Aetiology

The aetiology of PANS is not well understood, and it is a subject of ongoing research. PANS symptoms are thought to result from brain changes secondary to inflammation triggered by infections (e.g., influenza, mycoplasma, group A streptococcus [GAS] pharyngitis, Lyme disease), metabolic disturbances, other inflammatory reactions, and psychological trauma.[1][20]

Based on the available evidence, the authors of this topic suspect that an infection in an immunogenetically susceptible host triggers an inflammatory response, leading to sudden-onset psychiatric symptoms. Given the high rate of arthritis and other autoimmune conditions in patients with PANS, the authors suspect that the same infectious trigger could lead to immune destabilisation and the development of arthritis and other autoimmune conditions. It is well established that GAS infection can trigger arthritis (post-streptococcal reactive arthritis), acute glomerulonephritis, acute rheumatic fever, and Sydenham's chorea.[22]​ Also consistent with an immune-mediated hypothesis for PANS aetiology is the improvement of psychiatric symptoms seen after immunomodulation in patients with PANS.[23][24][25][26][27][28][29]

In PANDAS research criteria, abrupt symptom onset and some exacerbations are coincident with GAS infection (by definition), particularly streptococcal pharyngitis.[6] Studies have shown preceding GAS infection in 40% to 77% of children with PANS.[3][6][7]​ Population-based studies have provided additional evidence of a link between GAS and PANDAS-like neuropsychiatric syndromes.[30][31][32]​ One such study showed an association between neuropsychiatric symptoms and GAS infection in the previous 3 months; another study showed the same association in the previous year (but not in the previous 3 months).[30][31]​ Evidence of an epidemiological link is further supported by the fact that symptoms in PANS/PANDAS overlap with symptoms of Sydenham's chorea (one of the major clinical manifestations of acute rheumatic fever), pointing to these conditions likely having a similar aetiology.[32][33][34][35][36]

Causation, however, can only be assessed through epidemiology and animal models. Clinicians should be cautious about ascribing causation in clinical practice and keep an open mind to all the possibilities for the child's neuropsychiatric deterioration.

Pathophysiology

The pathophysiology of PANS is not completely understood, as is the case for most inflammatory disorders. Imaging studies suggest basal ganglia inflammation and injury, including basal ganglia swelling in the acute stage, microglia activation (via positron emission tomography [PET] imaging) and microstructural changes as demonstrated by diffusion-weighted magnetic resonance imaging.[37][38][39][40]

Emerging evidence shows a role for both the innate and adaptive immune system. One study found elevated levels of pro-inflammatory monocytes in patients with a flare versus those in recovery and controls, and a potential role for repairing brain-homing monocytes in PANS.[41]​​ Other studies have identified subsets of autoantibodies variably distinguishing PANDAS patients from controls, and autoantibodies specifically targeting and altering the function of cholinergic interneurons in the basal ganglia.[42][43][44]​​ Animal models of PANDAS have demonstrated an adaptive immune response, involving autoantibodies and Th17 cells, leading to central nervous system pathology including neurovascular damage.[43][45][46][47]

Classification

International classification of diseases 11th revision (ICD-11)[12]​

Published by the World Health Organization, the ICD-11 classifies paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) in the chapter 'Diseases of the nervous system' under 'Paraneoplastic or autoimmune disorders of the central nervous system, brain or spinal cord' with code 8E4A.0.

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