Prevalence and Predictors of Pain and Fatigue in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

Objectives: Patients with pediatric acute-onset neuropsychiatric syndrome (PANS) frequently report pain and fatigue. While some patients experience resolution of pain and fatigue following improvement in psychiatric symptoms, others develop persistent symptoms resembling fibromyalgia. Understanding these trajectories is critical for early identification and intervention in patients at risk for chronic pain or fatigue. In this study we characterize fibromyalgia symptoms in PANS and identify predictors of symptom progression following a PANS flare. Design: Prospective observational cohort study. Setting: Stanford University Immune Behavioral Health (IBH) Clinic in Menlo Park, California, USA. Participants: 204 consecutive patients with PANS evaluated by the IBH Clinic. The average (SD) age at first neuropsychiatric deterioration was 8.2 (3.3) years. Main outcome measures: We prospectively collected data on pain, fatigue, and other fibromyalgia symptoms using the 2016 American College of Rheumatology (ACR) Fibromyalgia Survey Questionnaire (FSQ), which includes the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS). For the reference standard, clinician-documented diagnoses of pain syndromes were ascertained through a retrospective review of participants' electronic medical records. We report the prevalence of these symptoms in PANS patients and controls and evaluate factors associated with time to meeting ACR fibromyalgia criteria threshold scores following clinic presentation using a Cox proportional hazards model. Results: Among 204 patients with PANS (110 boys [54%]), eighty-five (42%) met ACR fibromyalgia criteria threshold scores at least once during follow-up (95% CI at 10 years follow-up time: 60.5 [46.7-74.5]). Twenty-eight of these 85 patients (13.7% of total cohort) progressed to meet full ACR fibromyalgia criteria (95% CI at 10 years follow-up time: 24.1 [15.6-36.2]). Compared with controls, patients with PANS reported substantially elevated rates of pain, daytime fatigue, waking unrefreshed, and cognitive symptoms (brain fog). Higher scores on the WPI and SSS at presentation were associated with a higher hazard of subsequently meeting ACR fibromyalgia criteria threshold scores. Conclusions: Fibromyalgia symptoms were common in this PANS cohort, with a notable subset developing symptoms meeting full ACR fibromyalgia criteria. These findings suggest that pain and fatigue may represent post-inflammatory sequelae of PANS and may overlap mechanistically with other post-infectious conditions. Recognizing these symptom patterns may inform clinical management, development of outcome measures, and future clinical trials in these patients, as well as support investigation into shared neuroimmune mechanisms underlying post-infectious pain and fatigue syndromes.