More than 70% of children with PANS have a family history of autoimmunity.

One of the pathologies that has shown an increase in cases in the panorama of children's health is the Pediatric Acute Onset Neuropsychiatric Syndrome, also known by its acronym in English as PANS (Pediatrics Acute-onset Neuropsychiatric Syndrome) that research into this pathology has boomed in the last decade. 

What is PANS syndrome and why does it concern pediatricians and families?

This syndrome has multifaceted characteristics that have represented a challenge for pediatricians, requiring a comprehensive approach and a deep understanding of the underlying mechanisms of its pathophysiology.

PANS is defined as an acute-onset neuropsychiatric disorder, as its name implies, characterized by the sudden onset of a wide range of neurological and psychiatric symptoms such as obsessions, emotional lability, irritability, sleep disorders, behavioral disorders, attention deficit, emotional disturbances, cognitive and academic impairment.

Common symptoms of PANS: an abrupt onset that is disconcerting

These symptoms often appear abruptly, many reported by parents as having begun after an infection or a stressful event, and can have a significant impact on the child's and family's quality of life. PANS follows a relapsing and remitting course, with sudden deterioration of psychiatric symptoms observed between periods of relative symptom inactivity. 

PANS DIAGNOSIS: Current criteria

The diagnosis of PANS is established by specific criteria which are:

• Sudden and dramatic onset of OCD or severely restricted food intake
• Simultaneous presence of additional neuropsychiatric symptoms (with similar acute onset and severity) from at least two of the following seven categories:
  • Anxiety
  • Emotional lability or depression
  • Irritability, aggression, or severe oppositional behavior
  • Behavioral (developmental) regression
  • Deterioration of academic performance
  • Sensory or motor difficulties
  • Somatic signs or symptoms, including sleep disturbances, enuresis, or urinary frequency
• The symptoms are not better explained by a known neurological or medical disorder, such as Sydenham's chorea, systemic lupus erythematosus, Tourette syndrome, or others.

We must understand and establish that the PANS is the "diagnosis of exclusion» correct by performing a comprehensive diagnostic evaluation.

Treatment of PANS: A three-pronged medical strategy

The treatment of PANS is based on three complementary modes of intervention:

1. Provide symptomatic relief with psychiatric medications and behavioral interventions, prioritizing treatment of symptoms that cause the most distress and interference 
2. Treat underlying infections and consider therapeutic or prophylactic antibiotics.
3. Treat symptoms resulting from neuroinflammation or post-infectious autoimmunity with anti-inflammatory and immunomodulatory therapies, chosen based on symptom severity and disease progression.
4. Evaluate the effectiveness of the treatment regimen at frequent intervals, making modifications as warranted by improvement or worsening of symptoms.
5. Treatment can be gradually reduced or discontinued when symptoms resolve. However, treatment may be necessary again at some point in the future, given the relapsing-remitting nature of PANS symptoms.

What do immunological markers say in children with PANS?

Therefore, it is important to study the entire immune system and how it responds through specific immunological profiles.

A study reviewed medical records, which collected information on immune markers analyzed during an attack, characteristics, and imaging findings of arthritis and other autoimmune diseases. Some studies identified autoantibodies that attacked and altered the function of cholinergic interneurons in the basal ganglia.

Patients with PANS or PANDAS have rapid eye movement sleep movements, researchers found subsets of autoantibodies that distinguish patients with PANDAS from control patients.

Furthermore, animal models of PANDAS demonstrate an adaptive immune response, involving autoantibodies and Th17 cells, leading to pathological findings in the central nervous system, including neurovascular damage affecting the basal ganglia.

This collection was able to observe markers of immune activation in the affected population that included: 

• Ssigns of autoimmunity: It was observed in a nonspecific manner in 52,4% of the children with PANS studied.
  • Antinuclear antibody
  • Antihistone Antibody
  • Antithyroglobulin
  • C1q binding assay
  • Complement levels C3 and C4
  • Specific autoantibodies in blood.
• Signs of immune dysregulation or inflammationinformation: 12% of the studied population presented altered markers or suggestive nonspecific signs, especially during outbreaks of psychiatric symptoms.
  • Leukopenia.
  • Thrombocytosis.
  • Altered C-reactive protein and erythrocyte sedimentation rate.
• Signs of vasculopathy: In a 35.8%.
  • Livedo reticularis.
  • Periungual redness and swelling.
  • Abnormally prominent onychodermal band.
  • Palatal petechiae.
  • High von Willebrand factor antigen.
  • High D-dimer

Some researchers suggest that immune dysfunction may occur at multiple levels: local (directed) dysfunction related to cross-reactive antibodies that recognize specific CNS antigens; regional dysfunction related to inflammation within neuronal tissues or the basal ganglia vasculature; and systemic abnormalities in cytokine and chemokine production. Disruption of the blood-brain barrier (BBB) and CNS function has also been observed.

The cumulative risk of developing arthritis and autoimmune diseases was also estimated using the Kaplan-Meier product limit survival probability. Other studies have observed that inflammatory and post-infectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75% of patients.

Can PANS trigger other autoimmune diseases?

Because these patients with PANS present with signs of immune activation and vasculopathy during psychiatric symptom flares, they are at increased risk of developing arthritis and other autoimmune diseases compared to the general pediatric population. The most common arthritis was related to enthesitis.

As with these autoimmune disorders, treatment focuses on improving the current episode and preventing future recurrences. Research suggests that patients with PANS who present with severe symptoms and a chronic/static or chronic/progressive course require consideration of more intensive immunomodulatory approaches such as those used for neuropsychiatric systemic lupus erythematosus (NPSLE), central nervous system (CNS) vasculitis, autoimmune encephalitis (AD), chronic/progressive multiple sclerosis (MS), chronic/progressive Behçet's disease, and other persistent neuroinflammatory disorders.

In these chronic diseases, as in PANS, infections and other environmental triggers are thought to play a role in a sustained brain inflammatory response, which evolves into a chronic or progressive neuroimmune disorder. Another study shows that approximately 711 patients with PANS had one or more first-degree relatives with autoimmune/inflammatory disorders. These findings suggest that PANS may generate multisystem inflammatory conditions, rather than as it is currently managed as an isolated psychiatric or neuroinflammatory disorder.

Some of the mechanisms by which autoimmune diseases with PANS develop are through a mechanism in which the immune response to an infection can become dysfunctional due to defects in the adaptive or innate immune system, which reduces its response or due to dysregulated immune responses such as PANS, which are characterized by autoimmunity, recurrent episodes of autoinflammation, dysregulation of lymphocyte homeostasis or hypersensitivity reactions.

This results in an overproduction of antibodies, which can begin to attack not only pathogens but also healthy cells in the body. This phenomenon, known as cross-reactivity, can create an environment conducive to the development of autoimmune diseases.

Genetics, infections, and the environment: a cocktail of risks for PANS

These disorders can be caused by genetic defects, which encompass approximately 273 genes currently under study. These types of diseases have a prevalence ranging from 1/5,000 to 1/100,000 for some diseases. For almost all autoimmune-related diseases, genetic risk factors have been identified and thoroughly investigated, indicating that the human leukocyte antigen (HLA) haplotype has by far the greatest influence on the development of autoimmunity. However, the advent of genome-wide association studies (GWAS) has facilitated the identification and unbiased analysis of many additional risk factors. 

But when it is previously associated with PANS, it may subsequently be associated with inflammatory bowel disease, which includes Crohn's disease, ulcerative colitis, celiac disease, recurrent respiratory infections, aphthous stomatitis, adenitis, eosinophilic esophagitis, periodic fevers, otitis, genitourinary infections, skin infections such as psoriasis, systemic lupus erythematosus, Behcet's disease, type 1 diabetes. 

Since studies suggest PANS as a predisposing factor due to the chronic alterations it generates in the immune system, 28,3% presented arthritis, being the autoimmune disease with the highest incidence observed after the diagnosis of PANS.

Several abnormalities were also observed, such as livedo reticularis, periungual redness and swelling, and prominent onychodermal bands resembling fingernails, a known nonspecific indicator of systemic inflammation, suggesting small-vessel vasculitis. Capsulitis was also diagnosed in 55% of the patients who presented with peripheral arthritis and is suggested to be an early marker of psoriatic arthritis in patients with PANS.

Some studies suggest that infections that trigger PANS can lead to chronic inflammation, which has been linked to several neuropsychiatric conditions and may influence the development of autoimmune diseases by disrupting normal brain and immune system function. Neuroinflammation has been linked to disorders such as multiple sclerosis and Alzheimer's disease.

Recent research suggests that there are links between PANS and certain autoimmune disorders. For example, some studies have found that children with PANS have a higher incidence of autoimmune disorders such as autoimmune thyroiditis or systemic lupus erythematosus. This is because autoimmunity doesn't just affect a specific system; it can present a spectrum of symptoms affecting multiple body systems.

In addition to infections, other environmental factors can contribute to a predisposition to autoimmune diseases. For example, exposure to toxins, an unhealthy diet, or stress can interact with an individual's genetics and affect their immune system in ways that increase the risk of developing autoimmune diseases after an episode of PANS.

Thus, the studies provide us with further insight into an unexpectedly high frequency of signs of immune activation, arthritis, and autoimmune disease, suggesting that PANS itself is part of an inflammatory diathesis, similar to neuropsychiatric lupus or Sydenham's chorea, where neuroinflammation is comorbid with arthritis and other inflammatory signs.

Below, we've included other articles on neurodevelopmental disorders that might be of interest to you.

Also, you can access our website at www.eneviahealth.com To check out the services we offer, as well as advice from our team of specialists, visit www.eneviacare.com.

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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