INFORMATION AND RESEARCH

 Wells, L.; O’Hara, N.; Frye, R.E.; Hullavard, N.; Smith, E. Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population. J. Pers. Med. 2024, 14, 166. https://doi.org/10.3390/jpm14020166

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• Folate Receptor Alpha Antibodies (FRAA) may contribute to the symptomatology of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)
• PANS/PANDAS are clinical diagnoses based on thorough family, medical, psychiatric history and physical exams, infectious and autoimmune evaluations.  No lab test alone confirms or denies this diagnosis.
• Treatment is based on a 3-pronged approach of treating underlying infectious triggers with appropriate antimicrobials, providing immunomodulatory interventions, and symptom relief through therapy (CBT/DBT) and necessary psychoactive and nutraceutical support.
• Not all children improve with this 3-pronged approach and so we dive deeper looking for other etiologic issues and comorbid conditions.  One of these etiologies we found to be Cerebral Folate Deficiency (CFD or insufficient folate reaching the brain), with the overlapping symptoms of OCD, repetitive behaviors, tics and more.
• FRAAs (obtained through a specialty blood test) have been found in previous studies to be an accurate proxy for folate abnormalities in the brain and together with the safe and often effective treatment trial of leucovorin can be a much safer, easier, and less risky assessment of Cerebral Folate Deficiency than a lumbar puncture.
• Previous meta-analysis demonstrated that 71% of children with ASD have FRAAs.  Treatment of CFD in FRAA-positive children with ASD has shown improvements clinically in our practice and in previous research in communication and repetitive behaviors.
• The implementation of leucovorin or a reduced folate like 5-MTHF in FRAA-positive children with PANS/PANDAS/BGE helped reduce symptoms of OCD, anxiety clinically in our practice and as demonstrated in this study.
• More study is needed as this one is limited by sample size, its retrospective nature, the lack of a double blinded format…but it is a compelling start to a better understanding of other factors that may be involved in our children with Basal Ganglia and Autoimmune Encephalitis.
• FRAT (Folate Receptor Antibody Testing by Religen (more info at fratnow.com) can be an important adjunctive test for our kids with BGE/AE/PANS/PANDAS/ASD.
  
  
  PANS/PANDAS/BGE and FRAAs: So Many Questions and Starting to Uncover Some Answers
  
  We have posted over the past two weeks (lindseywellsnd.com, aspire.care, drohara.com) about our recently published paper on the link (in 63.8% of children) between possible Cerebral Folate Deficiency (CFD) and PANS/PANDAS.  Here are some answers to questions you have asked:
• How do I get my child tested for CFD? Ask your doctor to order a specialty test from Religen called FRAT (Folate Receptor Antibody Test).  Find more info at fratnow.com.
• Does a positive FRAT prove my child has CFD?  If your child has a positive binding or blocking antibody and improvement with folinic acid (prescription leucovorin) or 5-MTHF this indicates that your child has folate abnormalities in the brain and this treatment can help reduce anxiety, tics, OCD, brain fog and more.
• Does having a genetic MTHFR defect mean my child has CFD?  No, though a child with a positive FRAT may also possess the MTHFR defect, these are different findings (and a child with no MTHFR genetic defect can still have cerebral folate deficiency).
• Can just adding a MVI with folinic acid treat this?  No, with FRAAs and CFD, dosages of folinic acid or 5-MTHF need to be high, often 2 mg/kg, slowly increasing dosage and basing treatment on each child’s response.
• What else impacts Folate Receptor Alpha Antibodies (FRAAs)? Dairy consumption so when treating, clinically, we recommend that the child be 100% dairy free!
• Is any supplement with folinic acid or 5-MTHF worthwhile?  I find that prescriptive leucovorin is better than most nutraceutical brands of folinic acid and the brand of 5-MTHF is very important to its bioavailability, so check with your practitioner or join our community!
• How does this relate to B12? B12 and folate are involved in some of the same metabolic pathways and stdies have shown that children with ASD may have intracellular B12 deficiencies.  Some of the OCD symptoms seen in PANS/PANDAS may be related to B12 deficiency or malabsorption.  Clinically, I have found that adding SQ injections of meB12 have helped many children symptomatically.
• What symptoms do Leucovorin and 5-MTHF help or is it treating germs?  These interventions help decrease the symptoms of tics, anxiety, OCD and brain fog in our practices, not the underlying microbial triggers.
• Are there more studies coming?  This one was years in the making but other studies are in the pipeline for us and for other clinicians.  It takes a village of clinicians and families to help our kids!
• How do I learn more? Join my membership program!

Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference, Journal of Child and Adolescent Psychopharmacology, Feb 1, 2015, Kiki Chang, Jennifer Frankovich, Michael Cooperstock, et al

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Journal of Child and Adolescent Psychopharmacology, Volume 27, Issue 7, Mary Ann Liebert, Inc., September 2017, Swedo, MD, Frankovich, MD, MS, Murphy, MD, MS

List of Articles To Refer

Introduction - Overview of Treatment of Pediatric Acute-Onset Neuropsychiatric Syndrome Swedo, MD, Frankovich, MD, MS, Murphy, MD, MS
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Clinical Management of PANS

Part I - Psychiatric and Behavioral Interventions, Thienemann, MD, et al. Presents consensus guidelines for treating the psychiatric and behavioral symptoms of children with PANS/PANDAS. Symptom improvement is aimed at decreasing suffering, improving functioning, and making it easier for the children to adhere to therapeutic interventions.
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Part II - Use of Immunomodulatory Therapies, Frankovich, MD, et al. Provide recommendations to help guide the use of therapies targeting the neuroinflammation and post-infectious autoimmunity that are common in PANS-PANDAS.
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Part III - Treatment and Prevention of Infections, Cooperstock, MD, MPH, et al. Present a consensus guideline for managing the infection components of these neuropsychiatric conditions.
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Platt MP, Bolding KA, Wayne CR, Chaudhry S, Cutforth T, Franks KM, Agalliu D. Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis. Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6708-6716. doi: 10.1073/pnas.1911097117. Epub 2020 Mar 11. PMID: 32161123; PMCID: PMC7104239.

This article demonstrates that Th17 lymphocytes are critical for entry of autoantibodies into the CNS, persistent microglia activation, and neurophysiological deficits in odor processing, in a mouse model of postinfectious autoimmune encephalitis triggered by multiple infections with group A Streptococcus. Our findings emphasize the critical role that Th17 lymphocytes play in disease pathogenesis to impair CNS function in AE syndromes.

Dritan Agalliu, PhD is an Assistant Professor in the Departments of Neurology and Pathology and Cell Biology at Columbia University Irving Medical Center. Dr. Agalliu is a neuroscientist with 22 years of research experience in developmental, cellular and molecular neuroscience and specializing in the interaction of brain and blood vessels in the healthy and diseased Central Nervous System (CNS). Read more about Dr. Agalliu and other Professional Advisory Board Members.

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Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity Jian Xu, Rong-Jian Liu, Shaylyn Fahey, Luciana Frick, James Leckman, Flora Vaccarino, Ronald S. Duman, Kyle Williams, Susan Swedo, and Christopher Pittenger. Am Jrnl of Psychiatry 16 Jun 2020

• https://doi.org/10.1176/appi.ajp.2020.19070698

Also, see

• ASPIRE’s interview with Christopher Pittenger, MD, PhD, FAPA, FANA 

• Dr. Bob Naviaux’s suramin study at UCSD, published in May 2017: R. Naviaux, et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial Annals of Clinical and Translational Neurology 2017
• UCSD whiteboard animation on suramin study/cell danger response

1. Lyme Borreliosis and Associations With Mental Disorders and Suicidal Behavior: A Nationwide Danish Cohort Study. Brian A. Fallon, M.D., M.P.H., Trine Madsen, Ph.D., Annette Erlangsen, Ph.D., Michael E. Benros, M.D., Ph.D. Published Online:28 Jul 2021 https://doi.org/10.1176/appi.ajp.2021.20091347

“Having more than one episode of Lyme borreliosis was associated with increased incidence rate ratios for mental disorders, affective disorders, and suicide attempts, but not for death by suicide. Individuals diagnosed with Lyme borreliosis in the hospital setting had an increased risk of mental disorders, affective disorders, suicide attempts, and suicide. Although the absolute population risk is low, clinicians should be aware of potential psychiatric sequelae of this global disease.”

2. Breitschwerdt, E.B.; Bradley, J.M.; Maggi, R.G.; Lashnits, E.; Reicherter, P. Bartonella Associated Cutaneous Lesions (BACL) in People with Neuropsychiatric Symptoms. Pathogens 2020, 9, 1023. DOI: 10.3390/pathogens9121023.

 
Bartonella bacteria are increasingly recognized as an emerging infectious disease threat. A new study by North Carolina State University researchers has found additional instances of Bartonella infection in humans who exhibited neuropsychiatric symptoms, a subset of whom also had skin lesions. This research adds to the body of evidence that not only can Bartonella infection mimic a spectrum of chronic illnesses – including mental illness – but also that dermatological symptoms may accompany infection.

3. Brian A.Fallon, BarbaraStrobino, SeanReim, JulieStoner, Madeleine W.Cunningham Brain, Behavior, & Immunity – Health, Volume 2, February 2020, 100015. https://doi.org/10.1016/j.bbih.2019.100015

This study examines molecular mimicry targeting neural tissue after Borrelia burgdorferi (Bb) infection. Patients with Lyme disease have a greater frequency of specific anti-neuronal autoantibodies and functional neuronal activation compared to community controls without a history of Lyme disease.

• “Highlights The EM + prior LD group had significantly elevated anti-neuronal antibodies.
• The EM + prior LD group had significantly elevated CaM Kinase activation.
• Anti-Lysoganglioside Antibodies are significantly elevated in the PTLS group.
• Prior infection may lead to immune priming and increased autoantibodies.” 

4. Edward B Breitschwerdt , Rosalie Greenberg, Ricardo G Maggi, B Robert Mozayeni, Allen Lewis, Julie M Bradley
Journal of Central Nervous System-2019

This case report suggests that B henselae bloodstream infection may contribute to progressive, recalcitrant neuropsychiatric symptoms consistent with PANS in a subset of patients.

5. Rhee H, Cameron D. Lyme disease and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an overview. Int J Gen Med. 2012;5:163-174
https://doi.org/10.2147/IJGM.S24212

B. burgdorferi and GAβHS are very different microorganisms that evade the immune system and invade a wide variety of tissues, including the central nervous system (CNS). Lyme and PANS can have periods of active disease and periods of remission. Both infections cause physical, neurological, and cognitive symptoms.

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Super Sam! And the battle against PANS/PANDAS by Lindsey Wells, ND

“A terrific book for families who know someone with PANS/PADNAS, who are dealing with it themselves, or who just want to read a good story about Super Sam, his family’s journey to Dogotr Ed and the effects of PANS/PANDAS” – Nancy O’Hara, MD, MPH, FAAP

You Finished Treatment, Now What?  A Field Guide For Cancer Survivors by Amy Rothenberg, ND

You Finished Treatment, Now What? is a road map for lifestyle and natural medicine approaches to address health challenges that persist after cancer care, and to reduce the risk of recurrence. Written for cancer survivors/thrivers, those who care for them, as well as health-care providers, You Finished Treatment highlights the evidence for an integrative approach to healing. Dr. Amy Rothenberg, a licensed naturopathic doctor and cancer survivor/thriver herself, makes sense of an overwhelming topic, in a user- friendly accessible way, providing actionable information and inspiration. 

The First Rule of Climate Club By Carrie Firestone

In this companion to Dress Coded, an eighth-grader starts a podcast on climate activism and rallies her friends to create lasting change in their local community and beyond. The First Rule of Climate Club, a mid-grade novel, focuses on an eighth grader’s efforts to help diagnose her friend’s “mystery illness,” which eventually is identified as PANS from Lyme disease.

"Break The Mold" By Dr. Jill Crista  

More than 1 in 4 buildings have had enough water damage to grow toxic mold. Mold could be affecting your health. This book helps you to spot mold symptoms to help you break the mold and get back to health.