Research

Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation

Salvucci F, Codella R, Coppola A, et al. Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. Front Cardiovasc Med. 2023;10:1202696. doi:10.3389/fcvm.2023.1202696.

Mast cell activation in Long COVID (related work)

  • Observational study evaluating Long COVID patients treated with H1/H2 antihistamines.

  • Reports improvement in fatigue, cognitive symptoms, tachycardia, and other systemic complaints.

  • Supports the hypothesis that mast cell activation contributes to Long COVID symptom persistence.

  • Suggests immune dysregulation—rather than viral persistence—may drive ongoing symptoms in a subset of patients.

PANDAS – a rare but severe disorder associated with streptococcal infections; Awareness is needed, Acta Oto-Laryngologica Case Reports,
Karin Frånlund & Charbél Talani (2023) PANDAS – a rare but severe disorder associated with streptococcal infections; Awareness is needed, Acta Oto-Laryngologica Case Reports, 8:1, 104-107, DOI: 10.1080/23772484.2023.2231146
“We present a case of PANDAS with the aim of raising awareness of its diagnosis. PANDAS is a rare condition with an impact on the patient’s quality of life; thus, awareness is needed. A multidisciplinary team is needed for diagnosis and treatment. Otorhinolaryngologists may play an important role in the well-being of these patients when performing tonsillectomy.”
Autoantibodies in patients with obsessive-compulsive disorder: a systematic review
Denzel D, Runge K, Feige B, Pankratz B, Pitsch K, Schlump A, Nickel K, Voderholzer U, Tebartz van Elst L, Domschke K, Schiele MA, Endres D. Autoantibodies in patients with obsessive-compulsive disorder: a systematic review. Transl Psychiatry. 2023 Jul 3;13(1):241. doi: 10.1038/s41398-023-02545-9. PMID: 37400462; PMCID: PMC10318087.

Emerging evidence suggests that biological components, especially autoimmune processes, may be associated with some cases of OCD and treatment resistance. Therefore, this systematic literature review summarizing all case reports/case series as well as uncontrolled and controlled cross-sectional studies investigating autoantibodies in patients with OCD and obsessive-compulsive symptoms (OCS) was performed. In summary, the available case reports suggest an association between OCD and autoantibodies in rare cases, which has been supported by initial cross-sectional studies. However, scientific data is still very limited. Thus, further studies on autoantibodies investigated in patients with OCD compared with healthy controls are needed.

  • Nine case reports with autoantibody-associated OCD/OCS were identified: five patients with anti-neuronal autoantibodies (against N-methyl-D-aspartate-receptor [NMDA-R], collapsin response mediator protein [CV2], paraneoplastic antigen Ma2 [Ma2], voltage gated potassium channel complex [VGKC], and “anti-brain” structures) and four with autoantibodies associated with systemic autoimmune diseases (two with Sjögren syndrome
  • one with neuropsychiatric lupus
  • one with anti-phospholipid autoantibodies).
  • Six patients (67%) benefited from immunotherapy.
  • In addition, eleven cross-sectional studies (six with healthy controls, three with neurological/psychiatric patient controls, and two uncontrolled) were identified with inconsistent results, but in six studies an association between autoantibodies and OCD was suggested.
Evaluation of C4 gene copy number in Pediatric Acute Neuropsychiatric Syndrome

Kalinowski A, Tian L, Pattni R, Ollila H, Khan M, Manko C, Silverman M, Ma M, Columbo L, Farhadian B, Swedo S, Murphy T, Johnson M, Fernell E, Gillberg C, Thienemann M, Mellins ED, Levinson DF, Urban AE, Frankovich J. Evaluation of C4 gene copy number in Pediatric Acute Neuropsychiatric Syndrome. Dev Neurosci. 2023 Jun 28. doi: 10.1159/000531707. Epub ahead of print. PMID: 37379808.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) were used to assess whether the time to juvenile idiopathic arthritis (JIA) or autoimmune disease (AI) onset was a function of total C4A or C4B CN. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes, and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (hazard ratio = 2.7, p value = 0.004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis, and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types.

Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls

Biria, M., Banca, P., Healy, M.P. et al. Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls. Nat Commun 14, 3324 (2023). https://doi.org/10.1038/s41467-023-38695-z

A Cambridge neuroimaging study found that compulsive behavior is associated with glutamate–GABA imbalance, particularly elevated glutamate, across both individuals with OCD and healthy controls. Using ultra–high field MRS, the authors show that compulsivity maps to excitatory–inhibitory imbalance in brain regions involved in habit formation and control. These findings support a mechanism-based view of compulsive symptoms, while underscoring the need for caution when targeting glutamatergic systems clinically due to their broader downstream effects. The findings are particularly relevant given increasing clinical interest in glutamate-modulating medications, which are sometimes used off-label in OCD and neuroimmune conditions. At the same time, the study reinforces the need for caution: altering glutamatergic systems can have complex downstream effects, especially in conditions where dopamine and immune signaling may also be involved. This work strengthens the rationale for mechanism-focused research while underscoring why individualized, carefully monitored treatment remains essential.

Exploring the Complex Associations Between Prenatal and Early-Life Infections and Obsessive-Compulsive and Tic-Related Disorders
Hirschtritt ME, Mathews CA. Exploring the Complex Associations Between Prenatal and Early-Life Infections and Obsessive-Compulsive and Tic-Related Disorders. Biol Psychiatry. 2023 Jun 1;93(11):959-961. doi: 10.1016/j.biopsych.2023.03.003. PMID: 37197834.
“techniques led to an understanding that autoimmunity induced by streptococcal
throat infection caused damage to multiple organ systems in … posited a diagnostic
entity named pediatric autoimmune neuropsychiatric disorders associated with …”
Long-term central nervous system (CNS) consequences of COVID-19 in children

Howe de la Torre, S., Parlatini, V., & Cortese, S. (2023). Long-term central nervous system (CNS) consequences of COVID-19 in children. Expert Review of Neurotherapeutics, 23(8), 703–720. https://doi.org/10.1080/14737175.2023.2239500

Read a deeper dive into Pediatric Long COVID: Neurological and Neuropsychiatric Symptoms

  • Neurological and neuropsychiatric symptoms are commonly reported in children and adolescents with long COVID, including headache, fatigue, cognitive difficulties, mood changes, and sleep problems
  • Reported prevalence varies widely due to study heterogeneity, small sample sizes, and limited long-term follow-up
  • Beyond mood and sleep issues, many neuropsychiatric conditions remain underexamined in pediatric long COVID
  • Persistent symptoms may significantly affect daily functioning and well-being
Arthritis in Children with Psychiatric Deteriorations: A Case Series
Ma M, Sandberg J, Farhadian B, Silverman M, Xie Y, Thienemann M, Frankovich J. Arthritis in Children with Psychiatric Deteriorations: A Case Series. Dev Neurosci. 2023;45(6):325-334. doi: 10.1159/000530854. Epub 2023 May 12. PMID: 37231875.

For a more in depth look at this study, please read Arthritis in Children with Psychiatric Deterioration: What This Case Series Shows

We found that 55/193 (28%) of consecutive patients meeting PANS criteria developed chronic arthritis and 25/121 (21%) of those with related psychiatric deteriorations developed chronic arthritis. Here we describe 7 of these patients in detail and one sibling.
  • Many of our patients often have “dry” arthritis (no effusions found on physical exam) but subtle effusions detected by imaging and features of spondyloarthritis, enthesitis, and synovitis. Joint capsule thickening, not previously reported in children, is a common finding in the presented cases and in psoriatic arthritis in adults.
  • Due to the severity of psychiatric symptoms in some cases, which often overshadow joint symptoms, and concomitant sensory dysregulation (making the physical exam unreliable in the absence of effusions), we rely on imaging to improve sensitivity and specificity of the arthritis classification.
  • We also report the immunomodulatory treatments of these 7 patients (initially nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation.
  • Patients with overlapping psychiatric syndromes and arthritis may have a unifying cause and pose unique challenges; a multi-disciplinary team can utilize imaging to tailor and coordinate treatment for this patient population.
Pathogenesis of autoimmune disease

Pisetsky, D.S. Pathogenesis of autoimmune disease. Nat Rev Nephrol 19, 509–524 (2023). https://doi.org/10.1038/s41581-023-00720-1

  • Autoimmune diseases lead to diverse patterns of inflammation and organ dysfunction.
  • Autoantibodies are valuable markers for diagnosis, classification and of disease activity.
  • Although T cells play a key part in disease, their assessment is challenging.
  • Autoimmune disease reflects the interplay of genetic and environmental factors.
  • Pre-clinical autoimmune disease provides a window of time for early or preventive treatment.
Pediatric Acute Onset Neuropsychiatric Syndrome Presenting with Atypical Eating Disorder: A Case Report
Biswas T, Sinha A, Abhijita B, Mishra S, Padhy SK. Pediatric Acute Onset Neuropsychiatric Syndrome Presenting with Atypical Eating Disorder: A Case Report. Journal of Indian Association for Child and Adolescent Mental Health. 2022;18(4):364-366. doi:10.1177/09731342231170695
“This case illustrates an atypical eating disorder presentation, resulting from PANS wherein a meticulous ruling out of organic causes andtimely institution of specific serotonin reuptake inhibitor facilitated remission. Through this case report the authors highlight the need of awareness of other medical practitioners regarding the symptomatology and presentation of PANS so as to facilitate early intervention in a collaborative approach.”
Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis
Wayne CR, Bremner L, Faust TE, Durán-Laforet V, Ampatey N, Ho SJ, Feinberg PA, Arvanitis P, Ciric B, Ruan C, Elyaman W, Delaney SL, Vargas WS, Swedo S, Menon V, Schafer DP, Cutforth T, Agalliu D. Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis. bioRxiv [Preprint]. 2023 May 9:2023.03.10.532135. doi: 10.1101/2023.03.10.532135. PMID: 37215000; PMCID: PMC10197575.

Group A Streptococcus (GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown. Using single-cell RNA sequencing and spatial transcriptomics, we found that ECs downregulate BBB genes and microglia upregulate interferon-response, chemokine and antigen-presentation genes after GAS infections. Several microglial-derived chemokines were elevated in patient sera. Administration of a neutralizing antibody against interleukin-17A (IL-17A), but not ablation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, partially rescued BBB dysfunction and microglial expression of chemokine genes. Thus, IL-17A is critical for neuropsychiatric sequelae of GAS infections and may be targeted to treat these disorders.

Pharmacotherapy for Sydenham’s chorea: where are we and where do we need to be?

Roberta Bovenzi, Matteo Conti & Tommaso Schirinzi (2023) Pharmacotherapy for Sydenham’s chorea: where are we and where do we need to be?, Expert Opinion on Pharmacotherapy, 24:11, 1317-1329, DOI: 10.1080/14656566.2023.2216380

  • Sydenham’s chorea (SC) is the most common acquired chorea in children worldwide; still, its therapeutic strategies are empirical and non-evidence based.
  • Current pharmacotherapy for SC basically consists of three pillars: antibiotic, symptomatic and immunomodulant medications.
  • Antibiotic prophylaxis should be initiated as soon as SC is diagnosed, according to the WHO guidelines, to prevent beta-hemolytic streptococcal (GABHS) re-infection and reduce the risk of cardiac involvement.
  • Symptomatic treatments, which consist in anti-seizure medications (ASMs) and dopamine depleting agents, should be considered when symptoms are clinically relevant; however, no consensus exist on which should be the first choice.
  • Immunomodulant strategies are gaining increasingly attention given the autoimmune pathogenesis of SC, with promising results.
  • There are numerous gaps and unmet needs in SC management and treatment, which highlights the necessity of a deeper comprehension of its pathogenesis and sizable controlled studies to define standardized guidelines.