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Revisiting Anti-NMDA Receptor Encephalitis and Autism

EncBy Teresa Conrick

It was four years ago that I first became interested in the connections of Autism and a particular type of encephalitis on the rise:

Late Onset Autism and Anti-NMDA-Receptor Encephalitis: Part 1

Late Onset Autism and Anti-NMDA Receptor Encephalitis Part 2

Anti-NMDA-Receptor Encephalitis Added to DSM A Medical Causation of Autism

In 2016, Brain on Fire , the book written by Susannah Cahalan, describing her descent into Anti-NMDA Receptor Encephalitis, is scheduled to be on the big screen.  It should be an excellent film as her book is a best-seller. I emailed back and forth with Susannah back when I read her book, as my daughter, Megan, who has both an Autism diagnosis and an autoimmune diagnosis, was having some symptoms that seemed to parallel what research was beginning to show and which  Susannah had described in her book. She was very kind and thoughtful, and since then, the connections of more cases seem to be increasing. This quote from Susannah in Brain on Fire, made this significance even more dramatic and real:

Many children ultimately diagnosed with anti-NMDA autoimmune encephalitis were first determined to be autistic.  How many children originally first diagnosed with autism weren't able to find their autoimmune diagnosis?  p 224  

There is no question that the immune system is involved in both.  As time marches on, more research is showing the connections:

Anti-NMDA receptor encephalitis is a recently described autoimmune disorder mediated by antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor.,,,,,We report about a 15-year-old female patient who was diagnosed with anti-NMDA receptor encephalitis after receiving a booster vaccination against tetanus/diphtheria/ pertussis and polio (TdaP-IPV). Within the first 24 h after the injection she developed a low-grade fever and general fatigue. During the following weeks, her family observed an unusual need for sleep. Psychiatric symptoms became apparent 5 weeks after the immunization....The onset of prodromal symptoms shortly after the immunization is intriguing and suggests the vaccination as a possible trigger of anti-NMDA receptor encephalitis........ To our knowledge, this is the first possible case of vaccination associated anti-NMDA receptor encephalitis. Therefore, not only infectious agents and tumor antigens but also vaccines should be considered as a possible trigger of immune response in this recently described disorder.  

This study on Autism and Anti-NMDA skims the surface and relies on “genetic ablation or pharmacological rescue” – translation – a drug to be invented with little regard on causation: NMDA receptor dysfunction in autism spectrum disorders

Abnormalities and imbalances in neuronal excitatory and inhibitory synapses have been implicated in diverse neuropsychiatric disorders including autism spectrum disorders (ASDs). Increasing evidence indicates that dysfunction of NMDA receptors (NMDARs) at excitatory synapses is associated with ASDs.    

This gives us more of an accurate picture:

Two patients developed the disorder after vaccination against H1N1 influenza (JD, personal observation), and one patient after a booster vaccination against tetanus, diphtheria, pertussis, and poliomyelitis.43 A 3-year-old child had a microdeletion in the short arm of chromosome 6 that involved the HLA cluster, leading investigators to suggest a predisposition to autoimmunity.44 A similar propensity to autoimmunity has been suggested in patients, mostly children, who had, in addition to NMDAR antibodies, antinuclear or thyroid peroxidase antibodies, or both.12 These findings suggest that racial and genetic factors might predispose individuals to this type of autoimmunity, as shown in myasthenia gravis and Lambert-Eaton syndrome, which also occur as paraneoplastic or non-paraneoplastic syndromes.4547 In this context, non-specific systemic infections or vaccinations can act as an adjuvant of the autoimmune response. 

More recently we see yet another reported case but how many cases are not being investigated? :

Abstract

Anti N-methyl-d-aspartate (NMDA) receptor encephalitis in children is associated with psychiatric changes, seizures, and dyskinesias. We present the first report of autistic regression in a toddler caused by this entity. A 33-month-old boy presented with decreased appetite, irritability, and insomnia following an upper respiratory tract infection. Over the next few weeks he lost language and social skills, and abnormal movements of his hand developed. Within a month, this patient came to fit the diagnostic criteria for autistic spectrum disorder. Upon investigation, anti-NMDA receptor antibodies were found in the boy's cerebrospinal fluid. He was treated with intravenous immunoglobulins and steroids, resulting in reacquisition of language and social skills and resolution of movements. Our case emphasizes the significance of suspecting anti-NMDA receptor encephalitis as the cause of autistic regression, even in an age group where the diagnosis of autistic spectrum disorder is typically made, and especially when presentation follows a febrile illness.

Let’s add in more puzzle pieces that may fill in the picture:

.....several studies have revealed that mercury levels in brain tissues are 2–10 fold higher in patients with dental amalgam fillings, Alzheimer’s disease, autism spectrum disorders, epilepsy or hydrocephalus [35–38]....NMDA receptors have been shown to play a pivotal role in mercury-induced neurotoxicity [19, 28].

The results reveal complex interactions of thimerosal and mercuric ions with the GABA(A) and NMDA receptors. 

NR1 and NR2b [NMDA] glutamate receptor immunoreactivity patterns are abnormal in the hippocampi of thimerosal treated SJL mice 

A patient with encephalitis associated with NMDA receptor antibodies  

NMDAR antibodies are present in serum and CSF, usually with intrathecal synthesis, and are sometimes only detected in the CSF. The main target epitopes are in the NR1/NR2 heteromers of the NMDAR. The major antigen is NR1/NR2B, which is predominantly expressed in the hippocampus and forebrain….

Because I see many connections with the MICROBIOME to Autism, I wondered if there were any possible connections to NMDA receptors. There could be and I hope some researchers will investigate more as there seems to be an interplay here that really needs more attention.  Follow the connection:

Gut bacteria [ie.CLOSTRIDIA]  > Propionic Acid  > Inflammation  > NMDA RECEPTOR ENCEPHALITIS

Children with autism had 9 species of Clostridium not found in controls

Clostridia, a family of heterogeneous anaerobic, spore forming Gram-positive rods. Clostridia are major gut colonizers in early life and many of which are producers of PPA [propionic acid]

Propionic acid can increase N-methyl-D-aspartate (NMDA) receptor sensitivity

Colonization of Clostridium or other bacterial species in the gut could promote immune responses    that cross-react with the AQP4 and NMDA receptor proteins. Alternately, we speculate that NMO-related inflammation could “reveal” CNS antigens to the immune system, resulting in a secondary inflammatory response similar to that proposed for HSV and NMDA receptor encephalitis.7 We suggest that patients presenting with encephalitis be systematically screened for the presence of anti-NMO/AQP4 and anti-NMDA receptor antibodies in serum and CSF.

Last year, this study was done as the numbers were increasing of young children being diagnosed with Anti-NMDA Receptor Encephalitis:

In the pediatric population, reports of anti-neuronal antibody-mediated autoimmune encephalitis have also been rapidly increasing, thus leading to an expansion of the clinical spectrum of this type of encephalitis.

All patients were required to be immunocompetent, younger than 18 years, and present with acute encephalopathy plus one or more of the following features: seizure, dyskinesia, psychiatric symptom, and behavioral symptom. Among them, patients with a proven viral or bacterial etiology in the early stage of disease by culture, or with a strong suspicion of other central nervous system (CNS) inflammatory disease by imaging studies, such as acute disseminated encephalomyelitis, were excluded from the study…. Among the 23 patients enrolled in the study, eight patients (35%, 8/23) were positive for the anti-NMDA receptor antibody… One 7-month-old girl (Patient 1) presented with developmental regression accompanied by loss of expressive language skills, including babbling or cooing…. Three patients (Patients 1–3) showed selective aphasia or mutism without definite decrease in consciousness. One patient (Patient 7) who had underlying insulin-dependent diabetes mellitus and autism showed bizarre, violent behavior and loss of communication skills in his clinical course without decreased mentality…. The present study, which tested six anti-neuronal antibodies, showed that nine out of 23 patients (45%, 9/23) had a positive result. Most of the positive test results were confined to anti-NMDA receptor antibody (eight out of nine positive patients)…… Of the 10 infant- and toddler-onset patients listed in these reports, seven patients exhibited speech arrest or mutism, in addition to seizures, behavioral changes, and dyskinesia. Although the clinical features were not uniformly described in detail, most of the patients did not appear to experience typical multistage illness. Thus, aphasia or mutism needs to be carefully examined in this age group and warrants further research on the possible age-specific pathogenesis of anti-NMDA receptor encephalitis on language function and development…. When considering expanding the clinical spectrum of these diseases, especially in infant- and toddler-onset anti-NMDA receptor encephalitis, testing a broad spectrum of suspected patients is recommended.

Much research is showing a picture of increasing diagnoses and those in the trenches of these studies want the children to be helped quickly:

We suggest that patients presenting with encephalitis be systematically screened for the presence of anti-NMO/AQP4 and anti-NMDA receptor antibodies in serum and CSF.

When considering expanding the clinical spectrum of these diseases, especially in infant- and toddler-onset anti-NMDA receptor encephalitis, testing a broad spectrum of suspected patients is recommended.

Positive clinical outcome is dependent on immediate testing, especially in REGRESSION, BEHAVIORAL CHANGES and LOSS OF LANGUAGE, symptoms often seen in Autism.

Teresa Conrick is Contributing Editor to Age of Autism.

Comments

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Michelle

Are there any Doctors that will currently test Children with Autism for the NMDA antibodies? My youngest child has Autism but also Dystonia a movement disorder. His involuntary movements started after his very 1st set of immunizations which he got very sick from. As a side note I had an ovarian teratoma removed when I was younger. I also have E-Antigen antibodies in my RH that caused complications in 2 of my pregnancies. Any info would be greatly appreciated.

twinrn29

Teresa,
My research for my son has headed exactly in this direction. Look at primary immunodeficiency. Look at the compliment immune system and the mannose binding lectin pathway. MBL is a send out to Mayo clinic. Look at AH50 and CH50....they are the end of the cascade of the complement immune system. The compliment immune system also has been found to have a role in synapse pruning. Interestingly there are findings that excess of MBL is implicated in schizophrenia. I always love your work!

Linda1

Teresa and All,
I will double post this interview that Jeffrey Smith did a few days ago with Zach Bush MD. Talking about the healing the microbiome. He has a product called Restore. I have not read the whole transcript yet. Looks important (audio and transcript):

http://restore4life.com/conference-call-with-jeffrey-smith-zach-bush/

Benedetta

And so Teresa;

You did or did not do the spinal tap for Meg?

We to have high antinuclear antibodies in my husband's blood and daughter's blood only! It was explained to us that the muscles are being broken down and that is what causing it. Simple and wrong explanation I am sure. IT probably is the very thing that is breaking down the muscles, causing pain and interfering with the mitochondria. My guess?

WE did have a spinal tap -- well 2 when my daughter was two and she had kawasakis. And for my husband recently because he thought he had meningitis - his neck and head hurt so bad.

Apparently this is not what they are looking for; they are looking for white blood counts that points to infection. cause the medical field is geared to infectious diseases. So, even if they did find them they would not have mentioned them and that is why I guess it is good to get a copy of a lab report in our own hot little hands.

They dismissed the author of this book's slightly high antinuclear antibody count from her spinal tap, and they would ours too.

Even when the did pay attention to the abnormal count in her spinal fluid - they still went on ahead and did a brain biopsy. Was that because it was to prove her condition? Probably.

Benedetta

I ordered the book and I guess it is close to the season and things have really geared up because it came the 19th - Three days!

Thanks for drawing my attention to this book.
It was excellent.

Susannah did a great job - of explaining how she perceived the world and then explained at the same time what parts of the brain are affected and how it controlled her preceptions of the world.

She did mention in the end of the book; since she too is thinking hard what it could be; that after her inflammation of her brain - that her cat while she was in the hospital also had inflammation problems with it's stomach.

This sort of thing has been going on for a long time - stories and all cultures.
But the national stats -I hate to give the CDC any credit but I guess they are collecting them - tells us that mental illness and auto immune diseases are rising.

And in our pets too.

But her having the most dangerous skin cancer at such a young age also shows that she was having trouble with her immune system before all of this.

She mentions eating jelly beans - I wonder if she watches her diet now?

Susan

Thank you, Teresa. Just bought the book and read the reactions of NMDA autoimmune encephalitis. My daughter, just got back from Japan and was experiencing these same reactions. Fortunately, we got her to a gastroenterologist and removed the tumor which was causing her the problem. She is much better now and is almost back to her old self. This is a serious illness and hoping others look into it, as it truly causes tremendous harm. We had gone to three doctors before we got on the right path. Keep educating the parents. And parents keep asking questions!

Lisa

Thank you, Teresa and others, for this information.

Visitor

"Good health starts with brain health." Lol this is a hospital's slogan. When are the Peds going to speak up?

BCL

We also just had this testing done on our child (not the CSF). It came back negative.

BTW, Dr. Souhel Najjar is the leading expert in Anti-NMDA Receptor Enceph. if anyone is interested in looking into this further.

Jeannette Bishop

Thank you for compiling these reports.

Teresa Conrick

Need to add that Meg is 22. She is not little and has been battling immune and now autoimmune issues her whole life. It is horrendous that there is not enough help for these very sick kids and now adults.

Teresa Conrick

Hi,

We did blood and I do think Blue Cross paid...but I would call first to confirm. We did not do csf. Not sure if this was the lab but it's similar. Meg was negative on Anti-NMDA but came back positive on antinuclear antibodies and GAD65. We may need to educate some of the doctors as they are just not familiar with some of this.

http://ltd.aruplab.com/Tests/Pub/2004221

kapoore

I hope this information is going down the food chain to your average pediatrician who never bother to test for any type of encephalitis after vaccination.

Lisa

I have exactly the same questions as AnneJ has. Are these serum tests available through LabCorp and/or Quest, or do these require specialty labs (which are usually out of network for us)? Also, are these tests considered valid, or is this still considered to be in the realm of experimental?

AnneJ

..."We suggest that patients presenting with encephalitis be systematically screened for the presence of anti-NMO/AQP4 and anti-NMDA receptor antibodies in serum and CSF."

How do you test for this? What type of specialists would order this test (and what reputable laboratories perform this testing)?

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