What Does the Immune System Reveal About PANDAS in Children?

The immunological characterization of a group of patients with PANDAS Syndrome (Obsessive-Compulsive Disorder Associated with Streptococcal Infection) is a broad and complex topic, which addresses multiple aspects of the relationship between streptococcal infection, the immune response and neuropsychiatric manifestations. 

PANDAS Syndrome (Obsessive-Compulsive Disorder Associated with Streptococcal Infection) is a neuropsychiatric disorder that primarily affects children and is characterized by the sudden onset of obsessive-compulsive symptoms and/or motor or vocal tics following a streptococcal infection. Streptococcus pyogenes (group A streptococcus). Symptoms usually appear between 3 and 12 years of age and occur acutely, often within a few weeks of infection.

The term PANDAS was coined in 1998 by Dr. Susan Swedo and her team at the US National Institutes of Health (NIH). They observed that a group of children with OCD symptoms developed these symptoms after streptococcal infections. The initial study identified the relationship between streptococcal infection and the abrupt onset of neuropsychiatric symptoms, prompting investigations into the underlying mechanism.

The concept gained traction in clinical and academic care over the years, linking PANDAS to autoimmune responses that might develop in response to infections. This approach suggested that the immune system, in fighting infection, might mistakenly attack neural tissue in predisposed children, triggering symptoms.

The prevalence and identification of PANDAS is challenging due to similarities with other psychiatric disorders and variability in symptoms and clinical presentations. However, some estimates indicate that PANDAS may affect approximately 11% of the pediatric population, increasing recognition of this syndrome has led to higher reported incidence, and as more health care professionals consider the relationship between streptococcal infections and neuropsychiatric problems.

It is important to mention that not all children who suffer from streptococcal infections will develop PANDAS; genetic, environmental and neurobiological factors play a crucial role in the predisposition to this disorder.

Clinical manifestations

• Obsessive-Compulsive Symptoms: They may include intrusive thoughts and repetitive rituals that significantly interfere with daily activities.
• Tics: Involuntary movements or sounds that may be motor (blinking, jerking) and/or vocal (grunts, repeating phrases).
• Mood Disorders: Irritability, behavioral changes, anxiety and depression.
• Motor Regulation Problems: Difficulties in coordination and motor skills.
• Attention Deficit Hyperactivity Disorder: Sometimes symptoms similar to ADHD occur.

Diagnosing PANDAS can be complicated by the overlap of symptoms with other neuropsychiatric disorders. Differential diagnosis is essential to ensure appropriate management. Some of the disorders that should be considered in the differential diagnosis include:

1. Obsessive-Compulsive Disorder (OCD):
   • OCD can present with symptoms similar to PANDAS, but in the case of PANDAS, symptoms onset abruptly following a strep infection.
   • In PANDAS, there may be a clear temporal relationship with infections, whereas OCD itself may begin more gradually and not necessarily following infections.
2. Attention Deficit Hyperactivity Disorder (ADHD):
   • Symptoms of hyperactivity and impulsivity may be confused with irritability and inattention in PANDAS. However, in PANDAS, the rapid onset of obsessive-compulsive symptoms and other related behaviors are more prominent.
3. Autism Spectrum Disorders (ASD):
   • Although they share certain characteristics, the sudden onset of symptoms and the relationship with infections are distinctive in PANDAS.
4. Tourette Syndrome:
   • Motor and vocal tics in PANDAS may resemble symptoms of Tourette syndrome, but the latter are not usually associated with streptococcal infections.
5. Anxiety disorders and depression:
   • Anxiety and depressive symptoms may be prominent in PANDAS, but abrupt onset and infectious context are important differentiators.
6. Schizophrenia or psychotic disorders:
   • Rarely, psychotic symptoms may arise. The abrupt onset and temporal association with infections are key to differentiating them.

A comprehensive clinical evaluation is necessary, including medical history, exposure to infections, psychiatric evaluation, and, when appropriate, laboratory testing to detect streptococcal infections.

Infections caused by Streptococcus pyogenes, also known as group A strep (GAS), can cause a variety of illnesses ranging from mild infections to life-threatening illnesses. Common infections include:

• Strep throat: Inflammation of the throat, common in children and adolescents, often associated with fever and pain when swallowing.
• Scarlet fever: It usually occurs after pharyngitis and is characterized by a skin rash, fever and raspberry-red tongue.
• Skin and soft tissue infections: Such as impetigo (skin infection) and cellulitis. It can also cause infected wounds.
• Necrotizing fasciitis: A serious infection that rapidly destroys soft tissue, often referred to as “devouring bacteremia.”
• Streptococcal toxic shock syndrome: Characterized by rapid and severe onset, leading to multiorgan failure.
• Other complications: These may include rheumatic fever and poststreptococcal glomerulonephritis, which are late complications of GAS infections.

Streptococcus pyogenes is a gram-positive, non-motile, spherical-looking bacillus (coccus) that tends to organize in chains. It carries out hemolysis because it is a beta-hemolytic streptococcus, which means that it can lyse red blood cells in culture media, producing a clear halo around the colonies on a blood agar medium.

Biochemical tests such as catalase are negative since it does not produce oxygen bubbles in a medium with hydrogen peroxide, and it also ferments carbohydrates producing lactic acid such as glucose but does not produce gas. It is classified according to the Lancefield system, with group A (serotype A) corresponding to S. pyogenes. It can survive in adverse conditions and shows a wide variability in the expression of virulence factors.

Pathogenicity mechanisms

Streptococcus pyogenes uses several mechanisms to evade the immune system and cause disease:

• Accession:
  • Surface proteins: Including the M protein, which promotes adherence to epithelial cells and may interfere with phagocytosis.
• Evading the immune system:
  • Hyaluronic acid capsule: Acts as a shield that helps prevent phagocytosis.
  • M protein: Not only does it act as an adhesion factor, but it can also deactivate the complement (immune system).
• Toxinogens:
  • Exotoxins: Production of exotoxins (such as exotoxin A) that can cause significant tissue damage and are responsible for severe clinical manifestations such as toxic shock.
• Enzymes:
  • Hyaluronidase: Facilitates the dissemination of bacteria through tissues.
  • Streptokinase: Allows the bacteria to spread.
• Infection and tissue damage: The production of different enzymes and toxins contributes to tissue destruction and the establishment of more serious infections, such as necrotizing fasciitis.

Syndromes associated with PANDAS

PANDAS is primarily associated with the onset of neuropsychiatric symptoms following S. pyogenes infections. Associated syndromes and conditions include:

• Obsessive-Compulsive Disorder (OCD):
  • Sudden onset of obsessive-compulsive symptoms, which can be debilitating and disruptive to a child's daily life.
• Tics:
  • Motor or vocal tics that may appear suddenly and may vary in severity.
• Anxiety symptoms:
  • They may include school phobias, increased social anxiety, and panic attacks.
• Mood Disorders:
  • Depression, irritability, and behavioral changes that are more marked compared to the child's previous functioning.
• Emotional Regulation Difficulties:
  • Difficulties that the child faces in regulating emotions, which can manifest in emotional outbursts and frustrations.
• Cognitive symptoms:
  • Difficulty concentrating and memory problems, which can impact school performance.
• Comorbidities:
  • PANDAS can often co-occur with other neuropsychiatric disorders such as ADHD, anxiety disorders, and conduct disorders.

Innate and Adaptive Immune Response to Infection in PANDAS

The innate immune response is the body's first line of defense against infection, and it acts quickly when a pathogen, such as Streptococcus pyogenes, invades the body. Its characteristics include:

• Pathogen Recognition: Innate immune system cells, such as macrophages and dendritic cells, recognize components of the streptococcal cell wall through pattern recognition receptors (PRRs).
• Cytokine Production: Following recognition, cytokines and chemokines are released that promote inflammation and activation of the immune system.
• Phagocytosis: Macrophages and neutrophils phagocytose and destroy bacteria.
• Inflammatory Response: Inflammation results in dilation of blood vessels and migration of immune cells to the site of infection.

Adaptive Immune Response

The adaptive immune response develops more slowly and is pathogen-specific:

• Lymphocyte Activation: Antigen presentation by antigen-presenting cells (APCs) activates T cells, which can differentiate into CD4+ and CD8+ T cells.
• Antibody Production: B cells, after being activated, differentiate into plasma cells that produce specific antibodies against S. pyogenes.
• Immunological Memory: Some B and T cells become memory cells, allowing for a faster response in the event of new exposure to the pathogen.

Role of Antibodies (ASO – Anti Streptolysin O Antibodies)

Anti-streptolysin O (ASO) antibodies are a type of antibody produced in response to S. pyogenes infection. Their role includes:

• Infection Detection: The presence of elevated levels of ASO is a serologic indicator of a recent group A streptococcal infection.
• Toxin Neutralization: ASOs neutralize streptolysin O, an exotoxin that can cause cellular damage and contribute to the pathogenicity of infection.
• Contribution to Inflammation: Formation of immune complexes (antibody-antigen) upon binding of ASOs to their antigens may contribute to inflammation and, in some cases, autoimmune responses.

Involvement of immune complexes in the CNS

Immune complex formation may have significant implications for the central nervous system (CNS), particularly in the context of PANDAS disorder:

1. D Immune Response Uncoupling: In some cases, immune complexes can cross the blood-brain barrier, triggering a local inflammatory response in the CNS.
2. Neuronal Effects: Inflammation caused by these complexes can alter neuronal function, contributing to psychiatric and neurological symptoms in children with PANDAS, such as OCD and tics.
3. Autoantibodies: An autoimmune response may be generated where the immune system attacks neuronal structures as a result of molecular mimicry or indirect damage from inflammation and the immune response.
4. Clinical Implications: Dysfunction caused in the CNS by the presence of immune complexes can manifest as changes in behavior, cognition, and emotional state in affected children.

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection) is characterized by the appearance of neuropsychiatric symptoms following an infection by Streptococcus pyogenesImmunological characterization in PANDAS involves several areas of study, including antibody assessment and cytokine production.

Antibody Analysis

There are antibodies that will be requested to be able to make the differential diagnosis, such as Anti-Streptolysin O (ASO) antibodies, which indicate a recent group A streptococcal infection. Elevated levels can corroborate a history of a streptococcal infection.

And anti-neural antibodies, the investigation of the presence of autoantibodies that attack neural tissue, is a topic with a lot of focus right now, these may include antibodies against neurotransmitter receptors or proteins of the central nervous system, potentially causing dysfunction.

• Cytokine Production:
  • In PANDAS, there may be an altered profile of cytokine production. This includes an increase in proinflammatory cytokines such as:
    • IL-6: Associated with inflammatory processes and may be elevated in response to infection.
    • TNF-α: Contributes to inflammation in the CNS and may exacerbate neuropsychiatric symptoms.
• Chemokines:
  • Chemokines are responsible for attracting immune cells to the site of infection or inflammation. In PANDAS, an increase in chemokines that facilitate the infiltration of inflammatory cells into the CNS could be observed.

Cytokine Production Profile in Patients with PANDAS

The cytokine profile in PANDAS patients suggests an active inflammatory response:

• Increases in Proinflammatory Cytokines:
  • An increase in cytokines such as IL-1β, IL-6 and TNF-α has been recorded, which may be related to inflammation and neuronal damage.
• Alterations in Anti-inflammatory Cytokines:
  • There may be an imbalance between pro- and anti-inflammatory cytokines, which contributes to the persistence of inflammation and neuropsychiatric symptoms.

Rol of Inflammation in Neuropsychiatry

Inflammation plays a crucial role in neuropsychiatry, and its involvement in PANDAS manifests itself in several ways:

1. Neurochemical Dysfunction:
   • Inflammation can disrupt neurotransmission by releasing cytokines that affect neurotransmitter function, which may contribute to symptoms of anxiety, Tourette's, and OCD.
2. Alteration in Neuronal Development:
   • Inflammation can interfere with processes such as neurogenesis and synaptic plasticity, which are essential for brain development and cognitive function.
3. Neuropsychiatric Syndromes:
   • There is evidence linking chronic inflammation to disorders such as depression, schizophrenia and anxiety disorders. In the case of PANDAS, inflammation triggered by the infection may be an additional trigger for neuropsychiatric disorders.
4. Autoimmune Mechanisms:
   • Inflammation can trigger or worsen autoimmunity, where the immune system attacks neural tissues and contributes to cognitive impairments and behavioral disturbances.

T cells are key components of the adaptive immune system and play a crucial role in the response to infections. Here are some key features of T cells in response to infection:

• Activation:
  • T cells are activated by the presentation of specific antigens by antigen-presenting cells (APCs) expressing the major histocompatibility complex (MHC) and costimulators.
  • CD4+ T cells (T helper) recognize antigens presented by MHC class II, while CD8+ T cells (cytotoxic) do so through MHC class I.
• Proliferation:
  • Once activated, T cells proliferate significantly, generating T cell clones that are specific for the antigen presented.
• Differentiation:
  • T cells differentiate into specific subtypes, such as helper T cells (Th1, Th2, Th17) and cytotoxic T cells (CTL), each with specific functions:
    • Th1: They promote cellular immune response and macrophage activation.
    • Th2: They facilitate the production of antibodies by B cells.
    • Th17: Involved in inflammatory responses and defense against fungi and some bacteria.
• Cytokine Production:
  • Activated T cells produce cytokines that modulate the immune response, promoting the inflammatory response or regulating the activity of other cells of the immune system.
• Memory:
  • After resolution of the infection, some T cells become memory T cells, which provide a rapid and effective response to future exposures to the same pathogen.

The activation status of T cells can be assessed by a number of characteristics:

• Surface Markers:
  • Activation can be observed through the expression of surface markers, such as CD69, CD25 (IL-2Rα), and decreased expression of inhibitory molecules such as PD-1 on effector T cells.
• Cytokine Production:
  • Activated T cells show an increase in the production of specific cytokines, such as IFN-γ in CD4+ Th1 T cells, indicating their activation and functionality.
• Metabolic Changes:
  • Activated T cells exhibit increased metabolic activity, marked by increased glycolysis and oxidative phosphorylation.

Aberrant Response in PANDAS

In the context of PANDAS, the immune response presents aberrant features such as dysregulated antibody production; in PANDAS, the production of autoantibodies that attack antigens in the CNS has been observed, possibly in response to autoimmune processes triggered by streptococcal infection.

In addition to an imbalance in cytokines, there may be an altered cytokine profile, where there is excessive production of proinflammatory cytokines (such as IL-6 and TNF-α) and a possible deficiency in regulatory cytokines, contributing to chronic inflammation and neuropsychiatric symptoms.

Studies have observed compromised T cell activation, which may lead to an ineffective or exaggerated response to infection, and an inability to adequately regulate the immune response. In addition to CNS infiltration, immune cell activation and autoantibody production may result in T cell infiltration into the CNS, contributing to neuroinflammation and the development of psychiatric symptoms.

Cross-reactivity between bacterial antigens and neuronal epitopes may lead to the activation of specific T cells that attack neuronal components, which is characteristic of PANDAS.

TCognitive-Behavioral therapies in PANDAS

Cognitive-behavioral therapies (CBT) are widely used in the treatment of OCD and, by extension, PANDAS symptoms. CBTs are designed to help patients identify and manage dysfunctional thoughts and behaviors. Specific strategies include:

1. Exposure and Response Prevention (E/R):
   • This technique involves gradually exposing the child to situations that trigger anxiety, while preventing him from performing the compulsive rituals. Over time, this can reduce the intensity of the symptoms.
2. Cognitive Restructuring:
   • It involves helping the patient recognize and change negative or irrational thought patterns that contribute to their anxiety and obsessive behaviors.
3. Coping Skills Training:
   • Teach coping skills such as relaxation techniques, deep breathing, and mindfulness.
4. Psychoeducation:
   • Information about the disorder, its relationship to infections, and the importance of treatment. This helps to normalize experiences and reduce fear about the disease.
5. Family Involvement:
   • Interventions can also include parents and caregivers, providing tools and strategies to support the child at home.

Management Strategies for Parents and Caregivers in PANDAS

Managing PANDAS requires a comprehensive approach that involves not only medical treatment but also emotional and practical support for caregivers. Some effective strategies include:

• Education and Understanding:
  • Parents should educate themselves about PANDAS and its implications. Understanding the disorder can help parents feel more empowered in their approach to symptom management.
• Emotional Support:
  • Providing a child with an emotionally safe environment is essential. Parents can help children express their feelings and fears by validating their experiences.
• Establishing Routines:
  • Creating daily routines can provide a sense of stability and predictability, helping to reduce anxiety.
• Stress Management Techniques:
  • Teaching and practicing relaxation techniques, such as deep breathing or meditation, can help both parents and children manage stress.
• Collaboration with Health Professionals:
  • Maintaining open communication with treating physicians can provide valuable information for symptom management and therapy adjustments.
• Support Networks:
  • Finding support groups for parents of children with PANDAS can be beneficial. Sharing experiences and strategies with others can help reduce isolation and offer new perspectives.
• Promote Physical Activity:
  • Regular physical activity can be an effective tool for managing anxiety and improving overall well-being.

Effective management of PANDAS involves a multidisciplinary approach and clear communication between parents, the medical team, and therapists. Collaboration and support are key to helping children cope with the challenges of this disorder.

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At Enevia, we believe that no person should be diagnosed with autism without first having ruled out organic problems.

Because at Enevia, we care about your health!

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Bibliographic references

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• Kulumani Mahadevan LS, Murphy M, Selenica M, Latimer E, Harris BT. Clinicopathologic Characteristics of PANDAS in a Young Adult: A Case Report – PubMed. Dev Neurosci. 2023;45(6):335-341. doi:10.1159/000534061. Epub 2023 Sep 12. PMID: 37699369; PMCID: PMC10753865.
• Marazziti D, Palermo S, Arone A, Massa L, Parra E, Simoncini M, Martucci L, Beatino MF, Pozza A. Obsessive-Compulsive Disorder, PANDAS, and Tourette Syndrome: Immuno-inflammatory Disorders. Adv Exp Med Biol. 2023;1411:275-300. doi: 10.1007/978-981-19-7376-5_13. PMID: 36949315.