• neurodegenerative Langerhans cell histiocytosis
• overt clinical symptoms
• severe brain MRI
• standardized diagnostic protocoll

Neurodegenerative involvement in Langerhans cell histiocytosis (ND-LCH) is a rare but potentially devastating complication that can progress to disabling neurological manifestations. Despite advances in scientific research, there are still many open questions. Effective therapy is lacking: various treatments have been proposed achieving best results when initiated early. However, a standardized diagnostic approach to early identify patients in need of treatment is still a matter of debate. Lastly, only small cohorts of patients with short follow-up are reported so far, hampering knowledge about its natural history.
Therefore, the aim of this study is to describe the long term follow-up of ND-LCH through the analysis of a large cohort of patients enrolled in the Italian LCH registry. In addition, we sought to identify predictors of ND-LCH progression to overt clinical manifestations.
Out of the 637 patients enrolled in the Italian LCH Registry, 63 were referred for ND-LCH (10%) from 8 italian centres. Male to female ratio was 1.6. Median age at LCH diagnosis was 22 months. ND-LCH developed at a median of 59 months, with a delay of 2.9 years from the LCH diagnosis. Out of the 63 patients, 43 (68%) had multisystem disease, 13/43 with risk organ involvement. Diabetes insipidus and/or craniofacial bone lesions were reported in 51/63 (81%) patients; the remaining 12 patients were BRAF V600E mutated in 11/11 cases tested. Overall, 60% (38/63) patients were completely asymptomatic, 24% (15/63) had mild clinical manifestations including abnormal neurological examination and/or evoked potentials but without overt clinical picture, 16% (10/63) developed overt symptoms. The patients were followed-up for a median of 8.5 years (1– 22.5 years) from ND-LCH diagnosis with a multidisciplinary protocol including: brain MRI, evoked potential and neurological examination. Brain MRI worsened in 13/63 (21%) patients over a median of 1.5 years (1-12 years). Clinical ND-LCH developed after a median time of 2.5 years (range, 0-8 years) from ND-LCH diagnosis. Thirty of the 63 patients (17 pauci-symptomatic, 11 symptomatic, 2 asymptomatic but with severe alterations on brain MRI) received high dose immunoglobulin (n=24), chemotherapy (n=3), mitogen-activated protein kinase inhibitors alone (n=2) or combined with immunoglobulin (n=1). Overall, 17/30 patients (57%) were stable or improved, the others worsened and started second line therapy. The remaining 33 patients (27 asymptomatic, 3 mild and 3 overt clinical symptoms) were not treated and remained stable in 94% of cases (31/33). At univariable analysis, the risk of overt clinical symptoms increased with reactivations (OR 6.40, 95%CI 1.31-31.16, p=0.018), severe brain MRI alteration (grading 3-4) at ND-LCH diagnosis (OR 10.40, 95%CI 2.94-36.81, p<0.001) and MRI worsening during follow-up (OR 10.25, 95%CI 2.58-40.79, p=0.001). The predictive value of reactivation and MRI worsening were confirmed at multivariable analysis.
In conclusion, patients with ND-LCH accounts for the 10% of the Italian cohort and were follow-up for a median time of 8.5y, that is the longest follow-up reported so far. Patients presenting with mild radiological lesions (grading 1-2) at ND-LCH onset and the absence of clinical and neurophysiological alterations remained almost stable during follow-up; conversely, history of LCH reactivation and the presence of severe radiological alterations (grading 3-4) or worsening on brain MRI predisposed to the onset of neurological overt clinical symptoms. These results may lay the basis for patient selection for treatment and different monitoring strategies.