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. 2024 Jul;271(7):4441-4452.
doi: 10.1007/s00415-024-12355-8. Epub 2024 Apr 29.

Diagnostic value of neurofilaments in differentiating motor neuron disease from multifocal motor neuropathy

Camilla Wohnrade  1 , Tabea Seeliger  2 , Stefan Gingele  2 , Bogdan Bjelica  2 , Thomas Skripuletz  2 , Susanne Petri  2   3
Affiliations

Diagnostic value of neurofilaments in differentiating motor neuron disease from multifocal motor neuropathy

Camilla Wohnrade et al. J Neurol. 2024 Jul.

Erratum in

Abstract

Objective: To evaluate the performance of serum neurofilament light chain (NfL) and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNfH) as diagnostic biomarkers for the differentiation between motor neuron disease (MND) and multifocal motor neuropathy (MMN).

Methods: This retrospective, monocentric study included 16 patients with MMN and 34 incident patients with MND. A subgroup of lower motor neuron (MN) dominant MND patients (n = 24) was analyzed separately. Serum NfL was measured using Ella automated immunoassay, and CSF pNfH was measured using enzyme-linked immunosorbent assay. Area under the curve (AUC), optimal cutoff values (Youden's index), and correlations with demographic characteristics were calculated.

Results: Neurofilament concentrations were significantly higher in MND compared to MMN (p < 0.001), and serum NfL and CSF pNfH correlated strongly with each other (Spearman's rho 0.68, p < 0.001). Serum NfL (AUC 0.946, sensitivity and specificity 94%) and CSF pNfH (AUC 0.937, sensitivity 90.0%, specificity 100%) performed excellent in differentiating MND from MMN. Optimal cutoff values were ≥ 44.15 pg/mL (serum NfL) and ≥ 715.5 pg/mL (CSF pNfH), respectively. Similar results were found when restricting the MND cohort to lower MN dominant patients. Only one MMN patient had serum NfL above the cutoff. Two MND patients presented with neurofilament concentrations below the cutoffs, both featuring a slowly progressive disease.

Conclusion: Neurofilaments are valuable supportive biomarkers for the differentiation between MND and MMN. Serum NfL and CSF pNfH perform similarly well and elevated neurofilaments in case of diagnostic uncertainty underpin MND diagnosis.

Keywords: Amyotrophic lateral sclerosis; Biomarker; Diagnostic performance; Motor neuron disease; Multifocal motor neuropathy; Neurofilaments.

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Conflict of interest statement

Camilla Wohnrade received travel compensations from ITF Pharma GmbH outside the submitted work. Tabea Seeliger received financial support for conference attendance fees by Abbvie, honoraria for preparation of a manuscript by Springer and a research grant by Novartis Pharma GmbH outside the submitted work. Stefan Gingele received research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer and Merck all outside the submitted work. Bogdan Bjelica received travel compensations from ITF pharma GmbH outside the submitted work. Thomas Skripuletz reports honoraria for lectures and travel expenses for attending meetings from Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Grifols, Hexal AG, Janssen-Cilag, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Swedish Orphan Biovitrum, Teva, Viatris. His research is supported by the German Ministry for Education and Research (BMBF), Bristol-Myers Squibb Foundation for Immuno-Oncology, Claudia von Schilling Foundation for Breast Cancer Research, Else Kröner Fresenius Foundation, Hannover Biomedical Research School (HBRS), Alnylam Pharmaceuticals, CSL Behring, Novartis, Sanofi Genzyme, and VHV Foundation. Susanne Petri received honoraria as a speaker/consultant from Biogen GmbH, Roche, Novartis, Teva, Cytokinetics Inc., Desitin, Italfarmaco, Zambon, Amylyx; and grants from DGM e.V, Federal Ministry of Education and Research, German Israeli Foundation for Scientific Research and Development, EU Joint Programme for Neurodegenerative Disease Research outside the submitted work.

Figures

Fig. 1
Fig. 1
Participant flow. a Flow of participants from screening until inclusion and number of serum and CSF samples analyzed. b Cross-tabulation of the clinical diagnosis by Nf concentrations. Dotted boxes constitute false positives and false negatives, whereas boxes with solid border represent true positives and true negatives applying the estimated cutoffs. MMN multifocal motor neuropathy, MND motor neuron disease, CIDP chronic inflammatory demyelinating polyneuropathy, CSF cerebrospinal fluid, MN motor neuron, NfL neurofilament light chain, pNfH phosphorylated neurofilament heavy chain
Fig. 2
Fig. 2
Neurofilament concentrations in MMN versus MND. Depicted are median and range for serum NfL and CSF pNfH concentrations. Each grey/black dot represents an individual MMN/MND patient. MND patients had significantly higher Nf concentrations compared to MMN patients (p < 0.001). a Serum NfL in MMN versus MND. b CSF pNfH in MMN versus MND. MMN multifocal motor neuropathy, MND motor neuron disease, NfL neurofilament light chain, CSF cerebrospinal fluid, pNfH phosphorylated neurofilament heavy chain, ***p < 0.001
Fig. 3
Fig. 3
ROC curves for the evaluation of diagnostic accuracy of serum NfL and CSF pNfH to discriminate MND from MMN a ROC curve of serum NfL in all MND patients (n = 32) versus MMN patients (n = 16). b ROC curve of CSF pNfH in all MND patients (n = 30) versus MMN patients (n = 10). c ROC curve of serum NfL in lower MN dominant MND patients (n = 23) versus MMN patients (n = 16). d ROC curve of CSF pNfH in lower MN dominant MND patients (n = 21) versus MMN patients (n = 10). MND motor neuron disease, MMN multifocal motor neuropathy, NfL neurofilament light chain, CSF cerebrospinal fluid, pNfH phosphorylated neurofilament heavy chain
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