Autism Spectrum Disorders and Lyme Disease: Exploring Shared Neuro-Inflammatory and Immune Pathways
Main Article Content
Abstract
Building on Part 1’s exploration of Chronic Inflammatory Response Syndrome (CIRS) in pediatric neuroimmune disorders, this article (part 2 in a series of four) examines Lyme disease and its associated co-infections as infectious drivers of neuroinflammation overlapping with autism spectrum disorder (ASD). In a cohort of 1,722 children with treatment-resistant ASD and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS/PANDAS), all met clinical CIRS criteria through bedside diagnosis, with notable improvements in cognition, motor skills, and gastrointestinal function following CIRS-directed therapies. Within this cohort, 47 children living in tick-endemic regions presented with Lyme-specific features—including facial palsy, joint pain and swelling, difficulty chewing, cyclical fevers, and low muscle tone. They were diagnosed clinically according to CDC guidelines, supported by parental reports of bull’s-eye rashes or tick attachments. Borrelia burgdorferi and co-transmitted pathogens such as Babesia microti and Bartonella henselae can sustain immune dysregulation through mechanisms including blood–brain barrier disruption, Th17/Treg imbalance, complement activation, mitochondrial dysfunction, and microglial priming, contributing to cognitive, behavioral, and developmental impairments. Clinically, these children exhibited fatigue, attention deficits, anxiety, obsessive-compulsive behaviors, and developmental regression—features that complicate differential diagnosis with ASD. Conventional serologic testing shows limited sensitivity in early or chronic cases, underscoring the importance of clinical evaluation. While early antibiotic therapy remains the standard of care, adjunctive strategies adapted from CIRS protocols—including immune modulation and environmental remediation—appear to improve outcomes. As the second article in a four-part series on pediatric neuroimmune conditions, this work highlights infectious contributions to neurodevelopmental disruption and sets the stage for Part 3’s focus on herbal therapeutics for CIRS, the primary driver of illness in this cohort.
Keywords:
Chronic Inflammatory Response Syndrome, Autism Spectrum Disorder, Pediatric Neuroimmune Disorders, Lyme Disease, Tick-Borne Infections, Neuroinflammation, Immune Dysregulation, Pediatric Acute-Onset Neuropsychiatric Syndrome
Article Details
How to Cite
DASHORE, Jodie A. et al.
Autism Spectrum Disorders and Lyme Disease: Exploring Shared Neuro-Inflammatory and Immune Pathways.
Medical Research Archives, [S.l.], v. 13, n. 11, nov. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7019>. Date accessed: 06 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i11.7019.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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https://doi.org/10.18103/mra.v13i11.6952
2. Krause PJ, Narasimhan S, Wormser GP, et al. Borrelia miyamotoi sensu lato seroreactivity and seroprevalence in the northeastern United States. Emerg Infect Dis. 2014 Jul;20(7):1183-90. PMID: 24960072
3. Marques A. Chronic Lyme disease: a review. Infect Dis Clin North Am. 2008;22(2):341-360.
4. Shoemaker RC, Maizel MS. Exposure to interior environments of water-damaged buildings causes a CFS-like illness in pediatric patients: a case/control study. Bull IACFS ME. 2009;17(2):69-81.
5. Kalkbrenner AE, Schmidt RJ, Penlesky AC. Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence. Curr Probl Pediatr Adolesc Health Care. 2014 Nov;44(10):277-318. PMID: 25199954
6. Goyal DK, Miyan JA. Neuro-immune abnormalities in autism and their relationship with the environment: a variable insult model for autism. Front Endocrinol (Lausanne). 2014 Mar 7;5:29. PMID: 24639668
7. Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev Neurobiol. 2012 Oct;72(10):1272-6. PMID: 22488761
8. Breitschwerdt EB, Maggi RG, Nicholson WL, Cherry NA, Woods CW. Bartonella sp. bacteremia in patients with neurological and neurocognitive dysfunction. J Clin Microbiol. 2008;46(9):2856-2861.
9. Barbour AG, Fish D. Biology of Borrelia burgdorferi. Clin Microbiol Rev. 1993;6(2):127-134. PMID: 3540570
10. Halperin JJ. Nervous system Lyme disease. Infect Dis Clin North Am. 2015 Jun;29(2):241-53. PMID: 25999221
11. Ramesh G, Didier PJ, England JD, Santana-Gould L, Doyle-Meyers LA, Martin DS, Jacobs MB, Philipp MT. Inflammation in the pathogenesis of Lyme neuroborreliosis. Am J Pathol. 2015 May;185(5):1344-60. PMID: 25892509
12. Livengood JA, Gilmore RD Jr. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes Infect. 2006 Nov-Dec;8(14-15):2832-40. Erratum in: Microbes Infect. 2015 Jun;17(6):e1. PMID: 17045505
13. Klemen Strle, Daša Stupica, Elise E. Drouin, Allen C. Steere, Franc Strle, Elevated Levels of IL-23 in a Subset of Patients With Post–Lyme Disease Symptoms Following Erythema Migrans, Clinical Infectious Diseases, Volume 58, Issue 3, 1 February 2014, Pages 372–380
14. Fallon BA, Keilp JG, Corbera KM, et al. Regional cerebral blood flow and cognitive deficits in chronic Lyme disease. J Neuropsychiatry Clin Neurosci. 2003;15(3):326-332. PMID: 12928508
15. Vannier EG, Krause PJ. Human babesiosis. N Engl J Med. 2012; 366(25):2397-2407. PMID: 22716978
16. Breitschwerdt EB, Maggi RG, Nicholson WL, Cherry NA, Woods CW. Bartonella sp. bacteremia in patients with neurological and neurocognitive dysfunction. J Clin Microbiol. 2008 Sep;46(9):2856-61. PMID: 18632903
17. Chomel BB, Kasten RW. Bartonellosis, an increasingly recognized zoonosis. J Appl Microbiol. 2010 Sep;109(3):743-50. PMID: 20148999
18. Dumic I, Jevtic D, Veselinovic M, et al. Human granulocytic anaplasmosis: a systematic review of published cases. Microorganisms. 2022;10(7):1433. PMID: 35889152
19. Paddock CD, Childs JE. Ehrlichia chaffeensis: a prototypical emerging pathogen. Clin Microbiol Rev. 2003;16(1):37-64. PMID: 12525424
20. Dantas-Torres F. Review: Rocky Mountain spotted fever. Lancet Infect Dis. 2007;7(4):201-207. PMID 17961858
21. Biggs HM, Behravesh CB. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis—United States. MMWR Recomm Rep. 2016;65(2):1-44.
22. Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev. 2017;30(2):747-809.
23. Atkinson TP, Balish MF, Waites KB. Epidemiology, clinical manifestations, pathogenesis, and laboratory detection of Mycoplasma pneumoniae infections. FEMS Microbiol Rev. 2008;32(6):956-73. PMID 18754792
24. Cutler SJ. Relapsing fever borreliae: a global review. Clin Lab Med. 2010;30(1):149-160.
25. Dworkin MS, Schwan TG, Anderson DE, Borchardt SM. Tick-borne relapsing fever. Infect Dis Clin North Am. 2008;22(3):449-68. PMID 18755384
26. Süss J. Tick-borne encephalitis 2010: epidemiology, risk areas, and virus strains in Europe and Asia—an overview. Ticks Tick Borne Dis. 2011 Mar;2(1):2-15. PMID 21771531
27. Bogović P, Lotrič-Furlan S, Avšič-Županc T, et al. Comparison of clinical, laboratory and immune characteristics of the monophasic and biphasic course of tick-borne encephalitis. Microorganisms. 2021 Apr 10;9(4):796. PMID 33920166
28. Robinson-Agramonte MLA, Noris García E, Fraga Guerra J, Vega Hurtado Y, Antonucci N, Semprún-Hernández N, Schultz S, Siniscalco D. Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It? Int J Mol Sci. 2022 Mar 11;23(6):3033. PMID: 35328471
29. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman RB. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov 1;43(9):1089-134. Clin Infect Dis. 2007 Oct 1;45(7):941. PMID: 17029130
30. Ismail N, Bloch KC, McBride JW. Human ehrlichiosis and anaplasmosis. Clin Lab Med. 2010 Mar;30(1):261-92. PMID: 20513551
31. Argaw AT, Asp L, Zhang J, et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Invest. 2012 Jul;122(7):2454-68. PMID:
22653056
32. Perides G, Charness ME, Tanner LM, Péter O, Satz N, Steere AC, Klempner MS. Matrix metalloproteinases in the cerebrospinal fluid of patients with Lyme neuroborreliosis. J Infect Dis. 1998 Feb;177(2):401-8. PMID: 9466528
33. Szczepanski A, Furie MB, Benach JL, Lane BP, Fleit HB. Interaction between Borrelia burgdorferi and endothelium in vitro. J Clin Invest. 1990 May;85(5):1637-47. PMID: 2332509
34. Talkington J, Nickell SP. Borrelia burgdorferi spirochetes induce mast cell activation and cytokine release. Infect Immun. 1999;67(3):1107-15. PMID: 10024550
35. Brissette CA, Bykowski T, Cooley AE, Bowman A, Stevenson B. Borrelia burgdorferi RevA antigen binds host fibronectin. Infect Immun. 2009 Jul;77(7):2802-12. PMID: 19398540
36. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4.Nature. 2016 Feb 11;530(7589):177-83. PMID: 26814963
37. Kebir H, Kreymborg K, Ifergan I, et al. Human Th17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007 Oct;13(10):1173-5. PMID: 17828272
38. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011 Jan;25(1):40-5. PMID: 20705131
39. Theoharides TC, Tsilioni I, Patel AB. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry. 2016 Jun;6(6):e844. PMID: 27351598
40. Halperin JJ. Nervous system Lyme disease. Infect Dis Clin North Am. 2015 Jun;29(2):241-53. PMID: 25999221
41. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. PMID: 15546155
42. Homer MJ, Aguilar-Delfin I, Telford SR 3rd, Krause PJ, Persing DH. Babesiosis. Clin Microbiol Rev. 2000 Jul;13(3):451-469. PMID: 10885987
43. Gowda DC. Structure and activity of glycosylphosphatidylinositol anchors of Plasmodium falciparum. Microbes Infect. 2002 Jul;4(9):983-90. PMID: 12106792
44. Shoemaker RC, Maizel MS. Exposure to interior environments of water-damaged buildings causes a CFS-like illness in pediatric patients: a case/control study. Bull IACFS ME. 2009;17(2):69-81
45. Choi GB, Yim YS, Wong H, et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016 Feb 26;351(6276):933-9. PMID: 26822608
46. Bransfield RC. Neuropsychiatric Lyme borreliosis: an overview with a focus on a specialty psychiatrist's clinical practice. Healthcare (Basel). 2018 Aug 25;6(3):104. PMID: 30149626
47. Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, Guastella AJ. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry. 2015 Apr;20(4):440-6. PMID: 24934179
48. Steere AC, Strle F, Wormser GP, et al. Lyme borreliosis. Nat Rev Dis Primers. 2016 Dec 15;2:16090. PMID: 27976670
49. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of Lyme disease. Expert Rev Anti Infect Ther. 2014 Sep;12(9):1103-35. PMID: 25077519
50. Marques A. Chronic Lyme disease: a review. Infect Dis Clin North Am. 2008 Jun;22(2):341-60. PMID: 18452806
51. Buhner S. Herbal Antibiotics, 2nd Edition: Natural Alternatives for Treating Drug-Resistant Bacteria. Storey Publishing; 2015.
52. Feng J, Leone J, Schweig S, Zhang Y. Evaluation of Natural and Botanical Medicines for Activity Against Growing and Non-growing Forms of B. burgdorferi. Front Med (Lausanne). 2020 Feb 21;7:6. PMID: 32154254
53. Pangrazzi, L.; Balasco, L.; Bozzi, Y. Oxidative Stress and Immune System Dysfunction in Autism Spectrum Disorders.Int. J. Mol. Sci. 2020, 21, 3293. PMID: 32384730
54. Tylee DS, Hess JL, Quinn TP, et al. Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis. Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):181-201. PMID: 27862943
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