Research

Avis Chan ¹, Angeline Truong ², Bahare Farhadian ³, Theresa Willett ², Melissa Silverman ¹, Paula Tran ¹, Margo Thienemann ² and Jennifer Frankovich⁴, ¹Stanford University School of Medicine, Palo Alto, ²Stanford University School of Medicine, Palo Alto, California, ³Stanford Immune Behavioral Health Clinic and PANS Research Program at Lucile Packard Children’s Hospital, Palo Alto, ⁴Stanford

Conclusion: Our study shows that CFS/ME occurs in 1 in 6 patients with AEO-OCD. The prevalence rate is much higher than the general adolescent population (1 in 100-200). This underscores the need to systematically assess fatigue in this group of patients. Future studies should determine possible shared biological underpinnings between AEO-OCD/PANS and CFS/ME.

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Zheng J, Frankovich J, McKenna ES, et al. Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging. JAMA Netw Open. 2020;3(5):e204063. doi:10.1001/jamanetworkopen.2020.4063

In this case-control study of 34 consecutive patients with pediatric acute-onset neuropsychiatric syndrome who had 3 Tesla magnetic resonance imaging, all assessed brain regions, particularly the deep gray matter (eg, the thalamus, basal ganglia, and amygdala), had statistically significantly increased mean diffusivity compared with 64 control participants. These diffusion abnormalities are consistent with the cardinal clinical symptoms of these patients, including obsessions, compulsions, emotional dysregulation, and sleep disturbances.

Meaning  Diffusion-weighted magnetic resonance imaging may offer valuable quantitative information to assist with the diagnostic workup of pediatric acute-onset neuropsychiatric syndrome.

Benefits of IVIG in Pediatric Acute-Onset Neuropsychiatric Syndrome

Isaac Melamed, Roger Kobayashi, Maeve O’Connor, Ai Lan Kobayashi, Andrew Schechterman, Melinda Heffron, Sharon Canterberry, Holly Miranda, Nazia Rashid Neurology Apr 14 2020, 94

“Conclusions: In PANS, which may be associated with an underlying immune dysregulation, IVIG [Octagam 5%] successfully ameliorated psychological symptoms and dysfunction, with sustained benefits for at least 8 weeks, and up to 46 weeks, following the final infusion. In addition, baseline immune and autoimmune profiles demonstrated significant elevations in a majority of subjects, which requires further evaluation, characterization, and study to clarify the potential immune dysfunction by which PANS manifests and progresses.”

Loffredo, L., Spalice, A., Salvatori, F., De Castro, G., Guido, C. A., Zicari, A. M., Ciacci, P., Battaglia, S., Brindisi, G., Ettorre, E., Nocella, C., Salvatori, G., Duse, M., Violi, F., & Carnevale, R. (2020). Oxidative stress and gut-derived lipopolysaccharides in children affected by paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. BMC pediatrics, 20(1), 127. https://doi.org/10.1186/s12887-020-02026-8

“This study shows that children affected by PANDAS have high circulating levels of sNOX2-dp, isoprostanes and of LPS that could be involved in the process of neuroinflammation.”

GiuseppaPiras, LorenzaRattazzi
Brain, Behavior, and Immunity, 29 February 2020

Patients with obsessive compulsive disorder (OCD) have increased levels of Immuno-moodulin (Imood), a protein in their lymphocytes, a type of immune cell.

Anxious mice returned to normal in a couple of days after being given an antibody that blocked Imood. Twenty-three people with OCD and twenty healthy people without OCD were tested; Imood expression was about six times higher in those with OCD. Additional research indicates the same protein, Immod, is elevated in ADHD.

Anti-lysoganglioside and other anti-neuronal autoantibodies in post-treatment Lyme Disease and Erythema Migrans after repeat infection

Brian A.Fallon, BarbaraStrobino, SeanReim, JulieStoner, Madeleine W.Cunningham Brain, Behavior, & Immunity – Health, Volume 2, February 2020, 100015. https://doi.org/10.1016/j.bbih.2019.100015

This study examines molecular mimicry targeting neural tissue after Borrelia burgdorferi (Bb) infection. Patients with Lyme disease have a greater frequency of specific anti-neuronal autoantibodies and functional neuronal activation compared to community controls without a history of Lyme disease.

“Highlights

• The EM ​+ ​prior LD group had significantly elevated anti-neuronal antibodies.
• The EM ​+ ​prior LD group had significantly elevated CaM Kinase activation.
• Anti-Lysoganglioside Antibodies are significantly elevated in the PTLS group.
• Prior infection may lead to immune priming and increased autoantibodies.”

Ajmone-Cat MA, Spinello C, Valenti D, Franchi F, Macrì S, Vacca RA, Laviola G. Journal of Clinical Medicine. 2019; 8(10):1514. DOI: 10.3390/jcm8101514

• Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions.
• Results show chronic psychosocial stress altered the expression of neuroinflammatory markers in the hippocampal and hypothalamic regions, exacerbated the neuroinflammatory alterations induced by experimental GAS exposures in the same areas.
• Psychosocial stress exacerbated individual response to GAS administrations whereby mice exposed to both treatments exhibited altered cytokine and immune-related enzyme expression in the hippocampus and hypothalamus.
• Showed impaired mitochondrial respiratory chain complexes IV and V, and reduced adenosine triphosphate (ATP) production by mitochondria and ATP content.
• These brain abnormalities, observed in GAS-Stress mice, were associated with blunted titers of plasma corticosterone.
• Present data support the hypothesis that challenging environmental conditions, in terms of chronic psychosocial stress, may exacerbate the long-term consequences of exposure to GAS processes through the promotion of central immunomodulatory and oxidative stress.

Platt, Maryann P.
Columbia Academic Commons-2019 Theses Doctoral

Taken together, these data demonstrate the pivotal role of Th17 lymphocytes in brain pathology and olfactory processing deficits after recurrent GAS infections in our mouse model. Our intranasal inoculation model supports the conclusion that post-infectious BGE is autoimmune in nature, despite the absence of behavioral symptoms in this model. Using multiple mouse models of post-infectious BGE may allow us to study distinct facets of disease pathogenesis. Finally, this work underscores the ability of T cells to incite neuroinflammation, provides a useful clinical diagnostic test in olfactory functional assessments, and lends support to T cell immunotherapy strategies in patients with post-infectious BGEs.

Madeleine W. Cunningham
Microbiology Spectrum-August 2019
Author manuscript – In advance of print

The studies suggest 1) that the antibodies against streptococci and brain in Sydenham chorea and related diseases produce CNS dysfunction through a neuronal signal transduction and subsequent excess dopamine release mechanism and 2) that the molecular targets of the chorea antibodies include lysoganglioside and the dopamine receptors in neuronal cell membranes. The anti-neuronal autoantibodies also target the group A streptococcal carbohydrate epitope N-acetyl beta-D-glucosamine present on the rhamnose backbone of the carbohydrate and present in the cell membrane and wall of the group A streptococci as well as the intracellular brain protein tubulin. The diagram in Figure 15 illustrates proposed events of how antineuronal autoantibodies against lysoganglioside and the dopamine receptors D1 and D2 may function in Sydenham chorea and PANDAS (3).

Mona Gerentes, Antoine Pelissolo, Krishnamoorthy Rajagopal, Ryad Tamouza, Nora Hamdani,
Anxiety Disorders-August 2019

This review highlights that OCD is associated with low-grade inflammation, neural antibodies, and neuro-inflammatory and auto-immune disorders. In some subset of OCD patients, autoimmunity is likely triggered by specific bacterial, viral, or parasitic agents with overlapping surface epitopes in CNS. Hence, subset-profiling in OCD is warranted to benefit from distinct immune-targeted treatment modalities.