Evaluation of the Cunningham Panel™ in pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS): Changes in antineuronal antibody titers parallel changes in patient symptoms

Abstract

Objective: This retrospective study examined whether changes in patient pre-and post-treatment symptoms correlated with changes in anti-neuronal autoantibody titers and the neuronal cell stimulation assay in the Cunningham Panel in patients with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). Methods: In an analysis of all tests consecutively performed in Moleculera Labs' clinical laboratory from April 22, 2013 to December 31, 2016, we identified 206 patients who were prescribed at least one panel prior to and following treatment, and who met the PANDAS/PANS diagnostic criteria. Patient follow-up was performed to collect symptoms and treatment or medical intervention. Of the 206 patients, 58 met the inclusion criteria of providing informed consent/assent and documented pre-and post-treatment symptoms. Clinician and parentreported symptoms after treatment or medical intervention were categorized as "Improved/Resolved" (n = 34) or "Not-Improved/Worsened" (n = 24). These were analyzed for any association between changes in clinical status and changes in Cunningham panel test results. Clinical assay performance was also evaluated for reproducibility and reliability. Results: Comparison of pre-and post-treatment status revealed that the Cunningham Panel results correlated with changes in patient's neuropsychiatric symptoms. Based upon the change in the number of positive tests, the overall accuracy was 86%, the sensitivity and specificity were 88% and 83% respectively, and the Area Under the Curve (AUC) was 93.4%. When evaluated by changes in autoantibody levels, we observed an overall accuracy of 90%, a sensitivity of 88%, a specificity of 92% and an AUC of 95.7%. Assay reproducibility for the calcium/calmodulin-dependent protein kinase II (CaMKII) revealed a correlation coefficient of 0.90 10 −6 ) and the ELISA assays demonstrated test-retest reproducibility comparable with other ELISA assays. Conclusion: This study revealed a strong positive association between changes in neuropsychiatric symptoms and changes in the level of anti-neuronal antibodies and antibody-mediated CaMKII human neuronal cell activation. These results suggest there may be clinical utility in monitoring autoantibody levels and stimulatory activity against these five neuronal antigen targets as an aid in the diagnosis and treatment of infection-triggered autoimmune neuropsychiatric disorders. Future prospective studies should examine the feasibility of predicting antimicrobial and immunotherapy responses with the Cunningham Panel.

Pro‐inflammatory dopamine‐2 receptor‐specific T cells in paediatric movement and psychiatric disorders

“…Some D2R-specific T-cellpositive patients, however, exhibited disease exacerbation upon infection, suggesting that an activated immune response could erroneously target self-proteins as a bystander effect of fighting an infection. 25,83 This notion has been demonstrated in a murine model wherein repeated infections led to the expansion and migration of Th17 cells from the peripheral lymph nodes to the brain. 26 Once in the brain, these reactive T cells induced secretion of IL-17A, activation of microglia and breakdown of the BBB, which could augment neuroinflammation.…”

“…This finding adds to the growing reports of neuroimmune encephalitis cases that are negative for known neuronal antibodies, but are responsive to immunotherapy. 49,50 D2R antibodies can be detected with methodologies such as an ELISA 13,15,16,22,25 ; however, the live cell-based assay used in this study is a widely accepted method for neuronal antibody detection. Thus, the detection of D2R-specific T cells may define a subset of movement and psychiatric disorders.…”

“…19 Additionally, D2R antibodies can be useful in identifying patients who can be amenable to immunotherapy. 17,[21][22][23][24][25] The field has focused predominantly on aberrant antibody responses and less is known about the autoreactive T-cell response against D2R in movement and psychiatric disorders. Cellular immunity is a major compartment of the adaptive immune response, and in particular, CD4 + T helper cells are key in orchestrating the effects of other immune cells and molecules.…”

“…The precise mechanisms underlying autoimmunity in these disorders remain unclear, but it has been postulated that D2R antibodies may alter dopaminergic signalling by stimulating excess dopamine secretion, 20 inducing inhibitory D2R signalling 16 and triggering receptor internalisation 19 . Additionally, D2R antibodies can be useful in identifying patients who can be amenable to immunotherapy 17,21–25 …”

Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge

“…Furthermore, Hashimoto encephalopathy in conjunction with psychiatric symptoms and thyroid autoimmunity must be excluded by thoroughly investigating the existence of antibodies against thyroid peroxidase (TPO) and thyroglobulin (TG) ( Barbero et al 2019;Barbuti et al 2017). In children, it is important to screen for pediatric autoimmune neuropsychiatric disorder, which is associated with streptococcal infections (PANDAS) entailing a tic disorder together with preceding streptococcal infections revealing antibodies against streptococcal proteins, human brain enolase or neural tissue (Nicollini et al 2015;Shimasaki et al 2020). Another neuropsychiatric syndrome occurring in children and young adults is Rasmussen encephalitis: a chronic neuroinflammation of one hemisphere along with drug-resistant seizures and severe cognitive dysfunction (Varadakar et al 2014).…”