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Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis

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Abstract

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

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Abbreviations

FHL:

Familial hemophagocytic lymphohistiocytosis

NK:

Natural killer cell

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

HSCT:

Hematopoietic stem cell transplant

MRI:

Magnetic resonance imaging

EBV:

Epstein-Barr virus

HSV:

Herpes simplex virus

sIL2-R:

Soluble interleukin-2 receptor

IT:

Intrathecal

VP-16:

Etoposide

CsA:

Cyclosporine A

MTX:

Methotrexate

IVIG:

Intravenous immunoglobulin

MMF:

Mycophenolate mofetil

ATG:

Anti-thymocyte globulin

CTL:

Cytotoxic T lymphocyte

APC:

Antigen-presenting cells

TLR:

Toll-like receptor

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Funding

This study was supported by the German Research Foundation (DFG SFB1160, TPA01), the Bundesministerium für Bildung und Forschung (01EO1303), the Deutsche Kinderkrebsstiftung (DKS 2016.04 and DKS 2018.11), and the Pediatric Immunology Research Chair, Bank of Montreal.

Author information

Author notes

  1. Annaliesse Blincoe, Maximilian Heeg, Stephan Ehl and Elie Haddad contributed equally to this work.

Authors and Affiliations

  1. CHU Sainte-Justine, Department of Pediatrics, Department of Microbiology, Infectious Diseases and Immunology, University of Montreal, Montreal, QC, H3T 1C5, Canada

    Annaliesse Blincoe, Fabien Touzot & Elie Haddad

  2. Department of Paediatric Immunology and Allergy, Starship Children’s Health, Auckland, New Zealand

    Annaliesse Blincoe

  3. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Breisacher Strasse 115, 79106, Freiburg, Germany

    Maximilian Heeg, Carsten Speckmann & Stephan Ehl

  4. Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Maximilian Heeg

  5. Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Maximilian Heeg

  6. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Patrick K. Campbell

  7. Department of Pediatric Medicine, Division of Critical Care, St Jude Children’s Research Hospital, Memphis, TN, USA

    Melissa Hines

  8. Department of Rheumatology, Ann and Robert H Lurie Children’s Hospital and Children’s Hospital of Chicago, Chicago, IL, USA

    Amer Khojah & Marisa Klein-Gitelman

  9. Department of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Marisa Klein-Gitelman

  10. Pediatric Hematology and Oncology, Children’s Hospital of Wisconsin-Milwaukee Campus, Milwaukee, WI, USA

    Julie-An Talano

  11. Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Carsten Speckmann

  12. Willem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands

    Arjan Lankester

  13. Department of Pediatrics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands

    Geertje E. Legger

  14. Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

    Jacques G. Rivière & Marina Garcia-Prat

  15. Jeffrey Modell Foundation Excellence Centre, Barcelona, Spain

    Jacques G. Rivière & Marina Garcia-Prat

  16. Pediatric Hematology and Oncology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

    Laura Alonso

  17. Department of Pediatrics, University of Padua Medical School, Padua, Italy

    Maria C. Putti

  18. Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center, Hamburg, Germany

    Kai Lehmberg & Sarah Maier

  19. Hematology and Oncology Unit, Alexandria University Children’s Hospital, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Yasmine El Chazli

  20. Neurology Unit, Alexandria University Children’s Hospital, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Marwa Abd Elmaksoud

  21. Department of Pediatrics, Hospital Universitario Cruces, IIS BioCruces Bizkaia, Department of Pediatrics, Faculty of Medicine, UPV/EHU, Barakaldo, Bizkaia, Spain

    Itziar Astigarraga

  22. Stradins Clinical University Hospital, Riga, Latvia

    Natalja Kurjane & Inita Bulina

  23. Department of Biology and Microbiology, Rigas Stradins University, Riga, Latvia

    Natalja Kurjane & Viktorija Kenina

  24. Department of Rheumatology, Stradins Clinical University Hospital, Riga, Latvia

    Inita Bulina

  25. Department of Neurology, Hospital Gailezers, Riga, Latvia

    Viktorija Kenina

  26. Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Yenan Bryceson

  27. Center for Pediatric Oncology and Hematology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania

    Jelena Rascon

  28. Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania

    Jelena Rascon

  29. CHU Sainte Justine, Department of Neurology, Cerebral Electrophysiology Laboratory, Department of Neurosciences, University of Montreal, Montreal, QC, Canada

    Anne Lortie

  30. Department of Pediatric Hematology-Oncology, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel

    Gal Goldstein

  31. Department of Pediatric Immunology, Great Ormond Street Hospital, London, WC1N 3JH, UK

    Claire Booth & Austen Worth

  32. Department of Neurology, Birmingham Women’s and Children’s Hospital, Birmingham, UK

    Evangeline Wassmer

  33. Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Erica G. Schmitt, Julia T. Warren & Jeffrey J. Bednarski

  34. Division of Hematology/Oncology/BMT, The Hospital for Sick Children, Toronto, ON, Canada

    Salah Ali, Kuang-Yueh Chiang & Joerg Krueger

  35. Department of Pediatrics, University of Toronto, Toronto, ON, Canada

    Kuang-Yueh Chiang & Joerg Krueger

  36. Centre for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, USA

    Michael M. Henry

  37. Division of Intramural Research, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA

    Steven M. Holland

  38. Department of Pediatrics, University of Cincinnati, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Medical Centre, Cincinnati, OH, USA

    Rebecca A. Marsh

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  1. Annaliesse Blincoe
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  2. Maximilian Heeg
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  3. Patrick K. Campbell
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  4. Melissa Hines
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  5. Amer Khojah
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  34. Salah Ali
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  38. Steven M. Holland
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  39. Rebecca A. Marsh
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  40. Stephan Ehl
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  41. Elie Haddad
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Contributions

AB, MH, EH, and SE wrote the manuscript. All other authors provided clinical information. SE and EH supervised the project. All authors commented on the manuscript.

Corresponding authors

Correspondence to Stephan Ehl or Elie Haddad.

Ethics declarations

The study was approved by the ethics committee of the University of Freiburg (EK No. 159/19).

Conflict of Interest

SE was part of an Advisory Board at UCB and has received research support from UCB. EH is a consultant for Leadiant. KL is part of an Advisory Board at SOBI. AL is member of the advisory board at Neovii and has received research support from Medac. The remaining authors declare that they have no competing interests.

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Blincoe, A., Heeg, M., Campbell, P.K. et al. Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis. J Clin Immunol 40, 901–916 (2020). https://doi.org/10.1007/s10875-020-00814-6

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