Imagine you’re a bright twenty-something with a new job and a new relationship. Everything seems to be going your way until you start becoming paranoid and acting erratically. Then come the hallucinations and seizures. You’re admitted to a hospital where you’re (incorrectly) diagnosed with a psychiatric disorder. You swing from violence into a state of immobility and stupor. And perhaps even scarier? You don’t remember any of it. Sound like a nightmare? Well, it actually happened to Susannah Calahan, who details her terrifying story first-hand in her 2012 book Brain on Fire: My Month of Madness.
What caused these frightening symptoms? The answer was a disease that had only been discovered a few years earlier (right here at Penn!): NMDAR encephalitis. There are four main phases of the disorder. In the prodromal phase, many but not all patients experience a flu-like illness for up to 3 weeks. The psychotic phase is accompanied by delusions, auditory and visual hallucinations, depression, paranoia, agitation, and insomnia. At this stage, most patients are taken to the hospital, where around 40% are misdiagnosed as having a psychiatric disorder like schizophrenia. As this phase progresses, seizures are very common (although they can occur at any time throughout the illness), as well as involuntary muscle movements like lip-smacking or grimacing, catatonia (muscular rigidity and mental stupor), impaired attention, and memory loss. The next phase is unresponsiveness, which includes symptoms like the inability to speak, loss of voluntary movement, and sometimes abnormal muscle contractions that cause involuntary writhing movements. The last phase is the hyperkinetic phase and is characterized by instability of involuntary bodily functions such as breathing, blood pressure, heartbeat, and temperature. Many patients who breathe too slowly often need to be placed on a ventilator at this stage. The decline to ventilator support can progress very rapidly after several weeks in the psychotic stage, and ultimately patients can be hospitalized for several months with the disease1–3.
What does NMDAR encephalitis actually mean? This disease is an autoimmune disorder, meaning the body’s immune system mistakenly attacks its own healthy cells. Normally the body identifies foreign substances by making something called an antibody that recognizes a unique part of the invader, thus targeting it for attack and destruction. In NMDA encephalitis though, the immune system attacks the brain (that’s where to term encephalitis comes from), specifically a type of neurotransmitter receptor called an NMDA receptor (NMDAR). These receptors bind the neurotransmitter glutamate, and play an important role in learning, memory, cognition, and behavior. In fact, the symptoms of NMDAR encephalitis resemble those caused by drugs such as ketamine or PCP that prevent the activation of NMDARs. For instance, at low doses ketamine and PCP cause paranoia, false perceptions, and impaired attention (like the early stages of NMDAR encephalitis), and at higher doses these drugs cause psychosis, agitation, memory and motor disturbances, and eventually unresponsiveness, catatonia, and coma2. Several mechanisms have been proposed to explain the symptoms caused by antibodies targeting the NMDAR, but most of the evidence seems to support the idea that the receptors get removed from the cell surface and internalized. For instance, experiments in the laboratory demonstrate that when animal neurons grown in a dish are exposed to patients’ anti-NMDAR antibodies, the number of NMDARs on the cell surface decreases as the amount of antibodies increase. When the antibodies are removed, the number of NMDAR receptors on the cell surface returns to baseline within 4 days1.
It’s easy to remove antibodies in a dish, but how do doctors get the body to stop producing antibodies against itself? Step one is identifying what triggers antibody production in the first case. Interestingly, NMDAR encephalitis predominantly affects women, and ovarian teratomas (a type of tumor made up of multiple types of tissues, which can include nervous system tissue) are responsible for 50% of cases in young women2. In patients who have some sort of tumor, removal improves symptoms in 75% of cases. Interestingly, herpes simplex virus can also cause encephalitis (inflammation of the brain), and about 20% of these patients also develop antibodies against NMDAR2. Treatment consists of immunotherapy: corticosteroids, IV infusion of immunoglobulins, and/or plasma exchange1, however patients with a viral trigger tend to be less responsive to treatment than those with a teratoma trigger or the 50% of patients with an unknown trigger2. Once treatments begin improvements in symptoms start within a few weeks, though return to baseline functioning can take up to three years. Rehabilitation is required for many patients after they leave the hospital. Deficits in attention, memory, and executive function may linger for years, but luckily over 75% of patients with the disease recover to at or near baseline neurological functioning1.
Doctors and scientists hope to develop new treatments involving immunotherapy combined with small molecules that are able to access the brain to directly combat the effects of anti-NMDAR antibodies, ideally leading to faster control of symptoms and shorter recovery time2. A brand new animal model of the disease was just described last week that will hopefully lead to more discoveries about how the disease is triggered and potential new therapies4. And with increased awareness of autoimmune disorders against the brain, doctors will be able to more quickly correctly diagnose patients with this illness and get them the treatment they need.
References:
Venkatesan, A. & Adatia, K. Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem. Neurosci.8, 2586–2595 (2017).
Dalmau, J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology87, 2471–2482 (2016).
Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol.7, 1091–1098 (2008).
Jones, B. E. et al. Anti-NMDA receptor encephalitis in mice induced by active immunization with conformationally-stabilized holoreceptors. bioRxiv 467902 (2018). doi:10.1101/467902
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Autoimmune encephalitis (AE) is the name for a group of conditions that occur when the body’s immune system mistakes its own healthy brain cells for invaders, leading to brain inflammation that ultimately triggers a number of other symptoms. Normally, the body’s immune system has only limited access to the brain, as it is protected by the blood-brain barrier (BBB). When this barrier is healthy, it can prevent an immune system attack by blocking immune cells and antibodies targeting brain cells from actually entering the brain. Like any fortress, however, the BBB isn’t completely impenetrable. Given that AE symptoms occur when immune cells or antibodies manage to cross the BBB, researchers think that the weakening of this barrier plays a critical role in AE and may even be a target for future therapies to reduce or prevent AE symptoms. But what causes the BBB to weaken, allowing cells, antibodies, and other molecules to invade the brain?
The blood-brain barrier: gatekeeper of the brain
Before discussing how the BBB becomes impaired, we need to understand how the healthy BBB functions. The BBB is often referred to as a “gateway”, made up of tightly joined endothelial cells that surround the blood vessels in the brain and spinal cord1. Outside of the brain, the endothelial cells lining blood vessels have small spaces between them, allowing for the exchange of substances between the blood and the surrounding tissue. However, the endothelial cells of the BBB are connected to each other by proteins called tight junction proteins, which squeeze the cells tightly together, blocking larger cells and molecules from freely flowing between the blood supply and the brain (Figure 1).
Figure 1: The blood-brain barrier is made up of endothelial cells that are tightly connected to each other by tight junction proteins (purple). These tight connections prevent unwanted substances from traveling between the blood and the brain. Different types of transporter proteins (yellow & blue) shuttle only certain types of molecules between the blood and brain.
The BBB is selectively permeable, meaning it allows only certain substances to enter and leave the brain. One way that molecules can cross the BBB is by endocytosis, a process where the endothelial cells uses its cell membrane to take in a molecule on one side (say, the side facing the blood) and pass it through to the other side (facing the brain) where it is released1. The endothelial cells of the BBB also express a variety of transporter proteins, which actively move molecules between the blood and the brain (Figure 1). Additionally, small, fat-soluble molecules can cross the BBB without any help from endocytosis or transporter proteins, giving the brain access to important nutrients and energy sources1.
BBB permeability changes across the day
The permeability of the BBB is not always the same, however. Research has shown that its permeability actually changes depending on the time of day2. Like many cells in the body, BBB cells are controlled by circadian rhythms, biological processes that cycle roughly every 24 hours. These rhythms are driven by a molecular “clock” within each cell, and cells across the body are synchronized by the “master clock” located in the brain.
What do these rhythms mean for BBB permeability though? Interestingly, research in both flies and mice shows that the amount of hormones, inflammatory proteins, and other molecules that cross from the blood into the brain fluctuates across the day, with peak BBB permeability occurring at night2.
Sleep loss impairs BBB function
Circadian rhythms aren’t the only daily process that affects the integrity of the BBB. Sleep—or more appropriately, lack of sleep—is also known to affect the BBB’s protection of the brain. This relationship between sleep and the BBB is increasingly important as sleep restriction becomes more and more common in our modern society.
Sleep loss is also highly relevant to the AE community. One study found that 73% of AE patients surveyed reported sleep disturbances, including gasping/snoring and insomnia. Even further, patients with AE had decreased total sleep time and increased fragmentation of sleep compared to people without AE3. But how exactly does sleep loss affect the BBB?
Figure 2: After periods of sleep loss, the blood-brain barrier is negatively affected in many ways (left). Inflammatory signaling caused by TNFα and IL-6 increases, leading to the breakdown of tight junction proteins (purple). This causes gaps between endothelial cells, allowing unwanted immune cells and antibodies to enter the brain. After sleep loss, the endothelial cells also make fewer of the transporter proteins (blue and yellow) that are required to shuttle necessary molecules between the brain and blood.
Multiple studies have now shown that sleep restriction weakens the BBB. One reason is due to the increase in inflammatory signaling that results from extended periods of wakefulness. Increases in inflammatory proteins, like TNFα and IL-6, are known to break down the tight junction proteins that keep the endothelial cells tightly joined together2 (Figure 2). Sleep-deprived mice and rats showed decreased numbers of tight junction proteins, leading to increased BBB permeability.
In addition to weakened tight junctions between endothelial cells, sleep loss also increases permeability by enhancing the rate of endocytosis across the BBB2, meaning that the endothelial cells shuttle more molecules from the blood into the brain. Relevant to AE, this increased permeability means that more immune cells and antibodies can enter the brain after sleep loss compared to after a full night’s sleep.
While these results are a bit frightening, there is good news. All of the damage to the BBB caused by sleep loss returns to normal after getting enough sleep! One study found that even an extra 1-2 hours of sleep following sleep loss restored BBB function in most brain areas4. Given even more time to sleep, the BBB throughout the brain returned to normal function5. These results suggest that treating the sleep disorders commonly associated with AE may help strengthen the BBB, increasing the brain’s protection against the immune system’s cells and antibodies and improving long-term outcomes for patients.
The BBB as a treatment target
Given that AE is caused by immune cells and antibodies infiltrating and attacking the brain, researchers are now looking at the BBB as a potential therapeutic target1. Treatments that strengthen the BBB will hopefully reduce the number of immune cells and antibodies that make it into the brain, and may also increase the effectiveness of some AE medications, such as anti-inflammatory drugs or immune-suppressants. Because these AE medications are specifically designed to cross a healthy BBB and access the brain, strengthening a weakened BBB will protect against molecules that aren’t supposed to be in the brain, while still allowing the necessary medication in.
The known circadian effects on BBB permeability can also be used in determining when to give medication that needs to cross the BBB. Medication can be given at the time of day when BBB permeability is highest to increase the amount of drug that makes it into the brain. In fact, this has already been studied with anti-seizure medication in epilepsy. For instance, in both flies and humans, when medication was given at night during peak BBB permeability, it was most effective at controlling seizures6,7.
This new strategy of “chronotherapeutic” dosing schedules has the potential to improve the efficacy of medication in many diseases. By administering drugs when it is easiest for them to enter the brain, doctors may be able to see results at lower doses of the drug, potentially reducing the risk of harmful side effects. As we continue to learn more about the BBB, scientists may identify even more ways to improve BBB health in the many disease states where it is compromised.
Your generous Donationsallow IAES to continue our important work and save lives!
Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org
Image References: Figure 1 and 2 created with BioRender.com
References:
Platt MP, Agalliu D, Cutforth T (2017) Hello from the other side: How autoantibodies circumvent the blood-brain barrier in autoimmune encephalitis. Front. Immunol. 8:442. doi: 10.3389/fimmu.2017.00442
Cuddapah VA, Zhang SL, Sehgal A (2019) Regulation of the blood-brain barrier by circadian rhythms and sleep. Trends Neurosci 42(7):500-510. doi: 10.1016/j.tins.2019.05.001
Blattner MS, de Bruin GS, Bucelli RC, Day GS (2019) Sleep disturbances are common in patients with autoimmune encephalitis. J Neurol 266(4):1007-1015. doi: 10.1007/s00415-019-09230-2
Gomex-Gonzalez B, et al. (2013) Rem sleep loss and recovery regulates blood-brain barrier function. Curr. Neurovasc. Res. 10, 197-207
He J, Hsuchou H, He Y, Kastin AJ, Wang Y, &Pan W (2014) Sleep restriction impairs blood-brain barrier function. J Neurosci 34(44)14697-14706. doi: 10.1523/jneurosci.2111-14.2014
Zhang SL, Yue Z, Arnold DM, Artiushin G, Sehgal A (2018) A circadian clock in the blood-brain barrier regulates xenobiotic efflux. Cell 173(1):130-139. doi: 10.1016/j.cell.2018.02.017
Yegnanarayan R, et al. (2006) Chronotherapeutic dose schedule of phenytoin and carbamazepine in epoleptic patients. Chronobiol. Int 23, 1035-1046
When we catch a cold, get an infection, or otherwise become sick, our bodies use a natural defense mechanism called the immune system to fight off what’s attacking us. The immune system has two ways of responding1. The first, called innate immunity, involves physical and chemical barriers like the skin and saliva, as well as many different types of cells that “eat” and destroy whatever is causing the trouble. While this innate response happens very quickly, then the downside is that it’s not very specific, and the immune cells can damage healthy parts of the body while trying to gobble up the foreign invaders. In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. This response can take days or weeks to develop but is also able to remember what the foreign invader looked like, so if it attacks again a targeted reaction can occur faster than the first time. To acquire this immunity against a particular foreign substance, the body uses two types of cells that act in different ways: T cells (which develop in an organ called the thymus, that’s where the “T” comes from) and B cells (which mature in the bone marrow, hence the “B”).
These two cell types are able to attack so specifically because each one recognizes a particular structure, called an antigen, on a foreign substance. For instance, one T cell might recognize a certain part of an influenza virus, while another could recognize a specific part of a bacterium; the same situation also holds true for B cells. The T and B cells travel around between different lymphoid tissues (organs like the spleen, tonsils, and lymph nodes, the last which are spread throughout the body) until they encounter their particular antigen. Once activated by their antigen, the T and B cells leave the lymph tissues and work in different ways to fight off the foreign invader (Figure 1).
Types of T and B cells
T cells come in many varieties, but the two major types are cytotoxic and helper. Cytotoxic T cells (sometimes referred to as CD8+ T cells due to a particular identifier on their surface) travel to the disease site to search for cells that also bear the antigen that activated them, and destroy them. Helper T cells (sometimes referred to as CD4+ T cells), as the name might suggest, help activate other parts of the immune system. There are many subtypes of helper T cells that activate different types of responses; for instance, some promote the cytotoxic T cell response, while others activate B cells. Another kind of CD4+ T cell called regulatory cells actually tells the immune system, not to attack2.
Unlike T cells, B cells do not destroy their target. Instead, once they are activated by their antigen and T helper cells, they mature into plasma cells that produce antibodies, proteins that recognize the same antigen as the B cell. These antibodies essentially enhance the innate immune system and act in several ways, including neutralizing toxins, signaling to other immune cells that a cell should be attacked and destroyed, or activating complement. Complement is a group of proteins (not cells) that make up yet another arm of the immune system. These complement proteins can recruit immune cells or directly kill foreign cells themselves1.
T and B Cells in Autoimmune Encephalitis
So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE3,4. Which cells are responsible for causing the disease depends on what antigen sets off the immune response.
In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. When proteins from inside neurons like Hu, Yo, or Ma2 are the antigens, that usually indicates that the immune system first encountered the proteins in a cancerous tumor, which can express proteins from all sorts of cell types (this cancer association is why these antibodies and diseases are called “onconeural,” or “paraneoplastic”). Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons5. This cell death is likely part of the reason why patients with these diseases have poor recovery. Antibodies from B cells that have matured into plasma cells can also be produced in response to the tumor, but they do not contribute to AE symptoms6.
Antibodies do have a strong role in producing AE symptoms when the antigen comes from the outside surface of a neuron, like the NMDA receptor for instance. These antibodies can still be formed in reaction to a tumor, but this is less common. Research on NMDAR encephalitis, in particular, has revealed the presence of B cells and antibody-secreting plasma cells in the brain7,8. Because the antibodies have access to the surface proteins they target, they can bind to them and interfere with their function. In the case of NMDAR encephalitis, it’s thought that the antibodies cause the receptors, which normally are exposed to the outside of the cell, to be taken back inside so that they can’t function properly. Once the antibodies are gone the receptors can return to the cell surface, reversing many of the symptoms9. Unlike diseases in which the antibodies target intracellular proteins, in NMDAR encephalitis there are few to no cytotoxic T cells in the brain or neuronal death5,7,8. But while there are little to no cytotoxic T cells, there have been reports of helper T cells around blood vessels in the brain, including one type called Th17 that act to enhance the immune response10.
In other cases of encephalitis with antibodies again a cell surface protein, such as LGI1, CASPR2, or GABA receptors, the precise immune reaction is less certain and in some ways seems to be a little different from NMDAR encephalitis. B cells and plasma cells are still found in the brain, and antibodies also play a major role in causing symptoms5,11. For instance, antibodies against the GABAB receptor block it from functioning, while antibodies against LGI1 can disrupt interactions between proteins and lead to a decrease in AMPA receptors12. The involvement of T cells is unclear and may vary depending on the disease-causing antibody. For example, cytotoxic and helper T cells have been found in the brain of anti-GABAB receptor patients11, while few T cells were found in anti-VGKC-complex patients5. In addition, scientists sometimes observe signs of complement, the protein arm of the immune system that can kill cells5,6. In line with the presence of cytotoxic T cells and complement, neuronal loss is sometimes reported5,13.
Overall, the type of immune response the body produces appears to be dependent on the specific antigen. In general, diseases with antibodies that target intracellular proteins like Hu, Yo, or Ma2 involve cytotoxic T cells that kill neurons. In contrast, diseases with antibodies that target cell surface proteins like NMDAR, LGI1, and GABAR involve B cells in symptom production. In this second category, the role of T cells and complement may vary depending on the particular antigen.
Your generous Donationsallow IAES to continue our important work and save lives!
Become an Advocate by sharing your story. It may result in accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to IAES@autoimmune-encephalitis.org
References
Parkin, J. & Cohen, B. An overview of the immune system. Lancet357, 1777–1789 (2001).
Corthay, A. How do regulatory T cells work? Scand. J. Immunol.70, 326–336 (2009).
Venkatesan, A. & Adatia, K. Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem. Neurosci.8, 2586–2595 (2017).
Dalmau, J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology87, 2471–2482 (2016).
Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: Clues for pathogenesis. Brain135, 1622–1638 (2012).
Damato, V., Balint, B., Kienzler, A. K. & Irani, S. R. The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders. Mov. Disord.33, 1376–1389 (2018).
Martinez-Hernandez, E. et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology77, 589–593 (2011).
Tüzün, E. et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol.118, 737–743 (2009).
Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol.7, 1091–1098 (2008).
Zeng, C. et al. Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis. Acta Biochim. Biophys. Sin. (Shanghai).50, 1266–1273 (2018).
Golombeck, K. S. et al. Evidence of a pathogenic role for CD8 + T cells in anti-GABA B receptor limbic encephalitis. Neurol. Neuroimmunol. NeuroInflammation3, 1–8 (2016).
Dalmau, J. & Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med.378, 840–851 (2018).
Shin, Y.-W. et al. Treatment strategies for autoimmune encephalitis. Ther. Adv. Neurol. Disord.11, 1–19 (2018).
Our names are Carolyn and Sarah, and we are happy to announce the partnership between IAES and our blog, PennNeuroKnow (PNK). We are working with IAES to learn about topics that patients and families in the AE community have trouble understanding, in order to create handouts and blog posts that explain these issues in a way that’s easy to digest. We’re excited to begin this alliance and to introduce our team to the AE community.
PNK is a blog we founded in early 2018 to dive into the complex field of neuroscience and simplify it so that anyone can understand. Including the two of us, we have 6 writers creating weekly articles ranging from general topics likehow the brain produces curiosity, to breaking down specific journal articles on subjects like how the bacteria in your gut may be linked to depression. All of us are PhD students in the University of Pennsylvania’s Neuroscience Graduate Group who are committed to better communicating science. We know that scientific studies are sometimes difficult to both access and understand, so we want to use our training as scientists to share our passion for neuroscience and make our field more accessible to everyone.
We were first introduced to IAES in July 2019, when Carolyn wrote about NMDAR encephalitis in a blog post called WhenYour Brain is on Fire. IAES saw the post and shared it on their Facebook page, giving the article much greater reach than we normally experience. The amount of positive feedback we have received from the AE community has been overwhelming, and we are truly grateful to have been able to help so many people understand the science behind the disease that has affected themselves or a loved one. Now thanks to IAES President Tabitha Orth reaching out to us about forming a partnership, we are excited to produce more easy-to-read articles on complex topics important to the AE community.
All of our writers are looking forward to learning more about AE and the issues that are difficult for patients and families to grasp. Already we are hard at work learning and writing about how AE relates to the immune system, memory loss, and FDG-PET scans, just to name a few topics. We hope that we can use our strengths as neuroscientists to help translate complicated subjects and journal articles into something everyone can understand, and are excited to contribute to this wonderful community. We want to make sure we are writing about topics that are most important to you and your family members, so please do not hesitate to reach out to either Tabitha or us with topics you would like to learn more about!
Your generous Donationsallow IAES to continue our important work and saves lives!
Become an Advocate by sharing your story. It may result in an accurate diagnosis for someone suffering right now who is yet to be correctly identified. Submit your story with two photos to: IAES@autoimmune-encephalitis.org
Our website is not a substitute for independent professional medical advice. Nothing contained on our website is intended to be used as medical advice. No content is intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice. Although THE INTERNATIONAL AUTOIMMUNE ENCEPHALITIS SOCIETY provides a great deal of information about AUTOIMMUNE ENCEPHALITIS, all content is provided for informational purposes only. The International Autoimmune Encephalitis Society cannot provide medical advice.
International Autoimmune Encephalitis Society is a charitable non-profit 501(c)(3) organization founded in 2016 by Tabitha Andrews Orth, Gene Desotell and Anji Hogan-Fesler. Tax ID# 81-3752344. Donations raised directly supports research, patients, families and caregivers impacted by autoimmune encephalitis and to educating healthcare communities around the world. Financial statement will be made available upon request.
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