The Intersection of PANDAS/PANS with Lyme Disease and Bartonellosis

Instructor

Charlotte Mao MD, MPH
Invisible International

Description

This course explores the multiple hits model of illness, the overlapping symptomatology of Borrelia and Bartonella infections, and the limitations of diagnostic testing for these conditions.  It also hypothesizes how PANDAS/PANS symptoms might result from a wide variety of triggers, both infectious and non-infectious.

Learning objectives

1. Review historical scientific background that laid foundation for concept of PANDAS/PANS, including commonalities with Sydenham’s chorea
2. Develop ability to recognize and diagnose neuropsychiatric manifestations of Lyme borreliosis and bartonellosis and understand significant overlap with PANDAS/PANS symptoms
3. Review some key features of Bartonella infection, including concepts of latent, asymptomatic infection and “stealth” pathogenesis
4. Describe proposed mechanisms of PANDAS/PANS pathogenesis, including my personal hypothesis of how Bartonella might play a central role in more cases than generally appreciated
5. Understand limitations of serologic testing and interpretation criteria for diagnosis of Borrelia and Bartonella infection and importance of clinical diagnosis of Lyme borreliosis and bartonellosis

CME Credit Pending. Application for CME credit has been filed with the American Academy of Family Physicians. Determination of credit is pending.

References

Alpert B, Esin J, Sivak SL, Wormser GP. Incidence and prevalence of Lyme disease in suburban Westchester community  NY State J Med 1992; 92:5-8.

Aubry A, Corvilain E, Ghelfenstein-Ferreira T, Camilana F, Meignin V, Bercot B, Le Goff, J, Salmona M. Unmasking Bartonella henselae infection in the shadows of long COVID thanks to clinical metagenomics. Eur J Clin Microbiol Infect Dis 2024; 43:1025-1029. doi: 10.1007/s10096-024-04801-2. 

Baker J, Ruiz-Rodriguez R, Whitfield M, Heon V, Berger TG. Bacillary angiomatosis: a treatable cause of acute psychiatric symptoms in human immunodeficiency virus infection.  J Clin Psychiatry 1995;56:161-6.

Bartley CM, Johns C, Ngo TT Dandekar R, Loudermilk RL, Alvarenga BC, Hawes IA, Zamecnik CR, Zorn KC, Alexander JR et al.  Anti-SARS-CoV-2 and autoantibody profile in the cerebrospinal fluid of 3 teenaged patients with COVID-19 and subacute neuropsychiatric symptoms.  JAMA Neurol 2021;78:L1503-9. doi: 10.1001/jamaneurol.2021.3821.

Ben-Takaya H, Gorvel JP, Dehio C.  Bartonella and Brucella—Weapons and strategies for stealth attack Cold Spring Harb Perspect Med  2013;3(8):a010231. doi: 10.1101/cshperspect.a010231.

Berger TG, Tappero JW, Kaymen A, LeBoit PE.  Bacillary (epithelioid) angiomatosis and concurrent Kaposi’s sarcoma in acquired immunodeficiency syndrome.  Arch Dermatol 1989;125:1543-7.

Berloffa S, Salvati A, Pantalone G, Falcon L, Rizzi MM, Naldini F, Masi G, Gagliano A.  Steroid treatment response to post-SARS-CoV-2 PANS symptoms: case series  Front Neurol 2023;14:1085948. doi: 10.3389/fneur.2023.1085948.

Bianchi G, Monteforte P, Brites C et al. Antibodies against B. burgdorferi in blood donors living in a Lyme borreliosis endemic region, IV International Conference on Lyme Borreliosis, Stockholm, Sweden, June 18-21, 1990. 

Bransfield RC, Mao C, Greenberg R. Microbes and mental illness: past, present, and future. Healthcare 2024;12:83. doi.org/10.3390/healthcare12010083.

Breitschwerdt EB, Bradley JM, Maggi RG, Lashnits E, Reicherten P.  Bartonella Associated Cutaneous Lesions (BACL) in people with neuropsychiatric symptoms.  Pathogens 2020;9:1023. doi: 10.3390/pathogens9121023.

Breitschwerdt EB, Greenberg R, Maggi RG, Mozayeni BR, Lewis A, Bradley JM. Bartonella henselae bloodstream infection in a boy with Pediatric Acute-onset Neuropsychiatric Syndrome. J Cent Nerv Syst Dis 2019;11:1179573519832014.

Breitschwerdt EB, Sontakke S, Hopkins S.  Neurological manifestations of bartonellosis in immunocompetent patients: A composite of reports from 2005-2012.  J Neuroparasitol 2012;3:1-15.

Breitschwerdt EB, Diagnosis of Bartonella species infections, Invisible International CME course 2024

Carithers HA, Margileth AM.  Cat scratch disease. Acute encephalopathy and other neurologic manifestations  Am J Dis Child 1991;145:98-101. doi: 10.1001/archpedi.1991.02160010104026.

Centers for Disease Control and Prevention (CDC). Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 1995; 44: 590–591.

Chang K, Frankovich  Cooperstock M, Cunningham MW, Latimer ME, Murphy TK, Pasternack M, Thienemann M, Williams K, Walter J, Swedo SE. Clinical evaluation of youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS consensus conference. J Child Adolesc Psychopharmacol 2015 ;25(1):3-13. doi: 10.1089/cap.2014.0084.

Christen HJ, Hanefeld F. Lyme borreliosis in childhood and pregnancy in Weber K, Burgdorfer W (eds.), Aspects of Lyme borreliosis, Berlin/Heidelberg: Springer-Verlag, 1993

Dale RC. Autoimmunity and the basal ganglia: new insights into old diseases  QJM 2003;96(3):183-91. doi: 10.1093/qjmed/hcg026.

Dale RD, Candler PM, Church AJ, Wait R, Pocock JM, Giovannoni G. Neuronal surface glycolytic enzymes are autoantigen targets in post-streptococcal autoimmune CNS disease. J Neuroimmunol 2006;17:187-97. doi: 10.1016/j.jneuroim.2005.10.014.

Dehio  Bartonella interactions with endothelial cells and erythrocytes Trends Microbiol 2001;9(6):279-85.  doi: 10.1016/s0966-842x(01)02047-9.

Dileepan T, Smith ED, Knowland D, Hsu M, Platt M, Bittner-Eddy P, Cohen B, Southern P, Latierm E, Harley E, Agalliu D, Cleary PP. Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells.  J Clin Invest 2016;126:303-17. doi: 10.1172/JCI80792 .

Dong Y, Zhou G, Cao W et al Global seroprevalence and sociodemographic characteristics of Borrelia burgdorferi sensu lato in human populations: a systematic review and meta-analysis.   BMJ Glob Health 2022;7(6):e007744. doi: 10.1136/bmjgh-2021-007744.

Dong Y, Alhaskawi A,Zou X, Zhou H, Abdullah Ezzi SH, Goutham Kota V, Hasan Abdulla MHA,  Olga A, Abdalbary SA, Lu H.  Post-COVID reactivation of latent Bartonella henselae infection: a  case report and literature review  BMC Infect Dis 2024;24:422. doi: 10.1186/s12879-024-09336-7.

Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis 1993;167: 392–400.

Efe A. SARS-CoV-2/COVID-19 associated pediatric acute-onset neuropsychiatric syndrome: a case report of female twin adolescents.  Psychiatry Res Case Rep 2022;1:100074. doi: 10.1016/j.psycr.2022.100074.

Fahrer H, van der Linden SM, Sauvain MJ, Gern L, Zhioua E, Aeschlimann A. The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk.  J Infect Dis 1991;163:305-10. doi: 10.1093/infdis/163.2.305.

Fox JW, Studley JK, Cohen DM.  Recurrent expressive aphasia as a presentation of cat-scratch encephalopathy. Pediatrics 2007;119:e760-3. doi: 10.1542/peds.2006-1885

Fried Schairer Madigan Bal.  Bartonella henselae is associated with heartburn, abdominal pain, skin rash, mesenteric adenitis, gastritis and duodenitis. J Pediat Gastroenterol Nutr 2002;35:459-462 (abstract 158).

Harms A, Dehio C. Intruders below the radar: molecular pathogenesis of Bartonella spp.  Clin Microbiol Rev 2012;25(1):42078. doi: 10.1128/CMR.05009-11.

Harvey RA, Misselbeck WJ, Uphold RE.  Cat-scratch disease: an unusual cause of combative behavior Am J Emerg Med 1991;9:52-3. doi 10.1016/0735-6757(91)90016-d.

Huycke MM, D’Alessio DD, Marx JJ. Prevalence of antibody to Borrelia burgdorferi by indirect fluorescent antibody assay, ELISA, and western immunoblot in healthy adults in Wisconsin and Arizona.  J Infect Dis 1992;165:1133-7. doi: 10.1093/infdis/165.6.1133.

Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 2000;165:6107-6115. doi: 10.4049/jimmunol.165.11.6107.

Johnston D, Kelly JR, Ledizet M, Lavoie N, Smith RP, Parsonnet J, Schwab J, Stratidis J, Espich S, Lee G et al. Frequency and geographic distribution of Borrelia miyamotoi, Borrelia burgdorferi, and Babesia microti infections in New England residents. Clin Infect Dis 2022; doi: 10.1093/cid/ciac107

Kebir H, Kreymborg K, Ifergan I et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 2007;13:1173-5. doi: 10.1038/nm1651.

Kiessling LS, Marcotte AC, Culpepper L. Antineuronal antibodies in movement disorders  Pediatrics 1993;92(1):39-43.

Kinderlehrer DA.  Anorexia nervosa caused by polymicrobial tick-borne infections: A case study.   Int Med Case Rep J 2021l 14:279-87. doi: 10.2147/IMCRJ.S311516.

Kolls JK, Khader SA. The role of Th17 cytokines in primary mucosal immunity. Cytokine Growth Factor Rev 2019;21:443-8. doi: 10.1016/j.cytogfr.2010.11.002

Kugeler KJ, Schwartz AM, Delorey MJ, Mead PS, Hinckley AF. Estimating the frequency of Lyme disease diagnoses, United States, 2010-2018. Emerg Infect Dis 2021;27:616-619. doi: 10.3201/eid2702.202731.

LeBoit PE.  The expanding spectrum of a new disease, bacillary angiomatosis.  Arch Dermatol 1990;126:808-11.

Lewis DW, Tucker SH.  Central nervous system involvement in cat scratch disease. Pediatrics 1986;77:714-21. 

Lyon  Neurologic manifestations of cat-scratch disease  Arch Neurol 1971

Macallini P, Bonin W, Trevisan G. Autoimmunity against a glycolytic enzyme as a possible cause for persistent symptoms in Lyme disease. Med Hypotheses 2018;110:1-8. doi: 10.1016/j.mehy.2017.10.024.

Maggi Ericson Mascarelli Bradley Breitschwerdt   Bartonella henselae bacteremia in mother and son potentially associated with tick exposure Parasites Vectors 2013;6:101. doi: 10.1186/1756-3305-6-101.

Maluki A, Breitschwerdt E, Bemis L, Greenberg R, Mozayeni BR, Dencklau J, Ericson M. Imaging analysis of Bartonella species in the skin using single-photon and multi-photon (second harmonic generation) laser scanning microscopy.  Clin Case Rep 2020;8:1564-1570. doi: 10.1002/ccr3.2939.

Mändle T, Einsele H, Schaller  Neumann D, Vogel W, Autenrieth  IB, Kempf VAJ  Infection of CD34+ progenitor cells with Bartonella henselae results in intraerythrocytic presence of B henselae Blood 2005;106(4):1215-22. doi: 10.1182/blood-2004-12-4670.

Melis K, Bochner A, Vandengerghe P, Janssens G.  Cat-scratch Disease With Reversible Encephalopathy.  Eur J Pediatr 1989;149:24-5.  doi: 10.1007/BF02024328.

Merrell DS, Falkow S. Frontal and stealth attack strategies in microbial pathogenesis. Nature 2004;430(6996):250-6. doi: 10.1038/nature02760.

Mhalu FS, Matre R. Serological evidence of Lyme borreliosis in Africa: results from studies in Dar es Salaam Tanzania  East Afr Med J 1996;73:583-5.

Molloy EN, Casjens SR, Cox CL, Maxon T, Ethridge NA, Margos G, Fingerle V, Mitchell DA. Identification of the minimal cytolytic unit for streptolysin S and an expansion of the toxin family.  BMC Microbiol 2015;15:141. doi: 10.1186/s12866-015-0464-y.

Murphy Pichichero. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infections (PANDAS). Arch Pediatr Adolesc Med 2002;156:356-61. doi: 10.1001/archpedi.156.4.356

Nadal D, Zbinden R.  Serology to Bartonella (Rochalimaea) henselae may replace traditional diagnostic criteria for cat-scratch disease.  Eur J Pediatr 1995;154:906-8. doi: 10.1007/BF01957503.

Osler W. On chorea and choreiform affections. P. Blakiston, Son & Company 1894.

Pachner AR, Duray P, Steere AC. Central nervous system manifestations of Lyme disease. Arch Neurol 1989;46:790-5. doi: 10.1001/archneur.1989.00520430086023.

Pallanti S, Di Ponzio M. PANDAS/PANS in the COVID-19 age: autoimmunity and Epstein-Barr virus reactivation as trigger agents?  Children (Basel) 2023;10:648. doi: 10.3390/children10040648.

Pavone P, C  Ceccarelli M, Marino S, Caruso D, Falsaperla R, Berretta M, Venanzi Rullo E, Nunnari G. SARS-CoV-2 related pediatric acute-onset neuropsychiatric syndrome.  Lancet Child Adolesc Health 2021;5:e19-e21. doi: 10.1016/S2352-4642(21)00135-8

Paxson EM, McKay RJ.  Neurologic symptoms associated with cat scratch disease.  Pediatrics 1957;20:13-22.

Pollen RH. Cat-scratch encephalitis. Neurology 1968;18:1031-3. doi: 10.1212/wnl.18.10.1031.

Regnery RL, Olson JG, Perkins BA, Bibb W. Serological response to “Rochalimaea henselae” antigen in suspected cat-scratch disease. Lancet 1992;339:1443-5. doi: 10.1016/0140-6736(92)92032-b.

Schaller JL, Burkland GA, Langhoff PJ. Do Bartonella infections cause agitation, panic disorder, and treatment-resistant depression?  MedGenMed 2007;9:54.

Shutikova AL, Leonova GN, Popov AF, Shchelkanov MY. Clinical and diagnostic manifestations of tickborne mixed infection in combination with COVID-19. Klin Lab Diagn 2021;66:689-694. doi: 10.51620/0869-2084-2021-66-11-689-694.

Stahl M, Fressle R, Wilske B. Lyme-Neuroborreliose unter dem Bild einer Anorexia nervosa. Münchener Medzinische Wochenschrift 1990;132:615-619.

Stevens H. Cat-scratch fever encephalitis. AMA Am J Dis Child 1952;84:218-22. doi: 10.1001/archpedi.1952.02050020082009.

Vermeulen MJ, Herremans M, Verbakel H, Bergmans AMC, Roord JJ, van Kijken PJ, Peeters MF. Serological testing for Bartonella henselae infections in The Netherlands: clinical evaluation of immunofluorescence assay and ELISA. Clin Microbiol Infect 2007;13:627-34. doi: 10.1111/j.1469-0691.2007.01700.x.

Weinstein L, Meade RH. The neurological manifestations of cat scratch disease. Am J Med Sci 1955;229:500-5. doi: 10.1097/00000441-195505000-00005.

Williams LR, Austin FE. Hemolytic activity of Borrelia burgdorferi. Infect Immun 1992;60:3224-30. doi: 10.1128/iai.60.8.3224-3230.1992