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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Familial hemophagocytic lymphohistiocytosis
Natural killer cell
Central nervous system
Hematopoietic stem cell transplant
Magnetic resonance imaging
Herpes simplex virus
Soluble interleukin-2 receptor
Cytotoxic T lymphocyte
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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.
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
- Familial hemophagocytic lymphohistiocytosis
- CNS disease
- CNS inflammation