Select Page

August 29, 2020 | Greer Pettyman, PennNeuroKnow

Autoimmune encephalitis (AE) is a disorder that can be hard to diagnose. Typically, early symptoms are flu-like, making it difficult to distinguish from many other illnesses. Psychiatric symptoms and behavior changes are often among the first signs of autoimmune encephalitis, especially NMDAR encephalitis, and a majority of patients are seen first by psychiatrists upon entering the emergency room1. Other neurological symptoms of AE, such as seizures and problems with movement and memory typically develop later than the psychiatric symptoms1. However, AE is not usually diagnosed until the appearance of these neurological symptoms since the early psychiatric symptoms are often misdiagnosed as a psychiatric disorder, which leads to a delay in treatment for AE1. Understanding the psychiatric symptoms and behavior changes that often signal the onset of AE can lead to quicker detection, earlier treatment, and better outcomes for patients.  

One study of AE found that 77% of patients with anti-NMDAR encephalitis initially came to the hospital due to psychiatric symptoms2. Usually, the psychiatric symptoms caused by AE include agitation, aggression, irritability, hallucinations, delusions, and depressed mood3. The most common symptom was agitation or irritability, appearing in 59% of adults and 66% of children2. Psychotic symptoms such as hallucinations were the second most common2. These psychiatric symptoms are often misdiagnosed as a psychiatric disorder rather than being investigated as early symptoms of AE. 

An additional challenge in diagnosing AE from psychiatric symptoms is that the pattern of symptoms often differs between adults and children. Adults are more likely than children to experience psychotic symptoms like hallucinations2. Children, unlike adults, are likely to have temper tantrums as a symptom4. Children also often have some early neurological symptoms like seizures in addition to the behavior changes, while adults usually begin with psychiatric but not neurological symptoms6. The differences in type and timeline of symptoms between children and adults could be explained by different underlying causes of AE. For example, in adults AE is often the result of a tumor, but tumors are usually not the cause of AE in kids7  

How might AE affect behavior? 

While the exact mechanisms by which AE causes behavior changes are not well understood, anti-NMDAR encephalitis research provides some potential insights into processes in the brain that might lead to these symptoms. Anti-NMDAR encephalitis, as the name suggests, involves antibodies against a type of neurotransmitter receptor called NMDARs. These NMDARs bind a neurotransmitter called glutamate. Several conditions must be met for NMDARs to become active: glutamate must bind to the NMDAR and the electrical voltage of the cell must reach a certain level8. When NMDARs are active, they allow charged ions to cross the cell membrane, which can then send a signal to other cells. NMDAR activation is involved in processes like learning, memory, and behavior.  

In anti-NMDAR encephalitis, antibodies in the immunoglogbulin G (IgG) subclass target the NMDA receptors9. These IgG antibodies bind to part of the NMDA receptor and make it so they are not able to signal as usual. Neurons from rats that were treated with IgG from AE patients had a decreased number of NMDARs on the cell surface. When the antibodies were removed, the NMDARs returned back to normal levels10. This indicates that IgG antibodies can cause removal of NMDARs from the surface of the cell, where they can no longer interact with neurotransmitters. Many NMDARs are found on a type of cell called GABAergic neurons9. These neurons typically suppress activation of nearby neurons and help to regulate levels of activity in the brain. The attack on NMDARs in AE may lead to reduced activity of GABAergic neurons, which in turn causes too much activity in other parts of the brain.  

How does this change in glutamate signaling that is mediated by NMDARs relate to psychiatric symptoms? One theory about the mechanisms underlying schizophrenia, a psychiatric disorder characterized by hallucinations and delusions, also includes reduced availability of NMDARs11. The subsequent deactivation of GABAergic neurons is believed to produce too much activity that leads to many of the psychiatric symptoms of schizophrenia. Drugs that block NMDARs, such as ketamine, are known to cause psychosis, agitation, and difficulties with memory11. All of these are also common symptoms of anti-NMDAR encephalitis. The progressive loss of NMDARs due to antibody attack could create these same psychiatric symptoms in people with AE.  

How are psychiatric symptoms addressed? 

Getting a better handle on understanding and treating the behavioral symptoms of AE requires improved diagnosis and intervention. When someone arrives in the hospital with significant behavioral changes or psychiatric symptoms, it would be beneficial if doctors could screen for and diagnose AE even before some of the more severe neurological symptoms begin to appear. 

Many patients receive medications that target the psychiatric symptoms that are later diagnosed as related to AE12. These medications include antipsychotics for people who are having symptoms of psychosis. However, in some cases, antipsychotic medications have been shown to cause adverse effects such as catatonia and coma in AE patients, so doctors need to give these medications with care2. Earlier diagnosis of AE can prevent patients from getting incorrect diagnoses and psychiatric treatments that can actually worsen their AE. Importantly, while medications may help to manage the psychiatric symptoms, they do not target the underlying causes of AE and patients will still need standard treatments like immunotherapy or tumor removal to treat the AE itself.  

Typically, once patients receive immunotherapy, the behavior symptoms of AE begin to go away. Most patients recover fully and no longer have any psychiatric symptoms after recovery.  However, approximately 30% of patients may have lasting neuropsychiatric deficits after treatment for AE13. In patients who have psychiatric symptoms after immunotherapy, continued use of antipsychotic medications such as clozapine can help to alleviate symptoms14. 

In children who recover from AE, behavioral symptoms may continue and pose particular challenges for parents7. Some children were reported to have academic difficulties after recovering from AE15. Parents and caregivers dealing with bad behavior from a child who had AE can learn behavior management techniques to help address these behavioral difficulties. These strategies, as well as early screening of psychiatric symptoms and behavioral changes, could help to improve diagnosis, treatment, and recovery from AE.  


  1. Finke, C. (2019). A transdiagnostic pattern of psychiatric symptoms in autoimmune encephalitis. The Lancet Psychiatry. 6 191-193.
  2. Sarkis, R. A., Coffey, M. J., Cooper, J. J., Hassan, I., & Lennox, B. (2019). Anti- N -Methyl-D-Aspartate Receptor Encephalitis: A Review of Psychiatric Phenotypes and Management Considerations: A Report of the American Neuropsychiatric Association Committee on Research. The Journal of Neuropsychiatry and Clinical Neurosciences, 31(2), 137–142.
  3. Al-Diwani, A., Handel, A., Townsend, L., Pollak, T., Leite, M. I., Harrison, P. J., … Irani, S. R. (2019). The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. The Lancet Psychiatry, 6(3), 235–246.
  4. Brenton, J. N., & Goodkin, H. P. (2016). Antibody-mediated autoimmune encephalitis in childhood. Pediatric Neurology. 60 13-23. 
  5. Suthar, R., Saini, A. G., Sankhyan, N., Sahu, J. K., & Singhi, P. (2016). Childhood Anti-NMDA Receptor Encephalitis. Indian Journal of Pediatrics, 83(7), 628–633. 
  6. Esposito, S., Principi, N., Calabresi, P., & Rigante, D. (2019). An evolving redefinition of autoimmune encephalitis. Autoimmunity Reviews. 18 155-163.
  7. Armangue, T., Petit-Pedrol, M., & Dalmau, J. (2012). Autoimmune encephalitis in children. Journal of Child Neurology. 27(11) 1460-1469. 
  8. Husi, H. (2004). NMDA Receptors, Neural Pathways, and Protein Interaction Databases. International Review of Neurobiology, 61, 49–77. 
  9. Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M. R., & Balice-Gordon, R. (2011). Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. The Lancet Neurology. 10(1) 63-74. 
  10. Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., … Lynch, D. R. (2008). Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. The Lancet Neurology, 7(12), 1091–1098.
  11. Uno, Y., & Coyle, J. T. (2019). Glutamate hypothesis in schizophrenia. Psychiatry and Clinical Neurosciences, 73(5), 204–215.
  12. Kuppuswamy, P. S., Takala, C. R., & Sola, C. L. (2014). Management of psychiatric symptoms in anti-NMDAR encephalitis: A case series, literature review and future directions. General Hospital Psychiatry, 36(4), 388–391. 
  13. Liu, X., Zhang, L., Chen, C., Gong, X., Lin, J., An, D., … Hong, Z. (2019). Long‐term cognitive and neuropsychiatric outcomes in patients with anti‐NMDAR encephalitis. Acta Neurologica Scandinavica, 140(6), 414–421. 
  14. Yang, P., Li, L., Xia, S., Zhou, B., Zhu, Y., Zhou, G., … Li, F. (2019). Effect of clozapine on anti-N-methyl-D-aspartate receptor encephalitis with psychiatric symptoms: A series of three cases. Frontier 13(315)
  15. Basheer, S., Nagappa, M., Mahadevan, A., Bindu, P. S., Taly, A. B., & Girimaji, S. C. (2017). Neuropsychiatric Manifestations of Pediatric NMDA Receptor Autoimmune Encephalitis. The Primary Care Companion For CNS Disorders, 19(04), 0–0.



IAES PNK Partnership logo 500x419 - Behaviour Change from Autoimmune Encephalitis


Your generous Donations allow IAES to continue our important work and save lives!

seal - Behaviour Change from Autoimmune Encephalitis



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

International Autoimmune Encephalitis Society (IAES), home of the AEWarrior®, is the only Family/Patient-centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey. Your donations are greatly appreciated and are the direct result of IAES’ ability to develop the first product in the world to address the needs of patients, Autoimmune Encephalitis Trivia Playing Cards. Every dollar raised allows us to raise awareness and personally help Patients, Families, and Caregivers through their Journey with AE to ensure that the best outcomes can be reached. Your contribution to our mission will help save lives and improve the quality of life for those impacted by AE.


Trivia Playing cards 3 FB 500x419 - Behaviour Change from Autoimmune Encephalitis

For this interested in face masks, clothing, mugs, and other merchandise, check out our AE Warrior Store!  This online shop was born out of the desire for the AE patient to express their personal pride in fighting such a traumatic disease and the natural desire to spread awareness. Join our AE family and help us continue our mission to support patients, families and caregivers while they walk this difficult journey.  


AE Warrior Store 300x200 - Behaviour Change from Autoimmune Encephalitis


Be a part of the solution by supporting IAES with a donation today.


why zebra - Aphasia as a Symptom of Autoimmune Encephalitis

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.

Translate »