Yuhuan Xie

All Publications

• New-onset OCD and juvenile enthesitis related arthritis after COVID-19 (Three Cases). Developmental neuroscience Saini, T., Ma, M., Sandberg, J., Farhadian, B., Manko, C., Xie, Y., Madan, J., Bauer, K., Tran, P., Frankovich, J. 2025: 1-29

  Abstract

  Introduction Obsessive-compulsive disorder (OCD) is a mental health disorder characterized by obsessions and compulsions. There is a mounting body of evidence suggesting a link between OCD and inflammation. Neuropsychiatric deteriorations have been reported to follow COVID-19 infections, including OCD. Additionally, symptomatic arthritis has also been reported following COVID-19 infection. We aim to describe post-COVID-19 clinical deteriorations presenting to our multi-discplinary immune behavioral health clinic. Methods 151 pre-screened patients were evaluated in our clinic between March 1, 2020 and August 1, 2024. We systematically searched charts for infection with SARS-CoV-2 and found three cases of confirmed COVID-19 infection that preceded an abrupt neuropsychiatric deterioration (in the absence of other detected infections). Per our clinic's latest protocol, all patients underwent a full rheumatology and arthritis evaluation (regardless of joint complaints) including ultrasound imaging which were used to objectively assess for effusions, synovitis, and capsulitis. Results Two of the three patients met criteria for a PANS diagnosis. All three patients had new-onset OCD or re-escalation of OCD with new obsessions/compulsions/rituals post-COVID-19 and all three had imaging findings of effusions +/- synovitis +/- capsulitis despite not having significant complaints of joint pain. Joint pain complaints evolved after psychiatric symptoms improved (because the capacity of the patient to articulate joint pain improved when they were less overwhelmed by intrusive thoughts). Immunomodulatory treatment began with nonsteroidal anti-inflammatory drugs (NSAIDs) and was escalated to disease-modifying antirheumatic drugs (DMARDs) in the two patients with synovitis +/- capsulitis. All three patients eventually returned to baseline neuropsychiatric health (minimal-to-no OCD and resolution of intense anxiety and mood instability) and also had improvement in arthritic findings after introduction of NSAID +/- DMARDs. Conclusion Infections may result in systemic immune activation leading to inflammation. Thus, when patients have an acute neuropsychiatric deterioration (hypothesized to have been triggered by an infection), the situation may warrant evaluation for inflammation in other more accessible sites (e.g. joints). Use of this evidence of inflammation (as a sign of immune activation) is helpful since it is difficult to assess for brain inflammation, as clinical brain imaging has poor sensitivity for inflammation and biopsy of the striatum (and other areas involved in OCD) is difficult and limited by risk. In our cases, early joint imaging not only helped confirm signs of systemic inflammation in the setting of neuropsychiatric symptoms, it also allowed for earlier initiation of immunomodulatory treatment.

  View details for DOI 10.1159/000545137

  View details for PubMedID 40174578

• Obsessive-Compulsive Disorder Associated with Autoimmunity in Youth: Clinical Course before and after Rituximab +/- Adjunctive Immunomodulation. Developmental neuroscience Frankovich, J., Calaprice, D., Ma, M., Knight, O., Miles, K., Manko, C., Hernandez, J. D., Sandberg, J., Farhadian, B., Xie, Y., Silverman, M., Madan, J., Strand, V., Chang, K., Thienemann, M. 2025: 1-19

  Abstract

  Multiple lines of evidence suggest that some cases of obsessive-compulsive disorder (OCD) are underlain by autoimmune and/or inflammatory processes that act on the brain to create neuropsychiatric symptomatology. However, studies of immunomodulatory treatments for such cases are sparse. Here we present consecutive cases of presumed-neuroimmune OCD in youth that have been treated with rituximab +/- adjunctive immunomodulatory treatments.Of the 458 cases evaluated by our clinic between September 15, 2012, and January 6, 2023, 23 patients were treated with rituximab +/- adjunctive immunomodulation orchestrated by our team (based on evidence of autoimmunity) and were followed routinely by the outpatient clinic team. Patients who presented for a second opinion and were not diagnosed, treated, and/or followed by our outpatient clinic (n = 5) or did not have OCD (n = 1) are not included. We present the immunological and psychiatric profiles (prior to treatment), selection criteria for the use of rituximab, rituximab treatment protocol, recovery status, and reasons for discontinuation (if applicable). Data were obtained from chart review of clinical records. Determination of recovery status was confirmed by the clinical team caring for the patients; patients were classified as did not recover, partial recovery (PR), or full recovery (FR). Since multiple treatments (psychotherapy, psychiatric medication, and immunomodulation) together contributed to recovery, the team additionally assessed the attribution of response to rituximab and details are documented.Patients were between the ages of 4 and 20 at initiation of rituximab treatment. All suffered from severe, debilitating neuropsychiatric symptoms prior to rituximab initiation in the context of evidence for systemic autoimmunity. Approximately 70% had an unequivocal recovery following treatment with rituximab (+/- induction and adjunctive immunomodulation) which in most cases allowed the patients to achieve normal levels of function and cease psychotropic medications. Interpretation of attribution in many cases is complicated by the use of induction and adjunct immunomodulation. Most patients experienced transient increases in symptoms before improving; 11 experienced mild self-limited infusion-related reactions, and 14 experienced hypogammaglobulinemia. No patient had an organ or life-threatening reaction or infection following rituximab. One patient developed recurrent sinusitis following rituximab, and thus, rituximab was stopped despite neuropsychiatric improvements, then rituximab was restarted later due to recrudescence of psychiatric symptoms; the approval to use rituximab with intravenous immune globulin (IVIG) permitted its use. Patients who received adjunctive immunomodulation (IVIG, methotrexate, leflunomide, etc.) had a higher likelihood of achieving recovery (FR or PR) after rituximab (Fisher's exact test, one-sided, p < 0.0001).For a small fraction of our patients, systemic autoimmunity and severe, debilitating psychiatric symptoms (including but not limited to OCD) led to a trial of rituximab. A randomized placebo-controlled trial will be necessary to objectively determine efficacy with regard to OCD/complex neuropsychiatric disease in the setting of systemic autoimmunity. Patients may have better responses to rituximab when given with adjunctive immunomodulation (IVIG, methotrexate, etc.). Reasons for the benefit of adjunctive immunomodulation are likely multifactorial: controlling infections, addressing inflammation driven by immune pathways beyond T and B cells (i.e., proinflammatory monocytes which have been linked to OCD), and preventing anti-rituximab antibodies.

  View details for DOI 10.1159/000544993

  View details for PubMedID 40064151

• Neurological Soft Signs at Presentation in Patients With Pediatric Acute-Onset Neuropsychiatric Syndrome. JAMA network open Zebrack, J. E., Gao, J., Verhey, B., Tian, L., Stave, C., Farhadian, B., Ma, M., Silverman, M., Xie, Y., Tran, P., Thienemann, M., Wilson, J. L., Frankovich, J. 2025; 8 (3): e250314

  Abstract

  Importance: Studies of brain imaging and movements during rapid eye movement sleep indicate basal ganglia involvement in pediatric acute-onset neuropsychiatric syndrome (PANS). Characterizing neurological findings that commonly present among patients with PANS could improve diagnostic accuracy.Objectives: To evaluate the prevalence of neurological soft signs (NSSs) that may be associated with basal ganglia dysfunction among youths presenting with PANS and assess whether clinical characteristics of PANS correlate with NSSs that may be associated with basal ganglia dysfunction.Design, Setting, and Participants: This cohort study included 135 new patients who met strict PANS criteria and were evaluated at the Stanford Children's Immune Behavioral Health Clinic between November 1, 2014, and March 1, 2020. Data on these patients were retrospectively reviewed between December 13, 2020, and September 25, 2023. Sixteen patients were excluded because they had no neurological examination within the first 3 visits and within 3 months of clinical presentation. Statistical analysis was conducted between September 26, 2023, and November 22, 2024.Main Outcomes and Measures: The following NSSs that may be associated with basal ganglia dysfunction 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. Data from prospectively collected symptoms and impairment scales (Global Impairment Score [GIS; score range, 1-100, with higher scores indicating greater impairment] and Caregiver Burden Inventory [score range, 0-96, with higher scores indicating greater caregiver burden]) were included.Results: The study included 119 patients; the mean (SD) age at PANS onset was 8.2 (3.6) years, the mean (SD) age at initial presentation was 10.4 (3.6) years, and 66 (55.5%) were boys. At least 1 NSS that may be associated with basal ganglia dysfunction was observed in 95 patients (79.8%); the mean (SD) number of NSSs was 2.1 (1.6). Patients with 4 or more NSSs had higher GISs (mean [SD] score, 56.0 [22.6] vs 40.6 [26.7]; P=.05) and more symptoms (mean [SD] number, 15.1 [4.9] vs 11.5 [4.2]; P=.008) than patients with 0 NSSs. There was no significant difference in age at visit or in Caregiver Burden Inventory score. On Poisson and linear regression, the number of NSSs was associated with global impairment, with 1 more sign increasing the GIS by 2.86 (95% CI, 0.09-5.62; P=.04), and with the number of symptoms, with 1 more sign increasing the number of symptoms by 5% (1.05; 95% CI, 1.02-1.08; P=.002), but not with age or duration of PANS at presentation.Conclusions and Relevance: This cohort study of patients with PANS found a high prevalence of NSSs that may be associated with basal ganglia dysfunction and an association between these NSSs and disease severity that was not associated with younger age. PANS may have a unique profile, suggesting that targeted neurological examinations may support PANS diagnosis.

  View details for DOI 10.1001/jamanetworkopen.2025.0314

  View details for PubMedID 40053347

• Cerebrospinal fluid characteristics of patients presenting for evaluation of pediatric acute-neuropsychiatric syndrome. Frontiers in behavioral neuroscience Pooni, R., Zheng, W., Ma, M., Silverman, M., Xie, Y., Farhadian, B., Thienemann, M., Mellins, E., Frankovich, J. 2024; 18: 1342486

  Abstract

  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.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).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.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.

  View details for DOI 10.3389/fnbeh.2024.1342486

  View details for PubMedID 39224487

  View details for PubMedCentralID PMC11367679

• Prevalence of Neurological Soft Signs at Presentation in Pediatric Acute-Onset Neuropsychiatric Syndrome. medRxiv : the preprint server for health sciences Zebrack, J. E., Gao, J., Verhey, B., Tian, L., Stave, C., Farhadian, B., Ma, M., Silverman, M., Xie, Y., Tran, P., Thienemann, M., Wilson, J. L., Frankovich, J. 2024

  Abstract

  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.Key Points: Question: Do patients with pediatric acute-onset neuropsychiatric syndrome present with neurological soft signs reflective of basal ganglia dysfunction, and are these examination findings associated with disease severity?Findings: In this cohort study of 119 patients with pediatric acute-onset neuropsychiatric syndrome, most patients presented with at least one neurological soft sign pertaining to the basal ganglia. The number of signs was associated with global impairment and the number of PANS symptoms. These findings are consistent with basal ganglia pathology in pediatric acute-onset neuropsychiatric syndrome.Meaning: Targeted neurological exams may help support the diagnosis of pediatric acute-onset neuropsychiatric syndrome.

  View details for DOI 10.1101/2024.04.26.24306193

  View details for PubMedID 38746142

• Development of Autoimmune Diseases Among Children With Pediatric Acute-Onset Neuropsychiatric Syndrome JAMA network open Ma, M., Masterson, E. E., Gao, J., Karpel, H., Chan, A., Pooni, R., Sandberg, J., Rubesova, E., Farhadian, B., Willet, T., Xie, Y., Tran, P., Silverman, M., Thienemann, M., Mellins, E., Frankovich, J. 2024; 7 (7)

  View details for DOI 10.1001/jamanetworkopen.2024.21688

• Arthritis in Children with Psychiatric Deteriorations: A Case Series DEVELOPMENTAL NEUROSCIENCE Ma, M., Sandberg, J., Farhadian, B., Silverman, M., Xie, Y., Thienemann, M., Frankovich, J. 2023: 1

  Abstract

  Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS), Sydenham chorea and other post-infectious 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 non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation. Conclusion: 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.

  View details for DOI 10.1159/000530854

  View details for Web of Science ID 001008111700001

  View details for PubMedID 37231875