Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections Research Articles

Retrospective evaluation of stuttering cases with and without PANDAS comorbidity

Purpose: The aim of this study is to evaluate the clinical, demographic, and autoimmune characteristics of stuttering cases with and without Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) comorbidity. Materials and Methods: The study included 271 children and adolescents aged 2-17 years who were brought to our outpatient clinic between 2012 and 2022 and diagnosed with stuttering. The demographic information and medical characteristics of the patients and their families, such as infections, allergies, rheumatic diseases, and tonsillectomy or penicillin prophylaxis, were evaluated retrospectively. Their routine laboratory test results were also documented. Results: In total, 55 girls (20.3%) and 216 (79.7%) boys at a mean age of 7.6±3.6 years were included. Forty-eight cases (17%) were in the PANDAS group, and 223 (82.3%) were in the non-PANDAS group. The comparison of the PANDAS and non-PANDAS groups showed that the PANDAS group had significantly higher rates of history of tonsillectomy, history of adenoidectomy, and history of frequent infections. The rates of psychiatric, autoimmune, and allergic diseases in the families of the cases in the PANDAS group were significantly higher. The PANDAS group had a significantly greater frequency of comorbid conditions such as obsessive-compulsive disorder, tics, attention-deficit/hyperactivity disorder, and anxiety, as well as a greater mean number of comorbid conditions with at least one diagnosis. Additionally, the age at onset of psychiatric symptoms and the mean age of cases were higher in the PANDAS group. The mean initial anti-streptolysin O level of the PANDAS group was 326.5±335.3 IU/mL, while the mean level in the non-PANDAS group was 155.6±215.1 IU/mL. Conclusion: Both the individuals in the PANDAS group and their families had high rates of comorbidities and inflammatory and autoimmune disorders. In cases of stuttering, there is a need to evaluate these conditions, determine the required methodologies, and explain the relevant pathophysiological mechanisms.

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Immunological Features Underpinning Controversial Entities.

Pediatric acute-onset neuropsychiatric syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), represent an overlapping group of disorders which is characterized by acute-onset obsessive compulsive disorders, eating restriction, tics, cognitive and behavioral deterioration which typically follows a relapsing-remitting course but some patients have a primary or secondary persistent progress. This condition is likely caused by heterogeneous inflammatory mechanisms (autoantibodies, complement activation, pro-inflammatory cytokine production) involving the basal ganglia as evidenced by imaging studies (patients vs. controls), sleep studies that found movements and/or atonia during REM sleep, and neurological soft signs that go along with basal ganglia dysfunction. The condition causes significant psychiatric and behavioral symptoms, caregiver burden and sleep abnormalities. Autoantibodies resulting from molecular mimicry of infectious agents (namely group A Streptococcus) and neuronal autoantigens that map to the basal ganglia play also a subtle role. This narrative review aims to describe the key immunological features documented thus far and that likely play a role in the pathogenesis and clinical manifestations of this disorder.

Reliability and validity of a newly developed PANDAS/PANS questionnaire

ObjectiveThis study aimed to examine the reliability and validity of a newly developed questionnaire for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). The aim was to contribute to future standardisation of screening methods for symptoms and comorbidity, as well as the measurement of symptom severity, daily life impairment, and treatment effectiveness in individuals diagnosed with PANDAS/PANS. Methods27 items from the PANDAS/PANS questionnaire concerning symptoms and comorbidities associated with PANDAS/PANS were divided into ten domains. To assess the external validity, 119 PANDAS/PANS questionnaires from a cohort of 65 children with PANDAS/PANS were correlated with three well-known validated questionnaires: the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), and the Strengths and Difficulties Questionnaire (SDQ). The internal validity of the PANDAS/PANS questionnaire was assessed by correlating the PANDAS/PANS items with the domains. ResultsInternal consistency of the PANDAS/PANS questionnaire was high, measuring moderate to very strong correlations. The external correlations for the PANDAS/PANS questionnaire showed a higher correlation with the ADHD-RS and CY-BOCS (rs ≥ 0.60) than with the SDQ (rs < 0.40). ConclusionThe validity and clinical feasibility of the PANDAS/PANS questionnaire were confirmed as an effective tool for screening symptoms, assessing symptom severity, and evaluating comorbidity and daily life impairment in individuals with PANDAS/PANS. These findings can potentially enhance the management of PANDAS/PANS patients in both clinical and research settings.

PANDAS: Twenty-Five Years Later

Background: It has been 25 years since the definition of the concept of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The abrupt onset of neuropsychiatric symptoms requires a comprehensive differential diagnosis involving complementary tests and optimal treatment selection. Methods: This paper describes aspects related to the diagnosis and clinical management of PANDAS. A clinical perspective is developed starting from an example that meets the Swedo's criteria. Discussion: A comprehensive approach, including interdisciplinary management and urgent evaluation of potential organic causes, is crucial for effective treatment. Treatment decisions should consider severity, symptoms, and available evidence. Collaboration with neuropediatric or neurological services is needed. ASLO/anti-DNase B and 25-OH-Vitamin D tests are valuable for atypical OCD/Tic presentations, always maintaining a broader organic screening.

Developmental Impacts of PANS/PANDAS and Inadequate Support for Children and Families.

This article examines the degree to which major domains of child development are affected by Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). Using cross-sectional survey data collected with an international sample of parents who identify as having children with PANS/PANDAS (N = 402), this study analyzed parent-reported developmental impacts and access to treatment and adequate supports. Parents reported that PANS/PANDAS negatively impacted their children's development across all domains: Emotional Development (92% of children), Social Development (90%), Cognitive Development (86%), Academic Growth (86%), Identity Development (83%), Talent Development (73%) and Language Development (50%). In addition, developmental impacts were likely to be more severe for children whose parents reported a greater number of inadequate supports with parenting, school, extracurricular activities, and crisis situations. These results indicate that children and families affected by PANS/PANDAS need better support to maximize children's opportunities, at home, in school, and in their communities, to continue developing despite challenging neuropsychiatric symptoms.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) in a two-year-old

Streptococcal pharyngitis testing and treatment is not routinely recommended in children under the age of 3 because of the unlikely occurrence of infection and negligible risk of serious complications. However, streptococcal pharyngitis and its resulting complications are not uncommon in this age group and can have serious consequences. We report a case of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections in a 2-year-old with streptococcal pharyngitis. Testing and treatment for streptococcal pharyngitis should be strongly considered when there is evidence of infection and/or an immune-mediated streptococcal complication to prevent and/or decrease the severity of short- and longterm complications.

Case report: Early use of whole exome sequencing unveils HNRNPU-related neurodevelopmental disorder and answers additional clinical questions through reanalysis

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient’s symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient’s life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system.

Gut microbiome alterations in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) suggests variation in the gut-brain axis and gut metabolic potential

PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections is a form of Children’s Post infectious Autoimmune Encephalopathy (CPAE), a neuropsychiatric condition characterized by the abrupt onset of diverse neuropsychiatric manifestations following streptococcal infection. It is an increasingly recognized neuropsychiatric disorder that affects a subset of children whose underlying etiology remains unclear. Gut microbiome plays a crucial role in its host brain development and is implicated throughout the life in neurobehavior and neurological disorders. Emerging evidence suggest gut dysbiosis resulting in altered intestinal flora can impair gut barrier and increase leakiness in the blood-brain barrier leading to inflammation. We aimed to investigate if the microbiome is altered in pediatric patients with PANDAS. Stool (n=19), oral (n=20) and nasal swabs (n=18) were collected from patients diagnosed with PANDAS or healthy controls (HC) and used for 16S analysis. 13 stool samples (7 HC and 6 PANDAS) samples were further used for shogun metagenomics and 17 for untargeted metabolomics (8 HC and 9 PANDAS). 16S rRNA gene sequencing identified significant difference in microbial α diversity, with lower Shannon H’ in PANDAS compared to HC (Welch’s t-test t(16.95)=-2.6, p=0.02), and in β-diversity (PERMANOVA R2=0.08 p=0.04) between PANDAS and HC fecal but not throat and nasal samples. Shotgun metagenomics identified a significant reduction in gene diversity (Welch’s t-test t(9.9)=-3.06, p=0.01) and changes in various KEGG ortholog modules involved in gut metabolism and gut-brain axis. Significant differences were also detected in metabolite composition (PERMANOVA R2=0.10, p=0.02). We also identified a set of microbial groups and metabolites enriched or depleted in CPAE patients, involved in different aspects of host physiology and gut metabolism. Our results show that PANDAS patients have an altered gut microbial community, which may exacerbate their behavioral symptoms and it should be taken into consideration in unveiling the complex pathogenesis and selection of treatment options. Arizona Department of Health Services RFGA2022-010-23 (PK) and ADHS17-00007403 (SR, MD); The Alex Manfull Fund (PK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Microglia as a Target of Immunomodulation in Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal Infections (PANDAS)

PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, is a neuropsychiatric condition characterized by the abrupt onset of diverse neuropsychiatric manifestations following streptococcal infections in children. It's believed to involve immune dysregulation and autoimmune targeting of the brain basal ganglia. However, the precise mechanisms remain unclear. Hypothesis: considering the role of microglia in neuroinflammation, evidence for their activation in PET imaging of PANDAS patients, and increased number of CD68+/Iba1+ activated microglia in mice inoculated with group A Streptococcus (GAS), we hypothesized that as a consequence of disrupted blood-brain barrier (BBB), circulating factors modulate microglial functions towards a pro-inflammatory phenotype. Methods: Untargeted metabolomics was performed with sera from 10 children with PANDAS and 12 healthy controls. Human iPSC-derived microglia were generated and exposed to 5% serum from PANDAS patients or healthy controls in the presence or absence of Polymyxin B (PMB; endotoxin scavenger) and assessed for nitric oxide (NOx) production, immunophenotyped with flow cytometry (TMEM119, TREM2, CD68, and Iba-1) and bulk RNA-seq analysis. Results: Significant differences in serum metabolomic profile of PANDAS cases were observed, particularly in pathways associated with amino acid, fatty acid, lipid, steroid, and oxidative stress-related pathways. Treatment of iPSC-derived or primary human microglia with PANDAS serum led to a significant increase in NOx production, which was blunted by approx. 30% by PMB. Immunophenotyping revealed a significant reduction in homeostatic markers TMEM119 and TREM2, and expansion of CD68+ and Iba-1+ microglia associated with inflammatory response. Regulation of TMEM119 and TREM2 was endotoxin-independent, while PMB partially blunted the increase in CD68 and Iba-1. RNAseq revealed dramatic effects of PANDAS sera on microglial gene expression pattern, with upregulated genes associated with C-type lectin receptor, TLR, TNF, and NFk-B signaling pathways among others. Conclusion: The results suggest that as a result of BBB disruption in PANDAS, associated systemic inflammatory mediators modulate the phenotype and function of the brain microglia, a mechanism that likely contributes to neuroinflammation and the observed symptoms. The observed contribution of endotoxin may also suggest a dysfunction of intestinal barrier which may compound the systemic immune responses in PANDAS. Arizona Department of Health Services RFGA2022-010-23 (PK) &amp; ADHS17-00007403 (SR, MD); The Alex Manfull Fund (PK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ocular Tics and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS).

Little is known about ocular tics in Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections (PANDAS). In this retrospective study, we examined the clinical records of children with motor tics referred to the Ophthalmology Unit, Azienda Ospedaliero-Universitaria di Sassari, Italy, in 2010-2019. The presence of ocular tics was investigated. Data about antistreptolysin O (ASO) and anti-DNase B antibody titers, erythrocyte sedimentation rate (ESR), plasma C-reactive protein (CRP), and antibiotic use were recorded. Forty children (thirty-four boys and six girls; mean age: 7.65 ± 2.5 years) with motor tics were identified; thirty-three (82.5%) showed ocular tics. Children with ocular tics had significantly higher titers of anti-DNase B antibodies (p = 0.04) and CRP (p = 0.016) than those with extraocular tics. A diagnosis of PANDAS was made in 24 (60%) children. PANDAS children with oculomotor tics had significantly higher titers of anti-DNase B antibodies (p = 0.05) than those with extraocular tics. Oral antibiotics were given to 25/33 (76%) children with ocular tics and 21/24 (87.5%) with PANDAS. All treated patients showed marked improvement/complete resolution of symptoms. Results suggest that higher titers of anti-DNase B antibodies may be implicated in the pathogenesis of ocular tics in PANDAS. Oral antibiotics may be beneficial in improving ocular tics. Further research is necessary to confirm our findings.

Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population.

The folate receptor alpha autoantibodies (FRAAs) are associated with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD). Both of these syndromes have overlapping characteristics with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Thus, we propose that the FRAAs may contribute to the symptomatology of PANS/PANDAS. To test this hypothesis, 1 mL of serum from 47 patients (age range = 6-18 years old) clinically diagnosed with PANS/PANDAS was sent to Vascular Strategies (Plymouth Meeting, PA, USA) for analysis of FRAAs. Moreover, 63.8% of PANS/PANDAS patients (male = 15; female = 15) were found to have either the blocking and/or blinding FRAAs, with 25 (83.3%; male = 14; female = 11) having binding FRAAs, two (6.7%; all female = 2) having blocking FRAAs, and 3 (10%; male = 1; female = 2) having both binding and blocking. Furthermore, surprisingly, ASD was associated with a 0.76 lower binding titer (p = 0.02), and severe tics were associated with a 0.90 higher binding titer (p = 0.01). A case of a FRAA-positive patient is provided to illustrate that a treatment plan including leucovorin can result in symptom improvement in patients with PANS/PANDAS who are FRAA-positive. These data, for the first time, demonstrate that PANS/PANDAS is associated with FRAAs and suggest folate metabolism abnormalities may contribute to PANS/PANDAS symptomatology. Further studies investigating the therapeutic nature of leucovorin in the treatment of PANS/PANDAS are needed. Such studies may open up an alternative, safe, and well-tolerated treatment for those with the PANS/PANDAS diagnosis.

Immunological characterization of an Italian PANDAS cohort.

This cross-sectional study aimed to contribute to the definition of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) pathophysiology. An extensive immunological assessment has been conducted to investigate both immune defects, potentially leading to recurrent Group A β-hemolytic Streptococcus (GABHS) infections, and immune dysregulation responsible for a systemic inflammatory state. Twenty-six PANDAS patients with relapsing-remitting course of disease and 11 controls with recurrent pharyngotonsillitis were enrolled. Each subject underwent a detailed phenotypic and immunological assessment including cytokine profile. A possible correlation of immunological parameters with clinical-anamnestic data was analyzed. No inborn errors of immunity were detected in either group, using first level immunological assessments. However, a trend toward higher TNF-alpha and IL-17 levels, and lower C3 levels, was detected in the PANDAS patients compared to the control group. Maternal autoimmune diseases were described in 53.3% of PANDAS patients and neuropsychiatric symptoms other than OCD and tics were detected in 76.9% patients. ASO titer did not differ significantly between the two groups. A possible correlation between enduring inflammation (elevated serum TNF-α and IL-17) and the persistence of neuropsychiatric symptoms in PANDAS patients beyond infectious episodes needs to be addressed. Further studies with larger cohorts would be pivotal to better define the role of TNF-α and IL-17 in PANDAS pathophysiology.

Pediatric acute-onset neuropsychiatric syndrome and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections: a delphi study and consensus document about definition, diagnostic criteria, treatment and follow-up.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) are broad diagnoses that encompass a range of sudden-onset neuropsychiatric symptoms in children, which can include obsessive-compulsive disorder (OCD), tics, anxiety, emotional instability, and cognitive difficulties. Unlike PANDAS, PANS is not strictly linked to group A streptococcal infections but can be triggered by various infectious or environmental factors. Lights and shadows remain upon the management of children with PANS and PANDAS and there is no clear consensus regarding definition, diagnostic criteria, treatment, and follow-up. The aim of the present study was to evaluate the level of agreement on PANS and PANDAS definition, diagnostic criteria, treatment and follow-up and to assess on the basis of recent studies whether there is a need to modify the current recommendations used by primary care pediatricians and hospital pediatricians in clinical practice in order to improve outcomes. Using the Delphi method, this consensus provides shared indications on PANS and PANDAS management in pediatric age, based on the most updated literature. This work represents, in our opinion, the most complete and up-to-date information on the diagnosis of PANS and PANDAS, as well as consensus statements about several aspects of clinical care. Undoubtedly, more randomized and controlled trials are needed in the pediatric population to better define the best management, also in terms of adequate follow-up examinations and period of observation.

Ocular tics in Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

Aims/Purpose: Little is known about ocular tics in Paediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections (PANDAS). The purpose of this retrospective study was to assess ocular symptoms in 40 children with PANDAS.Methods: The clinical records of children with PANDAS referred to the Ophthalmology Unit, Azienda Ospedaliero‐Universitaria di Sassari, Sassari, Italy, between 2010 and 2019 were examined. The detection of ocular tics was investigated. Data about plasma antistreptolysin O (ASO) and anti‐DNAse b titres, erythrocyte sedimentation rate (ESR), plasma C‐reactive protein (CRP), and antibiotic use were recorded and statistically analysed.Results: 40 children (34 boys, 6 girls; mean age: 7.6 ± 2.5 years) with PANDAS were identified; 33 (82.5%) showed ocular tics, whereas the remaining 7 (17.5%) had extraocular tics. Children with ocular tics had significantly higher plasma values of anti‐DNAse b antibodies (p = 0.04) and CRP (p = 0.016) than those with extraocular tics. A course of oral antibiotics was given to 25 (76%) out of 33 children with ocular tics. All the treated patients showed marked improvement/complete resolution of symptoms; conversely, no improvement was observed in those untreated. A post‐antibiotic recurrence occurred in 8 (32%) children.Conclusions: Results suggest that higher plasma values of anti‐DNAse b antibodies and CRP may play a role in the pathophysiological mechanisms underlying ocular tics in PANDAS. Oral antibiotics may be beneficial in improving ocular symptoms. Further research is necessary to confirm our findings.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Syndrome: A 10-Year Retrospective Cohort Study in an Italian Centre of Pediatric Rheumatology.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is a rare pediatric disorder consisting of a sudden onset of obsessive-compulsive disorder (OCD) and/or tics after a group A Streptococcus (GAS) infection. In the period between 2013 and 2023, 61 children presented to our Pediatric Rheumatology unit with a suspicion of PANDAS syndrome. Among these, a retrospective analysis was conducted, and 19 fulfilled the current classification criteria and were included in this study. The male-to-female ratio was 14:5, the median age at onset was 7.0 (2.0-9.5) years, and the median age at diagnosis was 8.0 (3.0-10.4) years. The median follow-up period was 16.0 (6.0-72.0) months. Family and personal history were relevant in 7/19 and 6/19 patients. Tics were present in all patients. Details for motor tics were retrospectively available in 18/19 patients, with the eyes (11/18) and neck/head (10/18) being most often involved. Vocal tics were documented in 8/19, behavioral changes in 10/19, and OCD in 2/19. Regarding the therapeutic response, all patients responded to amoxicillin, 12/13 to benzathine benzylpenicillin, and 7/9 to azithromycin. Our findings partially overlap with previous reports. Larger prospective studies are needed to improve treatment strategies and classification criteria.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is one of the most controversial diseases in pediatric rheumatology. Despite first being described more than 25 years ago as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine release in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.

Cerebrospinal fluid findings in patients with obsessive–compulsive disorder, Tourette syndrome, and PANDAS: A systematic literature review

BackgroundObsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are related mental disorders that share genetic, neurobiological, and phenomenological features. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is a neuropsychiatric autoimmune disorder with symptoms of OCD and/or TS associated with streptococcal infections. Therefore, PANDAS represents a strong link between OCD, TS, and autoimmunity. Notably, cerebrospinal fluid (CSF) analyses can provide insight into the central nervous processes in OCD, TS, and PANDAS. MethodsA systematic literature search according to the PRISMA criteria was conducted to collect all CSF studies in patients with OCD, TS, and PANDAS. The total number of cases and the heterogeneity of the low number of studies were not sufficient for a meta-analysis to provide a high level of evidence. Nevertheless, meta-analytical statistics could be performed for glutamate, 5-hydroxyindoleacetic acid (degradation product of serotonin), homovanillic acid (degradation product of dopamine), 3-methoxy-4-hydroxyphenylglycol (major metabolite of noradrenaline), and corticotropin-releasing hormone (CRH) in OCD. A risk-of-bias assessment was implemented using the Cochrane ROBINS-E tool. ResultsMeta-analytical testing identified elevated glutamate levels in the CSF of OCD patients compared with healthy controls, while no significant differences were found in other neurotransmitters or CRH. Single studies detected novel neuronal antibodies in OCD patients and elevated oligoclonal bands in TS patients. For TS and PANDAS groups, there was a dearth of data. Risk of bias assessment indicated a substantial risk of bias in most of the included studies. ConclusionsThis systematic review of available CSF data shows that too few studies are currently available for conclusions with good evidence. The existing data indicates glutamate alterations in OCD and possible immunological abnormalities in OCD and TS. More CSF studies avoiding sources of bias are needed.

A Bibliometric Analysis of Global Research on Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a clinical syndrome characterized by the abrupt onset of major personality, movement, and behavioral changes in a patient with a history of streptococcal infection. We aimed to do a bibliometric analysis of the published research on PANDAS. All the published articles available on the PubMed database from the time of inception till August 2022 were included in the study. All the PubMed IDs (PMID) of the articles were entered in Harvard Catalyst, a free online software, for bibliometric analysis, and data were extracted and verified. A total of 289 relevant published articles were identified. The average number of authors per article was 4.89 and the average number of times an article was cited was 11.19 (excluding self-citation). The H-index of the published articles was 31. The Journal of Child and Adolescent Psychopharmacology published the maximum number of articles ( n = 36). The highest number of average citations (39.50 citations/articles) was for the articles published in the American Journal of Psychiatry. The most common type of articles were journal articles ( n = 259) and of which 27 were original research articles. Most of the original research discusses the effectiveness of various interventions (penicillin and other antibiotic prophylaxis, role of immunoglobulin), neuropsychiatric symptoms, and outcomes in the longitudinal course. Though PANDAS is a well-researched entity, more clinical trials, and large-scale studies will help provide better insight on this subject.

Abnormal mTOR Signaling Pathway Activity in Autism Spectrum Disorders: Prospects of Mechanism-Based Therapy

Autism spectrum disorder (ASD) is a developmental disorder characterized by the early onset of communication, learning, and behavioral problems. The syndromic form of ASD is caused by monogenic mutations, in the case when it is not possible to find genetic or other known mechanisms, the term “idiopathic autism” is used. A significant part of both syndromic and idiopathic autism is associated with translational deregulation dependent on the mechanistic target of rapamycin (mTOR). In this review, we present both bioinformatic and experimental data that link the mTOR signaling pathway to maternal autoantibody-induced autism and childhood autoimmune neuropsychiatric disorders such as Sydenham’s chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). The need for ASD subtyping and the possibility of mechanism-based therapy with inhibitors of the mTOR signaling pathway are also discussed.

Infections and obsessive-compulsive disorder - results from a systematic review and meta-analysis

IntroductionObsessive-compulsive disorder (OCD) is a psychiatric disorder affecting 1.3% of the population worldwide where both genetic and environmental factors, such as perinatal events and neuroinflammation, are thought to contribute to the etiology of the disorder. In the past, the description of clinical entities such as Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS), in which an acute neuropsychiatric syndrome with prominent obsessive-compulsive features emerges in children infected with group-A beta-hemolytic streptococcus (GABHS), sparked the hypothesis that infections may be a risk-modifying factor for the development of OCD. Along with streptococcal infections, other pathogens such as Toxoplasma gondii have been implicated in the pathophysiological models of the disorder, although causal associations have not been established for any of beforementioned pathogens.ObjectivesTo perform a systematic review and meta-analysis about the presence of biological evidence of infection in patients diagnosed with OCD.MethodsWe conducted a systematic review and a meta-analysis (PROSPERO registration CRD42021223415) by performing a standardized electronic database search in MEDLINE/PubMed, Web of Science, Embase and Scopus. Search was conducted on 17/10/2022. Eligible papers included case-control and cohort studies using a comparator group, that tested for specific biomarkers providing evidence of infection in patients diagnosed with OCD; exclusion criteria included studies without quantitative or qualitative measures of infection, case reports, systematic or scope reviews, and animal studies. Selection process was conducted according to PRISMA 2020 statement guidelines. Study quality was assessed through Newcastle-Ottawa Quality Assessment Scale.ResultsWe identified 8911 records through the search after duplicate removal. A total of 22 studies met inclusion criteria after selection process, and 15 were eligible for meta-analysis. Most evidence concerned Toxoplasma gondii (10 studies), and patients with OCD appear to have higher odds of being infected compared to controls, with a meta-analytic odds ratio of 2.39 (95% IC 1.60-3.58), when comparing 467 patients with 5411 controls. However, most studies were methodologically heterogeneous, which compromises the interpretation of meta-analytic results. Information regarding other agents, including GABHS, Borna disease virus and Toxocara canis was gathered but due to an insufficient number of papers it was not possible to perform a meta-analysis for each of them.ConclusionsOur work suggests that albeit exhaustively reported in the literature, there is no strong evidence of the over-representation of biomarkers of infection in patients with OCD compared to control volunteers. Methodologically robust studies are needed to further test this hypothesis.Disclosure of InterestNone Declared