Serum Neurofilaments are a reliable biomarker to early detect PML in Multiple Sclerosis patients.

BACKGROUND

The earliest detection of progressive multifocal leukoencephalopathy (PML) is crucial in Natalizumab (NTZ)-treated Multiple Sclerosis (MS) patients. This study aims to assess serum Neurofilaments (sNFL) ability to early detect PML in longitudinal patients' follow-up.

METHODS

NFL were retrospectively measured in four PML cases occurred at the Regional Referring Center for MS (CRESM, Italy), in samples collected since one year before PML diagnosis, at PML diagnosis, during PML and in post-PML follow-up. sNFL levels were interpreted according to previously defined reference values. Clinical examination and EDSS were performed at each NTZ infusion. Routinary MRI was undertaken every six months; after PML diagnosis, MRI was performed according to clinical evaluation. sNFL were also measured in 45 NTZ-treated patients experiencing NEDA-3 status for at least 12 months.

RESULTS

Patients showed different PML onsets and manifestations: in 3 patients routinary brain MRI revealed radiological signs of PML preceding different clinical manifestations, while in one patient brain MRI was performed after the clinical onset. PML diagnosis was defined at the time of the first detection of JCV DNA in cerebrospinal fluid. The following different PML phases were considered: 1. Basal (up to 4 months before PML diagnosis): sNFL values were in the normal range in all patients' samples, except for one (median 9.1 pg/ml, range 6.2-15.1 pg/ml) 2. Pre-PML (within 3 months before PML diagnosis): sNFL were elevated in all available samples (median 19.50 pg/ml, range 15.50-33.80 pg/ml). 3. PML diagnosis: sNFL were elevated in all patients (median 59.20 pg/ml, range 11.1-101.50 pg/ml). 4. PML/IRIS: during this phase, sNFL levels reached their peak (median 96.35 pg/ml, range 20.5-272.9) in all patients. 5. Post-PML (recovery phase, starting from the first MRI without enhancement, up to the end of follow-up): sNFL levels showed a decrease (median 12.80 pg/ml, range 9.30-30.60); however, based on reference values, sNFL were still elevated in 2 out of 4 patients at the end of their follow-up (622 and 887 days after PML diagnosis). sNFL were always elevated when MRI scan suggested a suspicious of PML. In NEDA-3 patients, sNFL levels were in the normal range in all patients' samples (median 4.7 pg/ml, range 1.4-8.6 pg/ml).

CONCLUSION

Elevated sNFL were observed not only at PML diagnosis, but also in pre-PML phase. At PML recovery, sNFL weren't normalized in all patients' samples, suggesting ongoing neuronal degeneration. sNFL represent a reliable biomarker and should be introduced in clinical practice as an additional/alternative parameter to MRI to early detect and monitor PML.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of Competing Interest Valentino Paola received speaker honoraria from Roche, research support from Merck and grant support from Quanterix. Malucchi Simona received speaker honoraria from Biogen and Roche. Bava Cecilia Irene: nothing to discose Martire Serena: nothing to discose Capobianco Marco served on the scientific advisory board of Biogen, Sanofi Genzyme, Novartis, Roche, Becton-Dickinson, Alexion and Horizon and received speaker honoraria from Almirall, Biogen, Novartis, Sanofi Genzyme. Malentacchi Maria: nothing to discose Sperli Francesca: nothing to discose Oggero Alessandra: nothing to discose Di Sapio Alessia received personal compensation for speaking and consulting by Biogen, Novartis, Roche, Sanofi and Alexion and has been reimbursed by Merck, Biogen, Genzyme and Roche for attending several conferences. Bertolotto Antonio served on the scientific advisory board of Almirall, Bayer, Biogen, and Genzyme; received speaker honoraria from Biogen, Novartis and Sanofi and grant support from Almiral, Biogen, Associazione San Luigi Gonzaga ONLUS, Fondazione per la Ricerca Biomedica ONLUS, Mylan, Novartis and the Italian Multiple sclerosis Society.