Neurodegeneration in Langerhans Cell Histiocytosis: beyond a Sequela

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm with heterogeneous organ and system involvement. Neurodegenerative LCH (ND-LDH) is an uncommon late manifestation with progressive clinical and radiological features, substantial morbidity and an unpredictable course. Historically it was considered a paraneoplastic sequela for which treatment was largely ineffective. Multisystemic disease, central diabetes and orbital and/or skull base bone lesions are risk factors associated with the development of ND-LCH. Early diagnosis, guided by clinical, radiological, electrophysiological and neurocognitive evaluations, may enable timely treatment to halt or slow its progression. Recent identification of activating mutations in the mitogen-activated protein kinase (MAPK) pathway and the development of murine models have redefined ND-LCH as an active neuroinflammatory and neurodegenerative form of LCH, changing our understanding of its etiopathogenesis and identifying novel risk factors and targets for therapy.