Cerebrospinal fluid characteristics of patients presenting for evaluation of pediatric acute-neuropsychiatric syndrome.

Objectives: This study characterizes cerebral spinal fluid (CSF) indices including total protein, the albumin quotient, IgG index and oligoclonal bands in patients followed at a single center for pediatric acute-neuropsychiatric syndrome (PANS) and other psychiatric/behavioral deteriorations. Methods: In a retrospective chart review of 471 consecutive subjects evaluated for PANS at a single center, navigational keyword search of the electronic medical record was used to identify patients who underwent lumbar puncture (LP) as part of the evaluation of a severe or atypical psychiatric deterioration. Psychiatric symptom data was ascertained from parent questionnaires and clinical psychiatric evaluations. Inclusion criteria required that subjects presented with psychiatric deterioration at the time of first clinical visit and had a lumbar puncture completed as part of their evaluation. Subjects were categorized into three subgroups based on diagnosis: PANS (acute-onset of severe obsessive compulsive disorder (OCD) and/or eating restriction plus two other neuropsychiatric symptoms), autoimmune encephalitis (AE), and "other neuropsychiatric deterioration" (subacute onset of severe OCD, eating restriction, behavioral regression, psychosis, etc; not meeting criteria for PANS or AE). Results: 71/471 (15.0 %) of patients underwent LP. At least one CSF abnormality was seen in 29% of patients with PANS, 45% of patients with "other neuropsychiatric deterioration", and 40% of patients who met criteria for autoimmune encephalitis. The most common findings included elevated CSF protein and/or albumin quotient. Elevated IgG index and IgG oligoclonal bands were rare in all three groups. Conclusion: Elevation of CSF protein and albumin quotient were found in pediatric patients undergoing LP for evaluation of severe psychiatric deteriorations (PANS, AE, and other neuropsychiatric deteriorations). Further studies are warranted to investigate blood brain barrier integrity at the onset of the neuropsychiatric deterioration and explore inflammatory mechanisms.

Reliability and validity of a newly developed PANDAS/PANS questionnaire.

OBJECTIVE: This 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. METHODS: 27 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. RESULTS: Internal 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). CONCLUSION: The 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.

Intravenous immunoglobulin treatment improves multiple neuropsychiatric outcomes in patients with pediatric acute-onset neuropsychiatric syndrome.

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is defined by acute onset of diverse neuropsychiatric manifestations, presumably in the setting of underlying immune dysfunction. We used standardized neuropsychological testing to assess how intravenous immunoglobulins (IVIG) impact neurological and cognitive functions in PANS patients by comparing pretreatment with post-treatment scores. A 5-year retrospective study was undertaken in Children's Postinfectious Autoimmune Encephalopathy Center at University of Arizona. We identified 12 children diagnosed with PANS and treated with immunomodulatory IVIG doses, who also completed neuropsychological testing before and after treatment. We tracked multiple patient characteristics, type/timeline of testing, and number of IVIG courses. Score change of 1 standard deviation in any tested domain/subdomain was considered improvement. We further reviewed records for laboratory signs of triggering infection and immune dysfunction. Improvement occurred in 11/12 patients, in one or multiple domains/subdomains, independently of time between disease onset and IVIG initiation (0-7 years). Participants received 1-7 IVIG courses. Improvement was primarily seen in memory (58%), sensory-motor (37%) and visual-motor integration (30%). In 5/12 patients we detected hypogammaglobulinemia requiring ongoing IVIG replacement, one patient had isolated low IgA. Only one patient had to discontinue IVIG therapy due to severe adverse effects. Standardized neuropsychological testing represents an important tool to objectively measure improvement in PANS patients. IVIG was tolerated well and showed efficacy in the vast majority of participants, independently from timelapse since disease onset, emphasizing impact of immunomodulation in PANS. Significant presence of baseline hypogammaglobulinemia in children with PANS emphasizes the presumed role of immune dysfunction in disease pathogenesis.

Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome.

Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs.

Corrigendum: Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series.

[This corrects the article DOI: 10.3389/fneur.2023.1085948.].

Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series.

Background: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by a wide spectrum of symptoms, including the onset of obsessive-compulsive disorder and/or severely restricted food intake, associated with emotional symptoms, behavioral symptoms, developmental regression, and somatic symptoms. Among the possible triggering agents, infectious agents have been extensively explored. More recently, sporadic case reports describe a possible association between PANS and SARS-CoV-2 infection but data on clinical presentation and treatment are still scarce. Methods: We describe a case series (10 children) with acute onset or relapse of PANS symptoms after SARS-CoV-2 infection. Standardized measures (CBCL, CPRS, C-GAS, CGI-S, Y-BOCS, PANSS, and YGTSS) were used to describe the clinical picture. The efficacy of a pulse treatment with steroids for three consecutive months was assessed. Results: Our data suggest that the clinical presentation of the COVID-19-triggered PANS is largely similar to that reported in typical PANS, including acute onset, with OCD and/or eating disorders, and associated symptoms. Our data suggest that treatment with corticosteroids may be beneficial for both global clinical severity and global functioning. No serious adverse effects were observed. Both OCD symptoms and tics consistently improved. Among psychiatric symptoms, affective and oppositional symptoms appeared more sensitive to the steroid treatment than the other symptoms. Conclusion: Our study confirms that COVID-19 infection in children and adolescents could trigger acute-onset neuropsychiatric symptoms. Thus, in children and adolescents with COVID-19, a specific neuropsychiatric follow-up should be routinely included. Even if a small sample size and a follow-up with only two points (baseline and endpoint, after 8 weeks) limit the conclusions, it seems that steroid treatment in the acute phase may be beneficial and well tolerated.

Children With PANS May Manifest POTS.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by an abrupt-onset of severe psychiatric symptoms including OCD, anxiety, cognitive difficulties, and sleep issues which is thought to be a post-infection brain inflammatory disorder. We observed postural orthostatic tachycardia syndrome (POTS) which resolved with immunomodulation in a patient with Pediatric acute-onset neuropsychiatric syndrome (PANS). Here, we aim to present a case of POTS and to examine the prevalence of (POTS) in our PANS cohort, and compare the clinical characteristics of patients with and without POTS. Study Design: We conducted this cohort study of patients meeting PANS criteria who had at least three clinic visits during the study period. We included data from prospectively collected questionnaires and medical record review. We present a case followed by statistical comparisons within our cohort and a Kaplan-Meier analysis to determine the time-dependent risk of a POTS diagnosis. Results: Our study included 204 patients: mean age of PANS onset was 8.6 years, male sex (60%), non-Hispanic White (78%). Evidence of POTS was observed in 19/204 patients (9%) with 5/19 having persistent POTS defined as persistent abnormal orthostatic vitals, persistent POTS symptoms, and/or continued need for pharmacotherapy for POTS symptoms for at least 6 months). In this PANS cohort, patients with POTS were more likely to have comorbid joint hypermobility (63 vs 37%, p = 0.04), chronic fatigue (42 vs 18%, p = 0.03), and a family history of chronic fatigue, POTS, palpitations and syncope. An unadjusted logistic regression model showed that a PANS flare (abrupt neuropsychiatric deterioration) was significantly associated with an exacerbation of POTS symptoms (OR 3.3, 95% CI 1.4-7.6, p < 0.01). Conclusions: Our study describes a high prevalence of POTS in patients with PANS (compared to the general population) and supports an association between POTS presentation and PANS flare within our cohort.

Diagnostic Approach to Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS): A Narrative Review of Literature Data.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are clinical conditions characterized by the sudden onset of obsessive-compulsive disorder and/or tics, often accompanied by other behavioral symptoms in a group of children with streptococcal infection. PANDAS-related disorders, including pediatric acute-onset neuropsychiatric syndrome (PANS), childhood acute neuropsychiatric symptoms (CANS), and pediatric infection triggered autoimmune neuropsychiatric disorders (PITANDs), have also been described. Since first defined in 1998, PANDAS has been considered a controversial diagnosis. A comprehensive review of the literature was performed on PubMed and Scopus databases, searching for diagnostic criteria and diagnostic procedures of PANDAS and related disorders. We propose a test panel to support clinicians in the workout of PANDAS/PANS patients establishing an appropriate treatment. However, further studies are needed to improve our knowledge on these acute-onset neuropsychiatric conditions.

Clinical Features in Patients With PANDAS/PANS and Therapeutic Approaches: A Retrospective Study.

Objective: The clinical characteristics of patients with PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) and PANS (pediatric acute-onset neuropsychiatric syndrome) and the efficacy of antibiotic therapy with psychotherapy and antipsychotics were investigated to improve neurological symptoms as well as obsessive compulsive disorder (OCD). Methods: We retrospectively analyzed 62 patients with a clinical diagnosis of PANDAS/PANS enrolled from May 14, 2013 to September 15, 2020 in the Neurology Childhood Division, Department of Pediatrics at Sapienza, Rome. Clinical manifestations, neurological and psychiatric, laboratory investigations, and familiar history were collected to evaluate the differences between the two groups. The effects of various therapeutic approaches were examined. Descriptive and comparative statistical analyses were performed. Results: The mean age at onset of PANDAS/PANS symptoms was 6.2 ± 1.2 years. The most common diagnosis was PANDAS, followed by PANS. Neurological and psychiatric symptoms were mostly evident in both groups (>70% of the population), with no significant difference between them (P = 0.52 and P = 0.15, respectively). Irritability, aggressivity, and food restriction were more prevalent in children with PANS than in those with PANDAS (P = 0.024 and P = 0.0023, respectively). The levels of anti-streptolysin O and anti-DNAse B 10-fold higher in PANDAS than those in PANS (P < 0.0001). Antibiotics or psychotherapy were administered in most cases (90.3 and 53.2%, respectively), followed by antipsychotic treatments (24.2%). In the multivariate analysis, among the therapies used, psychotherapy significantly resulted in the most efficacious relief of OCD, reducing stress in patients and their parents (P = 0.042). Conclusion: Our findings confirm a clear clinical difference between the two groups, PANDAS and PANS, using different approaches. In fact, irritability, aggressivity, and food restriction were significantly more frequent in children with PANS and the levels of anti-streptolysin O and anti-DNAse B were higher in PANDAS. Another relevant finding is the efficacy of psychotherapy, especially for obsessive-compulsive disorder, and of antibiotic prophylaxis in managing acute neurological symptoms.

Patients with abrupt early-onset OCD due to PANS tolerate lower doses of antidepressants and antipsychotics.

OBJECTIVE: To characterize drug tolerability in pediatric patients with an abrupt-onset of obsessive-compulsive disorder (OCD) meeting criteria for pediatric acute-onset neuropsychiatric syndrome (PANS). METHODS: We reviewed charts of 188 consecutive patients with PANS seen in the PANS clinic, collecting starting, side effect, and tolerated doses, as well as side effect profile for each antidepressant and antipsychotic trial. RESULTS: Of 188 included patients: 57% had trials of antidepressants and/or antipsychotics. Patients prescribed psychotropics were older at PANS onset (mean 9.5 vs 7.1 years, p < 0.01) and had had a longer delay before presenting to clinic (median 1.4 vs 0.5 years, p < 0.01). Antidepressant indications (n = 146) were OCD (48%), anxiety (44%), and depression (32%). Antipsychotic indications (n = 119) were aggression (34%), psychotic symptoms (28%), and OCD (24%). Side effects requiring medication change occurred in 54% of patients: in 38% of antidepressant trials and 49% of antipsychotic trials. Antidepressants' most common side effects were anxiety, agitation, aggression, and akathisia. Antipsychotics' most common side effects were dystonia, aggression, self-injurious behavior, and movement abnormality. Side effects were common at doses lower than the suggested starting doses for these medications. Patients tolerated antidepressants and antipsychotics when doses were low. CONCLUSION: When antidepressants and antipsychotics are prescribed to patients with PANS, intolerable side effects were noted at doses lower than or equal to suggested starting doses. Patients with PANS can benefit from these therapies. However, when treating these patients, clinicians are advised to start with significantly lower doses than they might use in other disorders.

Pediatric Acute-onset Neuropsychiatric Syndrome and Mycoplasma Pneumoniae Infection: A Case Report Analysis with a Metabolomics Approach.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinical condition characterized by a sudden and dramatic obsessive-compulsive disorder with a suggested post-infectious immune-mediated etiology. This condition is accompanied by an extensive series of relatively serious neuropsychiatric symptoms. The diagnosis of PANS is made by "exclusion", as the individual PANS symptoms overlap with a multiplicity of psychiatric disorders with the onset in childhood. A number of researchers accumulated evidence to support the hypothesis that PANS was closely associated with a number of infections. In the last decade, metabolomics played an essential role in improving the knowledge of complex biological systems and identifying potential new biomarkers as indicators of pathological progressions or pharmacologic responses to therapy. The metabolome is considered the most predictive phenotype, capable of recognizing epigenetic differences, reflecting more closely the clinical reality at any given moment and thus providing extremely dynamic data. In the present work, the most recent hypothesis and suggested mechanisms of this condition are reviewed and the case of a 10 - year-old girl with PANS is described, before and after clarithromycin treatment. The main results of this case report are discussed from a metabolomics point of view. The alteration of several metabolic pathways concerning the microbial activity highlights the possible role of the microbiome in the development of PANS. Furthermore, different metabolic perturbations at the level of protein biosynthesis, energy and amino acid metabolisms are observed and discussed. Based on our observations, it is believed that metabolomics is a promising technology to unravel the mysteries of PANS in the near future.

Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity.

OBJECTIVE: In the clinical syndrome Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), obsessive compulsive disorder (OCD) and/or food refusal symptoms have an abrupt-onset (over 48 h) coupled with at least two other specified neuropsychiatric symptoms. We aimed to characterize in detail for the first time, psychotic symptoms experienced by children with PANS as well as the impact of psychotic symptoms on disease severity and course of illness. We inform about the diagnosis of the clinical description: PANS and hope to improve evaluation, treatment, diagnostic validity and future investigation. METHODS: Retrospective review of 143 consecutive PANS clinic patient charts meeting inclusion criteria. The Caregiver Burden Inventory, Global Impairment Score, and Children's Global Assessment Scale were used to assess impairment. RESULTS: Visual and auditory hallucinations were each experienced by 36%, of which most (83%) were transient and complex (non-threatening voices or figures). 6.3% and 5.5% of patients experienced delusions and thought disorganization respectively. Those with psychotic symptoms showed statistically significant differences in disease impairment and caregiver burden. There were no differences in time to treatment access or length of illness. CONCLUSIONS: Over 1/3 of children with PANS experienced transient hallucinations. They were more impaired than those without psychotic symptoms, but showed no differences in disease progression. This difference may point toward heterogeneity in PANS. When evaluating children with acute psychotic symptoms, clinicians should screen for abrupt-onset of a symptom cluster including OCD and/or food refusal, with neuropsychiatric symptoms (enuresis, handwriting changes, tics, hyperactivity, sleep disorder) before initiating treatment.

Individualized Immunological Data for Precise Classification of OCD Patients.

Obsessive⁻compulsive disorder (OCD) affects about 2% of the general population, for which several etiological factors were identified. Important among these is immunological dysfunction. This review aims to show how immunology can inform specific etiological factors, and how distinguishing between these etiologies is important from a personalized treatment perspective. We found discrepancies concerning cytokines, raising the hypothesis of specific immunological etiological factors. Antibody studies support the existence of a potential autoimmune etiological factor. Infections may also provoke OCD symptoms, and therefore, could be considered as specific etiological factors with specific immunological impairments. Finally, we underline the importance of distinguishing between different etiological factors since some specific treatments already exist in the context of immunological factors for the improvement of classic treatments.

CANS: Childhood acute neuropsychiatric syndromes.

The terms Pediatric Autoimmune Neuropsychiatric disorders associated with streptococcal infections (PANDAS), Pediatric acute-onset neuropsychiatric Syndrome (PANS), and Childhood Acute Neuropsychiatric Symptoms (CANS) have been used to describe certain acute onset neuropsychiatric pediatric disorders. This clinical characteristic was unusually abrupt onset of obsessive compulsive symptoms and/or severe eating restrictions and concomitant cognitive, behavioral or neurological symptoms. Because the CANS/PANS criteria define a broad spectrum of neuropsychiatric conditions, the syndrome is presumed to result from a variety of disease mechanisms and to have multiple etiologies, ranging from postinfectious autoimmune and neuroinflammatory disorders to toxic, endocrine or metabolic disorders. We suggest a diagnostic flow-chart in case of acute onset neuropsychiatric syndrome to better define diagnostic criteria, identify possible subtypes and delineate treatment.

[Pediatric acute-onset neuropsychiatric syndrome: clinical/laboratory characteristics]. / Kliniko-laboratornaia kharakteristika pediatricheskogo ostro voznikshego neiropsikhiatricheskogo sindroma.

AIM: Based on the current conceptions on the genesis of hyperkinetic syndromes in children and adolescents, to single out a group of patients with suggestive PANS, compare clinical and laboratory results and determine clinical/laboratory characteristics of this syndrome. MATERIAL AND METHODS: Sixty-nine patients with tics were studied using neurological examination, questionnaires and international scales for assessment of tics, obsessive-compulsive disorders and attention deficit hyperactivity disorder (ADHD). Laboratory tests included general blood tests, antistreptolysin O test, determination of rheumatoid factor, C-reactive protein, circulating immune complexes, nasopharyngeal wash for ß-hemolytic streptococcus, antineuronal antibodies and immunoglobulins A, M, G, E, CD4, CD8-lymphocytes. The same tests were performed in the control group. RESULTS AND CONCLUSION: Clinical symptoms were different by the severity and phenomenology of tic hyperkineses in patients with PANS compared to the patients with tics without immune disorders. Most of the patients were diagnosed with Tourette syndrome. ADHD was the most common diagnosis in the PANS group. Its frequency was 2.5 higher in the male patients. A chronic focus of infection did no predict the development of PANS. Based on the laboratory results, one can assume that ß-hemolytic streptococcus A infection, lower JgM levels and an elevated CD8+ lymphocytes predict the development of autoimmune mental and neurological disorders in the group of PANS patients.