This is a review of a recent narrative review led by Lucia Leonardi et al., published in Children (Basel) in August 2024, outlines the immunological mechanisms underlying Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). This synopsis highlights key insights from that review, focusing on how autoimmune inflammation, molecular mimicry, and blood-brain barrier disruption contribute to basal ganglia dysfunction and sudden-onset neuropsychiatric symptoms.
Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) are clinical entities marked by abrupt-onset neuropsychiatric symptoms, including obsessive-compulsive behaviors, motor tics, and eating restrictions. Increasing evidence suggests that in a subset of these patients, the symptoms are mediated by an autoimmune-inflammatory process targeting the basal ganglia.
While PANDAS represents a more narrowly defined post-streptococcal autoimmune response, PANS encompasses a broader spectrum of immune and metabolic triggers. The underlying pathophysiology of both appears to involve a convergence of molecular mimicry, blood-brain barrier disruption, and autoantibody-mediated neuronal interference.
Diagnostic Criteria
PANDAS criteria, as originally defined, require:
- Presence of obsessive-compulsive disorder and/or a tic disorder
- Pediatric onset (typically between 3 years and puberty)
- Abrupt symptom onset and episodic course
- Temporal association with Group A Streptococcus infection
- Presence of neurological abnormalities, such as motoric hyperactivity or choreiform movements
PANS, introduced to encompass non-streptococcal cases, is defined by:
- Abrupt, dramatic onset of obsessive-compulsive symptoms or food restriction
- Concurrent presence of at least two additional neuropsychiatric symptoms (e.g., anxiety, emotional lability, sensory or motor abnormalities, regression in behavior or academics)
- Symptoms not better explained by a known neurologic or medical disorder
These definitions are used clinically but remain the subject of ongoing debate, as no universally accepted biomarkers or gold-standard diagnostic tests currently exist.
Figure 1 illustrates the diagnostic framework for PANS and PANDAS, highlighting the clinical criteria and overlapping symptom profiles. Source: PANS/PANDAS Diagnostic Criteria. PANDAS Physicians Network. Retrieved from https://www.pandasppn.org. © PANDAS Physicians Network, used with permission or in accordance with their published usage guidelines.
Molecular Mimicry and Autoantibody Formation
Central to the autoimmune hypothesis in both PANS and PANDAS is the concept of molecular mimicry. In the case of PANDAS, Group A Streptococcus induces an antibody response that cross-reacts with neuronal epitopes in the basal ganglia. Several autoantibodies have been implicated, including those targeting:
- Dopamine D1 and D2 receptors
- Lysoganglioside GM1
- Tubulin
- Enzymes that activate calcium/calmodulin-dependent protein kinase II (CaMKII)
These antibodies interfere with normal dopaminergic signaling and intracellular processes. Animal models demonstrate that exposure to these antibodies can induce behavioral changes consistent with neuropsychiatric symptoms observed in children.
Moreover, the activation of CaMKII by these antibodies has been shown to upregulate tyrosine hydroxylase, thereby altering catecholaminergic neurotransmission within cortico-striatal-thalamic circuits.
The Role of the Th17 Axis and IL‑17 in Blood-Brain Barrier Dysfunction
Emerging evidence highlights the role of the Th17 immune response in the pathogenesis of these disorders. In both human and animal studies, an upregulation of interleukin-17A (IL-17A) and related Th17 cytokines has been observed.
IL-17A contributes to blood-brain barrier permeability by acting on endothelial cells, facilitating the entry of immune cells and autoantibodies into central nervous system structures such as the basal ganglia. This compromise in barrier integrity is a critical step that allows peripherally generated autoantibodies to exert direct effects on neuronal tissue.
This neuroimmune interaction is particularly evident in the nasal-associated lymphoid tissue, where immune activation may follow respiratory infection and subsequently access the brain via olfactory routes. In murine models, exposure to intranasal streptococcal antigens increased CNS-infiltrating Th17 cells and correlated with repetitive behaviors and anxiety-like symptoms.
Inflammation and Neurophysiological Evidence
Children with PANS and PANDAS often display elevated levels of systemic proinflammatory markers, including C-reactive protein, IL‑1β, IL‑6, and TNF-α. Complement pathway activation, particularly involving C3 and C4 components, has also been implicated in susceptibility.
Neuroimaging studies have consistently revealed basal ganglia volume changes, particularly in the caudate and putamen, during acute flares. Functional imaging using PET and SPECT further supports hypermetabolism or perfusion alterations in these regions.
Polysomnographic studies report abnormalities in rapid eye movement (REM) sleep, suggesting basal ganglia involvement in sleep-wake regulation. Motor overflow signs and fine motor disturbances are frequently noted during neurological examination, reinforcing subcortical circuit dysfunction.
Course and Treatment Considerations
The clinical course of PANS and PANDAS is typically relapsing-remitting, with symptom exacerbations following immune triggers such as infections, stress, or allergen exposure. In some cases, the symptoms become chronic or smoldering in nature.
Immunomodulatory therapies have shown efficacy in selected patients. These include:
- Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids to reduce acute neuroinflammation
- Intravenous immunoglobulin (IVIG) and therapeutic plasma exchange for autoantibody reduction
- Antibiotic prophylaxis or treatment in cases with documented streptococcal exposure
- Behavioral and psychopharmacologic interventions for symptom management
The Cunningham Panel, a commercially available assay designed to measure anti-neuronal antibodies and CaMKII activation, has been proposed as a potential biomarker tool, though its clinical utility and reproducibility remain under scrutiny.
Research Limitations and Future Directions
Despite growing support for the autoimmune hypothesis, PANS and PANDAS remain controversial. Criticisms include:
- Lack of standardized diagnostic biomarkers
- Limited replication of antibody assays across laboratories
- Variability in immune profiles among affected individuals
- Potential overdiagnosis and inappropriate use of immunomodulatory therapies
From the Clinic
Having treated over 80 children between the ages of 3 and 17 with PANS over the past 15 years, one consistent feature stands out across nearly every case: a parent will say, “It’s like they changed overnight.” This single observation is often the most reliable clinical indicator that an autoimmune process targeting the brain has been set in motion.
While Group A Streptococcus was the first identified microbial trigger in PANDAS, clinical experience has shown that a wide range of pathogens and environmental stressors can serve as the initiating event. Especially since the onset of the COVID-19 pandemic, the range of immune challenges associated with sudden neuropsychiatric changes has broadened significantly.
Triggers observed in clinical practice now include:
- SARS-CoV-2 (COVID-19)
- Influenza viruses
- Mycotoxins from mold exposure
- Borrelia burgdorferi (Lyme disease)
- Chronic psychosocial stress, including bullying
- Group A Streptococcus
Neurological and Motor Symptoms
- Basal Ganglia Dysfunction: Neuroimaging studies highlight abnormalities in the basal ganglia, including swelling during acute episodes, microglial activation in the caudate and putamen, and microstructural changes suggestive of inflammation or injury.
- Movement Abnormalities: Patients frequently display motor tics, choreiform movements, dystonia, and other involuntary motor dysfunctions, which parallel findings seen in Sydenham’s chorea (SC).
- REM Sleep Disturbances: Three studies report a high prevalence of excessive movement or lack of atonia during REM sleep. These sleep disturbances, often associated with basal ganglia dysfunction, have been identified as early predictors of Parkinson’s disease in adults.
Cognitive and Behavioral Symptoms
- Sudden Cognitive Decline: In addition to OCD, PANS/PANDAS can cause difficulties with executive function, memory, and attention. In some cases, a gradual cognitive deterioration occurs.
- Emotional Dysregulation: Patients frequently experience intense emotional outbursts, rage attacks, anxiety, depression, and mood swings.
- Sensory Sensitivities: Heightened sensitivity to light, sound, and touch is often reported, further impacting daily functioning.
In many cases, these are not isolated triggers but rather the final straw in a child with pre-existing immune vulnerabilities. Once initiated, the autoimmune process often becomes self-sustaining, independent of the original insult.
Effective clinical intervention requires a two-part strategy:
- Identification and resolution of the initiating trigger or ongoing exposure.
- Immune modulation to calm the neuroinflammatory response and stabilize basal ganglia function.
Without addressing both, the child may continue to cycle through exacerbations, even in the absence of infection. The abruptness of onset, particularly when corroborated by caregiver observation, remains one of the most critical criteria for recognizing a PANS-like autoimmune encephalopathy. The study recognizes that IVIG/antibiotics are limited in efficacy and work on a case-by-case basis. Suspecting PANS/PANDAS should prompt immediate evaluation by an experienced provider and multidisciplinary management.
Keywords:#PANS #PANDAS #Neuroinflammation #Autoantibodies #MolecularMimicry #BasalGanglia #Neuroimmunology #BloodBrainBarrier #Th17 #OCDinChildren
Source: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Immunological Features Underpinning Controversial Entities, by Lucia Leonardi et al. Children 2024, 11(9), 1043.
Author’s Affiliations: BG Mancini LAc, Advanced Certified Functional Medicine: is a Neurodevelopmental Researcher and Founder of the Brain & Gut Institute. She specializes in combining research with clinical experience through a lens of human connection and neuro-integrative medicine. You may contact her via her website, www.braingutinstitute.com or via linkedin.com/in/bg-mancini-62ab0410.
Cover Image Credit (right panel): PANS/PANDAS overlapping criteria. GABHS = Group A Streptococcus Infection. PANS criteria are agnostic to infection but cases may be temporally associated with GABHS. PANDAS Criteria require that the condition is temporarily associated with GABHS; however, these criteria miss cases since patients often present after the window of opportunity to detect GABHS.
These criteria are good for research but not practical for clinical care. Patients with abrupt-onset tics (when associated with GABHS) may satisfy PANDAS criteria but not PANS criteria. Patients with abrupt-onset eating restriction (regardless of the infectious trigger) satisfy PANS criteria but not PANDAS criteria. Both conditions are generally relapsing/remitting. PANS criteria require at least 2 other abrupt-onset neuropsychiatric symptoms in addition to OCD and or eating restriction but PANDAS criteria do not require adjunct symptoms. The PANS and PANDAS criteria strongly overlap since abrupt-onset OCD and preceding GABHS are highly prevalent in cohorts of patients meeting these criteria. From: Children (Basel), 2024 Aug 27;11(9):1043.
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