January 24, 2024 | by Ryan Rahman, PennNeuroKnow and IAES Collaboration
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The staff at IAES is proud to present to all of you another wonderful article/blog from the amazing team at PennNeuroKnow. Since 2019 IAES has been extremely lucky to be in partnership with the PennNeuroKnow(PNK) team to help us all better understand complex medical issues related to AE and neurology in general. The talented PNK team continues to keep us up-to-date and help clarify the complexities we face each day along our AE journey, and we are eternally grateful! You can find out much more about this stellar group at: https://pennneuroknow.com/
Our brains are what make us human – consciousness, emotion, and memory all come from a tapestry of over 100 trillion connections. When this intricate network is bombarded by misguided immune cells, as in the case of autoimmune encephalitis, the brain can no longer carry out some of its most important functions. One such function that is often prominently affected is memory.1,2 Memory is a central aspect of our daily lives, allowing us to recall cherished moments, learn from our experiences, and navigate the world. However, for individuals battling autoimmune encephalitis, memory can become a complex and challenging puzzle. In this blog post, we will describe the memory difficulties patients face when living with autoimmune encephalitis (AE).
What is memory?
Memory is a fundamental cognitive function that enables individuals to absorb, store, and recall information and experiences. It plays a crucial role in shaping our perception of the world and our ability to learn, make decisions, and navigate daily life. There are different types of memory that work together to enable us to learn, adapt, and navigate the complexities of life. Broadly, it can be helpful to think of grouping different types of memory by where they are in the brain because the brain organizes its functions into different locations. For example, the hippocampus is the main brain structure that helps record information and start the formation of memories.3 In addition, it is also important to consider the kind of information being stored and how long it is stored for (Figure 1). Here, we break down a few types of memory that are relevant to patients living with AE:
Sensory Memory: Sensory memory4 is responsible for briefly holding information from our sensory organs, such as vision and hearing. This short-lived memory lasts for a fraction of a second and is composed of all the information we get from our senses before our brain filters out the unimportant parts. It typically relies on parts of the brain that receive direct information from the sensory organs, such as the eyes and ears.
Short-Term Memory: Short-term memory4 is the next shortest type of memory, lasting for a few seconds to minutes. When you solve a quick math equation in your head or remember mid-conversation what someone just told you, you’re using your short-term memory.6 Short-term memory relies largely on communication between two parts of the brain called the prefrontal cortex and hippocampus.
Long-Term Memory (LTM): Long-term memory4 is exactly what it sounds like – the kind of memory that helps us remember things for long periods of time. It has an almost unlimited capacity and can last for a lifetime. Long-term memory includes our ability to remember personal experiences, facts, skills, and habits. Our ability to form these memories relies on the hippocampus and another part of the brain called the frontotemporal lobes, but where exactly long-term memory is stored is still unclear.
Procedural Memory: Procedural memory4 is a special type of long-term memory often mistakenly called “muscle memory” (because memory comes from the brain, of course!) that allows us to ride a bicycle, type on a keyboard, or tie our shoelaces with little conscious effort. Procedural memory does not depend on the hippocampus or prefrontal cortex. Instead, it tends to be formed and stored in the brain areas involved in planning motions, such as the cerebellum and the motor cortex.
Because different types of memory rely on different parts of the brain, sometimes patients with damage to only some parts of the brain can have deficits in only one type of memory, while the other types of memory are preserved.
Another concept that is central to most types of memory is the idea that brain cells, which are called neurons, can change the strength of their connections. Connections between neurons are called synapses, which are tiny gaps between the cells bridged by chemical and electrical signals.5 A bunch of neurons working together can mirror an electrical circuit, and the more synapses in a circuit are activated, the tighter and more numerous these connections become. This concept is known as synaptic plasticity, and the ability to retrieve memories may be dependent on how strong certain connections are.6
How does autoimmune encephalitis affect memory?
Over the course of many years and research studies, doctors and scientists have shown that AE causes changes in memory. Both short-term and long-term memory impairments can occur in patients with AE; however, procedural memory impairments do not usually occur in AE.1,7-9 For patients with AE, deficits in short term memory can take the form of confusion and attention challenges; whereas deficits in long term memory can take the form of difficulty remembering facts, struggles with planning/organizing, and loss of personal memories. Although many patients show significant improvement in their memory symptoms after treatment of AE, many patients can unfortunately continue to experience residual memory problems, even long after other symptoms of AE have gone away.10
As discussed in a prior IAES blog post, AE is divided into different types based on which brain protein is attacked by a patient’s immune system. People with some subtypes of AE are more likely to have certain memory challenges.11 For example, patients with LGI1 autoimmune encephalitis (patients who have antibodies against Leucine-rich Glioma Inactivated protein 1) tend to have the most severe memory deficits with a profound loss of memories about personal life events. In contrast, memory loss and confusion are less common in patients with GABAAR encephalitis (~27%) and GABABR encephalitis (~47%). The reason behind these differences may in part be due to the fact that some of these proteins are only present in specific parts of the brain, which, as we previously discussed, control specific types of memory. Additionally, these targeted proteins play different roles in the circuits of the brain and disruption of different parts may impair synaptic plasticity in various ways. Please see the table below for more details about the memory changes experienced in different types of AE.
To understand more about how AE causes memory changes, scientists first worked with patients using magnetic resonance imaging (MRI) to look at changes in the physical structure of their brains.12 Even as early as 1968, scientists saw drastic changes in the temporal lobes of patients with AE, which is a large region of the brain that contains the hippocampus.13 Importantly, recent studies have directly demonstrated that most patients with autoimmune encephalitis have structural changes in the hippocampus, and those with more damage in the hippocampus have more severe challenges with memory.14
In addition to large structural changes, the microscopic science behind how AE causes memory loss has been explored in animal studies, which are more manipulable models for scientists to determine how diseases work in an entire system.15,16 In one experiment, scientists injected mice with antibodies from human patients with AE. They then tested the mice for any memory changes. Mice that were given the AE-associated antibodies could not remember objects they had seen before and developed anxiety-like behaviors.15 Importantly, scientists also showed that antibodies targeting the N–methyl-D–aspartate (NMDA) glutamate receptor (as seen in patients with Anti-NMDAR encephalitis) reduced the number of these proteins at the connections between brain cells which in turn disrupted synaptic plasticity.16
As previously mentioned, synaptic plasticity refers to the dynamic strength of circuits in the brain which increases when more neurons are activated together. Since glutamate is the main activating signal of the brain, it may be that destruction of the glutamate signal in certain types of AE leads to impaired memory by changing the strength of connections in the brain.
Lastly, an exciting early development occurred when scientists discovered that injecting Ephrin-B2, a protein that helps in the development of connections in the brain, was able to prevent memory loss caused by anti-NMDA antibodies in mice.16,17 Based on these findings, Ephrin-B2 may one day become a potential treatment for memory loss in patients living with AE!
In conclusion, autoimmune encephalitis is a neurological disorder that can have a profound and lasting impact on memory. Memory deficits in autoimmune encephalitis are not only distressing for patients but can also pose challenges to their daily functioning and quality of life. A better understanding of the mechanisms underlying these memory impairments and the development of targeted treatments are crucial to improving outcomes for individuals affected by autoimmune encephalitis and their memory-related challenges.
Research in this field is ongoing, and with continued advancements in science and treatment, we can piece back together the lives of those affected by autoimmune encephalitis, one memory at a time.
1 Heine, J. et al. Long‐Term Cognitive Outcome in Anti–N‐Methyl‐D‐Aspartate Receptor Encephalitis. Annals of Neurology 90, 949-961 (2021). https://doi.org/10.1002/ana.26241
2 McKeon, G. L. et al. Cognitive outcomes following anti-N-methyl-D-aspartate receptor encephalitis: A systematic review. Journal of Clinical and Experimental Neuropsychology 40, 234-252 (2018). https://doi.org/10.1080/13803395.2017.1329408
3 Bird, C. M. & Burgess, N. The hippocampus and memory: insights from spatial processing. Nature Reviews Neuroscience 9, 182-194 (2008). https://doi.org/10.1038/nrn2335
4 Camina, E. & Güell, F. The Neuroanatomical, Neurophysiological and Psychological Basis of Memory: Current Models and Their Origins. Front Pharmacol 8, 438 (2017). https://doi.org/10.3389/fphar.2017.00438
5 Südhof, T. C. & Malenka, R. C. Understanding Synapses: Past, Present, and Future. Neuron 60, 469-476 (2008). https://doi.org/10.1016/j.neuron.2008.10.011
6 Citri, A. & Malenka, R. C. Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms. Neuropsychopharmacology 33, 18-41 (2008). https://doi.org/10.1038/sj.npp.1301559
7 Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7, 1091-1098 (2008). https://doi.org/10.1016/s1474-4422(08)70224-2
8 Finke, C. et al. Cognitive deficits following anti-NMDA receptor encephalitis. Journal of Neurology, Neurosurgery & Psychiatry 83, 195-198 (2012). https://doi.org/10.1136/jnnp-2011-300411
9 Hansen, N. Long-Term Memory Dysfunction in Limbic Encephalitis. Frontiers in Neurology 10 (2019). https://doi.org/10.3389/fneur.2019.00330
10 Titulaer, M. J. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12, 157-165 (2013). https://doi.org/10.1016/s1474-4422(12)70310-1
11 Gibson, L. L., McKeever, A., Coutinho, E., Finke, C. & Pollak, T. A. Cognitive impact of neuronal antibodies: encephalitis and beyond. Translational Psychiatry 10 (2020). https://doi.org/10.1038/s41398-020-00989-x
12 Kelley, B. P. et al. Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis. American Journal of Neuroradiology 38, 1070-1078 (2017). https://doi.org/10.3174/ajnr.a5086
13 CORSELLIS, J. A. N., GOLDBERG, G. J. & NORTON, A. R. “LIMBIC ENCEPHALITIS” AND ITS ASSOCIATION WITH CARCINOMA. Brain 91, 481-496 (1968). https://doi.org/10.1093/brain/91.3.481
14 Finke, C. et al. Structural Hippocampal Damage Following Anti-N-Methyl-D-Aspartate Receptor Encephalitis. Biological Psychiatry 79, 727-734 (2016). https://doi.org/10.1016/j.biopsych.2015.02.024
15 Haselmann, H. et al. Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction. Neuron 100, 91-105.e109 (2018). https://doi.org/10.1016/j.neuron.2018.07.048
16 Planagumà, J. et al. Ephrin‐B2 prevents N‐methyl‐D‐aspartate receptor antibody effects on memory and neuroplasticity. Annals of Neurology 80, 388-400 (2016). https://doi.org/10.1002/ana.24721
17 Hruska, M. & Dalva, M. B. Ephrin regulation of synapse formation, function and plasticity. Molecular and Cellular Neuroscience 50, 35-44 (2012). https://doi.org/10.1016/j.mcn.2012.03.004
Figure 1 and Table 1 made by Ryan Rahman in BioRender.com.
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