Search IconSearch

Could Serum Neurofilament Light Chain Level Help Guide MS Management?

Perhaps, with caveats: sNfL elevation has low sensitivity and lags MRI activity by at least a month

vial of blood labeled "neurofilament light chain"

Serum neurofilament light chain (sNfL) level correlates with the presence of gadolinium-enhancing (Gd+) MRI lesions, making the structural protein released in neuronal injury a potentially useful biomarker for research and clinical management of multiple sclerosis (MS). But while sNfL level has good specificity for the presence of active MRI lesions, it lacks sensitivity, as less than half of patients with active lesions have elevated levels. In addition, sNfL elevation usually occurs at least a month after lesions first appear on MRI.


Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

These findings, from a post hoc analysis of a subset of participants in the RESTORE trial who were regularly followed with MRI and blood tests, were published online ahead of print in Neurology.

“NfL in the blood reflects disease activity in MS,” says the study’s corresponding author, Robert Fox, MD, a staff neurologist in Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. “However, its low sensitivity for the presence of active Gd+ lesions and its delayed elevation after the appearance of radiological activity must be taken into account when considering its use as a biomarker for clinical and research purposes.”

Need for blood biomarker to monitor inflammation

Currently, MRI is the best method for monitoring central nervous system inflammation. However, it can be cumbersome for patients and too expensive to use for frequent monitoring. sNfL — a neuron-specific protein that enters the serum following neuronal damage — has been put forward as a promising blood biomarker candidate for use in the management of individual MS patients. However, its utility at the individual patient level has not been well understood.

The RESTORE trial (Neurology. 2014;82[17]:1491-1498) was a treatment interruption study of the monoclonal antibody natalizumab among patients with relapsing forms of MS who had been taking natalizumab the previous 12 months and had no Gd+ lesions at the start of the trial. During the study, patients either remained on natalizumab (25%), were put on an alternative immunomodulatory therapy (50%) or stopped all MS medications (25%). Data obtained from regular blood tests and MRI scans during the trial presented the opportunity to analyze the relationship between sNfL levels and MRI findings over time.

Study design and findings

The cohort for the new post hoc analysis consisted of 166 participants in the RESTORE trial. MRI scanning and blood draws were conducted every four weeks until week 28 and also at week 52. Over this period, 65 participants developed Gd+ lesions and 101 participants did not. Those who did not develop Gd+ lesions served as the control population, and the 95th percentile of sNfL levels in this group was 19.6 pg/mL.

Indicators of support for the utility of sNfL as a biomarker for MS activity included the following:

  • The mean increase from baseline to maximum sNfL level was significantly greater in patients who developed one or more Gd+ lesions than in those without Gd+ lesions (12.1 vs. 3.2 pg/mL; P = .003).
  • On average, participants with more Gd+ lesions had higher sNfL levels.

These findings were consistent with previous studies examining sNfL at group levels, Dr. Fox notes.

However, the following findings, indicating that use of sNfL as a biomarker would not be straightforward, were also evident:

  • More than two-thirds of patients who developed Gd+ lesions did not have elevations in sNfL above levels measured in the control group.
  • Increases in sNfL level were highly variable, even for patients with similar numbers of Gd+ lesions.
  • For most patients with Gd+ lesions, the increase in sNfL was delayed at least one month after initial development of MRI activity was detected; peak sNfL increase occurred an average of two months after the first Gd+ lesion was seen.


Sensitivity and specificity analyses of sNfL were also performed. sNfL elevation demonstrated good specificity (82%-92%) for development of Gd+ lesions but low sensitivity (28%-43%), even when adjusting for age.

Possible role for sNfL?

“These study findings suggest that elevation in sNfL is a strong indicator of MS disease activity and therefore could have utility in the clinic,” Dr. Fox notes. “However, its low sensitivity to MRI disease activity and the one- to two-month delay in elevation need to be recognized by clinicians.” As a result, he says, sNfL may be a useful supplement to MRI monitoring but should not be used as a replacement for such monitoring. He adds that the precise relationship of sNfL to disability progression in progressive MS is still unclear.

“Though it has limitations, sNfL might still be a useful biomarker of subclinical disease activity,” Dr. Fox concludes. “Because this simple blood test allows for close monitoring between MRIs, it could potentially help us improve patient outcomes.”


Related Articles

pills, syringes and vials on a tabletop
May 15, 2024/Neurosciences/Podcast
Multiple Sclerosis Medications: Making the Most of a Multitude of Options (Podcast)

Insights on the decision process for selecting a treatment approach

central vein sign on a brain MRI
CAVS-MS Advances Quest to Improve the Diagnosis of Multiple Sclerosis

New reports focus on neuroimaging biomarkers and features of atypical presentations

histology image of a gray matter lesion in a multiple sclerosis brain
Study Suggests Protective Role for Microglia at Borders of Gray Matter Lesions in Progressive MS

Findings challenge dogma that microglia are exclusively destructive regardless of location in brain

illustration of a neuron affected by multiple sclerosis
Clinical Trials in Progressive MS: An Assessment of Advances and Remaining Challenges

New review distills insights from studies over the past decade

September 27, 2022/Neurosciences/Pediatrics
Making Pediatrics More of a Priority in Multiple Sclerosis Treatment Trials

New review makes the case for earlier pediatric enrollment and other changes

Phase 2 Trial Hints at Promise of Cellular Therapy for Progressive MS

Single-arm, open-label study offers proof of concept for MSC-NTF cells

neuron affected by neuromyelitis optica
Novel Monoclonal Antibodies for NMOSD Show Strong Efficacy and Safety in Real-World Study

Early experience with the agents confirms findings from clinical trials

photo of doctor performing neurologic exam on a patient
A New Guide to the Differential Diagnosis of Multiple Sclerosis

Updated consensus approach helps clinicians efficiently improve diagnostic accuracy