Neurodegenerative Langerhans cell histiocytosis: long-term follow-up of 63 patients from the Italian Registry.

Neurodegenerative Langerhans cell histiocytosis (ND-LCH) is a potentially devastating complication of LCH. We analyzed the natural history and the long-term outcome of patients with ND-LCH enrolled in the Italian LCH registry. ND-LCH was diagnosed in 63 of 637 patients with LCH (10%). Overall, at ND-LCH diagnosis 60% (38/63) patients were asymptomatic, 24% (15/63) had mild clinical manifestations including abnormal neurological examination and/or evoked potentials, and 16% (10/63) had overt symptoms. Brain magnetic resonance imaging (MRI) showed progressive structural changes in 13 of 63 (21%) patients over a median time of 1.5 years. Clinical ND-LCH developed after a median of 2.5 years since ND-LCH diagnosis. Thirty of 63 patients (17 pauci-symptomatic, 11 symptomatic, two asymptomatic but with severe brain MRI) received treatment, and 17 of 30 (57%) were stable or improved at the last follow-up). Thirty-three of 63 patients (mostly asymptomatic) were not treated and 31 of 33 (94%) remained stable through follow-up. At univariable analysis, the risk of developing overt clinical symptoms increased with LCH reactivations (odds ratio [OR]=6.40; P=0.018), severe brain MRI abnormalities at ND-LCH diagnosis (OR=10.40; P<0.001), and MRI findings worsening during follow-up (OR=10.25; P=0.001). The association of overt neurodegeneration with reactivations and MRI findings worsening was confirmed at multivariable analysis (OR=8.15; P=0.040; and OR=7.31; P=0.034, respectively). In conclusion, asymptomatic patients presenting with mild radioneuroimaging lesions at ND-LCH onset remained stable during follow-up; conversely, a history of LCH reactivation and worsening of brain MRI findings were associated with the appearance of overt clinical symptoms. These results may lay the basis for patients selection for treatment and different monitoring strategies.