Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis

Annaliesse Blincoe, Maximilian Heeg, Patrick K. Campbell, Melissa Hines, Amer Khojah, Marisa Klein-Gitelman, Julie An Talano, Carsten Speckmann, Fabien Touzot, Arjan Lankester, Geertje E. Legger, Jacques G. Rivière, Marina Garcia-Prat, Laura Alonso, Maria C. Putti, Kai Lehmberg, Sarah Maier, Yasmine El Chazli, Marwa Abd Elmaksoud, Itziar AstigarragaNatalja Kurjane, Inita Bulina, Viktorija Kenina, Yenan Bryceson, Jelena Rascon, Anne Lortie, Gal Goldstein, Claire Booth, Austen Worth, Evangeline Wassmer, Erica G. Schmitt, Julia T. Warren, Jeffrey J. Bednarski, Salah Ali, Kuang Yueh Chiang, Joerg Krueger, Michael M. Henry, Steven M. Holland, Rebecca A. Marsh, Stephan Ehl*, Elie Haddad*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)901-916
Number of pages16
JournalJournal of Clinical Immunology
Issue number6
StatePublished - Aug 1 2020


  • CNS disease
  • CNS inflammation
  • Familial hemophagocytic lymphohistiocytosis
  • therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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