Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS)

Etiology

Most PANS cases reveal that more than half of patients are associated with streptococcus infection, the same causal agent of Sydenham chorea. Hence, studies have disputed PANDAS/PANS as a definite clinical entity and theorized that PANDAS is just a mild type or variant of Sydenham chorea due to overlapping clinical manifestations and a shared genetic predisposition to this condition.[6][8][15][16][17] However, some study results have mentioned differences in age groups and vulnerability windows to poststreptococcal sequelae between these diseases. Other infections that could be related to pediatric infection-triggered autoimmune neuropsychiatric disorders and PANS include Mycoplasma pneumoniae, Borrelia burgdorferi, Staphylococcus aureus, herpes simplex, Epstein–Barr virus, influenza, coxsackie virus,severe acute respiratory syndrome coronavirus 2, and varicella-zoster virus.[3][17] Studies have also observed patients with PANS demonstrating processing speed, visual-motor, visuospatial integration, and memory deficits that could be related to cortico-subcortical network dysfunction.[3][6][10][11]

Epidemiology

PANDAS lacks large-scale epidemiological studies to accurately determine its prevalence. PANDAS affects males more frequently than females, particularly boys between 3 and 12, with a mean age of 6.33 years (± 1.6 years). Additionally, first-degree relatives were described in more than half of all PANS cases.[13] Risk factors for the onset of PANDAS syndrome include multiple recurrences of group A streptococcal infections and a family history of autoimmune disease or rheumatic fever, especially on the maternal side.[8][17]

Pathophysiology

Several study results have described potential immune dysregulation associated with the pathophysiology of PANDAS, but the exact mechanism is still unknown.

Molecular Mimicry

A widely accepted hypothesis regarding the pathophysiology of PANDAS is molecular mimicry, similar to the well-established Sydenham chorea in rheumatic fever. Molecular mimicry occurs when antigens from pathogens are similar to host antigens in sequence and structure. Recent study results demonstrated that passive transfer of streptococcus-induced antibodies in mouse models produces neuropsychiatric symptoms of PANDAS.[4] Antibodies are produced against streptococcal proteins, such as N-acetyl-beta D-glucosamine, a streptococcal group A carbohydrate epitope.

Central Nervous System Pathophysiology

These streptococcus-induced antibodies cross the blood-brain barrier when its permeability is compromised by infectious or noninfectious triggers, causing circulating immunoglobulin G and CD4+ T cells to enter the brain.[6][18] They bind and cross-react with neuronal proteins in the brain, specifically lysoganglioside and dopamine D2 receptors, as seen in mouse models, leading to similar neuropsychiatric symptoms when these receptors are targeted.[1] This process results in microglial activation, with increased levels and signaling activation of calcium-calmodulin-dependent protein kinase II by monoclonal antibodies or cytoplasmic α-helical protein tubulin. An excess dopamine synthesis and subsequent loss of excitatory synaptic proteins occur, especially in the basal ganglia, thalamus, and cerebellum in the acute phase of PANDAS.[1][3][4][19] 

Biologic Markers

However, the biological link between infection and the onset of symptoms in the absence of biological markers is still limited and conflicting.[20] Several studies have collected cerebrospinal fluid (CSF) analyses with PANDAS for the possible presence of specific antibodies in the brains of patients with PANDAS. Biologic markers could lead to more accurate diagnosis, monitoring of symptom severity, and precise and tailored therapy.[2] Markers such as antistreptolysin O, anti-deoxyribonucleic acid-ase B, and C-reactive protein did not show significant differences in PANDAS compared to other etiologies.

Antineuronal Antibodies

Other proposed biomarkers for PANDAS include antineuronal antibodies found in Sydenham chorea, including the D1 and D2 dopamine receptors, calcium-calmodulin-dependent protein kinase II activity, β-tubulin, and lysoganglioside-GM1, which are assessed commercially through the Cunningham Panel.[2][6][8][15][16] Some study results have demonstrated at least 1 positive antineuronal autoantibody elevated abnormally in both serum and CSF in patients with PANDAS.[6] Anti-neuronal autoantibody titers in the serum were higher than in the CSF in patients with PANDAS. This study also showed that anti-neuronal antibody levels are not typically detected in the CSF of healthy individuals. These autoantibodies were found to decrease to normal or even negative levels at 6 months follow-up, with improvement observed in more than 80% of patients with PANDAS. However, data regarding the utility of antineuronal autoantibody titers are still inconclusive and inconsistent, as these titers have poor specificity (approximately 10%) and variable negative predictive values (44% to 74%) regarding their association with PANDAS.[2]

Additional Proposed Theories

Some studies have theorized that the degree of neuroimmunepathogenic response depends on an individual's altered and dysregulated immunogenicity, involving specific human leukocyte antigens, type of T response, regulatory T cell response, and cytokines. Other theories propose the contribution of specificity, affinity, and concentration of the autoantibodies and immunoglobulins, CSF oligoclonal bands, and immune-associated genes with the key role of Th17 cellular response.[4][18] These autoantibodies could be induced by other pathogens with the same cellular response (eg, influenza virus, mycoplasma, and Staphylococcus aureus) and produce clinical exacerbations. The findings of these studies support the observation that less than 25% of patients with flare-ups have group A beta-hemolytic streptococcus infection and a good response to antibiotics.

History and Physical

PANDAS syndrome is a diagnosis of exclusion based on the clinical presentation.[1][15] Excluding other medical conditions, including autoimmune and autoinflammatory diseases, immunodeficiency syndromes, neurological disorders, and psychiatric disorders, through a complete diagnostic evaluation is critical.[11] 

Diagnostic Evaluation

Psychoneurological assessment, evaluation for infectious, autoimmune, and endocrine diseases, assessment of somatic symptoms including polysomnography or sleep evaluation, and paraneoplastic evaluation should be part of the evaluation. Assessment of specific organ systems, including cardiac testing (eg, electrocardiogram and echocardiography), CSF analyses, electroencephalogram, and neuroimaging evaluation, is crucial.[2][3][8] Genetic evaluation could also aid in assessing patient predisposition to PANDAS.

Diagnostic Criteria

Neuropsychiatric symptoms typically occur approximately 4 to 6 weeks following a streptococcal infection, with symptoms worsening and peaking within 2 to 3 days. The following criteria have been proposed to guide PANDAS diagnosis:

• Presence of obsessive-compulsive or tic disorder
• Symptom onset during childhood to puberty (ie, between 3 and 12 years)
• Acute or subacute, sudden onset of symptoms with periodic exacerbation or worsening of existing symptoms for a short period (ie, relapsing and remitting episodes)
• Temporal association between confirmed streptococcal infection and onset or exacerbation of symptoms, confirmed by culture or the presence of antistreptococcal antibodies
• Association with neuropsychiatric symptoms, especially hyperactivity, choreiform motor movements, bedwetting, anxiety, emotional lability, developmental regression, or mood changes

Physical Symptoms

Physical symptoms may include the following:

• Tics and unusual movements
• Sensitivity to light, sound, and touch
• Deterioration of motor abilities, eg, handwriting, hyperactivity, or inability to concentrate
• Memory problems, sleep disorders
• Refusal to eat leading to weight loss
• Joint pain
• Frequent urination
• Enuresis
• Approaching a catatonic state

Psychological Symptoms

Psychological symptoms may include behavioral, anxiety, and emotional disorders, eg, repetitive, obsessive-compulsive behaviors, separation anxiety, fear, panic attacks, incessant screaming, emotional and developmental regression, visual or auditory hallucinations, irritability, frequent mood changes, depression, and suicidal thoughts.

Evaluation

Defined diagnostic clinical and immunological criteria, along with characteristic phenotypes among patients with PANDAS, have not been established. However, laboratory studies to confirm streptococcal infection and neuroimaging studies are frequently utilized.[2][7] 

Streptococcal Infection

Confirmation of streptococcal pharyngitis includes correctly performed throat cultures or rapid antigen tests. Cultures taken from other involved sites (eg, nasal cavity, skin and skin structures, and perianal or vaginal areas) should be conducted accordingly.[8] One cohort found antistreptolysin O and anti-deoxyribonucleic acid-ase B antibody titers to be positive in all PANDAS patients but negative in patients with PANS.[9] However, pharyngeal swabs and antistreptococcal antibodies are not considered markers of PANDAS. Positivity for these antibodies could indicate streptococcal exposure but does not distinguish a new acute infection from a chronic carrier state lasting for years.[15] 

Neuroimaging

One study proposes a pilot neuroimaging diagnostic protocol that can be prospectively used to compare and confirm the diagnosis of patients with PANS and PANDAS against other differential diagnoses, including obsessive-compulsive disorders, central nervous system vasculitis, Sydenham chorea, and autoimmune encephalitis. Magnetic resonance imaging of the brain has shown an enlargement of basal ganglia structures (eg, caudate nuclei, putamen, and globus pallidus) in patients with PANDAS.[15][17] Positron emission tomography (PET) imaging and messenger ribonucleic acid analysis of post-mortem specimens from affected individuals have also shown bilateral inflammation in the basal ganglia in PANDAS patients.[6][15] 

Treatment / Management

PANDAS treatment recommendations are debated due to a lack of consensus in the literature.[15] 

Antibiotic Therapy

According to the National Institute of Mental Health and the PANS/PANDAS Consortium, the primary therapeutic approach for acute episodes of PANDAS and PANS should involve an initial course of antibiotic therapy. Either β-lactams or macrolides are used to eradicate streptococcal infection alongside symptomatic treatment. Initiation of antibiotic treatment in all PANS cases, even without documented infections, was suggested in one study.[11] The efficacy of antibiotics in PANDAS and PANS lies in their direct effect against group A streptococcus infection and in their immunomodulatory and neuroprotective properties. (B3)

β-lactam molecules, including cephalosporins (eg, ceftriaxone and cefdinir) and penicillins, possess neuroprotective abilities. This modulates astroglia and microglia and minimizes glutamate neurotoxicity. The immunomodulatory effects of antibiotics facilitate serotonin or dopamine release and inhibit γ-aminobutyric acid (GABA)-A receptors in a dose-dependent manner. Macrolides (eg, azithromycin) act as immunomodulators, particularly in chronic inflammatory diseases. Macrolides modulate innate immunity and act on GABA-A receptors while reducing toll-like receptor 4 and interleukin 12. Additionally, the antioxidant and anti-inflammatory capabilities of antibiotics help to downregulate reactive oxygen. Results from studies in rats with PANDAS and group A beta-hemolytic streptococcus infection found that ampicillin prevented dysfunction by decreasing immunoglobulin G deposition in the brain and increasing levels of tyrosine hydroxylase.[4] Clavulanate, a β-lactamase inhibitor used with amoxicillin, crosses the blood-brain barrier and exhibits antidepressant and anxiolytic properties by reducing glutamate.

Antibiotic Prophylaxis

Some studies advocate antibiotic prophylaxis against streptococcal infection, particularly in cases with a complicated course of illness manifesting severe or recurrent exacerbations of neuropsychiatric symptoms similar to rheumatic fever and its complications (eg, Sydenham chorea).[4][9] A cohort study revealed that prophylaxis with benzathine benzylpenicillin for at least 5 years in patients with PANDAS or PANS showed reduced neurological symptoms.[9] However, the long-term use of low-dose antibiotics in PANDAS or PANS and its potential benefits remain largely unknown. Antibiotic resistance to group A streptococcus infection poses a potential threat that could lead to significant complications if PANDAS is left untreated. Appropriate monitoring should be provided to all high-risk patients.

Vaccinations

Vaccinations against group A streptococcus infection are also being studied for their potential benefits as prophylaxis against PANDAS.

Differential Diagnosis

Diagnosing PANDAS involves excluding various other conditions that cause similar symptoms. PANDAS is a diagnosis of exclusion, meaning other potential causes must be eliminated first. Eliminating other medical conditions, including autoimmune and autoinflammatory diseases, immunodeficiency syndromes, neurological disorders, and psychiatric disorders, through a comprehensive diagnostic evaluation is critical. Differential diagnoses also include obsessive-compulsive disorder, Tourette syndrome, other tic disorders, anxiety disorders, central nervous system vasculitis, Sydenham chorea, autoimmune encephalitis including Hashimoto disease with psychiatric features, schizophrenia, neuromyelitis optica spectrum disorder, other demyelinating diseases, infectious diseases, endocrine diseases, hormonal deficiencies, and dysfunctions. Additionally, conditions like Wilson disease and Lyme neuroborreliosis, which are known for their neuropsychiatric symptoms, should be considered in selected cases. 

Pertinent Studies and Ongoing Trials

Psychotherapy

Some studies have mentioned selective serotonin reuptake inhibitors (eg, fluoxetine, fluvoxamine, sertraline, and paroxetine), cognitive-behavioral therapy, and exposure response prevention as methods used to manage obsessive-compulsive disorder (OCD) and other severe psychiatric symptoms in patients with PANDAS. However, these studies were inconclusive when comparing the efficacy of these methods with that of a placebo.

Immunomodulatory Therapy

Additionally, some studies have investigated the potential role and benefits of immunomodulatory therapies in cases of PANDAS refractory to antibiotics and cognitive-behavioral therapy. Additionally, investigations are underway to identify diagnostic and therapeutic biomarkers defining patients with PANDAS likely to respond well to immunomodulatory interventions.[19]

Steroids

Corticosteroids have been shown to improve OCD symptoms but worsen tics and may lead to relapse upon discontinuation; therefore, they are not typically recommended in PANDAS treatment.

Intravenous Immunoglobulin

Intravenous immunoglobulin therapy has shown promise in treating PANDAS by reducing OCD symptoms and improving behavior, although further research is needed to confirm its efficacy and establish optimal treatment protocols. Despite some conflicting results, intravenous immunoglobulin remains a recommended treatment for PANDAS, with study results suggesting potential long-term benefits.

Therapeutic Plasma Exchange

Therapeutic plasma exchange or plasmapheresis has also been employed in severe and refractory cases of PANDAS, particularly in patients exhibiting symptoms of suicidality and violent behaviors. According to the 2019 American Society for Apheresis guidelines, therapeutic plasma exchange, which involves the removal of antineuronal antibodies in symptomatic patients with PANDAS or PANS, is reserved as a second-line therapy.[6][21][22] One study's results reported changes in volumetric magnetic resonance imaging scans, showing enlargements of the caudate nucleus, putamen, and globus pallidus in patients with PANDAS, with subsequent normalization after successful treatment with therapeutic plasmapheresis.[19] While few studies have reported a good response and tolerance with no adverse reactions after courses of apheresis treatment in individuals with PANDAS/PANS, these studies typically had small sample sizes. These studies also failed to identify specific populations with anti-neuronal antibodies that would predict a response to therapeutic plasma exchange.[20][22] 

Immunosuppressants

Immunosuppressant agents (eg, mycophenolate or rituximab) are also being researched. 

Prognosis

Most children fully recover from PANDAS. Studies investigating the efficacy of antibiotics in PANDAS management have results concluding that antibiotics are effective in reducing OCD symptoms regardless of evidence of infection. Additionally, other study results have shown improvement in neurological symptoms, particularly within 3 to 5 months of antibiotic treatment. However, antibiotics have not been found to reduce tic symptoms and neuropsychiatric exacerbations significantly.[4][9][11] 

Complications

Thorough investigations for PANDAS diagnosis are crucial because untreated or unrecognized manifestations of PANDAS could elevate the risk of persistent neuropsychiatric symptoms. These symptoms may include obsessive-compulsive manifestations, tics leading to subsequent handwriting difficulties, visual and motor impairments, sleep disruptions, and anxiety disorders that persist into adulthood. Furthermore, some individuals may experience worsening symptoms after each streptococcal infection.