New Research Identifies Key Differences Between Sydenham Chorea and PANDAS
A recent study has helped clarify how dopamine receptors and autoantibodies help identify symptoms in children with Sydenham chorea and PANDAS.
Dr. Madeleine Cunningham and Dr. Chandra Menendez are authoring a study outlining how autoantibody activation of D1 and D2 dopamine receptors may help create new diagnostic criteria for PANDAS.
A new study authored by Dr. Madeleine W. Cunningham and Dr. Chandra Menendez at the University of Oklahoma Health Sciences Center is addressing long-term gaps in research into the underlying causes of Sydenham chorea and PANDAS. Ultimately the hope is that a deeper understanding of these conditions and their common root cause will lead to better education and awareness for families and healthcare providers, enabling earlier, more accurate diagnoses, and ultimately earlier and more specific treatments.
Although Sydenham chorea is understood to be the major neurologic manifestation of rheumatic fever, Sydenham chorea has been historically understudied and is more common in developing countries, primarily in Africa and Latin America. Often researchers have focused instead on the joint pain and cardiac valvular injury of rheumatic fever that can lead to secondary heart failure. However, the neurological and behavioral complications of both Sydenham chorea and PANDAS can be quite debilitating for both patients and families. Research has shown proven similarities and connections between Sydenham chorea and PANDAS—but with no clear biomarkers for each disease and given the heterogeneity of both disorders, it can make it difficult for patients to get an accurate PANDAS diagnosis.
Dr. Menendez and Dr. Cunningham are working to identify underlying autoimmune risk factors that could help lead to an earlier, more accurate diagnoses for conditions like PANDAS/PANS and Sydenham chorea. One of the ways to advance diagnostic testing and criteria is to identify a clear biomarker for each disease. For the study, Cunningham and Menendez studied several blood samples in an attempt to understand the biological significance of specific D1 and D2-class dopamine brain receptors that are potentially activated in the disorders. Their findings that autoantibodies pathogenically target D1 receptors in PANDAS patients and D2 receptors in Sydenham chorea have the potential to help investigators understand underlying factors in the disorder and aid in the development of more accurate methods of diagnosis for both conditions.
We spoke with Dr. Menendez about her and Dr. Cunningham’s research, and how this work has the potential to improve diagnostic criteria and accuracy as well as treatments for both conditions.
“Their study provides insight that pathophysiology of infection-mediated autoimmune neuropsychiatric and movement disorders is due to an autoimmune encephalitis of the basal ganglia, where dopamine receptor density is highest”. Their work redefines current understanding of group A streptococcal neurologic and neuropsychiatric sequelae as a Basal Ganglia Encephalitis (BGE) that can be classified as two unique subtypes. These mechanistic insights are particularly relevant to 1) Sydenham chorea and 2) behavioral/neuropsychiatric disorders with acute-onset tics and OCD, including pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS). Dr. Menendez’s new evidence about pathogenic D1R autoantibodies presented in their paper takes the knowledge of PANDAS to a new level critical to the understanding of the complex disorder. Their work demonstrates that specific immune responses in chorea are separate from tics and OCD symptoms seen in PANDAS. They found that children with choreiform movements were defined by antibodies that target and signal D2R, while in PANDAS, the mechanism has been unknown.
What is Sydenham chorea?
Sydenham chorea is a neurological disorder resulting in short, involuntary movements, often in the tongue, face, and limbs. It typically affects children and develops weeks or months after a Group A beta-hemolytic streptococcus (GABHS) infection—a result of the same bacteria that causes rheumatic fever and strep throat.
Both Sydenham chorea and PANDAS are autoimmune disorders that can result from streptococcal infections, but symptoms can manifest in different ways. Children with Sydenham chorea primarily experience movement-based symptoms, including random and irregular movements, trouble with speech, and difficulty grabbing or holding things. These symptoms can range from subtle (including slight coordination issues or trouble writing) to severe (trouble walking or performing basic tasks like eating or getting dressed). In many cases of Sydenham chorea, major body movements are accompanied by milder psychological symptoms like anxiety and OCD, thus it can make it difficult to properly identify and treat these disorders that are a complex disease.
While the PANDAS autoimmune response is a reaction to the same bacterial infection, it is characterized by an onset of acute psychological symptoms. Anxiety, depression, OCD, and other behavioral disorders are the main symptoms of PANDAS. The presence of OCD and/or tics, are part of the main diagnostic criteria for the disorder. However, both disorders are associated with neurological abnormalities and are complex disorders that make them difficult to identify and treat.
Why study PANDAS and Sydenham chorea together?
Both PANDAS and Sydenham chorea are Group A streptococcal sequelae, meaning a strep infection is the common ground from which symptoms for each disease emerge. “Since we know [a strep-initiated autoimmune response] is a driving factor in the disease and part of the diagnostic criteria for Sydenham chorea and PANDAS, that’s where we start and that’s what we study,” says Menendez. Starting at this common ground enables researchers like Menendez and Cunningham to investigate underlying factors that may contribute to the disorders that can be therapeutically targeted.
“To ensure what you are measuring plays a role in disease, you want to make sure you study the disease in multiple ways and in multiple cohorts,” says Menendez. She says the current study with Cunningham was prompted by the question, “Can we apply what we know from rheumatic fever and Sydenham Chorea to PANDAS?” “Most of what we know about PANDAS are from studies of Sydenham Chorea, therefore, we wanted to see how much of what we know about Sydenham chorea also may apply with the related disorder, PANDAS. We are still just beginning to understand some of the underlying factors in both disorders and how much is true for each disease.”
The hope is that by better understanding the connection between the two diseases, they will be able to build on established research to identify clear biomarkers that can also provide clues to underlying pathogenic mechanisms. For example, Menendez notes that as far back as the 1970s, researchers have identified autoantibodies in children with Sydenham chorea. “We know autoantibodies are a large part of the disorder, but are obviously not the only factors involved in the disorder. We also realize it’s difficult to identify autoantibodies in every child as they may target different proteins,” she says. “For example, children with Sydenham chorea can have D2 autoantibodies that correlate with symptoms, [but] they can also have other anti-neuronal antibodies. We also do not know as much about the D1 autoantibodies.”
Much of Menendez and Cunningham’s research—and the potentially groundbreaking implications of their upcoming published study—revolve around better understanding the specific roles played by the different autoantibodies associated with both PANDAS and Sydenham chorea.
Identifying Specific Markers for PANDAS vs. Sydenham Chorea
One of the major findings of Cunningham and Menendez’s research is that the autoantibodies produced by the D1 and D2 dopamine receptors appeared at different levels in blood samples from people with PANDAS than those with Sydenham chorea. “When you look at the overall frequency of the dopamine receptor autoantibodies, D2 tends to be specific to Sydenham chorea,” says Menendez, while D1 autoantibodies are abnormally elevated in children with PANDAS.
Menendez is careful to point out that the presence of specific autoantibodies alone does not confirm that a child has PANDAS or Sydenham chorea, however, could potentially serve as a “clinical test” to aid in diagnosis. This research has clarified which autoantibodies are linked with particular symptoms that present for each disease. “We know that the D1 and D2 autoantibodies can actually cause pathology,” she says. “They are causing some type of dysregulation in the dopamine signaling pathways. So that’s [one] reason why we are so interested in studying not only the significance of using them as a clinical biomarker but also because they have specific biological mechanisms that can play a role in the disease process.”
Additionally, Menendez and Cunningham’s findings may help researchers clarify the roles these autoantibodies play in activating specific dopamine receptors in the brain. “We know that not only do [children with PANDAS] have the D1 autoantibodies, but they’re causing changes within the brain directly because they’re signaling the [D1] receptor,” says Menendez. Understanding this relationship may help develop clearer models of disease formation and progression. “We’re just beginning to understand how they’re doing that, their potential implications, and how that may affect current therapies or how they may benefit certain therapies. That’s basically the long-term goal of the work as well.”
Testing for Earlier, More Accurate Diagnoses
Many PANDAS symptoms manifest as other psychiatric or behavioral disorders. For this reason, children are often misdiagnosed and treated for just one condition (such as OCD or depression) rather than for the underlying cause of all of their symptoms. “Our goal is to help clarify the diagnosis for clinicians,” says Menendez. “The most important factor for these diseases is for physicians to recognize the autoimmune component or underlying systemic or brain inflammation, so they can be treated appropriately and early.”
Children with PANDAS do not always test positive for strep antibodies, even in cases where it is already known that a child had a strep infection. One implication of Cunningham and Menendez’s research is that testing for the presence of D1 autoantibodies could offer clinicians a more accurate way to confirm a suspected PANDAS diagnosis and indicate brain pathology.
“About 70% of children that are classic PANDAS or PANS children tend to have antibodies that accidentally target D1, or thus have D1 autoantibodies,” says Menendez. “Granted, not every child is going to have D1 autoantibodies—or you may not be able to measure them once they’ve been treated or during a period of low symptoms—but what we’re finding is that the presence of D1 as an autoantigen does have a good predictive diagnostic and potentially prognostic value for clinicians.”
Treating the Root Cause Rather Than Just Symptoms
Even with earlier and more accurate diagnoses, children with PANDAS will still need to be treated by neurologists and other specialists. By helping clinicians identify the root cause of the illness, Menendez hopes that the therapeutic approaches required to alleviate a child’s specific psychiatric and behavioral symptoms will be more effective.
“The point of our research is to help identify and treat underlying pathology promoting these complex disorders that should be treated as an autoimmune condition. If an infection and associated inflammation or autoimmune responses aren’t properly treated, therapies [addressing a child’s behavioral symptoms] may not be effective and are just putting a band-aid on the problem”, says Menendez. “We also know that children can respond well with antimicrobials and treatment aimed at reducing inflammation, and the earlier the treatment, the better. This is why we are passionate about our work which is aimed at trying to understand the root cause of these disorders and make it not only manageable but also reduce the associated pathology causing the symptoms.”
The current controversy over whether or not PANDAS is an autoimmune disorder linked to strep infections only serves to worsen the quality of care for children and families impacted by the disease. Menendez hopes clinicians and researchers will use the study’s findings to identify concrete, meaningful steps that can be taken toward treatment for children who present with PANDAS symptoms.
“Trying to get everyone on board to agree that the disease exists and that there could be an underlying autoimmune component [is] still a major problem,” she says. “There are still a lot of clinicians or physicians who have never heard about PANDAS, and if they do know about it, they don’t really know how to treat it, as it is truly a multidisciplinary disease, and can affect children differently.” A diagnostic test confirming the presence of D1 autoantibodies “gives us a tangible tool to identify and try to treat.”
Dr. Cunningham and Dr. Menendez’s full research study is under review in the scientific literature, and they hope it will be published by 2023.
If your family is dealing with PANDAS, know that you are not alone. PANDAS Network is here to help you find a doctor for PANDAS, locate PANDAS support groups in your area, and stay up-to-date on the latest clinical research.