Profiling Inflammatory Markers in Cerebrospinal Fluid of Importance in Active MS, Case Study Finds

Careful profiling of inflammatory markers in cerebrospinal fluid (CSF) of multiple sclerosis patients, coupled with standard exams and scans, helps in understanding disease evolution and treatment response, a case report suggests.

It followed a relapsing-remitting multiple sclerosis (RRMS) patient whose inflammatory markers in the CSF remained high over time, and who responded poorly to several immunomodulatory treatments.

The report “Increase of CSF inflammatory profile in a case of highly active multiple sclerosis” was published in the journal BMC Neurology.

Researchers detailed the case of a 31-year-old woman, diagnosed with RRMS in December 2006 and with a history of poor response to disease-modifying therapies. At her diagnosis, magnetic resonance imaging (MRI) scans revealed the presence of T2-weighted hyperintense lesions in certain brain regions; some of the lesions were positive for gadolinium, a contrast agent to enhance MRI images that identifies lesions in an inflammatory state.

The patient began treatment with Teva’s Copaxone (glatiramer acetate), but twice relapsed in 2008. New scans confirmed active disease, as shown by new T2 and gadolinium positive T1-lesions. She was switched to treatment with interferon (IFN) beta-1a, but the disease remained active, with two annual relapses and new brain lesions.

She was treated with Biogen’s Tysabri (natalizumab) from April to August 2013, but stopped due to a relapse with atypical brain MRI lesions.

In May 2014, she began treatment with cyclophosphamide, which was maintained until March 2015, and then switched to Biogen’s Tecfidera (dimethyl fumarate). This, however, failed to reduce disease activity with her level of disability, as measured by the EDSS score, increasing from 2 to 4.5. Cognitive difficulties, especially in memory and attention, were confirmed in tests.

She started on Lemtrada (alemtuzumab), by Sanofi-Genzyme, in June 2016. At her last follow-up in December 2017, she had no signs of disease activity and reported no treatment-related adverse effects. She had resumed most of her usual activities.

A protein analysis of the patient’s blood and cerebrospinal fluid (CSF, the fluid surrounding the brain and spinal cord) was performed in 2006 at diagnosis and again in 2013.

The first CSF analysis found levels of 42 inflammatory molecules at least twice as high as those in a control group of 26 patients, including 14 people with other inflammatory neurological diseases.

Seven years later, 11 of these inflammatory markers in her CSF still showed significantly high levels, in particular the markers CXCL13, IFNγ, TNF, CXCL12, LIGHT, IL6, and IL10. No significant changes in inflammatory markers were detected in blood samples.

From 2006 to 2013, her CSF levels of neurofilament light chain (NfL) — a proposed biomarker for MS — also increased significantly, rising from 4,400 pg/ml to 6,300 pg/ml.

These results suggest that unusually high levels of inflammatory markers in the CSF “could remain stable or increase over time in patients with active multiple sclerosis,” the researchers wrote.

Analysis of these inflammatory markers, along with changes in NfL over time, may help to identify possible biomarkers of disease activity and progression.

“[T]hese data suggest that, despite the several immunomodulatory treatments, a shift in the balance between pro- and anti-inflammatory pathways may induce and/or enhance disease evolution and severity in some MS patient[s],” the researchers concluded. “[W]e underline the usefulness of CSF assessment, combined with clinical and MRI follow-up, to identify the specific immune-inflammatory profile involved in the disease evolution of each MS patient.”