Bio


Co- Director, Director of Psychiatric Services
Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Clinic

Clinical Focus


  • Psychiatry
  • Psychiatry, Child and Adolescent
  • Pediatric Acute-Onset Neuropsychiatric Syndrome

Professional Education


  • Fellowship: Stanford University School of Medicine (1989) CA
  • Residency: Stanford University School of Medicine (1987) CA
  • Residency: University of Wisconsin School of Medicine Registrar (1986) WI
  • Board Certification: American Board of Psychiatry and Neurology, Psychiatry (1990)
  • Board Certification: American Board of Psychiatry and Neurology, Child and Adolescent Psychiatry (1990)
  • Board Certification: American Board of Internal Medicine, Internal Medicine (1984)
  • Residency: University of TX Hlth Science Ctr (1984) TX
  • Medical Education: Duke University School of Medicine (1981) NC

Current Research and Scholarly Interests


Pediatric Acute-Onset Neuropsychiatric Disorder

2023-24 Courses


All Publications


  • Group Psychotherapy for Parents of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of clinical psychology in medical settings Ellerkamp, H., Thienemann, M., Tinero, J., Shaw, R., Dowtin, L. L., Frankovich, J., Borkovi, T. C. 2022

    Abstract

    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.

    View details for DOI 10.1007/s10880-022-09926-0

    View details for PubMedID 36480109

  • Sex and Aggression Characteristics in a Cohort of Patients with Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of child and adolescent psychopharmacology Gao, J., Chan, A., Willett, T., Farhadian, B., Silverman, M., Tran, P., Ahmed, S., Thienemann, M., Frankovich, J. 2022

    Abstract

    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.

    View details for DOI 10.1089/cap.2021.0084

    View details for PubMedID 35998241

  • Children With PANS May Manifest POTS. Frontiers in neurology Chan, A., Gao, J., Houston, M., Willett, T., Farhadian, B., Silverman, M., Tran, P., Jaradeh, S., Thienemann, M., Frankovich, J. 2022; 13: 819636

    Abstract

    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.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.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).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.

    View details for DOI 10.3389/fneur.2022.819636

    View details for PubMedID 35557616

    View details for PubMedCentralID PMC9086964

  • Two distinct "brain-homing" monocyte subsets identified in pediatric acute-onset neuropsychiatric syndrome (PANS) are immunosuppressive and neuroprotective Rahman, S., Khatun, A., Gaertner, F., Macaubas, C., Licona, N., Columbo, L., Farhadian, B., Willett, T., Thienemann, M., Frankovich, J., Mellins, E. SPRINGER/PLENUM PUBLISHERS. 2022: S103-S104
  • Profiling Behavioral and Psychological Symptoms in Children undergoing treatment for Spondyloarthritis and Polyarthritis. The Journal of rheumatology McHugh, A., Chan, A., Herrera, C., Park, J. M., Balboni, I., Gerstbacher, D., Hsu, J. J., Lee, T., Thienemann, M., Frankovich, J. 1800

    Abstract

    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 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: JIA patients 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 Juvenile Arthritis Disease Activity Score (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 arthritis patients with cJADAS10 as the main predictor.RESULTS: There were 111 patients and 1753 healthy controls. Compared to healthy controls, SpA or PolyA patients 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 four-fold higher in patients with PolyA than healthy controls (OR 3.6, 95% CI 1.3-9.6, p=0.011).CONCLUSION: Our study shows that SpA and PolyA patients 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.

    View details for DOI 10.3899/jrheum.210489

    View details for PubMedID 35105715

  • Patients with abrupt early-onset OCD due to PANS tolerate lower doses of antidepressants and antipsychotics. Journal of psychiatric research Thienemann, M., Park, M., Chan, A., Frankovich, J. 2021; 135: 270–78

    Abstract

    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.

    View details for DOI 10.1016/j.jpsychires.2021.01.022

    View details for PubMedID 33513473

  • Low C4 Copy Number of Total C4 Gene, C4B Gene and C4BL Gene in Children with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Kalinowski, A., Lee, J., Hedlin, H., Pattini, R., Ollila, H., Mignot, E., Levinson, D., Swedo, S., Murphy, T., Chan, A., Thienemann, M., Urban, A., Frankovich, J. WILEY. 2020: 254–55
  • The Killer Immunoglobulin-like Receptor KIR3DL1 in Combination with HLA-Bw4 Is Associated with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Frankovich, J., Anderson, K., Montero-Martin, G., Chan, A., Thienemann, M., Farhadian, B., Willett, T., Mellins, E., Madden, A., Murphy, T., Swedo, S., Fernandez-Vina, M., Hollenbach, J. WILEY. 2020: 255–57
  • Familial Clustering of Immune-mediated Diseases in Children with Abrupt-onset OCD Chan, A., Phu, T., Farhadian, B., Willett, T., Silverman, M., Tran, P., Thienemann, M., Frankovich, J. WILEY. 2020: 250–52
  • Chronic Fatigue Symptoms in Children with Abrupt Early-onset OCD And/or PANS Chan, A., Truong, A., Farhadian, B., Willett, T., Silverman, M., Tran, P., Thienemann, M., Frankovich, J. WILEY. 2020: 252–54
  • Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging. JAMA network open Zheng, J. n., Frankovich, J. n., McKenna, E. S., Rowe, N. C., MacEachern, S. J., Ng, N. N., Tam, L. T., Moon, P. K., Gao, J. n., Thienemann, M. n., Forkert, N. D., Yeom, K. W. 2020; 3 (5): e204063

    Abstract

    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.To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS.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.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.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.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.

    View details for DOI 10.1001/jamanetworkopen.2020.4063

    View details for PubMedID 32364596

  • Association of pediatric acute-onset neuropsychiatric syndrome with microstructural differences in brain regions detected via diffusion-weighted magnetic resonance imaging. JAMA Network Open Zheng, J., Frankovich, J., McKenna, E. S., Rowe, N. C., MacEachern, S. J., Ng, N. N., Tam, L. T., Moon, P. K., Gao, J., Thienemann, M., Forkert, N. D., Yeom, K. W. 2020; 3 (5): 1-15
  • Familial Clustering of Immune-Mediated Diseases in Children with Abrupt-Onset Obsessive Compulsive Disorder. Journal of child and adolescent psychopharmacology Chan, A. n., Phu, T. n., Farhadian, B. n., Willett, T. n., Thienemann, M. n., Frankovich, J. n. 2020

    View details for DOI 10.1089/cap.2019.0167

    View details for PubMedID 32311283

  • Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome. Pediatric research Chan, A. n., Karpel, H. n., Spartz, E. n., Willett, T. n., Farhadian, B. n., Jeng, M. n., Thienemann, M. n., Frankovich, J. n. 2020

    Abstract

    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.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.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.More stringent ferritin level cut-offs than the comparison CDC dataset were used.Hypoferritinemia and iron deficiency appear to be more common in PANS patients. More research is needed to confirm and understand this association.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.

    View details for DOI 10.1038/s41390-020-1103-3

    View details for PubMedID 32746449

  • Profiling Behavioral and Psychological Symptoms in Children with Spondyloarthritis and Polyarthritis McHugh, A., Chan, A., Herrera, C., Thienemann, M., Frankovich, J. WILEY. 2019
  • Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity (vol 110, pg 93, 2019) JOURNAL OF PSYCHIATRIC RESEARCH Silverman, M., Frankovich, J., Nguyen, E., Leibold, C., Yoon, J., Freeman, G., Karpel, H., Thienemann, M. 2019; 113: 45
  • Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity JOURNAL OF PSYCHIATRIC RESEARCH Silverman, M., Frankovich, J., Nguyen, E., Leibold, C., Yoon, J., Freeman, G., Karpel, H., Thienemann, M. 2019; 110: 93–102
  • Action in the face of uncertainty? JOURNAL OF PEDIATRICS Thienemann, M., Frankovich, J. 2019; 204: 324
  • The Burden of Caring for a Child or Adolescent With Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): An Observational Longitudinal Study JOURNAL OF CLINICAL PSYCHIATRY Frankovich, J., Leibold, C., Farmer, C., Sainani, K., Kamalani, G., Farhadian, B., Willett, T., Park, J. M., Sidell, D., Ahmed, S., Thienemann, M. 2019; 80 (1)
  • The Burden of Caring for a Child or Adolescent With Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): An Observational Longitudinal Study. The Journal of clinical psychiatry Frankovich, J., Leibold, C. M., Farmer, C., Sainani, K., Kamalani, G., Farhadian, B., Willett, T., Park, J. M., Sidell, D., Ahmed, S., Thienemann, M. 2018; 80 (1)

    Abstract

    OBJECTIVE: To describe the longitudinal association between disease severity, time established in clinical treatment, and caregiver burden in a community-based patient population diagnosed with pediatric acute-onset neuropsychiatric syndrome (PANS).METHODS: The study included an observational longitudinal cohort design, with Caregiver Burden Inventories (CBIs) collected between April 2013 and November 2016 at the Stanford PANS multidisciplinary clinic. Inclusion criteria for this study were as follows: pediatric patients meeting strict PANS/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) diagnostic criteria (n = 187), having a caregiver fill out at least 1 complete CBI during a disease flare (n = 114); and having family who lives locally (n = 97). For longitudinal analyses, only patients whose caregiver had filled out 2 or more CBIs (n = 94 with 892 CBIs) were included. In the study sample, most primary caregivers were mothers (69 [71.1%] of 97), the majority of PANS patients were male (58 [59.8%] of 97), and mean age at PANS onset was 8.8 years.RESULTS: In a patient's first flare tracked by the clinic, 50% of caregivers exceeded the caregiver burden score threshold used to determine respite need in care receiver adult populations. Longitudinally, flares, compared with quiescence, predicted increases in mean CBI score (6.6 points; 95% CI, 5.1 to 8.0). Each year established in clinic predicted decreased CBI score (-3.5 points per year; 95% CI, -2.3 to -4.6). Also, shorter time between PANS onset and entry into the multidisciplinary clinic predicted greater improvement in mean CBI score over time (0.7 points per year squared; 95% CI, 0.1 to 1.3). Time between PANS onset and treatment with antibiotics or immunomodulation did not moderate the relationship between CBI score and time in clinic.CONCLUSIONS: PANS caregivers suffer high caregiver burden. Neuropsychiatric disease severity predicts increased caregiver burden. Caregiver burden tends to decrease over time in a group of patients undergoing clinical treatment at a specialty PANS clinic. This decrease could be independent of clinical treatment.

    View details for PubMedID 30549499

  • Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity. Journal of psychiatric research Silverman, M., Frankovich, J., Nguyen, E., Leibold, C., Yoon, J., Mark Freeman, G. J., Karpel, H., Thienemann, M. 2018; 110: 93–102

    Abstract

    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.

    View details for PubMedID 30605785

  • Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of child and adolescent psychopharmacology Leibold, C., Thienemann, M., Farhadian, B., Willett, T., Frankovich, J. 2018

    Abstract

    OBJECTIVES: This study validates the caregiver-rated Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Global Impairment Score (GIS), a single-item, 0-100 scale, for use in PANS.METHODS: We collected longitudinal data from community patients meeting PANS criteria. We included 128 patients with 1926 GISs, each from a unique clinic visit. To assess discriminant validity, we compared GISs from patients with PANS with scores from a population of healthy controls. To evaluate external validity, we compared global impairment with a clinician-reported global measure-the Child Global Assessment Scale (CGAS)-using the Bland-Altman plots and correlation coefficients. Then, we evaluated associations between the PANS GIS and symptom-specific disease severity variables by fitting mixed models with repeated measures.RESULTS: The GIS shows excellent discriminant validity, distinguishing patients with PANS from healthy controls. The scores on the GIS show an acceptable level of agreement with the clinician-reported CGAS. The regression line in the Bland-Altman plot had a positive slope, indicating that parents tend to report higher disease severity than clinicians at higher levels of disease severity. Correlation was higher during disease remissions than during disease flares (r=-0.69 vs. r=-0.48). All disease severity scales predicted GIS in the expected direction.CONCLUSION: The GIS has excellent discriminant validity and acceptable construct validity.

    View details for PubMedID 30421965

  • Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Leibold, C., Thienemann, M., Farhadian, B., Willett, T., Frankovich, J. 2019; 29 (1): 41–49
  • Action in the face of uncertainty? The Journal of pediatrics Thienemann, M., Frankovich, J. 2018

    View details for PubMedID 30318368

  • Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome. Pediatric allergy, immunology, and pulmonology Rosa, J. S., Hernandez, J. D., Sherr, J. A., Smith, B. M., Brown, K. D., Farhadian, B., Mahony, T., McGhee, S. A., Lewis, D. B., Thienemann, M., Frankovich, J. D. 2018; 31 (3): 158-165

    Abstract

    Background: The prevalence and impact of allergic and immune-mediated food disorders in pediatric acute-onset neuropsychiatric syndrome (PANS) are mostly unknown. Objective: We sought to explore the prevalence of atopic dermatitis (AD), asthma, allergic rhinitis (AR), IgE-mediated food allergies (FAs), and other immune-mediated food disorders requiring food avoidance in patients with PANS. In addition, to further understand the extent of food restriction in this population, we investigated the empiric use of dietary measures to improve PANS symptoms. Methods: Pediatric patients in a PANS Clinic and Research Program were given surveys regarding their caregiver burdens, allergic and food-related medical history, and whether food elimination resulted in perception of improvement of PANS symptoms. A review of health records was conducted to confirm that all responses in the survey were concordant with documentation of each patient's medical chart. Results: Sixty-nine (ages 4-20 years) of 80 subjects who fulfilled PANS criteria completed the surveys. Thirteen (18.8%) had AD, 11 (15.9%) asthma, 33 (47.8%) AR, 11 (15.9%) FA, 1 (1.4%) eosinophilic gastrointestinal disorders, 1 (1.4%) food protein-induced enterocolitis syndrome, 3 (4.3%) milk protein-induced proctocolitis syndrome, and 3 (4.3%) celiac disease. Thirty subjects (43.5%) avoided foods due to PANS; elimination of gluten and dairy was most common and was associated with perceived improvement of PANS symptoms (by parents). This perceived improvement was not confirmed with objective data. Conclusions: The prevalence of allergic and immune-mediated food disorders in PANS is similar to the general population as reported in the literature, with the exception of AR that appears to be more prevalent in our PANS cohort. More research will be required to establish whether diet or allergies influence PANS symptoms.

    View details for DOI 10.1089/ped.2018.0888

    View details for PubMedID 30283713

    View details for PubMedCentralID PMC6154445

  • Response to editor regarding "Improvement of psychiatric symptoms in youth following resolution of sinusitis" INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY Frankovich, J., Sidell, D., Gans, H., Brown, K., Mahony, T., Thienemann, M. 2018; 112: 208–9
  • Response to editor regarding "Improvement of psychiatric symptoms in youth following resolution of sinusitis". International journal of pediatric otorhinolaryngology Frankovich, J., Sidell, D., Gans, H., Brown, K., Mahony, T., Thienemann, M. 2018; 112: 208–9

    View details for PubMedID 29050812

  • Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY Rosa, J. S., Hernandez, J. D., Sherr, J. A., Smith, B. M., Brown, K. D., Farhadian, B., Mahony, T., McGhee, S. A., Lewis, D. B., Thienemann, M., Frankovich, J. D. 2018; 31 (3): 158–65
  • Psychometric Evaluation of the Caregiver Burden Inventory in Children and Adolescents With PANS. Journal of pediatric psychology Farmer, C. n., Thienemann, M. n., Leibold, C. n., Kamalani, G. n., Sauls, B. n., Frankovich, J. n. 2018

    Abstract

    To establish the psychometric properties of the Caregiver Burden Inventory (CBI) in patients with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), which is characterized by the abrupt onset of obsessive-compulsive disorder and/or restricted eating and at least two additional psychiatric symptoms. Parents of patients with PANS have reported high caregiver burden. However, no validated instrument of burden exists for this population.Study took place at a community-based PANS clinic where the CBI is administered as part of routine clinical care. The first CBI available during an active disease flare was analyzed (N =104). Construct validity was evaluated within a confirmatory factor analytic framework. Associations between the CBI and patient/family characteristics were explored, and preliminary normative data for this population are presented.Item-factor loadings were strong, and the overall fit of the model was good (root mean square error of approximation = .061). Strict/metric measurement invariance was demonstrated across age. The mean Total Score in this sample was 36.72 ± 19.84 (interquartile range 19-53). Total Scores on the CBI were significantly elevated for parents of children who switched schools because of their illness (Cohen's d = 0.75, 95% confidence interval [CI] 0.28-1.22) and for those who had reduced work hours to accommodate the child's illness (Cohen's d = 0.65, 95% CI 0.10-1.20). However, in this relatively high-status sample, socioeconomic variables did not predict Total Scores.Parents of patients with PANS experience high caregiver burden. The CBI may be confidently used to assess caregiver burden in this population.

    View details for PubMedID 29547961

  • Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I-Psychiatric and Behavioral Interventions. Journal of child and adolescent psychopharmacology Thienemann, M., Murphy, T., Leckman, J., Shaw, R., Williams, K., Kapphahn, C., Frankovich, J., Geller, D., Bernstein, G., Chang, K., Elia, J., Swedo, S. 2017; 27 (7): 566-573

    Abstract

    This article outlines the consensus guidelines for symptomatic treatment for children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection (PANDAS).Extant literature on behavioral, psychotherapeutic, and psychopharmacologic treatments for PANS and PANDAS was reviewed. Members of the PANS Research Consortium pooled their clinical experiences to find agreement on treatment of PANS and PANDAS symptoms.Current guidelines result from consensus among the Consortium members.While underlying infectious and inflammatory processes in PANS and PANDAS patients are treated, psychiatric and behavioral symptoms need simultaneous treatment to decrease suffering and improve adherence to therapeutic intervention. Psychological, behavioral, and psychopharmacologic interventions tailored to each child's presentation can provide symptom improvement and improve functioning during both the acute and chronic stages of illness. In general, typical evidence-based interventions are appropriate for the varied symptoms of PANS and PANDAS. Individual differences in expected response to psychotropic medication may require marked reduction of initial treatment dose. Antimicrobials and immunomodulatory therapies may be indicated, as discussed in Parts 2 and 3 of this guideline series.

    View details for DOI 10.1089/cap.2016.0145

    View details for PubMedID 28722481

    View details for PubMedCentralID PMC5610394

  • Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II-Use of Immunomodulatory Therapies. Journal of child and adolescent psychopharmacology Frankovich, J., Swedo, S., Murphy, T., Dale, R. C., Agalliu, D., Williams, K., Daines, M., Hornig, M., Chugani, H., Sanger, T., Muscal, E., Pasternack, M., Cooperstock, M., Gans, H., Zhang, Y., Cunningham, M., Bernstein, G., Bromberg, R., Willett, T., Brown, K., Farhadian, B., Chang, K., Geller, D., Hernandez, J., Sherr, J., Shaw, R., Latimer, E., Leckman, J., Thienemann, M. 2017; 27 (7): 574-593

    Abstract

    Introduction: Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%-80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections). Methods: The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared web-based document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with PANS, were consulted to create categories in disease severity and critically review final recommendations. All authors played a role in creating these guidelines. The views of all authors were incorporated and all authors gave final approval of these guidelines. Results: Separate guidelines were created for the use of immunomodulatory therapies in PANS patients with (1) mild, (2) moderate-to-severe, and (3) extreme/life-threatening severity. For mildly impairing PANS, the most appropriate therapy may be "tincture of time" combined with cognitive behavioral therapy and other supportive therapies. If symptoms persist, nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts are recommended. For moderate-to-severe PANS, oral or intravenous corticosteroids may be sufficient. However, intravenous immunoglobulin (IVIG) is often the preferred treatment for these patients by most PRC members. For more severe or chronic presentations, prolonged corticosteroid courses (with taper) or repeated high-dose corticosteroids may be indicated. For PANS with extreme and life-threatening impairment, therapeutic plasma exchange is the first-line therapy given either alone or in combination with IVIG, high-dose intravenous corticosteroids, and/or rituximab. Conclusions: These recommendations will help guide the use of anti-inflammatory and immunomodulatory therapy in the treatment of PANS.

    View details for DOI 10.1089/cap.2016.0148

    View details for PubMedID 36358107

  • Palatal Petechiae in the Absence of Group A Streptococcus in Pediatric Patients with Acute-Onset Neuropsychiatric Deterioration: A Cohort Study. Journal of child and adolescent psychopharmacology Mahony, T., Sidell, D., Gans, H., Cooperstock, M., Brown, K., Cheung, J. M., Farhadian, B., Gustafson, M., Thienemann, M., Frankovich, J. 2017

    Abstract

    Palatal petechiae are 95% specific for streptococcal pharyngitis. Despite this, and despite prior research demonstrating that Group A Streptococcus (GAS) is a common antecedent to pediatric acute-onset neuropsychiatric syndrome (PANS) episodes, we anecdotally observed a low rate of documented GAS in patients with PANS and palatal petechiae. This retrospective chart review was conducted to formally report the rate of palatal petechiae and concurrent GAS in a cohort of patients with PANS and investigate other etiologic factors.The clinical notes of 112 patients seen at the Stanford PANS Clinic who met PANS research criteria were reviewed for mention of palatal petechiae. The medical records of patients who demonstrated palatal petechiae on physical examination were reviewed for signs of infection, a clinical history of trauma, and laboratory results that could indicate other causes of petechiae.Twenty-three patients had documented palatal petechiae on physical examination (ages 5-16, 13/23 [57%] male). Fifteen patients had a rapid GAS test and GAS culture in the Stanford PANS clinic, all with negative results. Evidence of recent GAS infection was found in 8/23 (32%) patients (elevated GAS titers [n = 6] or documentation of a positive rapid GAS test at another facility [n = 2]), one of whom also had potential herpes simplex virus (HSV) infection. One patient had potential HSV infection and recent palatal trauma. No patients had thrombocytopenia. 14/23 (61%) of patients with palatal petechiae had no discernable cause of petechiae. 10/19 (53%) of patients had antihistone antibodies.Despite the established relationship between palatal petechiae and GAS, no patient with palatal petechiae in our clinic tested positive for GAS and only 32% had evidence of recent GAS. Most did not have an identifiable cause for the palatal lesions. This finding suggests the potential for alternative causes of palatal petechiae or undetectable GAS in our patient population. The high prevalence of palatal petechiae without GAS infection suggests that the pathogenesis of PANS is multifactorial and may involve disruption or inflammation of the microvasculature. Additional research is needed to further elucidate these findings.

    View details for DOI 10.1089/cap.2016.0153

    View details for PubMedID 28387528

  • Improvement of psychiatric symptoms in youth following resolution of sinusitis INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY Mahony, T., Sidell, D., Gans, H., Brown, K., Farhadian, B., Gustafson, M., Sherr, J., Thienemann, M., Frankovich, J. 2017; 92: 38-44

    Abstract

    Accumulating evidence supports a role for inflammation in psychiatric illness, and the onset or exacerbation of psychiatric symptoms may follow non-CNS infections. Here, we provide the first detailed description of obsessive-compulsive and related psychiatric symptoms arising concurrently with sinusitis.We reviewed the charts of 150 consecutive patients evaluated in our Pediatric Acute-onset Neuropsychiatric Syndromes clinic for documented sinusitis as defined by the American Academy of Pediatrics guidelines. Sinusitis treatments, sinonasal imaging, and neuropsychiatric symptoms before, during, and after sinusitis onset were noted. Patients were included in the final review if they had a clear diagnosis of isolated sinusitis (without concurrent illness and/or immunodeficiency), and were evaluated during an episode of sinusitis.10/150 (6.6%) patients had isolated sinusitis at the time of their neuropsychiatric deterioration. Eight patients received antibiotics to treat sinusitis, three of whom also received sinus surgery. Neuropsychiatric symptoms improved in all eight patients concurrent with resolution of sinusitis per parent report and clinician assessment. One patient did not follow through with recommended sinus surgery or antibiotics and her psychiatric symptoms persisted. One patient was lost to follow-up.Improvement of psychiatric symptoms correlated with resolution of sinus disease in this retrospective study. Identification, treatment, and resolution of underlying infections, including sinusitis, may have the potential to change the trajectory of some neuropsychiatric illnesses. Randomized clinical trials are needed.

    View details for DOI 10.1016/j.ijporl.2016.10.034

    View details for Web of Science ID 000393245100008

    View details for PubMedID 28012531

  • Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I—Psychiatric and Behavioral Interventions Journal of Child and Adolescent Psychopharmacology Thienemann, M., Murphy, T., Leckman, J., Shaw, R., Williams, K., Kapphahn, C., Frankovich, J., Geller, D., Bernstein, G., Chang, K., Elia, J., Swedo, S. 2017; 27 (7): 566-573

    Abstract

    This article outlines the consensus guidelines for symptomatic treatment for children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection (PANDAS).Extant literature on behavioral, psychotherapeutic, and psychopharmacologic treatments for PANS and PANDAS was reviewed. Members of the PANS Research Consortium pooled their clinical experiences to find agreement on treatment of PANS and PANDAS symptoms.Current guidelines result from consensus among the Consortium members.While underlying infectious and inflammatory processes in PANS and PANDAS patients are treated, psychiatric and behavioral symptoms need simultaneous treatment to decrease suffering and improve adherence to therapeutic intervention. Psychological, behavioral, and psychopharmacologic interventions tailored to each child's presentation can provide symptom improvement and improve functioning during both the acute and chronic stages of illness. In general, typical evidence-based interventions are appropriate for the varied symptoms of PANS and PANDAS. Individual differences in expected response to psychotropic medication may require marked reduction of initial treatment dose. Antimicrobials and immunomodulatory therapies may be indicated, as discussed in Parts 2 and 3 of this guideline series.

    View details for DOI 10.1089/cap.2016.0145

    View details for PubMedCentralID PMC5610394

  • Pediatric Acute-Onset Neuropsychiatric Syndrome Response to Oral Corticosteroid Bursts: An Observational Study of Patients in an Academic Community-Based PANS Clinic. Journal of child and adolescent psychopharmacology Brown, K. n., Farmer, C. n., Farhadian, B. n., Hernandez, J. n., Thienemann, M. n., Frankovich, J. n. 2017; 27 (7): 629–39

    Abstract

    Sudden-onset severe obsessive-compulsive symptoms and/or severely restrictive food intake with at least two coinciding, similarly debilitating neuropsychiatric symptoms define Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). When associated with Group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. Most patients have a relapsing-remitting course. Treatment outcome data for youth with PANS and PANDAS are limited.One hundred seventy-eight consecutive patients were seen in the Stanford PANS clinic between September 1, 2012 and January 15, 2016, of whom 98 met PANS or PANDAS criteria, had a single episode of PANS or relapsing/remitting course, and collectively experienced 403 flares. Eighty-five flares were treated with 102 total courses of oral corticosteroids of either short (4-5 days) or long (5 days-8 weeks) duration. Response to treatment was assessed within 14 days of initiating a short burst of corticosteroids and at the end of a long burst based on clinician documentation and patient questionnaires. Data were analyzed by using multilevel random-effects models.Patients experienced shorter flares when treated with oral corticosteroids (6.4 ± 5.0 weeks vs. 11.4 ± 8.6 weeks) than when not treated (p < 0.001), even after controlling for presumed confounding variables, including age at flare, weeks since onset of PANS illness, sex, antibiotic treatment, prophylactic antibiotics, previous immunomodulatory treatment, maintenance anti-inflammatory therapy, psychiatric medications, and cognitive behavioral therapy (p < 0.01). When corticosteroids were given for the initial PANS episode, flares tended to be shorter (10.3 ± 5.7 weeks) than when not treated (16.5 ± 9.6 weeks) (p = 0.06). This difference was statistically significant after controlling for the relevant confounding variables listed earlier (p < 0.01). Earlier use of corticosteroids was associated with shorter flare durations (p < 0.001). Longer courses of corticosteroids were associated with a more enduring impact on the duration of neuropsychiatric symptom improvement (p = 0.014).Corticosteroids may be a helpful treatment intervention in patients with new-onset and relapsing/remitting PANS and PANDAS, hastening symptom improvement or resolution. When corticosteroids are given earlier in a disease flare, symptoms improve more quickly and patients achieve clinical remission sooner. Longer courses of corticosteroids may result in more durable remissions. A double-blind placebo-controlled clinical trial of corticosteroids in PANS is warranted to formally assess treatment efficacy.

    View details for PubMedID 28714753

  • Effect of Early and Prophylactic Nonsteroidal Anti-Inflammatory Drugs on Flare Duration in Pediatric Acute-Onset Neuropsychiatric Syndrome: An Observational Study of Patients Followed by an Academic Community-Based Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic. Journal of child and adolescent psychopharmacology Brown, K. D., Farmer, C. n., Freeman, G. M., Spartz, E. J., Farhadian, B. n., Thienemann, M. n., Frankovich, J. n. 2017; 27 (7): 619–28

    Abstract

    Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the sudden onset of severe obsessive-compulsive symptoms and/or eating restriction along with at least two coinciding neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. We evaluated the impact of nonsteroidal anti-inflammatory drug (NSAID) treatment on flare duration in PANS/PANDAS.Patient inclusion criteria: Patients were included if they had at least one neuropsychiatric deterioration ("flare") that met strict PANS/PANDAS research criteria and for which flare duration could be assessed. Flare inclusion criteria: Any flare that started before October 15, 2016 was included and followed until the flare resolved or until the end of our data collection (November 1, 2016). Flare exclusion criteria: Flares were excluded if they were incompletely resolved, treated with aggressive immunomodulation, or treated with NSAIDs late (>30 days of flare onset). Ninety-five patients met study inclusion criteria and collectively experienced 390 flares that met flare criteria. Data were analyzed using multilevel linear models, adjusting for demographics, disease, and treatment covariates.NSAID use was associated with a significantly shorter flare duration. Flares not treated with NSAIDs had a mean duration of approximately 12.2 weeks (95% CI: 9.3-15.1). Flares that occurred while the child was on NSAID maintenance therapy were approximately 4 weeks shorter than flares not managed with NSAIDs (95% CI: 1.85-6.24; p < 0.0001). Flares treated with NSAIDs within 30 days of flare onset were approximately 2.6 weeks shorter than flares not managed with NSAIDs (95% CI: 0.43-4.68; p = 0.02). Flares treated prophylactically and those treated early with NSAIDs did not differ in duration (p = 0.26). Among the flares that received NSAID treatment within the first 30 days, earlier intervention was modestly associated with shorter flare durations (i.e., for each day that NSAID treatment was delayed, flare duration increased by 0.18 weeks; 95% CI: 0.03-0.33; p = 0.02), though it was not statistically significant after controlling for covariates (p = 0.06).NSAIDs given prophylactically or within 30 days of flare onset may shorten neuropsychiatric symptom duration in patients with new-onset and relapsing/remitting PANS and PANDAS. A randomized placebo-control clinical trial of NSAIDs in PANS is warranted to formally assess treatment efficacy.

    View details for PubMedID 28696786

  • Course of Neuropsychiatric Symptoms After Introduction and Removal of Nonsteroidal Anti-Inflammatory Drugs: A Pediatric Observational Study. Journal of child and adolescent psychopharmacology Spartz, E. J., Freeman, G. M., Brown, K. n., Farhadian, B. n., Thienemann, M. n., Frankovich, J. n. 2017; 27 (7): 652–59

    Abstract

    Accumulating evidence suggests that anti-inflammatory interventions can modulate neuropsychiatric symptoms. Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by an abrupt and dramatic onset of obsessive-compulsive (OC) symptoms and/or severely restrictive food intake and at least two coinciding, equally debilitating neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). Here, we describe the course of neuropsychiatric symptoms in patients diagnosed with PANS and PANDAS after introduction or removal of nonsteroidal anti-inflammatory drugs (NSAIDs).We reviewed the electronic medical records (EMR) of 218 consecutive patients evaluated in our Stanford PANS Clinic for patients who met strict PANS or PANDAS research criteria and received NSAIDs for arthritis, pain, and/or psychiatric symptoms. We describe neuropsychiatric symptoms that were noted in the EMR before, during, and after NSAIDs were introduced or removed as the sole change in pharmacologic treatment.Seventy-seven patients were included in the current study. Of the 52 trials in which NSAID addition was the sole change in treatment, 16 (31%) coincided with an improvement in patients' neuropsychiatric symptoms. Of the 57 trials in which removal of NSAID treatment was the sole change in treatment, 20 (35%) coincided with escalation in patients' neuropsychiatric symptoms. Thirty patients (39%) experienced side effects, mainly mild gastrointestinal symptoms, which self-resolved after removal of NSAID, reduction of dose, or change in NSAID.Improvement in neuropsychiatric symptoms was evident in roughly one-third of NSAID treatment trials. A randomized clinical trial will be necessary to confirm whether NSAIDs are successful in reducing neuropsychiatric symptoms in youth with PANS.

    View details for PubMedID 28696783

  • Clinical Management of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): Part II – Use of Immunomodulatory Therapies Journal of Child and Adolescent Psychopharmacology Frankovich, J., Swedo, S., Murphy, T., Dale, R. C., Agalliu, D., Williams, K., Daines, M., Hornig, M., Chugani, H., Sanger, T., Muscal, E., Pasternack, M., Cooperstock, M., Gans, H., Zhang, Y., Cunningham, M., Bernstein, G., Bromberg, R., Willett, T., Brown, K., Farhadian, B., Chang, K., Geller, D., Hernandez, J., Sherr, J., et al 2017; 27 (7): 574-593

    View details for DOI 10.1089/cap.2016.0148

  • Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. Journal of child and adolescent psychopharmacology Frankovich, J., Thienemann, M., Pearlstein, J., Crable, A., Brown, K., Chang, K. 2015; 25 (1): 38-47

    Abstract

    Abrupt, dramatic onset obsessive-compulsive disorder (OCD) and/or eating restriction with at least two coinciding symptoms (anxiety, mood dysregulation, irritability/aggression/oppositionality, behavioral regression, cognitive deterioration, sensory or motor abnormalities, or somatic symptoms) defines pediatric acute-onset neuropsychiatric syndrome (PANS). Descriptions of clinical data in such youth are limited.We reviewed charts of 53 consecutive patients evaluated in our PANS Clinic; 47 met PANS symptom criteria but not all met the requirement for "acute onset." Patients meeting full criteria for PANS were compared with patients who had a subacute/insidious onset of symptoms.Nineteen of 47 (40%) patients in the study had acute onset of symptoms. In these patients, autoimmune/inflammatory diseases and psychiatric disorders were common in first-degree family members (71% and 78%, respectively). Most acute-onset patients had a relapsing/remitting course (84%), prominent sleep disturbances (84%), urinary issues (58%), sensory amplification (66%), gastrointestinal symptoms (42%), and generalized pain (68%). Inflammatory back pain (21%) and other arthritis conditions (28%) were also common. Suicidal and homicidal thoughts and gestures were common (44% and 17%, respectively) as were violent outbursts (61%). Group A streptococcus (GAS) was the most commonly identified infection at onset (21%) and during flares (74%). Rates of the abovementioned characteristics did not differ between the acute-onset group and the subacute/insidious-onset groups. Low levels of immunoglobulins were more common in the subacute/insidious-onset group (75%) compared with the acute-onset group (22%), but this was not statistically significant (p=0.06).In our PANS clinic, 40% of patients had acute onset of symptoms. However, those with and without acute onset of symptoms had similar symptom presentation, rates of inflammatory conditions, somatic symptoms, and violent thoughts and behaviors. GAS infections were the most commonly identified infection at onset and at symptom flares. Because of the wide variety of medical and psychiatric symptoms, youth with PANS may require a multidisciplinary team for adequate care management.

    View details for DOI 10.1089/cap.2014.0081

    View details for PubMedID 25695943

  • Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference. Journal of child and adolescent psychopharmacology Chang, K., Frankovich, J., Cooperstock, M., Cunningham, M. W., Latimer, M. E., Murphy, T. K., Pasternack, M., Thienemann, M., Williams, K., Walter, J., Swedo, S. E. 2015; 25 (1): 3-13

    Abstract

    On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS.

    View details for DOI 10.1089/cap.2014.0084

    View details for PubMedID 25325534

  • Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. Journal of child and adolescent psychopharmacology Frankovich, J., Thienemann, M., Rana, S., Chang, K. 2015; 25 (1): 31-37

    Abstract

    Pediatric acute-onset neuropsychiatric syndrome (PANS) is diagnosed by the abrupt onset of new obsessive compulsive disorder (OCD) or food-restricting symptoms, and at least two of a variety of other neuropsychiatric symptoms. Detailed clinical presentation of youth with this condition has not yet been provided in the literature.We review the clinical charts of five youth meeting criteria for PANS in our PANS Clinic. These five patients were selected for differing underlying causes thought to be driving an inflammatory response that appeared to impact psychiatric symptoms.Five youth with varying potential etiologies impacting neuropsychiatric symptoms were identified. These youth were from 8 to 18 years old at the onset of their PANS illness, and had bacterial, autoimmune, and unknown etiologies. Treatment directed at presumed etiologies ranged from antibiotics to intravenous gamma globulin (IVIG) to other immunomodulatory regimens, and appeared to improve the psychiatric illness.Youth with PANS may present in differing ways, with psychiatric and physical symptoms overlapping with inflammatory or infectious diseases, pain syndromes, and other psychiatric diagnoses. Patients' psychiatric symptoms may respond to treatments targeting the underlying cause of physical illness. Faced with a pediatric patient demonstrating the abrupt onset or exacerbation of psychiatric and physical symptoms, clinicians should consider PANS in their differential diagnosis.

    View details for DOI 10.1089/cap.2014.0056

    View details for PubMedID 25695942

  • Activation During Observed Parent-Child Interactions with Anxious Youths: A Pilot Study JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT Gonzalez, A., Moore, P. S., Garcia, A. M., Thienemann, M., Huffman, L. 2011; 33 (2): 159-170

    Abstract

    Parent-child interaction paradigms are often used to observe dysfunctional family processes; however, the influence of such tasks on a participant's level of activation remain unclear. The aim of this pilot project is to explore the stimulus value of interaction paradigms that have been commonly used in child anxiety research. Twenty-nine parent-child dyads with clinically anxious (n = 16) and non-anxious (n = 13) youths engaged in a series of tasks (threat and non-threat) used in previous studies of parenting and youth anxiety. Heart rate (HR) data, as an indicator of physiological activation, were collected across tasks, and participants rated the perceived representativeness of their interactions in the laboratory to their usual behavior at home. Significant HR changes were observed for both parent and child. Change in child HR from baseline to non-threat task was smaller than change in HR from baseline to threat tasks. Change in parent HR from baseline to ambiguous situations tasks was smaller than changes from baseline to other threat tasks. Differences in HR change between anxious and non-anxious children were explored. Participants rated laboratory interactions as similar to those experienced in the home. Results suggest that presumably emotionally-charged discussion tasks may produce increased activation compared to tasks that were designed to be more neutral. Implications for future research and limitations are discussed.

    View details for DOI 10.1007/s10862-011-9216-y

    View details for Web of Science ID 000291169600002

    View details for PubMedCentralID PMC3105235

  • Anxiety Disorders in Children and Adolescents TEXTBOOK OF ANXIETY DISORDERS, 2ND EDITION Moore, P. S., March, J. S., Albano, A., Thienemann, M., Stein, D. J., Hollander, E., Rothbaum, B. O. 2009: 629–49
  • Learning evidence-based practices for anxious children JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Thienemann, M., Hamilton, J. D. 2007; 46 (10): 1367-1374

    View details for DOI 10.1097/chi.0b013e3181354811

    View details for Web of Science ID 000249802900015

    View details for PubMedID 17885579

  • Teaching evidence-based psychotherapies CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA Thienemann, M., Joshi, S. V. 2007; 16 (1): 183-?

    Abstract

    Currently our field is actively involved in developing new ways to characterize and treat children and adolescents with psychiatric disorders and in evaluating the effects of our therapies. We also are beginning to examine the effectiveness of our teaching methods. This article presents evidence for, ideas about, and a philosophy to guide individuals who are privileged to train child psychiatrists in psychotherapies. Specifically, it discusses the issues of the evidence base for diagnosis and for nonspecific and specific active elements of child psychotherapy. Evidence for methods of training is presented. The article addressed the need for supervising psychiatrists to keep abreast of developments in teaching methods so that we can best train competent, curious, and compassionate child psychiatrists.

    View details for DOI 10.1016/j.chc.2006.09.004

    View details for Web of Science ID 000243016300012

    View details for PubMedID 17141124

  • A parent-only group intervention for children with anxiety disorders: Pilot study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Thienemann, M., Moore, P., Tompkins, K. 2006; 45 (1): 37-46

    Abstract

    Working to optimize treatment outcome and use resources efficiently, investigators conducted the first test of an existing parent-only group cognitive-behavioral therapy protocol to treat 24 children 7 to 16 years old with primary anxiety disorder diagnoses.Over the course of 7 months, the authors evaluated a manual-based therapy protocol that teaches parents skills to work with their children as lay therapists in the context of their ongoing interactions and daily life. This was an uncontrolled pilot study, examining within-subject outcomes via measures from multiple informants, aimed at generating estimates of effect size.Children demonstrated significant improvement on parent- and clinician-rated measures of anxiety. Twenty-five percent of primary anxiety diagnoses fully remitted, and the average number of anxiety diagnoses dropped from 3.4 to 1.5. The intervention had a large effect on anxiety disorder severity and impairment, parental attitudes, targeted anxious behavior problems, and clinician-rated impairment. Children with anxiety-disordered parents reported more improvement than children whose parents were not anxious. The intervention was acceptable to families.The results of this pilot study suggest that parents acting as lay cognitive-behavioral therapists for their anxious children may be effectively and acceptably trained in a group format.

    View details for DOI 10.1097/01.chi.0000186404.90217.02

    View details for Web of Science ID 000234221200005

    View details for PubMedID 16327579

  • Group Cognitive-behavior Therapy with family involvement for middle-school-age children with obsessive-compulsive disorder: A pilot study CHILD PSYCHIATRY & HUMAN DEVELOPMENT Jacqueline, M., Margo, T. 2005; 36 (1): 113-127

    Abstract

    Middle-school-aged children with obsessive-compulsive disorder (OCD) are poised in development between the dependency of elementary-school-aged children and growing independence of adolescence. OCD patients of this age group may differ from older ones in the quality of symptoms and level of insight. We report the results of a naturalistic, pilot study of group Cognitive-behavior Therapy (CBT) for school-aged children with OCD with parents involved. The authors predicted symptom improvement and format acceptability.Over a 1.5 year period, 14 children with OCD aged 8-14 years and their parents received 14-week group CBT based on March and Mulle's OCD in Children and Adolescents: A Cognitive-Behavioral Treatment Manual in three consecutive sessions of four to six families. Age of onset averaged 8.7 years, 36% had undergone at least one medication trial, and 36% had previous CBT experience.OCD symptoms measured by the Children's Yale-Brown Obsessive Compulsive Scale improved significantly, both statistically and clinically (25%) from moderate-severe to mild-moderate. Mean Clinical Global Impression of Impairment (NIMH-CGI) Impairment ratings fell from clinical to sub-clinical and CGI Improvement ratings were "much improved". Children's self-reported depression decreased significantly from pre- to post-group. Parent ratings of the negative impact of OCD symptoms on the Children's OCD Impact Scale and of behavior problems on the Child Behavior Checklist each improved significantly.This pilot study, which included a non-selected clinical sample, demonstrates that a manual-based treatment protocol may be effectively adapted for group treatment of different developmental levels and be exported for clinical use. Clinical improvement justifies further investigation in a controlled study.

    View details for DOI 10.1007/s10578-005-3496-y

    View details for Web of Science ID 000203010200006

    View details for PubMedID 16049647

  • Introducing a structured interview into a clinical setting JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Thienemann, M. 2004; 43 (8): 1057-1060
  • Manual-driven group cognitive-behavioral therapy for adolescents with obsessive-compulsive disorder: A pilot study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Thienemann, M., Martin, J., Cregger, B., Thompson, H. B., Dyer-Friedman, J. 2001; 40 (11): 1254-1260

    Abstract

    Concerns about isolation, compromised development, partial pharmacotherapy response, therapist scarcity, and inadequate cognitive-behavioral therapy (CBT) adherence led the authors to adapt a CBT protocol to a group format for adolescents with obsessive-compulsive disorder (OCD). A naturalistic, open trial of group CBT for adolescent OCD is described. The authors predicted symptom improvement and format acceptability.Over a 1 -year period, 18 adolescents aged 13 to 17 years with OCD received 14-week group CBT based on March and Mulle's OCD in Children and Adolescents: A Cognitive-Behavioral Treatment Manual in four consecutive sessions of five to nine patients. Eighty-three percent had undergone at least one medication trial, and 78% had previous CBT experience.OCD symptoms measured by the Children's Yale-Brown Obsessive Compulsive Scale improved significantly, both statistically and clinically. Adolescents consistently shared information and designed exposure interventions for themselves and others during sessions. Repeated self-report measures confirmed adolescents' satisfaction with therapy.This pilot study demonstrates that a manual-based treatment protocol may be exported for clinical use, adaptable for the end-user's needs, and palatable to adolescent patients. Clinical improvement and patient satisfaction justify further investigation in a controlled study.

    View details for Web of Science ID 000171752900004

    View details for PubMedID 11699798

  • Cognitive-behavioral group therapy for social phobia in female adolescents: Results of a pilot study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hayward, C., Varady, S., Albano, A. M., Thienemann, M., Henderson, L., Schatzberg, A. F. 2000; 39 (6): 721-726

    Abstract

    To examine the efficacy of cognitive-behavioral group therapy for adolescents (CBGT-A) in females with social phobia and the effect of this treatment on the risk for major depression.Female adolescents with social phobia (N = 35) were randomly assigned to treatment (n = 12) or no treatment (n = 23) groups. Assessments were conducted at baseline, after treatment, and at a 1-year follow-up.Eleven subjects completed treatment. Sixteen weeks of treatment produced a significant improvement in interference and reduction in symptoms of social anxiety. There was a significant reduction in the number of subjects meeting DSM-IV criteria for social phobia in the CBGT-A versus the untreated group; however, at the 1-year follow-up there were no significant differences by treatment condition. There was also suggestive evidence that treatment of social phobia lowers the risk for relapse of major depression among those with a history of major depression. Combining social phobia and major depression as the outcome produced more robust treatment effects in the 1-year follow-up.This pilot study provides evidence for a moderate short-term effect of CBGT-A for treating female adolescents suffering from social phobia and indicates that treatment of social phobia may result in a reduction of major depression.

    View details for Web of Science ID 000087331200010

    View details for PubMedID 10846306

  • Defense style and family environment CHILD PSYCHIATRY & HUMAN DEVELOPMENT Thienemann, M., Shaw, R. J., Steiner, H. 1998; 28 (3): 189-198

    Abstract

    Prospective observations of the defense styles of normal individuals suggest that the quality of the childhood family environment may influence the maturity of defense styles used in adulthood. In this study, 106 female adolescent psychiatric patients completed the Defense Style Questionnaire, and the Family Environment Scale (FES). Positive family characteristics such as cohesion and expressiveness, as measured by the FES, were correlated with the report of Mature Defenses. Negative family characteristics such as conflict were correlated with the report of Immature Defenses. Similar although weaker correlations were found after controlling for the effects of depression and defensiveness on the self-report measures.

    View details for Web of Science ID 000072516800005

    View details for PubMedID 9540242

  • Quality of life for patients with obsessive-compulsive disorder AMERICAN JOURNAL OF PSYCHIATRY Koran, L. M., Thienemann, M. L., Davenport, R. 1996; 153 (6): 783-788

    Abstract

    The health-related quality of life of patients with obsessive-compulsive disorder was compared to published norms for the general U.S. population and for patients with either depressive disorders or diabetes.Sixty medication-free outpatients with moderate to severe obsessive-compulsive disorder were evaluated by using the Structured Clinical Interview for DSM-III-R and the Yale-Brown Obsessive Compulsive Scale. Health-related quality of life was measured with the self-rated Medical Outcomes Study 36-Item Short-Form Health Survey.The instrumental role performance and social functioning of the patients with obsessive-compulsive disorder were worse than those of the general population and of diabetes patients. The more severe the obsessive-compulsive disorder, the lower were the patients' social functioning scores, even after depression ratings were controlled for; scores on instrumental role performance did not correlate with severity of obsessive-compulsive disorder. The ratings of the obsessive-compulsive disorder patients on physical health domains resembled those of the general population and exceeded those of the diabetes patients. The general health and physical health ratings of the obsessive-compulsive disorder patients exceeded those of the depressed patients. In mental health domains, after adjustment for differences in gender distribution, quality of life ratings were similar for the patients with obsessive-compulsive disorder and those with depressive disorders.Moderate to severe obsessive-compulsive disorder is associated with impaired social functioning and impaired instrumental role performance, but only impairment in social functioning is linearly related to severity of obsessive-compulsive disorder.

    View details for Web of Science ID A1996UN63200008

    View details for PubMedID 8633690

  • DO SOFT SIGNS PREDICT TREATMENT OUTCOME IN OBSESSIVE-COMPULSIVE DISORDER JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES Thienemann, M., Koran, L. M. 1995; 7 (2): 218-222

    Abstract

    The authors examined 21 outpatients with obsessive-compulsive disorder for five neurological soft signs and abnormalities on two neuropsychological tests before and after 10 to 12 weeks of treatment with serotonin reuptake inhibitors. Patients showed a mean of 1.8 soft signs. Prevalences were finger-to-finger, 10%; adventitious movements, 29%; mirror movements, 33%; impaired cube drawing, 33%; and agraphesthesia, 76%. The Stroop Color and Word Test was abnormal in 10% and the Controlled Oral Word Association Test was abnormal in 14% of patients. Neither the presence of specific soft signs, the number of signs present, nor a combination of signs and test abnormalities predicted a poorer response to pharmacological treatment. Some baseline soft signs and abnormalities disappeared at endpoint in medication responders and nonresponders; no clear pattern of change emerged.

    View details for Web of Science ID A1995QV77600012

    View details for PubMedID 7626966

  • FAMILY ENVIRONMENT OF EATING-DISORDERED AND DEPRESSED ADOLESCENTS INTERNATIONAL JOURNAL OF EATING DISORDERS Thienemann, M., Steiner, H. 1993; 14 (1): 43-48

    Abstract

    We designed this study to replicate previous findings which suggest a relationship between the qualities found in family environments and specific eating disorders through the examination of subjects' reports of family environments. We also attempted to refine previous findings of such relationships by adding an additional psychiatric contrast group. Subjects included patients with the following diagnoses: (1) Anorexia nervosa, restrictor type; (2) anorexia nervosa with bulimic features; (3) normal weight bulimia; and, as a psychiatric control population (4) major depression. In contrast to previous findings, subjects in each diagnostic group do not differ statistically either from each other or from a normative population with regard to reported family environments. However, when we grouped subjects by self-reported level of depression, those with a high level of depression described family environments that are significantly different, independent of the severity of illnesses or diagnoses. We discuss the use of self-report instruments in measuring such complex phenomena as family environment.

    View details for Web of Science ID A1993LJ73800005

    View details for PubMedID 8339098

  • Defense style and adaptation in adolescents with depressions and eating disorders. Acta paedopsychiatrica Smith, C., Thienemann, M., Steiner, H. 1992; 55 (3): 185-186

    Abstract

    Maturity of defense style has been associated with the level of adaptive functioning, but few studies have assessed defense style using self-report questionnaires which can provide ratings with great reliability and objectivity. We compared self-perception of defense style (using Bond's Defense Style Questionnaire) with ratings of adaptation assessed retrospectively by two independent raters (using the DSM III-R Global Assessment of Functioning scale) in a population of 100 adolescent girls diagnosed as having either an eating disorder or depression. There was significant correlation between maturity of defense style and level of adaptation, with greater maturity of defense style being associated with higher levels of adaptive functioning. This effect was independent of diagnosis within this population.

    View details for PubMedID 1414355

  • Psychometric measures in clarifying diagnosis in malnourished adolescents. Acta paedopsychiatrica Thienemann, M., Steiner, H. 1992; 55 (4): 207-210

    Abstract

    Three cases of adolescent females suffering from unexplained weight loss are presented. Differential diagnoses included psychiatric and medical illnesses. We describe how psychometric measures were used in each case to clarify diagnosis.

    View details for PubMedID 1492549

  • VITREOUS REPLACEMENT BY GAS AS A THERAPEUTIC MODALITY IN BACTERIAL ENDOPHTHALMITIS GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY Mansour, A. M., Ferguson, E., LUCIA, H., Rajashekhar, M., Li, H., MARGO, T. 1991; 229 (5): 468-472

    Abstract

    We investigated vitreous replacement by long-lasting gas in the management of severe Staphylococcus aureus endophthalmitis in 19 rabbits randomized for vitrectomy (9 animals) and for vitrectomy followed by replacement of the vitreous by a 20% perfluoropropane-80% air mixture (10 animals). Both groups received systemic antibiotics and achieved comparable intraocular antibiotic levels. Clinically and histopathologically, gas-filled eyes demonstrated less inflammation than did eyes without gas (P less than 0.01). Replacement of vitreous by gas offers an effective adjunct to vitrectomy by eliminating a culture medium, preventing vitreous abscess formation, enabling fundus visualization, and delaying the onset of retinal detachment.

    View details for Web of Science ID A1991GF69600014

    View details for PubMedID 1937081