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Neurological Involvement in Childhood Evans Syndrome

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Abstract

Purpose

Immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are associated in the definition of Evans syndrome (ES). The occurrence of neurological involvement in this population is poorly described and suggests an underlying primary immunodeficiency (PID). We aimed to describe the clinical manifestations, evolution, and PID profiles of these patients.

Methods

OBS’CEREVANCE is a French, nationwide prospective cohort that includes children with chronic ITP, AIHA, and ES. Patients with a neurological involvement were described. Centralized radiological and pathological reviews and genetic analyses were performed.

Results

On October 2016, eight patients (7/181 ES, 1/371 AIHA, and 0/615 ITP) were identified, all male, with a median age (range) at cytopenia onset of 11.5 years (1.6–15.8). Neurological symptoms appeared with a median delay of 6 years (2.5–18) after cytopenia and were polymorphic: seizures (n = 4), cranial nerve palsy (n = 2), Brown-Sequard syndrome (n = 2), intracranial pressure (n = 2), vertigo (n = 1), and/or sensory neuropathy (n = 1). Magnetic resonance imaging (MRI) showed inflammatory lesions, confirmed by pathology for five patients with macrophagic or lymphoplasmocytic infiltrates. All patients had other relevant immunopathological manifestations: pulmonary nodules (n = 6), lymphoproliferation (n = 4), abnormal immunophenotype (n = 8), and hypogammaglobulinemia (n = 7). Treatment consisted of steroids that improved symptomatology and MRI. Five patients relapsed and three had an asymptomatic radiological progression. A PID was identified in 3/8 patients: 22q11.2 microdeletion (n = 1) and CTLA deficiency (n = 2).

Conclusion

Neurological involvement is a rare and severe late event in the course of childhood ES, which can reveal an underlying PID. Imaging and pathology examination highlight a causative immune dysregulation that may guide targeted therapeutic strategies.

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Authorship contributions.

TP, BN, JLP, FRL, and NA designed the research, analyzed the data, and participated in writing the paper. HDLP reviewed the MRI. PV and AG reviewed the pathology samples. HF was the data manager and performed the statistical analyses. FRL performed the biology molecular analyses. BN, JLP, NA, GL, TL, HC, GM, MP, FM, OH, AM, MHu, HZ, MHa, JMD, and YP were in charge of the patients and participated in data and blood sample collection. All authors critically read the manuscript, approved the final version, and agreed to be accountable for all aspects of the work.

Funding

The clinical database OBS’CEREVANCE was funded by the GIS-Institut des Maladies Rares (INSERM); the French Ministry of Health (Rare Disease Plan, PHRC 2005); the Association Bordelaise pour l’Avancement des Sciences Pédiatriques (ABASP) research charity; the Association pour la Recherche et les Maladies Hématologiques de l’Enfant (RMHE) research charity; and the AFSE and O-CYTO patient associations.

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Author notes

  1. Thomas Pincez

    Present address: Department of Pediatric Hematology-Oncology, Sainte-Justine University Hospital, Montreal University, Montréal, Québec, Canada

Authors and Affiliations

  1. Department of Onco-Hematology, APHP–Trousseau Hospital, Paris, France

    Thomas Pincez, Guy Leverger & Judith Landman-Parker

  2. Pediatric Hematology-Immunology Department, APHP–Necker-Enfants Malades Hospital, Paris, France

    Bénédicte Neven

  3. Pediatric Radiology department, APHP–Trousseau Hospital, Paris, France

    Hubert Ducou Le Pointe

  4. Neuropathology Department, Sainte-Anne Hospital, Paris, France

    Pascale Varlet & Albane Gareton

  5. Centre de Référence National des Cytopénies Autoimmunes de l’Enfant (CEREVANCE), University Hospital of Bordeaux, Bordeaux, France

    Helder Fernandes, Yves Perel & Nathalie Aladjidi

  6. CIC 1401, INSERM CICP, University Hospital of Bordeaux, Bordeaux, France

    Helder Fernandes, Yves Perel & Nathalie Aladjidi

  7. Department of Hematology, APHP–Robert Debré Hospital, Paris, France

    Thierry Leblanc

  8. Department of Pediatric Hematology, University Hospital Timone Enfants, Marseille, France

    Hervé Chambost & Gérard Michel

  9. Hôpital des Enfants, University Hospital of Toulouse, Toulouse, France

    Marlène Pasquet

  10. Department of Pediatric Hematology, University Hospital of Poitiers, Poitiers, France

    Frédéric Millot

  11. Department of Hematology, APHP–Necker-Enfants Malades Hospital, Paris, France

    Olivier Hermine

  12. Department of Internal Medicine 2, APHP–Pitié-Salpêtrière Hospital, Paris, France

    Alexis Mathian

  13. Department of Neurology, APHP–Necker-Enfants Malades Hospital, Paris, France

    Marie Hully

  14. Clinique Neurologique, Pôle des Neurosciences et de l’Appareil Locomoteur, Lille University, Lille, France

    Hélène Zephir

  15. Department of Internal Medicine, University Hospital of Nantes, Nantes, France

    Mohamed Hamidou

  16. Department of Internal Medicine, University Hospital Timone Enfants, Paris, France

    Jean-Marc Durand

  17. Department of Pediatric Hematology, University Hospital of Bordeaux, Bordeaux, France

    Yves Perel & Nathalie Aladjidi

  18. Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR-S1163, Paris Descartes University, Paris, France

    Fréderic Rieux-Laucat

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  1. Thomas Pincez
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Correspondence to Thomas Pincez.

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TP has received a funding support from LFB biomedicaments to attend the 2017 European Hematology Association Annual Meeting. The authors declare that they have no other conflict of interest.

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Figure S1

Radiological evolution of the lesions. Each patient’s ID is the upper number and the MRI sequence is the lower statement (T1 gado: T1-weighted sequence post gadolinium injection, FLAIR: T2-weighted sequence fluid-attenuated inversion recovery). The delay after manifestation’s onset is under each figure. (PDF 2642 kb)

Table S1

Complementary exams at neurological involvement (XLSX 305 kb)

Table S2

Pathology findings (XLSX 9 kb)

Table S3

Non-neurological organ involvement (XLSX 12 kb)

Table S4

Immunobiology (XLSX 491 kb)

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Pincez, T., Neven, B., Le Pointe, H.D. et al. Neurological Involvement in Childhood Evans Syndrome. J Clin Immunol 39, 171–181 (2019). https://doi.org/10.1007/s10875-019-0594-3

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