PANDAS Network is dedicated to improving the diagnosis and treatment of children with PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) and PANS (Pediatric Acute- onset Neuropsychiatric Syndrome) which can be described as forms of post-infectious basal ganglia encephalitis (BGE). This document provides a roadmap that will: a) identify research priorities; b) define better disease stages; and c) outline the areas of diagnosis and treatment with needs yet to be met. We believe this roadmap will help to build improved collaborative efforts at a global level as we work to accelerate the basic and clinical science that leads to improvement of diagnosis and development of treatments for those living with PANDAS/PANS.
PANDAS Network’s Scientific Advisory Board (SAB) will work closely with the Board of Directors to incorporate how individual research studies may fit within the priorities of our non-profit organization. We encourage you to reach out to our SAB chair, Dr. Dritan Agalliu, with any questions about the roadmap.
OVERVIEW
The roadmap is divided into three main goals – each with targets that we hope to achieve through research, education and advocacy. The individual targets include a list of: a) what we know; b) what we don’t know; c) what we need; and d) what we will do to meet these targets.
Goal 1: Stop Pathway – Detection
Target 1: Early Detection: Reduce or eliminate the impact before accumulated neurological changes/alterations occur.
Target 2: Precision Medicine: Develop personalized approaches to diagnose and treat the disease.
Goal 2: Restore Pathway – Treatment
Target 1: Develop/Improve Treatments/Outcomes (Acute Phase): Develop or improve treatment management and support to stop symptom progression during the acute phase of the disease.
Target 2: Implement Treatments (Chronic Phase): Advance implementation of rehabilitation and treatment
management strategies for the chronic phase of the disease.
Goal 3: End Pathway – Prevention
Target 1: Primary Prevention: Educate clinicians about the nature of the disease.
Target 2: Secondary Prevention: Reduce or eliminate impact by identifying and educating high risk populations.
GOAL 1: STOP PATHWAY – DETECTION
Understanding disease heterogeneity across diverse populations over time is important to create diagnostic tests to aid clinicians in early diagnosis of the disease.
TARGET #1: EARLY DETECTION
TARGET 1: Early Detection Reduce or eliminate the impact before accumulated neurological changes occur
WHAT WE KNOW
• Disease presentation can increase over time when interventions are not given.
• Early intervention leads to improved outcomes.
• MRI studies show basal ganglia inflammation during acute onset of PANDAS and PANS.
• Group A Strep infections generate immune responses that target the brain and the blood brain barrier.
• Repeated infections with Group A Strep lead to immune responses targeting the brain.
WHAT WE DON’T KNOW
• Which biomarkers (blood/CFS/Imaging) identify individuals in the acute or chronic phase of disease?
• What are the pathophysiological events leading to the initiation of PANDAS/PANS?
• Which strains of Group A Strep cause or promote PANDAS?
• What genetic risk factors predispose for disease development?
• How do antibodies that target the basal ganglia affect brain function?
WHAT WE NEED
• Diagnostic tests (blood, CSF, or MRI) for early detection and diagnosis of the disease.
• An understanding of the biological processes driving early vs. late stages of PANDAS/PANS.
• Interventions that target early disease pathways and determine if PANDAS/PANS will respond to
treatment.
• To understand how environment, immunity and genetic risk factors impact disease.
• Improve and expand on animal models to explain diverse outcomes and healing processes.
• Develop reliable repositories of patient registries, data, and biospecimens from disease.
WHAT WE WILL DO
• Advance basic and clinical research of immune, genetic, and neurological mechanisms that affect
disease initiation, progression and outcomes.
• Conduct clinical studies with biospecimens to understand disease heterogeneity and correlate it with
basic science studies.
• Create and share registries, data, and biospecimen repositories from PANDAS/PANS patients.
• Track the incidence of Group A Strep infections in PANDAS/PANS families.
• Define PANS in a way that allows clinicians to give an accurate diagnosis.
TARGET #2: PRECISION MEDICINE
TARGET 2: Precision Medicine Develop personalized approaches to diagnose and treat the disease
WHAT WE KNOW
• PANDAS/PANS/AE is likely heterogeneous (pathologically and clinically).
• Autoantibodies against a group of neuronal antigens have been identified in animal models and human
disease in blood, cerebrospinal fluid, and on basal ganglia neurons, and interneurons.
• Specific inflammatory cytokine/chemokines have been identified in sera of PANDAS/PANS children that
directly impair BBB integrity.
• Dopamine receptor autoantibodies are present in Sydenham chorea and PANDAS/PANS children.
• Lifestyle and psychiatric support influence disease course.
WHAT WE DON’T KNOW
• Are there subgroups of cases – stable, relapsing-remitting, chronic?
• Which biomarkers, immune or genetic factors identify who will respond to a particular therapy and
when a therapy is no longer effective?
• Which therapies pose an increased risk to an individual?
• The relationship between
WHAT WE NEED
• Identify biomarkers of stable, relapsing-remitting, and chronic phases of disease
• Improved utilization of resources (sample biorepositories; genetic testing) to enable improved
understanding of diseases outcomes and pathogenesis as well as therapeutic efficacies.
WHAT WE WILL DO
• Promote research to investigate clinical validation of biomarkers (autoantibodies, cytokines,
chemokines, genetics) together with response to treatment outcomes (IVIG, naproxen, antibiotics, etc)
• Encourage investigation in therapeutic strategies for relapsing-remitting & chronic cases.
GOAL 2: RESTORE PATHWAY – TREATMENT
Translation of knowledge from basic mechanisms to treatment options is needed to optimize treatment, manage symptoms, and restore quality of life to patients and families.
TARGET #1
TARGET 1: Develop/Improve Treatments/Out- comes (Acute Phase) Develop or improve treatment management and support to stop symptom progression during the acute phase of the disease
WHAT WE KNOW
• Immunomodulation treatments improve disease outcomes in some people.
• The identification of autoantibodies, T cells, & imaging data suggest that inflammatory processes
present in the brain require treatment interventions to stop processes cause CNS alterations.
• Dopamine receptors are targeted by autoantibodies in some forms of the disease state.
WHAT WE DON’T KNOW
• Key pathways/targets to stop disease advancement from relapsing-remitting to chronic.
• How to limit blood-brain barrier alterations and maintain its stability in the disease?
• How age, sex, ethnicity, race, and genetics impact repair/improve outcomes and identify
pathogenic mechanisms?
WHAT WE NEED
• Treatment plan(s) for stable, relapsing-remitting, and chronic cases.
• Treatments that are not off-label and are supported by research and clinical outcomes.
• Clarify the factors involved in disease severity.
• A better understanding of longitudinal outcomes based on sex, ethnicity, race, and genetics.
• New targets for therapeutics that promote prevention and cure of the disease.
• Accurate assessment of immune and neurological dysregulation in disease.
• Better imaging, biomarkers, and psychological profiles of patients and their outcomes.
WHAT WE WILL DO
• Encourage further study of psychological mechanisms involved in immunomodulation therapies.
• Develop outcome measures to detect successful psychological & immunomodulation therapies.
• Foster immunological, neurological, psychological testing methodologies that improve outcomes.
• Create a professional community to speed the development and use of treatment and testing
methodologies.
TARGET #2
TARGET 2: Implement Treatments (Chronic Phase) Advance implementation of rehabilitation and treatment management strategies for the chronic phase of the disease
WHAT WE KNOW
• Comorbidities affect symptoms, behaviors, and potentially progression.
• Patients with PANDAS/PANS have complex symptoms that impede their quality of life.
• Some immune modifying therapies do improve symptoms.
• Disease progression impacts care of self, family structure, employment status.
• Forms of OCD and other psychological issues are not well understood by the medical community.
• Poor access to psychological care and support prohibits the healing of the family and patient.
WHAT WE DON’T KNOW
• How to enhance proper treatment dosing of interventions to facilitate optimal recovery.
• How to achieve the best outcomes by tracking symptoms, monitoring progress, and tailoring
appropriate interventions (into adulthood).
• Mechanisms to improve psychological, neurological and immune function.
WHAT WE NEED
• Better treatments, outcome measures, quantitative and qualitative.
• Sensitive, valid, and clinically meaningful measures of impairment.
• Large clinical and treatment and outcome trials that are sufficiently powered.
• Expanded access to treatment therapies for all by expanding fellowship opportunities and
general education of clinicians and other health care professionals.
• Individually tailored treatment plans and interventions.
WHAT WE WILL DO
• Advance guidance and guidelines in trial design for clinical treatment trials – including
immunological, neurological, psychological factors.
• Promote expanded access to psychological and immunological therapies and testing.
• Support the research and development of psychological interventions that target recovery,
lifestyle and wellness strategies, and symptom management during the course of healing.
• Promote the use of outcomes with emerging technologies such as AI applications.
GOAL 3: END PATHWAY – PREVENTION
Ending PANDAS/PANS/AE is defined as no new cases. Preventing new cases will require population-based public health initiatives and individual -based interventions.
TARGET #1
TARGET 1: Primary Prevention Educate clinicians about the nature of the disease
WHAT WE KNOW
• Some of the infectious risk factors; strep infections, Lyme disease, influenzae, mycoplasma, other
infections for PANDAS/PANS.
• Risk incidence due to age factors (onset 4 to 12 years).
• Risk incidence increase with family history of Rheumatic Fever, familial history of chronic strep
and severe autoimmune disease in first and second generations of family history.
• Sydenham chorea has similar onset with clear treatment outcomes in plasmapheresis.
WHAT WE DON’T KNOW
• The critical time frame for best treatment outcomes.
• The complete genetic contribution to etiology and how genes interact with infectious risk factors
to cause PANDAS/PANS.
• Which public health interventions (e.g. schools) will reduce the risk for PANDAS/PANS?
• What are developing countries with higher incidence of Sydenham chorea doing to improve
treatment outcomes?
WHAT WE NEED
• A better knowledge of all relevant strep-related risk factors for PANDAS/PANS (e.g. correlation of
strep titers- positive only in 30-35% with disease or false negative tests for the group A strep
bacteria that is positive later).
• A full understanding of the potential genetic contribution to sudden onset psychiatric symptoms
in a child and the need for medical training to follow up with the family.
• Interventions that prevent the onset of PANDAS/PANS and its progression.
WHAT WE WILL DO
• Promote a better understanding of the genetic and infectious risk factors for PANDAS/PANS.
• Support the research and development of interventions that target PANDAS/PANS prevention in
the general population.
• Advance research of best medical practices that reduce the risk of PANDAS/PANS and promote
policies that support implementation of these behaviors in doctors
TARGET #2
TARGET 2: Secondary Prevention Reduce or eliminate impact by identifying and educating high risk populations
WHAT WE KNOW
• Emerging knowledge of imaging/biomarkers that identify PANDAS/PANS.
• Early evidence of detailed family medical history and neurological and immunological testing can
contribute to identification of high risk individuals for acute PANDAS/PANS.
• Ongoing immune modulation studies (including IVIG study cohorts US & Italy) show slowing and
prevention of acute symptoms in PANDAS/PANS.
• Genetic, immune, and autoantibody pathways are involved in the initiation of PANDAS/PANS.
WHAT WE DON’T KNOW
• Precisely which biomarkers identify risk for developing PANDAS/PANS, when they become
detectable, and what thresholds identify an individual as being at risk.
• Which interventions are going to stop further development of PANDAS/PANS?
• What aspects of a medical history and/or neurological test will contribute significantly to identifying
people at high risk for PANDAS/PANS?
• A full understanding of the early pathways/events that lead to the initiation of PANDAS/PANS.
• Whether interventions targeted at the very earliest stages of PANDAS/PANS will slow down or stop
disease progression.
WHAT WE NEED
• Screening tools to identify stable, relapsing-remitting, or chronic PANDAS/PANS coupled with
confidence that these tools will modify disease course.
• Discovery of biomarkers that detect the course of the disease.
• A better understanding of the differences between inflammatory pathways in typical Tourette’s,
OCD and subclinical PANDAS/PANS.
WHAT WE WILL DO
• Promote the development of biomarkers and screening tools that identify people at high risk for
PANDAS/PANS and subsequent implementation into clinical practice.
• Advocate & inform the research community on best practices in biomarker development.
• Accelerate discoveries that increase our knowledge of stable, relapse-remit, chronic pathologies.
• Support the development of therapeutic approaches targeting early pathological events in disease.
• Hold an annual meeting to expand current knowledge of PANDAS/PANS.
• Provide educational materials for clinicians, schools, and the general public.