Prevalence of Neurological Soft Signs at Presentation in Pediatric Acute-Onset Neuropsychiatric Syndrome.

Importance: Studies of brain imaging and movements during REM sleep indicate basal ganglia involvement in pediatric acute-onset neuropsychiatric syndrome (PANS). Characterizing neurological findings commonly present in patients with PANS could improve diagnostic accuracy. Objective: To determine the prevalence of neurological soft signs which may reflect basal ganglia dysfunction (NSS-BG) in youth presenting with PANS and whether clinical characteristics of PANS correlate with NSS-BG. Design, Setting, and Participants: 135 new patients who were evaluated at the Stanford Children's Immune Behavioral Health Clinic between November 1, 2014 and March 1, 2020 and met strict PANS criteria were retrospectively reviewed for study inclusion. 16 patients were excluded because they had no neurological exam within the first three visits and within three months of clinical presentation. Main Outcomes and Measures: The following NSS-BG were recorded from medical record review: 1) glabellar tap reflex, 2) tongue movements, 3) milkmaid's grip, 4) choreiform movements, 5) spooning, and 6) overflow movements. We included data from prospectively collected symptoms and impairment scales. Results: The study included 119 patients: mean age at PANS onset was 8.2 years, mean age at initial presentation was 10.4 years, 55.5% were male, and 73.9% were non-Hispanic White. At least one NSS-BG was observed in 95/119 patients (79.8%). Patients had 2.1 NSS-BG on average. Patients with 4 or more NSS-BG had higher scores of global impairment (p=0.052) and more symptoms (p=0.008) than patients with 0 NSS-BG. There was no significant difference in age at visit or reported caregiver burden. On Poisson and linear regression, the number of NSS-BG was associated with global impairment (2.857, 95% CI: 0.092-5.622, p=0.045) and the number of symptoms (1.049, 95% CI: 1.018-1.082, p=0.002), but not age or duration of PANS at presentation. Conclusions and Relevance: We found a high prevalence of NSS-BG in patients with PANS and an association between NSS-BG and disease severity that is not attributable to younger age. PANS may have a unique NSS-BG profile, suggesting that targeted neurological exams may support PANS diagnosis.

Psychometric Properties of the PANS 31-Item Symptom Rating Scale.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by sudden onset of obsessive-compulsive disorder and/or eating restriction with associated neuropsychiatric symptoms from at least two of seven categories. The PANS 31-Item Symptom Rating Scale (PANS Rating Scale) was developed to identify and measure the severity of PANS symptoms. The objective of this study was to define the psychometric properties of the PANS Rating Scale. Methods: Children with PANS (N = 135) and their parents participated. Parents completed the PANS Rating Scale and other scales on Research Electronic Data Capture. The PANS Rating Scale includes 31 items that are rated on a Likert scale from 0 = none to 4 = extreme. Pearson's correlations were run between the PANS Total score and scores on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Yale Global Tic Severity Scale (YGTSS), Modified Overt Aggression Scale (MOAS), Columbia Impairment Scale (CIS), PANS Global Impairment Score (GIS), and Children's Global Assessment Scale (CGAS). Results: Convergent validity was supported by significant correlations between the PANS Total and scores on the CY-BOCS, YGTSS, MOAS, CIS, GIS, and CGAS. The largest correlations were with measures of functional impairment: PANS Total and CIS (r = 0.81) and PANS Total and GIS (r = 0.74). Cronbach's alpha was 0.89 which demonstrates strong internal consistency of the 31 items. PANS Total score was significantly higher in children in a flare of their neuropsychiatric symptoms compared to children who were not in a flare. Conclusions: This study provides preliminary support for the PANS Rating Scale as a valid research instrument with good internal consistency. The PANS Rating Scale appears to be a useful measure for assessing children with PANS.

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

Synchrony 2022: The Role of Neuroinflammation in Behavioral Exacerbations in Autism Spectrum Disorder.

The BRAIN Foundation (Pleasanton, CA) hosted Synchrony 2022, a medical conference focusing on research for treatments to benefit individuals with neurodevelopmental disorders (NDD), including those with autism spectrum disorders (ASD) [...].

Evaluation of C4 Gene Copy Number in Pediatric Acute Neuropsychiatric Syndrome.

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.

Arthritis in Children with Psychiatric Deteriorations: A Case Series.

Pediatric acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections, Sydenham chorea, and other postinfectious psychiatric deteriorations are thought to be caused by inflammatory/autoimmune mechanisms, likely involving the basal ganglia based on imaging studies. Patients have a relapsing-remitting course and some develop severe refractory psychiatric disease. 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.

Neuroinflammation in Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, and Pediatric Acute Onset Neuropsychiatric Syndrome.

Sydenham chorea (SC), pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are postinfectious neuroinflammatory diseases that involve the basal ganglia and have obsessive-compulsive disorder as a major manifestation. As is true for many childhood rheumatological diseases and neuroinflammatory diseases, SC, PANDAS and PANS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. Research on the treatment of these disorders depend on three complementary modes of intervention including: treating the symptoms, treating the source of inflammation, and treating disturbances of the immune system. Future studies should aim to integrate neuroimaging, inflammation, immunogenetic, and clinical data (noting the stage in the clinical course) to increase our understanding and treatment of SC, PANDAS, PANS, and all other postinfectious/immune-mediated behavioral disorders.

Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness.

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

Group Psychotherapy for Parents of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome.

Parents of children with diagnoses of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS) may experience significant psychological distress related to their child's severe and relapsing illness and challenges with the traumatic nature of its treatment. No manualized or studied psychological interventions specifically for parents of youth with PANS have existed prior to this study. In this pilot study, we assessed the feasibility, satisfaction, and treatment fidelity of a brief 9-session group therapy intervention for parents based on principles of trauma-focused cognitive behavior therapy (CBT). We hypothesized that, if initially elevated, symptoms of depression, anxiety, and trauma would decrease and participants' utilization of positive coping mechanisms would increase post-intervention. We adapted an existing evidence-based group intervention developed for parents of children with premature infants to target sources of stress and coping in parents of children with PANS. Ten parents participated in the study. The 9-session intervention used a combination of techniques that included cognitive restructuring, coping skills, self-care, and a trauma narrative to address psychological stress, trust, grief, and unwanted emotions. Outcome measures included parental symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD), as well as rating of parental satisfaction with the intervention. The treatment was feasible and deliverable with high fidelity. The intervention was rated as useful and satisfactory by parents (overall average usefulness of 4.54 and satisfaction of 4.71 out of 5.0). Elevated symptoms of PTSD and depression decreased with large effect sizes (Cohen's d = 1.42 and Cohen's d = 1.38, respectively). Participating parents demonstrated significantly more active coping and acceptance behaviors and stances. A brief 9-session group therapy intervention based on principles of trauma-focused CBT was found to be effective in reducing symptoms of psychological distress in parents of children with PANS.

Sex and Aggression Characteristics in a Cohort of Patients with Pediatric Acute-Onset Neuropsychiatric Syndrome.

Objective: This study describes for the first time the characteristics by sex of patients with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), including clinical phenotype, treatment, and psychosocial aspects of disease. Methods: This cross-sectional study included 205 consecutive community patients evaluated between January 1, 2012 and March 30, 2019 and compared 87 females with 118 males. Our primary hypothesis was that males would display more aggression, as measured by the Modified Overt Aggression Scale (MOAS) and would be treated with immunotherapy earlier than females. The MOAS began to be administered 5 years into the study period, and 57 of the 205 families completed the MOAS for this study. Results: Our analysis revealed that males had a higher median MOAS score in the first year of clinic when compared with females (median 11, interquartile range [IQR] [4-24] vs. median 3, IQR [1-9]; p = 0.03) and a higher median subscore for physical aggression (median 4, IQR [0-12] vs. median 0, IQR [0-8]; p = 0.05). The median time from PANS symptom onset to first administration of immunotherapy, which did not include nonsteroidal anti-inflammatory drugs or short bursts of oral steroids, was 6.9 years for females and 3.7 years for males (p = 0.20). The two groups did not differ significantly in age of PANS onset, time from onset to clinic entry, other psychiatric symptom measures, or laboratory markers of inflammation. Conclusion: Among patients with PANS, males exhibit more aggressive behavior when compared with females, which may advance the decision to treat with immunotherapy. Scores that capture a more global level of functioning show that despite there being a higher level of aggression in males, female patients with PANS have similar levels of overall impairment.

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.

Profiling Behavioral and Psychological Symptoms in Children Undergoing Treatment for Spondyloarthritis and Polyarthritis.

OBJECTIVE: Few studies examine psychopathology in different juvenile idiopathic arthritis (JIA) subtypes and disease activity states. We aimed to (1) evaluate emotional and behavioral symptoms in children with juvenile spondyloarthritis (SpA) and polyarticular arthritis (PolyA) as compared to a national normative population using the Child Behavior Checklist (CBCL), and (2) evaluate the relationship between CBCL scores and disease activity. METHODS: Patients with JIA aged 6-17 years with SpA or PolyA were recruited from our pediatric rheumatology clinic from April 2018 to April 2019 and the CBCL and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10) were completed. Primary outcome measures were CBCL total competence, internalizing, externalizing, and total problems raw scores. We compared outcomes from each group to national CBCL normative data. To investigate the relationship between CBCL scores and disease activity, we ran a generalized linear regression model for all patients with arthritis with cJADAS10 as the main predictor. RESULTS: There were 111 patients and 1753 healthy controls (HCs). Compared to HCs, patients with SpA or PolyA had worse total competence and internalizing scores. Higher cJADAS10 scores were associated with worse total competence, worse internalizing, and higher total problems scores. Most of these differences reached statistical significance (P < 0.01). Self-harm/suicidality was almost 4-fold higher in patients with PolyA than HCs (OR 3.6, 95% CI 1.3-9.6, P = 0.011). CONCLUSION: Our study shows that patients with SpA and PolyA with more active disease have worse psychological functioning in activities, school, and social arenas, and more internalized emotional disturbances, suggesting the need for regular mental health screening by rheumatologists.

Autoantibodies targeting cytokines and connective tissue disease autoantigens are common in acute non-SARS-CoV-2 infections.

The widespread presence of autoantibodies in acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is increasingly recognized, but the prevalence of autoantibodies in infections with organisms other than SARS-CoV-2 has not yet been reported. We used protein arrays to profile IgG autoantibodies from 317 samples from 268 patients across a spectrum of non-SARS-CoV-2 infections, many of whom were critically ill with pneumonia. Anti-cytokine antibodies (ACA) were identified in > 50% of patients infected with non-SARS-CoV-2 viruses and other pathogens, including patients with pneumonia attributed to bacterial causes. In cell-based functional assays, some ACA blocked binding to surface receptors for type I interferons (Type I IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-6 (IL-6). Autoantibodies against traditional autoantigens associated with connective tissue diseases (CTDs) were also commonly observed in these cohorts, including newly-detected antibodies that emerged in longitudinal samples from patients infected with influenza. We conclude that autoantibodies, some of which are functionally active, may be much more prevalent than previously appreciated in patients who are symptomatically infected with diverse pathogens.

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.

Discovering prescription patterns in pediatric acute-onset neuropsychiatric syndrome patients.

OBJECTIVE: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a complex neuropsychiatric syndrome characterized by an abrupt onset of obsessive-compulsive symptoms and/or severe eating restrictions, along with at least two concomitant debilitating cognitive, behavioral, or neurological symptoms. A wide range of pharmacological interventions along with behavioral and environmental modifications, and psychotherapies have been adopted to treat symptoms and underlying etiologies. Our goal was to develop a data-driven approach to identify treatment patterns in this cohort. MATERIALS AND METHODS: In this cohort study, we extracted medical prescription histories from electronic health records. We developed a modified dynamic programming approach to perform global alignment of those medication histories. Our approach is unique since it considers time gaps in prescription patterns as part of the similarity strategy. RESULTS: This study included 43 consecutive new-onset pre-pubertal patients who had at least 3 clinic visits. Our algorithm identified six clusters with distinct medication usage history which may represent clinician's practice of treating PANS of different severities and etiologies i.e., two most severe groups requiring high dose intravenous steroids; two arthritic or inflammatory groups requiring prolonged nonsteroidal anti-inflammatory drug (NSAID); and two mild relapsing/remitting group treated with a short course of NSAID. The psychometric scores as outcomes in each cluster generally improved within the first two years. DISCUSSION AND CONCLUSION: Our algorithm shows potential to improve our knowledge of treatment patterns in the PANS cohort, while helping clinicians understand how patients respond to a combination of drugs.

Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome.

BACKGROUND: Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt debilitating psychiatric illness. We anecdotally observed hypoferritinemia and iron deficiency in a subset of patients with PANS, prompting this study. METHODS: In this IRB-approved prospective cohort study, we included patients seen at the Stanford PANS Clinic who met study criteria. The prevalence of hypoferritinemia (using cut-offs of 7 ng/ml in children ≤ 15 years and 18 ng/ml in adolescents > 15 years) and iron deficiency was estimated. Differences in patients with and without hypoferritinemia during PANS flare were explored. RESULTS: Seventy-nine subjects (mean age of PANS onset of 8.7 years) met study criteria. Hypoferritinemia was observed in 27% and three quarters occurred during a PANS flare. Compared to patients without hypoferritinemia during PANS flare, patients with hypoferritinemia had worse global impairment, more comorbid inflammatory diseases, and exhibited a chronic course of PANS illness. The estimated prevalence of iron deficiency was 3-8% in the PANS cohort, 1.4-2.0-fold higher than in the age- and sex-matched U.S. POPULATION: More stringent ferritin level cut-offs than the comparison CDC dataset were used. CONCLUSION: Hypoferritinemia and iron deficiency appear to be more common in PANS patients. More research is needed to confirm and understand this association. IMPACT: Our study suggests hypoferritinemia and iron deficiency are more common in patients with pediatric acute-onset neuropsychiatric syndrome (PANS) than in the sex- and age-matched US population. Hypoferritinemia was commonly observed during a disease flare but not associated with dietary or demographic factors. In patients with PANS and iron deficiency, clinicians should consider possibility of inflammation as the cause especially if iron deficiency cannot be explained by diet and blood loss. Future research should include larger cohorts to corroborate our study findings and consider examining the iron dynamics on MRI brain imaging in order to better understand the pathophysiology of PANS.

Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging.

Importance: Epidemiological studies indicate a link between obsessive-compulsive disorder and infections, particularly streptococcal pharyngitis. Pediatric acute-onset neuropsychiatric syndrome (PANS) manifests suddenly with obsessions, compulsions, and other behavioral disturbances, often after an infectious trigger. The current working model suggests a unifying inflammatory process involving the central nervous system, particularly the basal ganglia. Objective: To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS. Design, Setting, and Participants: Case-control study performed at a single-center, multidisciplinary clinic in the United States focusing on the evaluation and treatment of children with PANS. Sixty consecutive patients who underwent 3 Tesla (T) magnetic resonance imaging (MRI) before immunomodulation from September 3, 2012, to March 30, 2018, were retrospectively reviewed for study inclusion. Six patients were excluded by blinded investigators because of imaging or motion artifacts, 3 patients for major pathologies, and 17 patients for suboptimal atlas image registration. In total, 34 patients with PANS before initiation of treatment were compared with 64 pediatric control participants. Main Outcomes and Measures: Using atlas-based MRI analysis, regional brain volume, diffusion, and cerebral blood flow were measured in the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem. An age and sex-controlled multivariable analysis of covariance was used to compare patients with control participants. Results: This study compared 34 patients with PANS (median age, 154 months; age range, 55-251 months; 17 girls and 17 boys) and 64 pediatric control participants (median age, 139 months; age range, 48-213 months); 41 girls and 23 boys). Multivariable analysis demonstrated a statistically significant difference in MRI parameters between patients with PANS and control participants (F21,74 = 6.91; P < .001; partial η2 = 0.662). All assessed brain regions had statistically significantly increased median diffusivity compared with 64 control participants. Specifically, the deep gray matter (eg, the thalamus, basal ganglia, and amygdala) demonstrated the most profound increases in diffusivity consistent with the cardinal clinical symptoms of obsessions, compulsions, emotional dysregulation, and sleep disturbances. No statistically significant differences were found regarding volume and cerebral blood flow. Conclusions and Relevance: This study identifies cerebral microstructural differences in children with PANS in multiple brain structures, including the deep gray matter structures (eg, the thalamus, basal ganglia, and amygdala). Further study of MRI is warranted in prospective, clinical trials as a potential quantitative method for assessing patients under evaluation for PANS.

Subacute Neuropsychiatric Syndrome in Girls With SHANK3 Mutations Responds to Immunomodulation.

Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.