What else could it be?

Generating a differential diagnosis for Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) requires a careful, systematic approach. Both syndromes are characterized by the sudden onset of obsessive-compulsive behaviors and/or eating restrictions, often accompanied by a range of neuropsychiatric symptoms such as tics, anxiety, mood lability, urinary symptoms, handwriting changes, and sleep disturbances. Importantly, these syndromes are thought to result from an immune-mediated response following an infectious trigger (eg Group A Streptococcus in PANDAS), but the clinical overlap with other neuroinflammatory, infectious, autoimmune, and psychiatric disorders means that accurate differentiation is essential for appropriate treatment.

The first step in the differential diagnosis is history and timing. PANS/PANDAS is typically abrupt in onset, with symptoms often appearing within days or weeks, which differs from many primary psychiatric conditions or autoimmune disorders, which tend to have a more insidious onset (months, years). Additionally, PANDAS is specifically associated with recent streptococcal infection, so a positive throat culture or elevated anti-streptolysin O (ASO) or anti-DNase B titers can support the diagnosis.

Surprisingly gluten sensitivity and celiac disease can also cause a psychiatric difficulties. For this, doctors should look for gastrointestinal symptoms (chronic diarrhea, abdominal pain, malabsorption) and growth disturbances. Headaches and rashes may be part of this picture as well. Celiac's neuropsychiatric manifestations include depression, irritability, ADHD-like symptoms, and even ataxia (movement and balance abnormalities). Unlike PANS/PANDAS, the onset in celiac is rarely abrupt. Serologic tests (e.g., anti-tTG IgA, EMA) or even confirmatory small bowel biopsy can help with diagnosis; along with symptom improvement on a gluten-free diet.

Psoriasis, especially its variant psoriatic arthritis, is increasingly recognized as a systemic inflammatory disease with potential neuropsychiatric comorbidity such as depression and anxiety. The neuropsychiatric features are secondary to chronic inflammation. Psoriasis usually presents with visible dermatologic signs (e.g., scaly plaques on extensor surfaces), and joint aches which are absent in PANS/PANDAS, but sometimes these appear months or years after the psychiatric symptoms. Psoriasis without a visible rash is rare but not impossible—particularly in early or atypical cases, or in the context of psoriatic arthritis (PsA) where joint symptoms can precede or occur without skin lesions. However, there is no definitive blood test for psoriasis itself. Diagnosis remains primarily clinical, but doctors should ask about a personal or family history of psoriasis, subtle skin findings on scalp, ears, umbilicus, gluteal cleft, and nails, and evaluate for musculoskeletal symptoms like joint pain, stiffness (especially in the morning), swelling, or dactylitis (sausage digits).

Autoimmune encephalitis, including anti-NMDA receptor encephalitis, can closely mimic PANS/PANDAS. It often presents with psychiatric symptoms, cognitive decline, seizures, autonomic instability, and abnormal movements. This can be quite dramatic and acute. CSF (spinal fluid) analysis typically shows unusual findings like pleocytosis or oligoclonal bands, and MRI or EEG may be abnormal. Antibody testing in serum or CSF is critical here. In contrast, PANS/PANDAS patients often have normal neuroimaging and CSF studies, though subtle findings may be present in some.

Systemic lupus erythematosus (SLE), especially neuropsychiatric SLE (NPSLE), can cause mood disorders, psychosis, seizures, and cognitive impairment. Clues that point toward lupus include constitutional symptoms (fevers, fatigue), rash (malar, discoid), renal involvement, cytopenias, and positive autoantibodies (ANA, anti-dsDNA, anti-Sm). While SLE can present in pediatric populations, the systemic involvement and positive lab testing (serologies) help differentiate it from PANS/PANDAS.

Other conditions to consider include Sydenham chorea (post-streptococcal but with predominant abnormal choreiform movements and emotional lability), primary psychiatric disorders (e.g., early-onset OCD, Tourette’s), post-viral syndromes, and even metabolic or genetic disorders (e.g., Wilson’s disease, mitochondrial disorders).

Ultimately, a multidisciplinary evaluation involving pediatrics, neurology, psychiatry, immunology, and infectious disease is often warranted. Laboratory and imaging workup, infectious and autoimmune serologies, and careful clinical observation over time are key to reaching a precise diagnosis.