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Rare and Seronegative Autoimmune Encephalitis

Rare and Seronegative Autoimmune Encephalitis

October 28, 2022 | Written by Dr. Nabil Seery. Edited by Dr Mastura Monif, Ms Tiffany Rushen, Dr Loretta Piccenna, Ms Amanda Wells (consumer representative) and Ms Sasha Ermichina (consumer representative).

A message from IAES Blog Staff:

It is our honor and pleasure to present to all of you an overview of how autoimmune encephalitis can affect cognitive abilities. This overview is by the esteemed team at Monash University in Australia & lead by Dr. Mastura Monif, who is a member of IAES’ Medical Advisory Board.

We are proud to be in collaboration with Dr. Monif and her team in the Australian Autoimmune Encephalitis Consortium Project as we work closely with them to best support AE patients, caregivers and their families. This blog has been facilitated by IAES Support Services coordinator Mari Wagner Davis, with input from IAES volunteers Sasha Ermichina (impacted by GFAP AE) and Amanda Wells (caregiver for her daughter with AE). These IAES representatives provide input from their unique perspectives, helping to educate researchers in the difficulties that patients and families face.

You can find out more about the Australian Autoimmune Encephalitis Consortium and their efforts to help those with AE and their families via the following link:

https://www.monash.edu/medicine/autoimmune-encephalitis

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Rare and Seronegative Autoimmune Encephalitis

Source: Seery N, Butzkueven H, O’Brien TJ, Monif. M. Rare Antibody-Mediated and Seronegative Autoimmune Encephalitis: an Update. Autoimmunity Rev. 2022 May 18;21(7);103118. https://doi.org/10.1016/j.autrev.2022.103118

WHY WE DID THIS WORK

Autoimmune encephalitis (AE) is a form of autoimmune disease whereby immune cells in the body inappropriately target components of the nervous system. This causes dysfunction of nerve cells, and in some cases death of these cells, and further produces different clinical symptoms that are reversible. Such symptoms include (but are not limited to) cognitive symptoms, such as difficulties with memory and language, seizures, movement disorders, and psychiatric symptoms.

Antibodies are central to the diagnosis of many subtypes of autoimmune encephalitis. Generally, antibodies are proteins produced by the immune system to fight infections. In a proportion of patients with autoimmune encephalitis there can be an abnormal expression of antibodies, where, rather than targeting foreign molecules (e.g. viruses, bacteria), they mistakenly target self-proteins on nerve endings or self-proteins inside the nerve cell or neuron. In up to half of cases, an antibody is not detectable using current available tests or assays. This group of cases is called “seronegative” autoimmune encephalitis, i.e. denoting a lack of antibodies in the serum (a component of a patient’s blood) or cerebrospinal fluid (a clear fluid the surrounds the brain and spinal cord, obtained via a lumbar puncture, a procedure involving a fine needle being inserted in the lower back). ‘Seronegative’ autoimmune encephalitis most likely represents a broader collection of disorders.

Over the last two decades, antibody-mediated subtypes of autoimmune encephalitis continue to be discovered, with over ten such forms now recognised. Further, following the respective discovery of such new forms of autoimmune encephalitis, disease mechanisms and clinical features have been revealed. However, seronegative autoimmune encephalitis remains less well characterised, possibly in part to because of its heterogeneous nature – meaning that a variety of diseases forms may be included by the definition.

The purpose of our review was to explore advances regarding five rare antibody-mediated forms of autoimmune encephalitis, namely, anti-g-aminobutyric acid B (GABAB) receptor-, anti-a-amino-3hydroxy-5-methyl-4-isoxazolepropinoic receptor- (AMPAR), anti-GABAA receptor-and anti-dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis and IgLON5 disease.

We also summarise current research and challenges in relation to ‘seronegative’ autoimmune encephalitis. For a detailed discussion of anti- NMDA autoimmune encephalitis, anti-LGI1 and anti-CASPR2 autoimmune encephalitis refer to (Contemporary advances in anti-NMDAR antibody (Ab)-mediated encephalitis -PubMed (nih.gov) (1) and Contemporary advances in antibody-mediated encephalitis: anti-LGI1 and anti-Caspr2 antibody (Ab)-mediated encephalitides -PubMed (nih.gov)) (2).

WHAT WE FOUND

GABAB, AMPAR and GABAA autoimmune encephalitis have common and distinguishing clinical features. These three forms of autoimmune encephalitis are diagnosed by the presence of antibodies found in the blood or cerebrospinal fluid of suspected patients. All three are relatively rare, compared to some other antibody-mediated forms of autoimmune encephalitis such as anti-N-methyl-D-aspartate receptor (NMDAR) and anti-leucine-rich gliomainactivated 1 (LGI1) Ab-mediated encephalitis. GABAA encephalitis in particular is exceedingly rare, with approximately fifty cases reported overall as at a few years ago.

In these diseases, antibodies target the GABAB, AMPAR and GABAA receptors (proteins present on nerve cell endings), causing neuronal dysfunction. GABAB and GABAA receptors both attract an inhibitory neurotransmitter called GABA. A neurotransmitter is a signalling molecule that helps with communication and transmission of impulses between neurons, and inhibitory neurotransmitters reduce the likelihood a given neuron will generate an electrical signal called an action potential.

Seizures in these diseases are a main feature, and may be particularly non-responsive to conventional anti-seizure treatment. Furthermore, cognitive and psychiatric symptoms are common in all three of these subtypes of autoimmune encephalitis. GABAB and AMPAR subtypes may have similar findings identified on MRI imaging of the brain, with inflammation and swelling seen in part of the brain called the mesial temporal lobe. The mesial temporal lobe is an area of the brain important for memory, emotion and behaviour.

The diagnosis of autoimmune encephalitis invariably necessitates that clinicians investigate for the possibility of a tumour (e.g. lung cancer, thyroid cancer, breast cancer) that may have triggered the disease. Treating the tumour or cancer where feasible and as promptly as possible has been linked to improvements in autoimmune encephalitis symptoms. Similarly, the presence of neurological symptoms, if preceding a cancer diagnosis, may allow for this to be facilitated more quickly than might have been the case otherwise, which may help afford a better chance of more effectively treating the underlying cancer.

In approximately half of patients diagnosed with GABAB encephalitis, an underlying tumour is found, most often small-cell lung cancer. In AMPAR encephalitis, almost two-thirds of patients have an underlying tumour, with thymus tumours and lung cancer most common. In GABAA encephalitis, approximately one third of patients have also been shown to have an underlying tumour.

DPPX encephalitis and IgLON5 disease are two rare and somewhat clinically unique forms of autoimmune encephalitis. In DPPX encephalitis, patients commonly present with profound weight loss or diarrhoea and have features of central-nervous system hyperexcitability. This is a state where the brain has increased responsiveness to a variety of external stimuli. In DPPX encephalitis, features attributed to CNS hyperexcitability include myoclonus, or rapid, involuntary muscle jerks, and tremor. IgLON5 disease on the other hand also has unique clinical features, such as a variety of sleep disturbances.

Seronegative autoimmune encephalitis overall requires further study and description to identify potential antibodies which may be the cause. Seronegative limbic encephalitis is a form of seronegative autoimmune encephalitis, where the limbic structures in the brain are affected. In this subset of the disease inflammation is observed in the mesial temporal lobes using Magnetic Resonance Imaging (MRI). Seronegative limbic encephalitis is typically seen in older patients, with conventional antibody testing not revealing an antibody. Patients typically have memory impairment, with or without psychiatric symptoms and seizures, and are treated with medications that lower effects of the immune system, as in other forms of autoimmune encephalitis.

HOW CAN WE USE THIS RESEARCH

These findings are intended to help researchers and clinicians better understand seronegative and rare forms of autoimmune encephalitis. By bringing this information together, it can assist with improving diagnosis and assisting with early treatment by clinicians.

It should be noted that antibody-related forms of autoimmune encephalitis are usually diagnosed as “possible autoimmune encephalitis” prior to the availability of antibody results, which can take up to a period of weeks. A diagnosis of autoimmune encephalitis is based on broad criteria involving consideration of a patient’s symptoms and test results, including MRI, electroencephalogram (EEG – a measure of the electrical activity of the brain) and cerebrospinal fluid biopsy results, combined with the exclusion other diseases, for example, viruses that could mimic the observed symptoms.

Prompt diagnosis of autoimmune encephalitis, and prompt exclusion of other causes such as viral encephalitis is very important, as there is a growing body of evidence indicating that earlier initiation of immune-lowering treatment for autoimmune encephalitis may be able to facilitate better recovery.

The seronegative form of autoimmune encephalitis can represent a large proportion of autoimmune encephalitis patients overall so its understanding is crucial for improvements in clinical care.

Regarding very rare subtypes of autoimmune encephalitis, an understanding of the characteristic features of these rare entities is crucial in forming a diagnostic workup plan. Further, awareness of the features of some of these rarer subtypes can ensure prompt and accurate investigation of underlying tumours. Knowledge of rarer subtypes may also be able to inform clinicians and patients about the possible outcomes of these conditions to inform day to day discussions with patients and their caregivers.

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For more information and resources from Dr. Monif and her group at the Australian Autoimmune Encephalitis Consortium Project, visit this link here. To download a plain language PDF of the paper summarized in this blog, click the button below:

 

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

 

Tabitha Orth 300x218 - Rare and Seronegative Autoimmune Encephalitis

On June 16 th, 2022, Tabitha Orth, President and Founder of International Autoimmune Encephalitis Society officially became the 7,315 th “point of light”. Recognized for the volunteer work she and IAES has done to spark change and improve the world for those touched by Autoimmune Encephalitis. The award was founded by President George H.W. Bush in 1990.

guidestar platinum logo 300x300 1 e1605914935941 - Rare and Seronegative 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 IAES@autoimmune-encephalitis.org  

 

 

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 - Rare and Seronegative 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 - Rare and Seronegative Autoimmune Encephalitis

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

why zebra - Aphasia as a Symptom of Autoimmune Encephalitis
Rare and Seronegative Autoimmune Encephalitis

Epilepsy and Autoimmune Encephalitis

October 12, 2022 | Written by Dr. Robb Wesselingh. Edited by Dr Mastura Monif, Ms Tiffany Rushen, Dr Loretta Piccenna, Ms Amanda Wells (consumer representative) and Ms Sasha Ermichina (consumer representative).

A message from IAES Blog Staff:

It is our honor and pleasure to present to all of you an overview of how autoimmune encephalitis can affect cognitive abilities. This overview is by the esteemed team at Monash University in Australia & lead by Dr. Mastura Monif, who is a member of IAES’ Medical Advisory Board.

We are proud to be in collaboration with Dr. Monif and her team in the Australian Autoimmune Encephalitis Consortium Project as we work closely with them to best support AE patients, caregivers and their families. This blog has been facilitated by IAES Support Services coordinator Mari Wagner Davis, with input from IAES volunteers Sasha Ermichina (impacted by GFAP AE) and Amanda Wells (caregiver for her daughter with AE). These IAES representatives provide input from their unique perspectives, helping to educate researchers in the difficulties that patients and families face.

You can find out more about the Australian Autoimmune Encephalitis Consortium and their efforts to help those with AE and their families via the following link:

 

https://www.monash.edu/medicine/autoimmune-encephalitis

 —-

Epilepsy and Autoimmune Encephalitis

Publication:

Source – Wesselingh, R., Broadley, J., Buzzard, K., Tarlinton, D., Seneviratne, U., Kyndt, C., Stankovich, J., San􀄀lippo, P., Nesbitt, C., D’Souza, W., Macdonell, R., Butzkueven, H., O’Brien, T. J., & Monif, M. (2022). Prevalence, risk factors, and prognosis of drugresistant epilepsy in autoimmune encephalitis. Epilepsy & behavior: E&B, 132, 108729. Advance online publication. https://doi.org/10.1016/j.yebeh.2022.108729

 —-

Seizures (or sudden, uncontrolled electrical disturbances in the brain) are a common initial neurological symptom that occurs in people with autoimmune encephalitis. In autoimmune encephalitis a person’s immune system mistakenly targets different proteins in their brain causing damage and inflammation. For some people, the seizures can progress to very severe and ongoing seizures called status epilepticus, requiring treatment to stop them happening. While some patients will stop having seizures after immune system suppressing treatment, others will continue to have seizures that do not respond, even to increasing amounts of anti-seizure medications. This is known clinically as treatment- or drug-resistant epilepsy.  Drug-resistant epilepsy has a significant impact on the quality of life of people with autoimmune encephalitis. We currently do not know why some patients with autoimmune encephalitis develop drug-resistant epilepsy whilst others do not.

It is important for doctors to be able to predict how and why people with autoimmune encephalitis develop drug-resistant epilepsy because it is a disabling complication that may be preventable. For this research, we wanted to find out answers to following questions –

  1. How common is drug-resistant epilepsy after autoimmune encephalitis?
  2. What are the risk factors for the development of drug-resistant epilepsy after autoimmune encephalitis?
  3. In the early part the disease, can the use of EEG tell us about a person’s likelihood of developing drug-resistant epilepsy?
  4. Can we use this information to predict which patients with autoimmune encephalitis are going to develop drug resistant epilepsy?

How we did this work

We looked through the medical records of seven hospitals in Victoria (Australia) for people who met the diagnosis of autoimmune encephalitis and had an EEG when they first became unwell. Two hundred and eight patients were identified and selected for analysis. We then collected available data from 69 patients of their symptoms, seizures, treatment, and whether they developed drug-resistant epilepsy at 12 months after their initial illness.

We analysed EEGs from patients to find any brain wave irregularities or signatures (called EEG biomarkers) that were more common in those with autoimmune encephalitis who developed drug-resistant epilepsy than those that did not develop drug-resistant epilepsy. Finally, we combined all the factors and created a tool that doctors can use to predict an individual’s risk of developing drug-resistant epilepsy after autoimmune encephalitis.

What were the interesting things we found

  • We found that it was not uncommon to develop drug-resistant epilepsy after autoimmune encephalitis. It occurred in 16% of patients with autoimmune encephalitis in our analysis.
  • We also identified that a key risk factor for the development of drug-resistant epilepsy after autoimmune encephalitis was people who experienced status epilepticus 
  • On EEG, large spikes of abnormal electrical activity called ‘periodic discharges’ combined with their specific location in the brain can predict the development of drug-resistant epilepsy after autoimmune encephalitis.

epilepsy ae 500x266 - Continuing My Way Up The Slippery Slope: A Poem

Figure 1: This figure shows a summary of our findings with 208 patients with autoimmune encephalitis, 16% had severe form of seizures (SE; status epilepticus), 75% of patients had 1 or more seizures, and 25% did not have seizures at their initial admission. Then after 12 months follow up, 16% of patients who completed follow up, had DRE (drug resistant epilepsy), and 33% of the patients were on anti-seizure medications (ASM) and 48% did not require ASMs.

 

What do these findings mean?

The research could help clinicians to –

  1. Identify those patients with autoimmune encephalitis at risk of developing drug-resistant epilepsy and potentially change their treatment strategy (creating a risk assessment tool to use in practice), and
  1. Address risk factors such as status epilepticus with the goal to try and reduce the long-term risk of drug-resistant epilepsy.

 —-

For more information and resources from Dr. Monif and her group at the Australian Autoimmune Encephalitis Consortium Project, visit this link here. To download a plain language PDF of the paper summarized in this blog, click the button below:

 

Click here or the image below to subscribe to our mailing list:

subscribe - Halloween Ideas

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

 

Tabitha Orth 300x218 - Epilepsy and Autoimmune Encephalitis

On June 16 th, 2022, Tabitha Orth, President and Founder of International Autoimmune Encephalitis Society officially became the 7,315 th “point of light”. Recognized for the volunteer work she and IAES has done to spark change and improve the world for those touched by Autoimmune Encephalitis. The award was founded by President George H.W. Bush in 1990.

guidestar platinum logo 300x300 1 e1605914935941 - Epilepsy and 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 IAES@autoimmune-encephalitis.org  

 

 

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 - Epilepsy and 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 - Epilepsy and Autoimmune Encephalitis

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

why zebra - Aphasia as a Symptom of Autoimmune Encephalitis
The Little AE Warrior Whose Story of Valor Became Legendary

The Little AE Warrior Whose Story of Valor Became Legendary

April 15, 2018 | Devon Frakes Fults

Preamble ~

Female warriors in history who engaged in war are found throughout mythology and folklore.  A mythological figure does not always mean a fictional one, but rather, someone of whom stories have been told that have entered the cultural heritage of a people as mortal heroines.

Some women warriors are documented in the written record and as such form part of history.  However, to be considered a warrior, the woman in question must have belonged to some sort of recognized legion. In this case, the autoimmune encephalitis community. Today we document the story of Hadley.  A little warrior whose battle over insurmountable odds lead her to victory. Hadley’s story is not a legend. Hadley’s story is legendary. Therefore, we enter it into the cultural heritage of our people, the AE community, and mark Hadley into our history as a mortal present-day heroine.

Just over two years ago we woke up to what we thought was a normal Monday and found ourselves by days end standing in the Texas Children’s emergency room with our three year old daughter Hadley in a coma and near death.

I laid down next to my perfectly healthy daughter on Sunday evening and didn’t wake up to the same girl next day. At some point during the night, her immune system launched a wicked attack on her brain. We would later be given a name for this incurable beast, Autoimmune encephalitis. Hadley awoke with a headache and mild vomiting. By early afternoon she would be hallucinating and unable to see. By the time we made the 45-minute trip to the emergency room, she would be mostly unconscious and no longer know who we were. By the time we would have her transported to Texas Children’s Hospital, her blood pressure had declined to a frightening and life threatening 45/25.  Hadley’s glucose level was only 11 and her core temperature had already begun to drop.  Hadley had entered coma.

 We arrived at Texas Children’s Hospital with her having only minutes to live. Within two days we were told her brain was swelling.  We faced saying what we feared were our final goodbyes just before the doctors placed her on a ventilator. Our Hadley was a Warrior. She fought the disease that was wreaking havoc with her brain and awakened from coma.  Having come out of the coma, Hadley was challenged to have to learn to walk, talk, and eat again.  She had to learn who her Mom and Dad were having lost all memory of her family and who and what was familiar to her.  She battled her way back through hallucinations and countless hours of therapy.

 

Little did we know what the next two years would hold… 30 days inpatient with 9 days in PICU, 10 days in a coma, 17 days on a feeding tube, 8 days on a ventilator, 45 outpatient appts, 1 72 HR EEG, 3 short EEGs, 3 MRIs, 1 MRA, 3 cat scans, 3 lumbar punctures, 2 radioactive thyroid scans, 3 ultrasounds, 1 central line. Too many IVs to possibly count.  20 months of IVIG. 1 5-day steroid burst, 2 ER visits.

We have been battling this beast, Autoimmune Encephalitis, for two years now and Hadley has been declared to be in remission! We have seen tremendous progress. God has been so good!  Of course, we are not the same people we were two years ago. You cannot walk a journey like this one and remain unscathed. I’d be lying if I told you we had it all figured out. There are days we still grieve but most days we find ourselves overwhelmed by Gods goodness.

The IAES has been a huge resource for us! They recently walked us through an insurance appeal when our daughter’s insurance denied her life saving IVIG treatment! Within 48 hours I had all I needed in hand to appeal and win! This treatment was vital to Hadley’s care.  International Autoimmune Encephalitis Society has been a huge support in helping us advocate for Hadley and help us get her to where she is today: remission.

 Hadley Today

 


Donate to Support IAES and our Life Saving Mission


International Autoimmune Encephalitis Society (IAES) is a Family/Patient centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey.

Driven by the knowledge that “Education is Power”, International Autoimmune Encephalitis Society manages an educational support group for patients diagnosed with Autoimmune Encephalitis and their loved ones, empowering them to be strong self-advocates and advocates that will lead them to best outcomes and recovery. We are the premiere organization leading in these vital roles.

The Dark side of anti-NMDAr encephalitis – A Mother’s Story

The Dark side of anti-NMDAr encephalitis – A Mother’s Story


Donate to Support IAES and our Life Saving Mission


International Autoimmune Encephalitis Society (IAES) is a Family/Patient centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey.

Driven by the knowledge that “Education is Power”, International Autoimmune Encephalitis Society manages an educational support group for patients diagnosed with Autoimmune Encephalitis and their loved ones, empowering them to be strong self-advocates and advocates that will lead them to best outcomes and recovery. We are the premiere organization leading in these vital roles.

Your Tax deductible donations help us save lives and quality of lives.

Young Texas Woman with anti-NMDAr Encephalitis fights for her Life and the Life of her unborn child

Young Texas Woman with anti-NMDAr Encephalitis fights for her Life and the Life of her unborn child


Donate to Support IAES and our Life Saving Mission


International Autoimmune Encephalitis Society (IAES) is a Family/Patient centered organization that assists members from getting a diagnosis through to recovery and the many challenges experienced in their journey.Driven by the knowledge that “Education is Power”, International Autoimmune Encephalitis Society manages an educational support group for patients diagnosed with Autoimmune Encephalitis and their loved ones, empowering them to be strong self-advocates and advocates that will lead them to best outcomes and recovery. We are the premiere organization leading in these vital roles.

Your Tax deductible donations help us save lives and quality of lives.

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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