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.45–47 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? :
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
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
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.
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.