CENTRAL NERVOUS SYSTEM INVOLVEMENT IN PEDIATRIC HEMOLYTIC UREMIC SYNDROME: FREQUENCY, IMAGING PATTERNS, AND CLINICAL OUTCOMES

Barbara Wardzyńska; Jolanta Barbara Mataśka; Natalia Sałkowska; Eliza Mędrek; Natalia Brzozowska; Jakub Magdziak; Oliwia Borowska; Sara Awad; Paulina Zegarska; Hanna Markowska

doi:10.31435/ijitss.2(50).2026.6206

Authors

Barbara Wardzyńska Independent Public Healthcare Complex in Wyszków, Komisji Edukacji Narodowej 1, 07-200 Wyszków, Poland https://orcid.org/0009-0002-4521-8911
Jolanta Barbara Mataśka Independent Public Healthcare Complex in Wyszków, Komisji Edukacji Narodowej 1, 07-200 Wyszków, Poland https://orcid.org/0009-0005-9662-9704
Natalia Sałkowska University Clinical Center of the Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland https://orcid.org/0009-0005-2518-3493
Eliza Mędrek Nowy Dwór Mazowiecki Medical Center, Miodowa 2, 05-100 Nowy Dwór Mazowiecki, Poland https://orcid.org/0009-0001-2830-014X
Natalia Brzozowska Nowy Dwór Mazowiecki Medical Center, Miodowa 2, 05-100 Nowy Dwór Mazowiecki, Poland https://orcid.org/0009-0003-6580-1714
Jakub Magdziak Independent Public Clinical Hospital named after Prof. W. Orłowski, CMKP, Czerniakowska 231, 00-416 Warsaw, Mazovia, Poland https://orcid.org/0009-0006-0297-7423
Oliwia Borowska Independent Public Clinical Hospital named after Prof. W. Orłowski, CMKP, Czerniakowska 231, 00-416 Warsaw, Mazovia, Poland https://orcid.org/0009-0006-1260-5711
Sara Awad Independent Public Clinical Hospital named after Prof. W. Orłowski, CMKP, Czerniakowska 231, 00-416 Warsaw, Mazovia, Poland https://orcid.org/0009-0004-0942-6240
Paulina Zegarska Grochowski Hospital, Grenadierów 51/59, 04-073 Warsaw, Mazovia, Poland https://orcid.org/0000-0001-6727-8128
Hanna Markowska Samodzielny Publiczny Wielospecjalistyczny Zakład Opieki Zdrowotnej Ministerstwa Spraw Wewnętrznych i Administracji w Bydgoszczy, ul. Ks. R. Markwarta 4-6, 85-015 Bydgoszcz, Poland https://orcid.org/0009-0006-7837-1989

DOI:

https://doi.org/10.31435/ijitss.2(50).2026.6206

Keywords:

HUS, CNS, Pediatrics

Abstract

Background: Hemolytic uremic syndrome (HUS) is the leading cause of typical thrombotic microangiopathy in children, most commonly triggered by Shiga toxin–producing Escherichia coli (STEC). Beyond the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, central nervous system (CNS) involvement is a major determinant of severity.

Methods: Narrative synthesis of clinical, epidemiologic, and neurodiagnostic literature addressing pediatric HUS with CNS involvement.

Results: Neurological complications in STEC-HUS occur in approximately the low-teens in contemporary cohorts and most often present with seizures and encephalopathy; PRES, focal deficits, movement disorders, and cerebrovascular complications are less frequent but clinically significant. STEC-HUS is initiated by Shiga toxin–mediated endothelial injury leading to thromboinflammation and microvascular thrombosis, while complement activation likely amplifies endothelial damage and contributes to CNS vulnerability. In aHUS, neurological involvement is more frequent and reflects systemic complement-mediated microangiopathy. MRI, particularly diffusion-weighted imaging and ADC mapping helps differentiate microangiopathic injury from PRES or infarction/hemorrhage and may support early risk stratification. EEG is useful for detecting epileptic activity and subclinical encephalopathy. Management is predominantly supportive and neurocritical (seizure control, blood pressure management, correction of metabolic derangements, and renal support). Eculizumab is essential in aHUS but remains controversial in STEC-HUS, with no consistent neurological benefit over standard care in recent syntheses.

Conclusions: CNS involvement identifies a high-risk pediatric HUS subgroup requiring early neurologic assessment, targeted MRI/EEG use, meticulous critical care, and structured long-term follow-up due to potential subtle neurocognitive sequelae.

References

Freedman, S. B., Van De Kar, N. C. A. J., & Tarr, P. I. (2023). Shiga toxin–producing Escherichia coli and the hemolytic–uremic syndrome. New England Journal of Medicine, 389(15), 1402–1414.

Karpman, D., Loos, S., Tati, R., & Arvidsson, I. (2017). Haemolytic uraemic syndrome. Journal of Internal Medicine, 281(2), 123–148.

Tarr, P. I., Gordon, C. A., & Chandler, W. L. (2005). Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. The Lancet, 365(9464), 1073–1086.

Karmali, M. A. (2004). Infection by Shiga toxin-producing Escherichia coli: An overview. Molecular Biotechnology, 26(2), 117–122.

Jenssen, G. R., Hovland, E., Bjerre, A., et al. (2014). Incidence and etiology of hemolytic-uremic syndrome in children in Norway, 1999–2008. BMC Infectious Diseases, 14, Article 265.

Zagożdżon, I., Szczepańska, M., Leszczyńska, B., et al. (2024). Changing epidemiology and outcomes of hemolytic uremic syndrome in children. Journal of Clinical Medicine, 13(21), Article 6499.

McGeoch, L. J., Quinn, O., Douglas, A., et al. (2025). The epidemiology of haemolytic uraemic syndrome in England, 2009–2023. Journal of Infection, 91(2), Article 106551.

Ardissino, G., Salardi, S., Colombo, E., et al. (2016). Epidemiology of haemolytic uremic syndrome in children. European Journal of Pediatrics, 175(4), 465–473.

Khalid, M., & Andreoli, S. (2019). Extrarenal manifestations of the hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC HUS). Pediatric Nephrology, 34(12), 2495–2507.

Costigan, C., Raftery, T., Carroll, A. G., et al. (2022). Neurological involvement in children with hemolytic uremic syndrome. European Journal of Pediatrics, 181(2), 501–512.

Tonkovic, U., Bogicevic, M., Manzar, A., et al. (2025). Neurological manifestations of hemolytic uremic syndrome: A comprehensive review. Brain Sciences, 15(7), Article 717.

Buelli, S., Zoja, C., Remuzzi, G., & Morigi, M. (2019). Complement activation contributes to the pathophysiology of Shiga toxin-associated hemolytic uremic syndrome. Microorganisms, 7(1), Article 15.

Fuller, C. A., Pellino, C. A., Flagler, M. J., Strasser, J. E., & Weiss, A. A. (2011). Shiga toxin subtypes display dramatic differences in potency. Infection and Immunity, 79(3), 1329–1337.

Brandal, L. T., Wester, A. L., Lange, H., et al. (2015). Shiga toxin-producing Escherichia coli infections in Norway, 1992–2012. BMC Infectious Diseases, 15, Article 324.

Byrne, L., Adams, N., & Jenkins, C. (2020). Association between Shiga toxin–producing Escherichia coli O157:H7 stx gene subtype and disease severity, England, 2009–2019. Emerging Infectious Diseases, 26(10), 2394–2400.

Iyoda, S., Manning, S. D., Seto, K., et al. (2014). Phylogenetic clades 6 and 8 of enterohemorrhagic Escherichia coli O157:H7. Open Forum Infectious Diseases, 1(2), Article ofu061.

Monnens, L., Molenaar, J., Lambert, P. H., et al. (1980). The complement system in hemolytic-uremic syndrome in childhood. Clinical Nephrology, 13(4), 168–171.

Thurman, J. M., Marians, R., Emlen, W., et al. (2009). Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clinical Journal of the American Society of Nephrology, 4(12), 1920–1924.

Orth, D., Khan, A. B., Naim, A., et al. (2009). Shiga toxin activates complement and binds factor H. Journal of Immunology, 182(10), 6394–6400.

Ehrlenbach, S., Rosales, A., Posch, W., et al. (2013). Shiga toxin 2 reduces complement inhibitor CD59 expression. Infection and Immunity, 81(8), 2678–2685.

Eisenhauer, P. B., Chaturvedi, P., Fine, R. E., et al. (2001). Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3. Infection and Immunity, 69(3), 1889–1894.

Fidan, K., Goknar, N., Gulhan, B., et al. (2018). Extra-renal manifestations of atypical hemolytic uremic syndrome in children. Pediatric Nephrology, 33, 1395–1403.

Doshi, K., et al. (2025). Extrarenal manifestations of atypical hemolytic uremic syndrome: A systematic review and meta-analysis. Pediatric Nephrology. PMID: 39676096.

Sheth, K. J., et al. (1986). Neurological involvement in hemolytic-uremic syndrome. PMID: 3947042.

Bauer, A., Loos, S., Wehrmann, C., et al. (2014). Neurological involvement in children with E. coli O104:H4-induced hemolytic uremic syndrome. Pediatric Nephrology, 29, 1607–1615.

Kenjale, S., et al. (2022). Atypical hemolytic uremic syndrome with posterior reversible encephalopathy syndrome in an adolescent. PMID: 36590999.

Fisler, G., Monty, M. A., Kohn, N., Assaad, P., Trope, R., & Kessel, A. (2020). Characteristics and outcomes of critically ill pediatric patients with posterior reversible encephalopathy syndrome. Neurocritical Care, 32(1), 145–151.

Hage, P., et al. (2018). Recurrent posterior reversible encephalopathy syndrome in a child with renal failure. PMID: 29990959.

Steinberg, A., et al. (1986). Stroke in a patient with hemolytic-uremic syndrome. PMID: 3706664.

Nakahata, T., et al. (2001). Thrombotic stroke in a child with diarrhea-associated hemolytic uremic syndrome. PMID: 11321053.

Pape, L., et al. (2015). Eculizumab in typical hemolytic uremic syndrome with neurological involvement. PMID: 26091445.

Toldo, I., et al. (2009). Diffusion-weighted imaging findings in hemolytic uremic syndrome with central nervous system involvement. PMID: 19074752.

Gitiaux, C., et al. (2013). Brain magnetic resonance imaging pattern and outcome in children with hemolytic uremic syndrome treated with eculizumab. PMID: 23659643.

Bültmann, E., et al. (2023). Cerebral microstructural changes in children suffering from typical hemolytic uremic syndrome. PMID: 37558834.

Ho, V. B., Fitz, C. R., Chuang, S. H., & Geyer, C. A. (1993). Bilateral basal ganglia lesions: Pediatric differential considerations. RadioGraphics, 13(2), 269–292.

Dhuna, A., et al. (1992). EEG and seizures in children with hemolytic-uremic syndrome. PMID: 1592024.

Gulleroglu, K., et al. (2013). Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab. PMID: 23389237.

Hu, H., et al. (2014). Eculizumab in atypical haemolytic uraemic syndrome with extrarenal complications. PMID: 24317637.

Giordano, P., et al. (2019). A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement. PMID: 30362078.

Loos, S., et al. (2018). Eculizumab in STEC-HUS: Need for a proper randomized controlled trial. PMID: 29774464.

Spagnol, R., et al. (2025). Eculizumab in severe pediatric STEC-HUS and its impact on neurological prognosis: A systematic review and meta-analysis. PMID: 40341411.

Qamar, I. U., et al. (1996). Long-term neurological sequelae of hemolytic uremic syndrome in children with major acute neurologic symptoms. PMID: 8865254.