders are associated with tumors, and that is not always the case with the autoimmune antibody-mediated encephalitis. So we're going to go over a couple of cases involving antibody-mediated encephalitis, and the first case we'll review is kind of a classic presentation of NMDA receptor encephalitis. So in this case, a 20-year-old female college student presents with two weeks of irritability and increased agitation and inability to sleep. And about one week prior to her presentation, she had developed hallucinations, and she seemed very paranoid, according to her roommate. So she was brought to the emergency room, admitted to inpatient psychiatry for evaluation of acute psychosis, and her initial workup was unrevealing. Her basic labs were within normal, and her toxicology screen was negative. Then on hospital day two, she sustained a prolonged generalized tonic-clonic seizure and ultimately required intubation due to status epilepticus. And this is a young woman who is an outstanding student, and her family says that she's overall been very healthy, there's no real significant past medical history. They do recall that she had kind of complained of bad flu-like symptoms about two months ago during winter break, but she seemed just, you know, really tired, febrile, but nothing too concerning, and ultimately she seemed to recover from it just fine. Okay, so now we're going to break this case down and examine it according to some key features that are commonly associated with NMDA encephalitis. In terms of the most common finding that you see on MRI, in the majority of cases the MRI will actually appear normal. In about 30% of patients, you may find some nonspecific flare, hyperintensities, and those can be cortical, subcortical, or cerebellar in location. Okay, so let's review what you might expect to find in the CSF profile. So for NMDA receptor encephalitis, as well as other antibody-mediated autoimmune encephalitis, usually there is only a mild to moderate pleocytosis, so less than 100 cells. And the CSF profile may, in fact, be normal without any elevation in white count. There is sometimes an association with elevated IgG index or oligoclonal bands, and that occurs in about 50% of cases. So in terms of laboratory testing to confirm the diagnosis, it's really important to send CSF antibody panels. Serum testing can yield false negative results in over 10% of cases, and so this is why you can miss the diagnosis if you only send a serum panel. And the CSF antibody panel, of course, in this case, would demonstrate an NMDA antibody. The tumor that's most commonly associated with NMDA receptor antibody-mediated encephalitis is ovarian teratoma in women, and so it's very important that you evaluate for this with a transvaginal ultrasound or other imaging modality. In males and children, the association with malignancy is less common than it is for young women. With regard to the EEG finding that can be seen in NMDA receptor encephalitis, in adults who are comatose, you can see what is called an extreme delta brush pattern. This can also be seen in neonates, just normal neonates having this pattern. This is an abnormal pattern, though, to see in adults, and you'll see in the red circles, you can see just kind of overall very slow waves, but superimposed on that is the extreme delta brush. Interestingly, about 20% of patients who have HSV encephalitis will later develop NMDAR antibodies. Now, just because they develop these antibodies does not mean they actually develop a clinical syndrome consistent with an autoimmune encephalitis. Many other viruses have also been implicated in a post-infectious autoimmune encephalitis syndrome, and VZB is one of these, as well as multiple other viruses. Let's now review a case of LGI1 encephalitis, which, as you recall from the table, is one of the more common autoimmune-mediated encephalitides. In this case, we have a 70-year-old man who presents with a past medical history of hypertension and type 2 diabetes, who has about a two-week prodrome of dizzy spells and confusion. It's gotten to the point that he's had to quit working as an accountant due to his memory problems. His wife also notes that in the week prior to admission, she's noticed twitching movements of his face, and that's what finally provoked him to come into the emergency room, such that he had near-continuous twitching of the face and arm. His initial labs are also notable for a sodium of 123. So let's also break this case down by some key features and work through each question in order. Okay, we'll start off by reviewing the classic clinical symptoms of LGI1. This is a bit of a trick question because, really, there aren't pathognomonic features, and it's important to recognize that there are many overlapping symptoms across these autoimmune-mediated encephalitides. However, with LGI1 encephalitis, kind of the textbook features include facial brachial dystonic seizures, memory loss, and hyponatremia, and hyponatremia is present in about 65% of patients on admission. LGI1 is a limbic encephalitis, and sometimes the MRI can be completely normal, although, again, in a classic textbook case, you might see bilateral T2 flare, temporal hyperintensities. Less commonly, they can be unilateral. Sometimes they will enhance as well. In terms of what laboratory tests should be obtained to confirm the diagnosis, it's important, as with many of these autoimmune-mediated encephalitides, to send both CSF and serum autoimmune panels as the antibodies may be detectable in only the CSF or only the serum and not necessarily both. With regard to what tumor is most commonly associated with LGI1, this is another somewhat trick question in that most of the time, LGI1 is not associated with a tumor. However, if there is an underlying tumor, thymoma tends to be more commonly identified in about 5% of cases. Let's take a moment now and review some of the therapies for antibody-mediated encephalitis. First, it's important to recognize that most of these recommendations are based on retrospective data and expert opinion, and we really don't have a high level of evidence to support these therapies. The mainstay of treatment is immunotherapy, which can consist of glucocorticoids, IVIG, or plasma exchange. If symptoms are refractory, you might consider rituximab or cyclophosphamide. Then, very importantly, if there is an associated tumor that is producing the autoimmune encephalitis, it's very important that this be diagnosed and treated as early diagnosis and treatment may portend a better outcome. Remember that if you are facing a case where there is relapsing symptoms of encephalitis, even if the first workup was negative for a tumor, it may be worth pursuing a second workup for a tumor, so re-imaging the patient to make sure that a tumor wasn't missed in the first go-round. All right, so now we're going to switch gears and review some of the key features of fulminant demyelinating diseases affecting the CNS, and we'll hit just the high points here for the purposes of board review. Let's start out by reviewing some classic imaging findings that may be associated with some of these key fulminant demyelinating diseases. Over here on the left, this is an example of neuromyelitis opticum. What you can see in the brain here is this demyelinating lesion involving the brain stem, and really demyelinating lesions can be anywhere throughout the brain, very commonly involving the optic nerves in an MO, and then one of the classic hallmarks of this disorder is longitudinal segments of demyelination extending across several spinal cord levels, so you can see that here in this panel where you see these T2 hyperintensities affecting the cervical and thoracic spine. Over here on the right panel is an example of ADEM in which we see these classic, fluffy demyelinating lesions that are bi-hemispheric and that are involving white matter as well as gray matter. Okay, so let's focus on a couple more examples of fulminant demyelinating diseases. Here on the left panel, you can see an example of tumifactive multiple sclerosis, and the characteristic radiographic feature of this is that you can see this mass-like lesion with surrounding vasogenic edema as well as midline shift exerted by the mass. And then here on the right panel is an example of balose concentric sclerosis, and the classic radiographic hallmark finding is this onion-wringing appearance representing the demyelination. So on the next three slides, you will see a table delineating different fulminant demyelinating disease conditions and some of their classic clinical imaging and pathology features. We won't spend time today going over those in great detail, but this table is here mostly as a reference and resource for studying for the board exam. Again, this is just more of this table, and I will point out the tumifactive MS tends to affect younger adults, and people may present with this not having been diagnosed with multiple sclerosis in the past. So sometimes the initial presentation can be quite fulminant. This is the final slide of the table, and I will just point out here a little bit on neuromyelitis optica spectrum disorder. So this tends to affect adults in the third and fourth decades and is classically associated with an optic neuritis and longitudinally extensive transverse myelitis, and it tends to be relapsing in most cases. One of the other things that I think is important to note and draw special attention to is that this is strongly associated with aquaphorin for IgG antibodies in the serum. So in working up these patients, that is the antibody that is important to test for. All right, let's spend a little bit of time diving into ADEM, or acute disseminated encephalomyelitis. So this is commonly a monophasic illness. It tends to affect children and adults who are younger than 40 years old, and most commonly adolescents or younger, and it's about one-to-one ratio between male and female. The symptoms can be quite varied in terms of the neurologic deficits and present with any of the symptoms listed here, and oftentimes it's preceded by an acute systemic infection, whether that's viral bacteria or a vaccination. In reviewing the diagnostic criteria for ADEM, these are derived from the International Pediatric MS Study Group, and if all five criteria are met, this is considered definite ADEM. So first of all, there needs to be a first multifocal clinical CNS event that's due to a presumed inflammatory cause. There needs to be encephalopathy that's not explained by fever alone. There needs to be an abnormal brain MRI, and again, there can be abnormalities that involve gray matter or white matter. And then no new clinical or MRI findings after three months of the initial index presentation. And finally, exclusion of other alternative causes. Okay, so let's review a case of a nine-year-old male who's presenting with subacute effusion, confusion, difficulty walking, and high fever. So his parents report that about a week prior to admission, he developed a severe headache as well as a viral prodrome characterized by runny nose, cough, shortness of breath, vomiting, and fever. And on his exam in the ED, he's noted to be disoriented. He has dysmetria on fingernails, finger testing, and he's unable to stand. He's febrile to 102.4, and in the ED, he has a witness-generalized tonic-clonic seizure that is treated with Ativan. So in this case, we're going to review the characteristic findings on brain MRI as well as what the CSF profile would demonstrate and also what antibody is present in almost 50% of these cases. So again, the very classic finding on MRI are large, diffuse, multiple, fluffy lesions that involve the white matter as well as the deep gray matter and can also involve the cerebellum and spinal cord. So the antibody that's present in almost 50% of cases in children and very frequently in adults as well who have ADEM is myelin oligodendrocyte glycoprotein or MOG. And this is something that has also been associated with NMO as well as other demyelinating disease conditions. So certainly, it may be something in your armament of studies that you send if you are working up a patient who presents with an unknown etiology of their encephalopathy and has white matter abnormalities. The therapy for ADEM is similar to what the therapy is for autoimmune-mediated encephalitis and includes some combination of glucocorticoids, IVIG, or plasma exchange. And usually, the first line is steroids and then if there is an inadequate response, moving on to IVIG or plasma exchange. And then if there are refractory cases or it's relapsing ADEM, utilizing cyclophosphamide or rituximab. In terms of the prognosis, patients usually recover within days to weeks and most will have a complete or near-complete recovery with a few having some persistent cognitive and neurologic deficits. It's very rarely fatal in the modern era with improved critical care. However, it is probably good to be aware of a variant, acute hemorrhagic glucoencephalitis, which is very severe and fulminant that's associated with rapid deterioration as well as cerebral edema and hemorrhage and oftentimes brain herniation. This now concludes the end of our section on neuroinfectious part two. I'm glad we could review this today and thank you for taking the time. And if you have additional questions, please reach out and I would be happy to answer those. Good luck on your board exam. Take care.

autoimmune encephalitis

fulminant demyelinating diseases

antibodies

NMDA receptor encephalitis

LGI1 encephalitis

acute disseminated encephalomyelitis