Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome

Abstract

Background

Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt debilitating psychiatric illness. We anecdotally observed hypoferritinemia and iron deficiency in a subset of patients with PANS, prompting this study.

Methods

In this IRB-approved prospective cohort study, we included patients seen at the Stanford PANS Clinic who met study criteria. The prevalence of hypoferritinemia (using cut-offs of 7 ng/ml in children ≤ 15 years and 18 ng/ml in adolescents > 15 years) and iron deficiency was estimated. Differences in patients with and without hypoferritinemia during PANS flare were explored.

Results

Seventy-nine subjects (mean age of PANS onset of 8.7 years) met study criteria. Hypoferritinemia was observed in 27% and three quarters occurred during a PANS flare. Compared to patients without hypoferritinemia during PANS flare, patients with hypoferritinemia had worse global impairment, more comorbid inflammatory diseases, and exhibited a chronic course of PANS illness. The estimated prevalence of iron deficiency was 3–8% in the PANS cohort, 1.4–2.0-fold higher than in the age- and sex-matched U.S. population. More stringent ferritin level cut-offs than the comparison CDC dataset were used.

Conclusion

Hypoferritinemia and iron deficiency appear to be more common in PANS patients. More research is needed to confirm and understand this association.

Impact

  • Our study suggests hypoferritinemia and iron deficiency are more common in patients with pediatric acute-onset neuropsychiatric syndrome (PANS) than in the sex- and age-matched US population.

  • Hypoferritinemia was commonly observed during a disease flare but not associated with dietary or demographic factors. In patients with PANS and iron deficiency, clinicians should consider possibility of inflammation as the cause especially if iron deficiency cannot be explained by diet and blood loss.

  • Future research should include larger cohorts to corroborate our study findings and consider examining the iron dynamics on MRI brain imaging in order to better understand the pathophysiology of PANS.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: A total of 294 patients was evaluated during the study period. After exclusion for several reasons, our final cohort included 79 patients for analysis.

References

  1. 1.

    Chang, K. et al. Clinical evaluation of youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J. Child Adolesc. Psychopharmacol. 25, 3–13 (2015).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Swedo, S. E., Leckman, J. F. & Rose, N. R. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr. Ther. 2, 1–8 (2012).

    Google Scholar 

  3. 3.

    Frankovich, J. et al. Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. J. Child Adolesc. Psychopharmacol. 25, 38–47 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Calaprice, D., Tona, J., Parker-Athill, E. C. & Murphy, T. K. A survey of pediatric acute-onset neuropsychiatric syndrome characteristics and course. J. Child Adolesc. Psychopharmacol. 27, 607–618 (2017).

    PubMed  Google Scholar 

  5. 5.

    Gromark, C. et al. Establishing a pediatric acute-onset neuropsychiatric syndrome clinic: baseline clinical features of the pediatric acute-onset neuropsychiatric syndrome cohort at Karolinska Institutet. J. Child Adolesc. Psychopharmacol. 29, 625–633 (2019).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hesselmark, E. & Bejerot, S. Clinical features of paediatric acute-onset neuropsychiatric syndrome: findings from a case–control study. Br. J. Psychiatry Open 5, e25 (2019).

    Google Scholar 

  7. 7.

    Gamucci, A. et al. PANDAS and PANS: clinical, neuropsychological, and biological characterization of a monocentric series of patients and proposal for a diagnostic protocol. J. Child Adolesc. Psychopharmacol. 29, 305–312 (2019).

    PubMed  Google Scholar 

  8. 8.

    Johnson, M. et al. Paediatric acute-onset neuropsychiatric syndrome in children and adolescents: an observational cohort study. Lancet Child Adolesc. Health 3, 175–180 (2019).

    PubMed  Google Scholar 

  9. 9.

    Zheng, J. et al. Association of pediatric acute-onset neuropsychiatric syndrome with microstructural differences in the deep grey matter. JAMA Netw. Open 3, e204063 (2020).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Giedd, J. N., Rapoport, J. L., Garvey, M. A., Perlmutter, S. & Swedo, S. E. MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. Am. J. Psychiatry 157, 281–283 (2000).

    CAS  PubMed  Google Scholar 

  11. 11.

    Kumar, A., Williams, M. T. & Chugani, H. T. Evaluation of basal ganglia and thalamic inflammation in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and tourette syndrome: a positron emission tomographic (PET) study using 11C-[R]-PK11195. J. Child Neurol. 30, 749–756 (2015).

    PubMed  Google Scholar 

  12. 12.

    Dale, R. C. & Brilot, F. Autoimmune basal ganglia disorders. J. Child Neurol. 27, 1470–1481 (2012).

    PubMed  Google Scholar 

  13. 13.

    Cutforth, T., DeMille, M. M., Agalliu, I. & Agalliu, D. CNS autoimmune disease after Streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors. Future Neurol. 11, 63–76 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Platt, M. P. et al. Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis. Proc. Natl Acad. Sci. USA 117, 6708–6716 (2020).

    CAS  PubMed  Google Scholar 

  15. 15.

    Brimberg, L. et al. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology 37, 2076–2087 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Frick, L. & Pittenger, C. Microglial dysregulation in OCD, Tourette Syndrome, and PANDAS. J. Immunol. Res. 2016, 8606057 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Lotan, D. et al. Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav. Immun. 38, 249–262 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Xu, J. et al. Antibodies from children with PANDAS bind specifically to striatal cholinergic interneurons and alter their activity. Am. J. Psychiatry. (2020). https://doi.org/10.1176/appi.ajp.2020.19070698. [ahead of print].

  19. 19.

    Yaddanapudi, K. et al. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Mol. Psychiatry 15, 712–726 (2010).

    CAS  PubMed  Google Scholar 

  20. 20.

    Dileepan, T. et al. Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells. J. Clin. Invest. 126, 303–317 (2016).

    PubMed  Google Scholar 

  21. 21.

    Suskind, D. L. Nutritional deficiencies during normal growth. Pediatr. Clin. North Am. 56, 1035–1053 (2009).

    PubMed  Google Scholar 

  22. 22.

    CDC. Iron deficiency—United States, 1999−2000. JAMA 288, 2114–2116 (2002).

    Google Scholar 

  23. 23.

    Camaschella, C. Iron-deficiency anemia. N. Engl. J. Med. 372, 1832–1843 (2015).

    PubMed  Google Scholar 

  24. 24.

    Lopez, A., Cacoub, P., Macdougall, L. C. & Peyrin-Biroulet, L. Iron deficiency anaemia. Lancet 387, 907–916 (2016).

    CAS  PubMed  Google Scholar 

  25. 25.

    Avrahami, M., Barzilay, R., HarGil, M., Weizman, A. & Watemberg, N. Serum ferritin levels are lower in children with tic disorders compared with children without tics: a cross-sectional study. J. Child Adolesc. Psychopharmacol. 27, 192–195 (2016).

    PubMed  Google Scholar 

  26. 26.

    Gorman, D. A., Zhu, H., Anderson, G. M., Davies, M. & Peterson, B. S. Ferritin levels and their association with regional brain volumes in Tourette’s syndrome. Am. J. Psychiatry 163, 1264–1272 (2006).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ghosh, D. & Burkman, E. Relationship of serum ferritin level and tic severity in children with Tourette syndrome. Childs Nerv. Syst. 33, 1373–1378 (2017).

    PubMed  Google Scholar 

  28. 28.

    Mader, R., Koton, Y., Buskila, D., Herer, P. & Elias, M. Serum iron and iron stores in non-anemic patients with fibromyalgia. Clin. Rheumatol. 31, 595–599 (2012).

    PubMed  Google Scholar 

  29. 29.

    Ortancil, O., Sanli, A., Eryuksel, R., Basaran, A. & Ankarali, H. Association between serum ferritin level and fibromyalgia syndrome. Eur. J. Clin. Nutr. 64, 308–312 (2010).

    CAS  PubMed  Google Scholar 

  30. 30.

    Shariatpanaahi, M. V., Shariatpanaahi, Z. V., Moshtaaghi, M., Shahbaazi, S. H. & Abadi, A. The relationship between depression and serum ferritin level. Eur. J. Clin. Nutr. 61, 532–535 (2007).

    Google Scholar 

  31. 31.

    Gottfried, R. J., Gerring, J. P., MacHell, K., Yenokyan, G. & Riddle, M. A. The iron status of children and youth in a community mental health clinic is lower than that of a national sample. J. Child Adolesc. Psychopharmacol. 23, 91–100 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Chen, M. H. et al. Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. BMC Psychiatry 13, 161 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Kwak, B. O., Kim, S. N. & Lee, R. Relationship between iron deficiency anemia and febrile seizures in children: a systematic review and meta-analysis. Seizure 52, 27–34 (2017).

    PubMed  Google Scholar 

  34. 34.

    Tomoum, H., Habeeb, N., Elagouza, I. & Mobarez, H. Paediatric breath-holding spells are associated with autonomic dysfunction and iron deficiency may play a role. Acta Paediatr. Int. J. Paediatr. 107, 653–657 (2018).

    CAS  Google Scholar 

  35. 35.

    Georgieff, M. K. Iron assessment to protect the developing brain. Am. J. Clin. Nutr. 106, 1588S–1593S (2017).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Barks, A., Fretham, S. J. B., Georgieff, M. K. & Tran, P. V. Early-life neuronal-specific iron deficiency alters the adult mouse hippocampal transcriptome. J. Nutr. 148, 1521–1528 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Leyshon, B. J., Radlowski, E. C., Mudd, A. T., Steelman, A. J. & Johnson, R. W. Postnatal iron deficiency alters brain development in piglets. J. Nutr. 146, 1420–1427 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Wiegersma, A. M., Dalman, C., Lee, B. K., Karlsson, H. & Gardner, R. M. Association of prenatal maternal anemia with neurodevelopmental disorders. JAMA Psychiatry 76, 1–12 (2019).

    Google Scholar 

  39. 39.

    Georgieff, M. K. The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus. Biochem. Soc. Trans. 36, 1267–1271 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Berglund, S. K. et al. The impacts of maternal iron deficiency and being overweight during pregnancy on neurodevelopment of the offspring. Br. J. Nutr. 118, 533–540 (2017).

    CAS  PubMed  Google Scholar 

  41. 41.

    Wang, W., Knovich, M. A., Coffman, L. G., Torti, F. M. & Torti, S. V. Serum ferritin: past, present and future. Biochim. Biophys. Acta 1800, 760–769 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Alkhateeb, A. A. & Connor, J. R. The significance of ferritin in cancer: anti-oxidation, inflammation and tumorigenesis. Biochim. Biophys. Acta 1836, 245–254 (2013).

    CAS  PubMed  Google Scholar 

  43. 43.

    Kernan, K. F. & Carcillo, J. A. Hyperferritinemia and inflammation. Int. Immunol. 29, 401–409 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Chan, A. L. & Frankovich, J. Infections, antibiotics, and mental health deteriorations. J. Child Adolesc. Psychopharmacol. 29, 647–648 (2019).

    PubMed  Google Scholar 

  45. 45.

    Orefici, G, Cardona, F, Cox, C. J. & Cunningham, M. W. in Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. (eds. Ferretti, J, Stevens, D, & Fischetti, V.) (University of Oklahoma Health Sciences Center, Oklahoma City, OK, 2016).

  46. 46.

    Frankovich, J. et al. The burden of caring for a child or adolescent with pediatric acute-onset neuropsychiatric syndrome (PANS): an observational longitudinal study. J. Clin. Psychiatry 80, 17m12091 (2018).

    PubMed  Google Scholar 

  47. 47.

    Agha, F., Akhter, P. & Khan, R. A. Serum ferritin levels in apparently healthy subjects. J. Pak. Med. Assoc. 37, 63–66 (1987).

    CAS  PubMed  Google Scholar 

  48. 48.

    Jacobs, A., Miller, F., Worwood, M., Beamish, M. R. & Wardrop, C. A. J. Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Br. Med. J. 4, 206–208 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Siimes, M. A., Addiego, J. E. & Dallman, P. R. Ferritin in serum: diagnosis of iron deficiency and iron overload in infants and children. Blood 43, 581–590 (1974).

    CAS  PubMed  Google Scholar 

  50. 50.

    Centers for Disease Control and Prevention. Second National Report on Biochemical Indicators of Diet and Nutrition in the US Population [Internet]. https://www.cdc.gov/nutritionreport/pdf/Nutrition_Book_complete508_final.pdf (2012).

  51. 51.

    Vollmer, S., Bommer, C., Krishna, A., Harttgen, K. & Subramanian, S. V. The association of parental education with childhood undernutrition in low- and middle-income countries: comparing the role of paternal and maternal education. Int. J. Epidemiol. 16, 312–323 (2017).

    Google Scholar 

  52. 52.

    Leibold, C., Thienemann, M., Farhadian, B., Willett, T. & Frankovich, J. Psychometric properties of the pediatric acute-onset neuropsychiatric syndrome global impairment score in children and adolescents with pediatric acute-onset neuropsychiatric syndrome. J. Child Adolesc. Psychopharmacol. 29, 41–49 (2018).

    PubMed  Google Scholar 

  53. 53.

    Novak, M. & Guest, C. Application of a multidimensional caregiver burden inventory. Gerontologist 29, 798–803 (1989).

    CAS  PubMed  Google Scholar 

  54. 54.

    Farmer, C. et al. Psychometric evaluation of the caregiver burden inventory in children and adolescents with PANS. J. Pediatr. Psychol. 43, 749–757 (2018).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Swedo, S. E. et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am. J. Psychiatry 155, 264–271 (1998).

    CAS  PubMed  Google Scholar 

  56. 56.

    Orlovska, S. et al. Association of streptococcal throat infection with mental disorders: testing key aspects of the PANDAS hypothesis in a nationwide study. JAMA Psychiatry 74, 740–746 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Nairz, M. et al. Iron and innate antimicrobial immunity—depriving the pathogen, defending the host. J. Trace Elem. Med. Biol. 48, 118–133 (2018).

    CAS  PubMed  Google Scholar 

  58. 58.

    Quagliariello, A. et al. Gut microbiota profiling and gut-brain crosstalk in children affected by pediatric acute-onset neuropsychiatric syndrome and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Front. Microbiol. 9, 675 (2018).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    McCarthy, R. C. et al. Inflammation-induced iron transport and metabolism by brain microglia. J. Biol. Chem. 293, 7853–7863 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Lane, D. J. R., Ayton, S. & Bush, A. I. Iron and Alzheimer’s disease: an update on emerging mechanisms. J. Alzheimers Dis. 64, S379–S395 (2018).

    CAS  PubMed  Google Scholar 

  61. 61.

    Bartzokis, G., Tishler, T. A., Shin, I. S., Lu, P. H. & Cummings, J. L. Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Ann. N. Y. Acad. Sci. 1012, 224–236 (2004).

    CAS  PubMed  Google Scholar 

  62. 62.

    Ropele, S., Enzinger, C. & Fazekas, F. Iron mapping in multiple sclerosis. Neuroimaging Clin. N. Am. 27, 335–342 (2017).

    PubMed  Google Scholar 

  63. 63.

    Hayflick, S. J., Kurian, M. A. & Hogarth, P. Neurodegeneration with brain iron accumulation. Handb. Clin. Neurol. 147, 293–305 (2018).

    PubMed  Google Scholar 

  64. 64.

    Challacombe, S. J., Scully, C., Keevil, B. & Lehner, T. Serum ferritin in recurrent oral ulceration. J. Oral. Pathol. Med. 12, 290–299 (1983).

    CAS  Google Scholar 

  65. 65.

    Frankovich, J. et al. HLA findings in youth with pediatric acute-onset neuropsychiatric syndrome (PANS). In CARRA Annual Meeting 614399 (2019).

  66. 66.

    Mohammad-Ebrahim, H. et al. Association of killer cell immunoglobulin-like receptor (KIR) genes and their HLA ligands with susceptibility to Behçet’s disease. Scand. J. Rheumatol. 47, 155–163 (2018).

    CAS  PubMed  Google Scholar 

  67. 67.

    Langkammer, C. et al. Quantitative susceptibility mapping in Parkinson’s disease. PLoS ONE 11, e0162460 (2016).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Langkammer, C., Ropele, S., Pirpamer, L., Fazekas, F. & Schmidt, R. MRI for iron mapping in Alzheimer’s disease. Neurodegener. Dis. 13, 189–191 (2014).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge Grace Goodwin, Kayla Brown, Gabbi Kamalani, and Dr. Mark Gorman for assistance with data collection. We also acknowledge all the clinicians and staff at the Stanford Immune Behavioral Health Clinic, and Lucile Packard Children’s Hospital for their excellent care of patients with PANS, which allows us to research this disease. J.F. received research funding from the PANDAS Physicians Network and the National Institute of Mental Health, Pediatrics and Developmental Neuroscience Branch. She has also received funding for CME activities through the Foundation for Children with Neuroimmune Disorders. These organizations did not partake in this study.

Author information

Affiliations

Authors

Contributions

J.F. conceptualized and designed the study, supervised research assistants, interpreted data, and provided intellectual review of the manuscript. M.J. provided expertise regarding ferritin, anemia and study design, and revised the manuscript. H.K. conceptualized using the CDC data as a comparison dataset and performed the initial data analysis. Both H.K. and E.S. collected data and prepared the first draft of the manuscript. A.C. contributed to further data acquisition, data analysis and interpretation, and manuscript writing. M.T., T.W., and B.F., FNP-c, provided expert advice on chart reviews/data collection, and revised the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Jennifer Frankovich.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent from research subjects

Consent was obtained from parents of minors and adult patients, and assent obtained from patients aged 7–17 years.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chan, A., Karpel, H., Spartz, E. et al. Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome. Pediatr Res (2020). https://doi.org/10.1038/s41390-020-1103-3

Download citation

Search