The autoimmune response and neuropsychiatric disorders

There are tens of thousands of in vitro diagnostic (IVD) tests commercially available, but assays to accurately diagnose neuropsychiatric and mental disorders are conspicuous by their absence from the diagnostic arsenal. Conditions such as Parkinson’s disease, Alzheimer’s disease, autism spectrum disorder (ASD), chronic depression, bipolar disorder, and schizophrenia have few, if any, accurate IVD tests. Is it because these conditions have been clinically diagnosed for so long that there is not a perceived need, or is it that the underlying etiologies of these conditions are not sufficiently understood? One such case—shown to be reversible with proper diagnosis and treatment—suggests it could be the latter.

Pediatric neuropsychiatric symptoms

In this instance, a healthy three-year-old boy’s life was abruptly altered by unexplained and uncontrollable neuropsychiatric symptoms and incapacitating anxiety. Isak was diagnosed with sensory processing disorders, oppositional defiance disorder, and obsessive-compulsive disorder (OCD). Prozac was prescribed, but by five years of age he showed no improvement. His life and that of his family were seemingly altered forever. Then, three-and-a-half years later, he was prescribed a common antibiotic for an infection—and most of his symptoms vanished within days. The results were, to say the least, dramatic.

Isak’s case was described in an article with the arresting title, “Yes, You Can Catch Insanity.”¹ Isak had a condition called PANDAS: pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection. PANDAS is an autoimmune neuropsychiatric condition that results in motor and neurologic symptoms such as OCD, motor tics, aggression, rage, phobia, and a host of other symptoms subsequent to a strep infection. Infections other than strep are now known to be associated with these same symptoms, and thus the broader term pediatric acute-onset neuropsychiatric syndrome, or PANS, has been coined.²

One mechanism believed to account for this post-infectious neuropsychiatric condition, as well as other autoimmune disorders, is a process known as molecular mimicry. Segments of the body have structural characteristics or protein sequences similar to those of natural invaders such as bacteria, viruses, parasites, and other infectious organisms. Although the immune system generally can distinguish “self” from “non-self,” somehow this recognition process goes awry, and it perceives the body’s own organs, tissues, and proteins as foreign.

How does this happen? The 20-amino acid alphabet that spells out the body’s proteins is finite, and at some point, invading organisms will have an “epitope” or recognition site that is homologous to some portion of the body’s own proteins. In certain cases, the immune system thus unleashes “friendly fire” on its own troops; it is programmed to attack “self.”

When the self-target is the brain, particularly the basal ganglia, an inflammatory reaction can result and produce various neurologic and neuropsychiatric symptoms. There are more than 80 known autoimmune diseases and disorders. Not all are known to be triggered by an infection. However, there is a growing body of evidence that many autoimmune disorders are indeed preceded by an infection in which there is homologous recognition of the infectious agent and self-targeting by the immune system.³

In the case of PANDAS/PANS, when the underlying root etiology is treated there is remarkable and often dramatic improvement in a patient’s neuropsychiatric symptoms. When these conditions are the result of an infection trigger, which is often subclinical and coupled with an immune system dysfunction, the most effective treatments are anti-infectives and immune system modulators.^4,5

Inflammation and neurological disorders

Medical researchers are thus concluding that inflammation, or an overactive immune system, may be linked to an array of mental and neurological disorders, including chronic depression, schizophrenia, and Alzheimer’s disease. In the past it has been presumed that the brain was a privileged organ system with very limited access and activity connected to the rest of the body. However, more research has proved that this is not the case. This area of medical research has been gaining acceptance and becoming better understood in a growing field known as neuroimmunology or immunopsychiatry. Certain targets in the basal ganglia that are responsible for cognition and motor movement, such as the dopamine D1 and dopamine D2 receptors, are autoimmune targets in patients with neuropsychiatric symptoms.^6,7

There is mounting evidence that neuroinflammation and various brain-specific antibodies are associated with ASD.⁸ There is a clear need for greater understanding of the immune system’s role in this condition, and an acute need for new biomarkers that can accurately diagnose or aid in the diagnosis of ASD and other neuropsychiatric disorders. Once the diagnostic validity of these biomarkers is confirmed, research may be able to help usher in better treatments that more precisely target the etiology of these disorders. These biomarkers also may be able to assist in monitoring a patient’s clinical outcome.

There is a growing population of individuals, some as young as three years old, who are routinely prescribed therapeutic regimens of psychotropic drugs without consideration of whether the underlying etiology is autoimmune-based. As our understanding of the immune system and its relationship to chronic debilitating neurological and neuropsychiatric disorders grows, better models for diagnosis and treatment may soon be available to children like Isak.

REFERENCES

1. Andrew Curry. Yes, You Can Catch Insanity. Nautilus, 2015. http://nautil.us/issue/23/dominoes/yes-you-can-catch-insanity.
2. Chang K, Frankovich J, Copperstock M, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2015;25(1):3-13.
3. Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol. 2012;42(1):102-111.
4. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. The Lancet. 1999;354(9185):1153-1158.
5. Kovacevic M, Grant P, Swedo SE. Use of intravenous immunoglobulin in the treatment of twelve youths with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):65-69.
6. Ben-Pazi H, Stoner JA, Cunningham MW. Dopamine receptor autoantibodies
   correlate with symptoms in Sydenham’s chorea. PLoS One. 2013;8(9):p.e73516.
7. Cunningham MW, Cox CJ. Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond. Acta Physiol (Oxf). 2016;216(1):90-100.
8. Goine P, Van de Water J. The immune system’s role in the biology of autism. Curr Opin Neurol. 2010;23(2):111-117.

Craig Shimasaki, PhD, MBA is President and CEO of Moleculera Labs, a precision medicine diagnostic laboratory that focuses on testing for neuropsychiatric disorders triggered by an autoimmune response. The company is a CLIA/COLA accredited clinical laboratory that provides the Cunningham Panel, a sequence of five assays that measures autoimmune antibody activity against brain and neurological receptors.