TY - JOUR
T1 - Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis
AU - Blincoe, Annaliesse
AU - Heeg, Maximilian
AU - Campbell, Patrick K.
AU - Hines, Melissa
AU - Khojah, Amer
AU - Klein-Gitelman, Marisa
AU - Talano, Julie An
AU - Speckmann, Carsten
AU - Touzot, Fabien
AU - Lankester, Arjan
AU - Legger, Geertje E.
AU - Rivière, Jacques G.
AU - Garcia-Prat, Marina
AU - Alonso, Laura
AU - Putti, Maria C.
AU - Lehmberg, Kai
AU - Maier, Sarah
AU - El Chazli, Yasmine
AU - Elmaksoud, Marwa Abd
AU - Astigarraga, Itziar
AU - Kurjane, Natalja
AU - Bulina, Inita
AU - Kenina, Viktorija
AU - Bryceson, Yenan
AU - Rascon, Jelena
AU - Lortie, Anne
AU - Goldstein, Gal
AU - Booth, Claire
AU - Worth, Austen
AU - Wassmer, Evangeline
AU - Schmitt, Erica G.
AU - Warren, Julia T.
AU - Bednarski, Jeffrey J.
AU - Ali, Salah
AU - Chiang, Kuang Yueh
AU - Krueger, Joerg
AU - Henry, Michael M.
AU - Holland, Steven M.
AU - Marsh, Rebecca A.
AU - Ehl, Stephan
AU - Haddad, Elie
N1 - Funding Information:
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.
Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - CNS disease
KW - CNS inflammation
KW - Familial hemophagocytic lymphohistiocytosis
KW - therapy
UR - http://www.scopus.com/inward/record.url?scp=85087567833&partnerID=8YFLogxK
U2 - 10.1007/s10875-020-00814-6
DO - 10.1007/s10875-020-00814-6
M3 - Article
C2 - 32638196
AN - SCOPUS:85087567833
SN - 0271-9142
VL - 40
SP - 901
EP - 916
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
IS - 6
ER -