Research

Tetracyclines for COVID-19 Neurological and Neuropsychiatric Manifestations to treat Neuroinflammation

Highlights

• Neuropsychiatric symptoms were reported during COVID-19.
• Coronaviruses have neuroinvasive potential and induce a potent neuroinflammatory response.
• Tetracyclines can counteract neuroinflammation caused by neurotrophic viruses.
• Tetracyclines interact with viral proteins presenting antiviral effects.
• Tetracyclines represent a potential treatment for COVID-19 neuropsychiatric symptoms.

Chaves Filho, A.J.M., Gonçalves, F., Mottin, M. et al. Repurposing of Tetracyclines for COVID-19 Neurological and Neuropsychiatric Manifestations: A Valid Option to Control SARS-CoV-2-Associated Neuroinflammation?. J Neuroimmune Pharmacol (2021). https://doi.org/10.1007/s11481-021-09986-3

Cross Amy, Bouboulis Denis, Shimasaki Craig, Jones Charles Ray. Case Report: PANDAS and Persistent Lyme Disease With Neuropsychiatric Symptoms: Treatment, Resolution, and Recovery. Frontiers in Psychiatry. Vol 12, 2021. DOI:10.3389/fpsyt.2021.505941  

The subject of this case report had a concomitant diagnosis of Lyme borreliosis and PANDAS, both of which are consistent with the neuropsychiatric symptoms she experienced. As evidenced by her recovery and resolution of symptoms, treating both the Lyme infection and streptococcal infection, as well as treating the underlying autoimmune etiology of her neuropsychiatric symptoms resulted in a successful outcome. This case report and treatment history reiterates the complex and challenging nature of infection-triggered autoimmune neuropsychiatric disorders such as PANDAS and PANS and that multiple concomitant infectious agents can frequently be identified in patients suffering from these complex neuropsychiatric disorders. The presence of elevated antineuronal antibodies identified by the Cunningham Panel™ provided an aid in the diagnosis and in directing immunomodulatory treatment. The post-treatment resolution of these autoantibodies provided pathophysiological support for addressing both the infection(s) and the underlying immune system dysfunction which resulted in a positive medical outcome for this patient.

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Badenoch, J., Searle, T., Watson, I. et al. Tics in patients with encephalitis. Neurol Sci (2021). DOI: 10.1007/s10072-021-05065-w

“Tics were most commonly reported in the post-encephalitic period and involvement of the basal ganglia was frequently observed….Despite these limitations, the first literature review evaluating the presence of tics in reported cases of encephalitis showed that tics have been sporadically reported in cases of encephalitis resulting from autoimmune, infective, and unknown aetiology. Specifically, tics have been more commonly reported in the post-encephalitic period and involvement of the basal ganglia was frequently found. Furthermore, the association of new-onset tics and encephalitis, in the background of other neuropsychiatric abnormalities, has clinical implications in potentially improving the detection of encephalitis based on clinical features. Future research should focus on the categorisation and treatment of hyperkinetic movement disorders associated with encephalitis.”

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum

Frick LR, Rapanelli M, Jindachomthong K, et al. Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum. Brain Behav Immun. 2018;69:304-311. doi:10.1016/j.bbi.2017.12.004

“In summary, our in vivo approach to characterizing antibody reactivity in patients with PANDAS has identified a novel candidate pathophysiology: specific autoantibody binding to striatal cholinergic interneurons. This focus on cholinergic interneurons fits well with the developing appreciation of the role of these cells in tic disorders. Identification of the specific antigens on these cells and the functional consequences of antibody binding may open new avenues for the understanding and treatment of PANDAS and related conditions.”

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Maternal Autoimmunity and Inflammation are Associated with Childhood Tics and Obsessive-Compulsive Disorder: Transcriptomic Data show Common Enriched Innate Immune Pathways

Hannah F. Jones, Velda X. Han, Shrujna Patel, Brian S. Gloss, Nicolette Soler, Alvin Ho, Suvasini Sharma, Kavitha Kothur, Margherita Nosadini, Louise Wienholt, Chris Hardwick, Elizabeth H. Barnes, Jacqueline R. Lim, Sarah Alshammery, Timothy C. Nielsen, Melanie Wong, Markus J. Hofer, Natasha Nassar, Wendy Gold, Fabienne Brilot, Shekeeb S. Mohammad, Russell C. Dale,
Maternal Autoimmunity and Inflammation are Associated with Childhood Tics and Obsessive-Compulsive Disorder: Transcriptomic Data show Common Enriched Innate Immune Pathways,
Brain, Behavior, and Immunity, 2021,ISSN 0889-1591 DOI: 10.1016/j.bbi.2020.12.035.

Highlights

• Autoimmune disease is more frequent in mothers of children with tics/OCD.
• Maternal inflammatory states are generally associated with childhood tics/OCD.
• Maternal blood and Tourette brain transcriptomes show common innate immune pathways.
• Inflammation may be an important environmental modifier in tic/OCD expression.
• Targeting inflammation may mitigate risk and improve treatment of tics/OCD.

“Our findings demonstrate that maternal pro-inflammatory states, including autoimmune disease, are associated with tics/OCD in children, and support a possible role for maternal inflammation, in addition to immunogenetic and ‘neurogenic’ mechanisms in the aetiology of tic disorders and OCD. (Mataix-Cols et al., 2018) The breadth of immune conditions, including the heterogeneity of autoimmune diseases, and overlapping pathways in transcriptomic analysis of maternal blood and Tourette brain samples indicate that the innate immune response may be an important factor in disease expression. Inflammation is likely to be a more modifiable risk factor than susceptibility genes, and prospective studies which comprehensively assess pro-inflammatory states in mothers during pregnancy paired with detailed immunophenotyping, genomic and epigenomic testing, and careful evaluation of postnatal pro-inflammatory exposures in children, are needed to fully assess the role of inflammation as an environmental risk factor for neurodevelopmental disorders. Further understanding of the role of the immune system in neurodevelopment could unveil opportunities to mitigate risk to children by reducing exposure to inflammation and open new avenues for treatment.”

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Investigational and Experimental Drugs to Treat Obsessive-Compulsive Disorder

Grassi G, Cecchelli C, Vignozzi L, Pacini S. Investigational and Experimental Drugs to Treat Obsessive-Compulsive Disorder. J Exp Pharmacol. 2021;12:695-706. Published 2021 Jan 5. doi:10.2147/JEP.S255375

Editor’s Note:
Genes, Cells, and Neural Circuits Relevant to OCD and Autism Spectrum Disorder
Ned H. Kalin, M.D.
Published Online:1 Jan 2021 DOI 10.1176/appi.ajp.2020.20111605

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“These cross-species translational data are potentially exciting and serve to focus the search for the pathophysiology of PANDAS toward a specific class of inter-neurons within the striatum that are known to fine tune and regulate striatal output via their influences on the abundant medium spiny GABAergic neurons that project to effector sites. Because of the similarities between PANDAS and bonafide OCD, these studies raise the possibility that striatal cholinergic interneurons are mechanistically involved in the pathophysiology of childhood OCD. In his editorial (9), Dr. Steve Hyman from Harvard University critically appraises this study and suggests that, in addition to the mechanism suggested by the findings in this article, other immune-related molecular pathways may also be important.”

• Catatonia is a neuropsychiatric syndrome characterized by diverse features including mutism, posturing, negativism, staring, rigidity, and echophenomenon.
• The mechanism of catatonia is still being elucidated; in this case, catatonia triggered by GAS infection is one potential mechanism.
• Further systematic study of catatonia in the pediatric population is warranted to better understand pathogenesis and long-term neuropsychiatric outcomes.

Predictors and Prospective Course of PANS: A Pilot Study Using Electronic Platforms for Data Collection

Conclusion: Our study highlights the utility of electronic methods for tracking longitudinal symptoms in children with PANS and suggests that particular baseline characteristics (e.g., delay in identification and treatment of PANS, greater caregiver burden) may be indicative of a differential trajectory of PANS course, with more severe symptoms over the short term. clinicaltrials.gov NCT04382716.