ResearchSpeak: Neurofilaments as a predictor of conversion to MS

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“The title of the paper below is misleading ‘Neurofilament light is a weak risk factor for the development of MS’. What the study shows that people presenting with a CIS (clinically isolated syndromes), or  an initial demyelinating event compatible with demyelination, and are found to have raised spinal fluid NFL (neurofilament light) levels are more likley to go onto develop a second attack; in the past we would call this clinically definite MS. In 2016  this distinction is blurred as the majority of people with CIS can be diagnosed as having MS before their second attack.”

“It is important to realise that from a biological perspective there is no difference between CIS and MS; the majority of people with CIS (>80%) have MS. Therefore all this study is showing that CISers with more damage at baseline (raised NFL levels) are more likely to have ane earlier second attack during follow-up. It is important to note that NFL levels correlated with brain atrophy another marker of end-organ damage. Not surpring the predictive power of NFL (damage marker) was less than T2 lesions (focal inflammation) and oligoclonal IgG bands or OCBs (immunological marker) in terms of the second attack. Baseline NFL levels was not associated with disability; this is not surprising as the number of subjects in the study was relatively small (<40 per group) and the mean follow-up of 7-8 years. A large number of CISers don’t become disabled, as defined using the EDSS, over this sort of time period; particulalry if they are on DMTs. There is no mention of DMTs in the paper; so I am not sure if this is a confounder or not.”

“Does this paper have relevance for clinical practice? Yes, I think it does. Knowing the baseline spinal fluid neurofilament level is important in defining the prognostic profile of CISers and may affect treatment decisions, i.e. if you have raised levels you may be more tempted to choose a higher efficacy therapy as a first line treatment. The fact that NFL levels correlate so well with brain atrophy makes it easier and more practical at an individual patient level to use spinal fluid analysis as a marker of end organ damage rather than relying on progressive brain atrophy as measured by MRI. I say this because the current brain volume measurement algorithms are still too variable to be used in individual patienst over short periods of time. The variabilty is related to biological factors, for example dehydration, co-medication, etc., and the variability of the MRI scanner, postioning of the head in the scanner, the scanner and analysis software.”

Arrambide et al. Neurofilament light chain level is a weak risk factor for the development of MS. Neurology. 2016 Aug 12. pii: 10.1212/WNL.0000000000003085. 

OBJECTIVE: To determine the prognostic value of selected biomarkers in clinically isolated syndromes (CIS) for conversion to multiple sclerosis (MS) and disability accrual.

METHODS: Data were acquired from 2 CIS cohorts. The screening phase evaluated patients developing clinically definite MS (CIS-CDMS) and patients who remained as CIS during a 2-year minimum follow-up (CIS-CIS). We determined levels of neurofascin, semaphorin 3A, fetuin A, glial fibrillary acidic protein, and neurofilament light (NfL) and heavy chains in CSF (estimated mean [95% confidence interval; CI]). We evaluated associations between biomarker levels, conversion, disability, and magnetic resonance parameters. In the replication phase, we determined NfL levels (n = 155) using a 900 ng/L cutoff. Primary endpoints in uni- and multivariate analyses were CDMS and 2010 McDonald MS.

RESULTS: The only biomarker showing significant differences in the screening was NfL (CIS-CDMS 1,553.1 [1,208.7-1,897.5] ng/L and CIS-CIS 499.0 [168.8-829.2] ng/L, p < 0.0001). The strongest associations were with brain parenchymal fraction change (rs = -0.892) and percentage brain volume change (rs = -0.842) at 5 years. NfL did not correlate with disability. In the replication phase, more NfL-positive patients, according to the cutoff, evolved to MS. Every 100-ng/L increase in NfL predicted CDMS (hazard ratio [HR] = 1.009, 95% CI 1.005-1.014) and McDonald MS (HR = 1.009, 95% CI 1.005-1.013), remaining significant for CDMS in the multivariate analysis (adjusted HR = 1.005, 95% CI 1.000-1.011). This risk was lower than the presence of oligoclonal bands or T2 lesions.

CONCLUSIONS: NfL is a weak independent risk factor for MS. Its role as an axonal damage biomarker may be more relevant as suggested by its association with medium-term brain volume changes.

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