{"product_id":"two-new-biomarkers-that-could-transform-multiple-sclerosis-diagnosis-the-kappa-free-light-chain-index-and-the-central-vein-sign","title":"Two New Biomarkers That Could Transform Multiple Sclerosis Diagnosis: The Kappa Free Light Chain Index and the Central Vein Sign","description":"\u003cp\u003eNew research presented at the 2024 ECTRIMS meeting (the largest European multiple sclerosis conference) proposes that multiple sclerosis (MS) can now be diagnosed before any symptoms ever appear. Two biomarkers take center stage in this proposed shift: the kappa free light chain index (kFLC index), a blood-and-spinal-fluid test that detects immune system activity inside the central nervous system, and the central vein sign (CVS), a specific MRI pattern. The kFLC index has an estimated sensitivity of 88% and specificity of 89% for MS, comparable to the traditional oligoclonal band (OCB) test, while also predicting future disease activity. Together with the addition of the optic nerve as a fifth location for \"dissemination in space,\" these changes aim to catch the disease earlier and avoid both misdiagnosis and harmful delays in treatment.\u003c\/p\u003e\n\n\u003ch1\u003eTwo New Biomarkers That Could Transform Multiple Sclerosis Diagnosis: The Kappa Free Light Chain Index and the Central Vein Sign\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eWhy the MS Diagnostic Criteria Are Changing\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#consider\"\u003eThe 2024 Proposal: Diagnosing MS Before Symptoms Begin\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#csf\"\u003eThe Biology Behind the kFLC Index: What Spinal Fluid Reveals\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#accuracy\"\u003eHow Accurate Is the kFLC Index for Diagnosing MS?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#prognosis\"\u003eThe kFLC Index as a Crystal Ball: Predicting Future Disease Activity\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ocb\"\u003ekFLC Index vs. Oligoclonal Bands: The Same Story, Two Tests\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#laboratory\"\u003eLaboratory Practicalities: How kFLC Testing Works\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#cvs\"\u003eThe Central Vein Sign: A New MRI Biomarker\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eWhat These Changes Mean for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What the Research Could Not Yet Prove\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eThe 2024 proposed McDonald criteria introduce preclinical MS diagnosis using typical MRI lesions in at least 2 of 5 locations plus one biomarker.\u003c\/li\u003e\n\u003cli\u003eThe kFLC index has 88% sensitivity and 89% specificity for MS, similar to oligoclonal bands, and can predict future disease activity.\u003c\/li\u003e\n\u003cli\u003eThe central vein sign on specialized MRI, with at least 6 lesions, is one of three acceptable diagnostic biomarkers in the proposal.\u003c\/li\u003e\n\u003cli\u003eIn RIS, 34% had a first MS event at 5 years and 51.2% at 10 years; two trials showed early therapy reduced first events 4- to 5-fold.\u003c\/li\u003e\n\u003cli\u003eThe 2024 criteria were presented at ECTRIMS 2024 but not yet formally published; evidence in RIS is limited to one study of 36 people.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eWhy the MS Diagnostic Criteria Are Changing\u003c\/h2\u003e\n\n\u003cp\u003eMultiple sclerosis (MS) is a chronic disease of the central nervous system (the brain and spinal cord), in which the immune system attacks the protective coating around nerve fibers. Diagnosis has relied for years on the McDonald criteria, most recently revised in 2017. Those criteria combine clinical symptoms, MRI findings, and laboratory tests to diagnose MS early — often after a first neurological event.\u003c\/p\u003e\n\n\u003cp\u003eThe 2017 criteria had three unintended consequences, however. First, they raised the risk of misdiagnosis because their specificity was lower than the 2010 version. Second, the term \"clinically isolated syndrome\" (CIS) — used for patients who had one attack but did not yet meet MS criteria — virtually disappeared from use. Third, an older biological marker called the elevated IgG index was removed from cerebrospinal fluid testing as a useful diagnostic tool.\u003c\/p\u003e\n\n\u003cp\u003eAt the same time, understanding of a condition called radiologically isolated syndrome (RIS) has grown dramatically. RIS was first described in 2009. It refers to people who have no MS symptoms at all but whose brain MRIs, taken for unrelated reasons (such as headaches or trauma), show white matter lesions that look like MS. For years, experts hesitated to call RIS \"preclinical MS\" because the evidence was insufficient.\u003c\/p\u003e\n\n\u003cp\u003eThat evidence has now arrived. The RIS Consortium (RISC), an international research group, followed people with RIS prospectively and found that \u003cstrong\u003e34% experienced a first clinical event suggestive of MS after 5 years of follow-up\u003c\/strong\u003e, and \u003cstrong\u003e51.2% did so after 10 years\u003c\/strong\u003e. Young age, spinal cord lesions, and gadolinium-enhancing lesions (areas of active inflammation seen on MRI) at the time of RIS diagnosis predicted conversion to MS within the first 2 years.\u003c\/p\u003e\n\n\u003cp\u003eTwo international randomized, placebo-controlled trials provided further proof. In people with RIS, teriflunomide (Aubagio) and dimethyl fumarate (Tecfidera) — both disease-modifying therapies already used for relapsing-remitting MS — reduced the occurrence of a first clinical event at week 96 by a factor of 4 to 5 compared with placebo.\u003c\/p\u003e\n\n\u003cp\u003eThe RISC also showed that even people with fewer MRI lesions than the 2009 RIS criteria required were not safe: \u003cstrong\u003e29% of asymptomatic individuals with a low number of demyelinating-appearing lesions transitioned to symptomatic MS within 5 years\u003c\/strong\u003e. That number rose to \u003cstrong\u003e38% when they also had a spinal cord MRI lesion plus oligoclonal bands (OCB)\u003c\/strong\u003e — specific immune proteins found in spinal fluid. In 2023, the RIS diagnostic criteria were revised to identify people at risk of symptomatic MS within 5 years, with an accuracy of 60%.\u003c\/p\u003e\n\n\u003cp\u003eGiven this evidence, most experts now agree that most people with RIS actually have preclinical MS — that is, the disease is present and active, just not yet symptomatic. In 2024, an international panel of experts from 16 countries, co-sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the National MS Society, met to update the McDonald criteria. Their goal included a major step: making it possible to diagnose MS at a preclinical stage.\u003c\/p\u003e\n\n\u003ch2 id=\"consider\"\u003eThe 2024 Proposal: Diagnosing MS Before Symptoms Begin\u003c\/h2\u003e\n\n\u003cp\u003eThe proposed 2024 revision introduces several key changes. The optic nerve has been added as a \u003cstrong\u003efifth topography\u003c\/strong\u003e (location) for fulfilling \"dissemination in space\" (DIS) — the requirement that MS lesions appear in multiple separate areas of the nervous system. Previously, only four locations in the brain and spinal cord counted.\u003c\/p\u003e\n\n\u003cp\u003eUnder the proposal, a diagnosis of \u003cstrong\u003epreclinical MS\u003c\/strong\u003e could be made in a person with no MS symptoms if they meet both of the following conditions:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003eThey have typical demyelinating white matter lesions on T2-weighted MRI in at least \u003cstrong\u003e2 of the 5 DIS locations\u003c\/strong\u003e (now including the optic nerve).\u003c\/li\u003e\n  \u003cli\u003eThey have at least one specific MRI or biological diagnostic biomarker.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThree biomarkers can fulfill that second requirement:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDissemination in time (DIT):\u003c\/strong\u003e at least one gadolinium-enhancing lesion (active inflammation) or a new T2-weighted lesion on a follow-up MRI.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIntrathecal immunoglobulin synthesis:\u003c\/strong\u003e evidence that the immune system is producing antibodies inside the spinal fluid, detected either by oligoclonal bands (OCB) or by a positive kappa free light chain (kFLC) index.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAt least six lesions showing the central vein sign (CVS):\u003c\/strong\u003e a specific MRI feature described below.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eImportantly, the proposal adds an extra layer of caution for certain patients. In people with comorbidities — such as vascular risk factors, a known vascular or headache disorder — or in people older than 50, the panel recommends that one additional biomarker be required from this list: intrathecal immunoglobulin synthesis, at least 6 CVS-positive lesions, or at least one spinal cord lesion consistent with demyelination. The extra biomarker used must be different from the one already used to fulfill the diagnostic biomarker requirement. This safeguard helps avoid misdiagnosing conditions that can mimic MS on MRI, such as small vessel disease from high blood pressure or diabetes.\u003c\/p\u003e\n\n\u003cp\u003eThis proposed definition of preclinical MS differs slightly from the 2023 RIS criteria. The 2024 criteria require lesions in 2 of 5 DIS locations (versus fulfilling older 2005 RIS criteria) and require one diagnostic biomarker (versus two of three for RIS). Both approaches converge on the same idea, but the 2024 version is designed specifically for making a formal MS diagnosis.\u003c\/p\u003e\n\n\u003cp\u003eA crucial caveat: at the time of this review, the 2024 McDonald criteria had been presented at the ECTRIMS meeting in Copenhagen (September 17–20, 2024) but had \u003cstrong\u003enot yet been formally published\u003c\/strong\u003e. This article is based on the presentation by Montalban and colleagues.\u003c\/p\u003e\n\n\u003ch2 id=\"csf\"\u003eThe Biology Behind the kFLC Index: What Spinal Fluid Reveals\u003c\/h2\u003e\n\n\u003cp\u003eTo understand the kFLC index, it helps to start with what happens in the spinal fluid of people with MS. Most people with MS who undergo a lumbar puncture (spinal tap) have evidence of inflammation in their cerebrospinal fluid (CSF). This inflammation is driven largely by immune cells called meningeal follicular plasmocytes and activated B cells.\u003c\/p\u003e\n\n\u003cp\u003eIn clinical practice, doctors look for a specific sign of this process: CSF-restricted B-cell immunoglobulin production, also called \u003cstrong\u003eintrathecal Ig synthesis\u003c\/strong\u003e. This means the immune system inside the brain and spinal cord is producing antibodies (immunoglobulins) in greater quantities than would be expected from blood alone.\u003c\/p\u003e\n\n\u003cp\u003eTwo standard methods detect this synthesis. The first calculates an \u003cstrong\u003eIgG index\u003c\/strong\u003e by comparing IgG concentrations in CSF and serum (blood). The second looks for \u003cstrong\u003eoligoclonal bands (OCB)\u003c\/strong\u003e using a technique called isoelectric focusing. OCB testing is considered the gold standard.\u003c\/p\u003e\n\n\u003cp\u003eOCB positivity supports an MS diagnosis, with an overall sensitivity ranging from \u003cstrong\u003e80 to 100%\u003c\/strong\u003e and specificity ranging from \u003cstrong\u003e54 to 94%\u003c\/strong\u003e, depending on the control population used for comparison. The wide range stems from differences in laboratory methods and from the fact that interpreting OCB results can vary between readers. Techniques such as isoelectric focusing on polyacrylamide gels with silver staining achieve higher sensitivity but are not used in every laboratory.\u003c\/p\u003e\n\n\u003cp\u003eOCB also predicts future disease. In patients with CIS, OCB positivity is associated with more MRI and clinical activity during follow-up, adding important information to the baseline MRI. This evidence led to OCB being added as a diagnostic biomarker in the 2017 McDonald criteria. In people with RIS, OCB is found in almost \u003cstrong\u003e70% of cases\u003c\/strong\u003e, and it is linked to a higher risk of clinical attacks and conversion to symptomatic MS.\u003c\/p\u003e\n\n\u003cp\u003eBut the story does not end with IgG. Healthy immune cells (plasmocytes) produce antibodies made of two heavy chains and two light chains. Plasmocytes actually overproduce light chains relative to heavy chains, secreting the excess as \u003cstrong\u003efree light chains (FLC)\u003c\/strong\u003e. Since the 1990s, researchers have known that MS involves an oligoclonal overproduction of the \u003cem\u003ekappa\u003c\/em\u003e type of free light chain — but not the lambda type.\u003c\/p\u003e\n\n\u003cp\u003eThe \u003cstrong\u003ekFLC index\u003c\/strong\u003e is a calculated value that compares kappa free light chain and albumin levels in CSF and serum. The formula is:\u003c\/p\u003e\n\u003cp\u003e\u003cem\u003eFLC index = QFLC \/ QA = (FLC in CSF ÷ FLC in serum) ÷ (Albumin in CSF ÷ Albumin in serum)\u003c\/em\u003e\u003c\/p\u003e\n\n\u003cp\u003eAlbumin serves as a reference molecule to account for how much protein normally crosses from blood into spinal fluid. An elevated index means kappa light chains are being produced \u003cem\u003einside\u003c\/em\u003e the central nervous system — a hallmark of MS-related inflammation.\u003c\/p\u003e\n\n\u003cp\u003eSome researchers prefer a graphical method called \u003cstrong\u003eReiber's diagram\u003c\/strong\u003e, which uses a hyperbolic function to account for the non-linear relationship between the FLC quotient and the albumin quotient. Some studies report very good results with this approach, including higher sensitivity than the index but lower specificity — and it can turn positive in non-MS inflammatory and non-inflammatory conditions. However, large studies directly comparing the two techniques found similar diagnostic accuracy. Because the 2024 McDonald criteria specifically include the kFLC index (not Reiber's diagram) as the intrathecal synthesis biomarker, this review focuses on the index.\u003c\/p\u003e\n\n\u003ch2 id=\"accuracy\"\u003eHow Accurate Is the kFLC Index for Diagnosing MS?\u003c\/h2\u003e\n\n\u003cp\u003eMany multicenter cohort studies have compared kFLC index values between people with MS and control groups. Overall, the kFLC index performs impressively. When a positive kFLC index is defined using site-specific thresholds, its \u003cstrong\u003eoverall sensitivity for diagnosing MS is 88%\u003c\/strong\u003e and its \u003cstrong\u003eoverall specificity is 89%\u003c\/strong\u003e — remarkably similar to OCB testing. Notably, the kFLC index has a slightly higher sensitivity than OCB, likely because kappa light chains reflect overproduction of IgM and other antibody types, not just IgG.\u003c\/p\u003e\n\n\u003cp\u003eThe following table summarizes 17 major studies of the kFLC index's ability to separate people with MS from control participants. The \"accuracy\" values represent the proportion of people correctly classified by the test (for example, 0.94 means 94 out of 100 people were correctly classified). Studies marked with a symbol pooled MS and CIS patients into one group.\u003c\/p\u003e\n\n\u003ctable border=\"1\" cellpadding=\"6\" cellspacing=\"0\"\u003e\n  \u003cthead\u003e\n    \u003ctr\u003e\n      \u003cth\u003eStudy (Year)\u003c\/th\u003e\n      \u003cth\u003ePatients (MS\/Control)\u003c\/th\u003e\n      \u003cth\u003eMethod (Analyzer\/Assay)\u003c\/th\u003e\n      \u003cth\u003ekFLC Index Cutoff\u003c\/th\u003e\n      \u003cth\u003eAccuracy\u003c\/th\u003e\n    \u003c\/tr\u003e\n  \u003c\/thead\u003e\n  \u003ctbody\u003e\n    \u003ctr\u003e\n\u003ctd\u003ePresslauer et al. 2016*\u003c\/td\u003e\n\u003ctd\u003e120\/60\u003c\/td\u003e\n\u003ctd\u003eBehring\/Freelight\u003c\/td\u003e\n\u003ctd\u003e5.9\u003c\/td\u003e\n\u003ctd\u003e0.94\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eChristiansen et al. 2018*\u003c\/td\u003e\n\u003ctd\u003e133\/97\u003c\/td\u003e\n\u003ctd\u003eSPAplus\/Freelight\u003c\/td\u003e\n\u003ctd\u003e5.2\u003c\/td\u003e\n\u003ctd\u003e0.88\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eVasilij et al. 2018*\u003c\/td\u003e\n\u003ctd\u003e101\/50\u003c\/td\u003e\n\u003ctd\u003eSiemens\/Freelight\u003c\/td\u003e\n\u003ctd\u003e8.8\u003c\/td\u003e\n\u003ctd\u003e0.85\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eSenel et al. 2019\u003c\/td\u003e\n\u003ctd\u003e75\/1149\u003c\/td\u003e\n\u003ctd\u003eBehring\/N-latex\u003c\/td\u003e\n\u003ctd\u003e9.6\u003c\/td\u003e\n\u003ctd\u003e0.94\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eCrespi et al. 2019\u003c\/td\u003e\n\u003ctd\u003e127\/258\u003c\/td\u003e\n\u003ctd\u003eBehring\/N-latex\u003c\/td\u003e\n\u003ctd\u003e5.0\u003c\/td\u003e\n\u003ctd\u003e0.93\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eEmersic et al. 2018\u003c\/td\u003e\n\u003ctd\u003e80\/50\u003c\/td\u003e\n\u003ctd\u003eBehring\/N-latex\u003c\/td\u003e\n\u003ctd\u003e5.3\u003c\/td\u003e\n\u003ctd\u003e0.96\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eReiber et al. 2020\u003c\/td\u003e\n\u003ctd\u003e95\/256\u003c\/td\u003e\n\u003ctd\u003eSiemens\/N-latex\u003c\/td\u003e\n\u003ctd\u003e5.0\u003c\/td\u003e\n\u003ctd\u003e0.93\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eGaetani et al. 2020*\u003c\/td\u003e\n\u003ctd\u003e64\/106\u003c\/td\u003e\n\u003ctd\u003eBehring\/Freelight\u003c\/td\u003e\n\u003ctd\u003e7.8\u003c\/td\u003e\n\u003ctd\u003e0.85\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eCavalla et al. 2020\u003c\/td\u003e\n\u003ctd\u003e140\/233\u003c\/td\u003e\n\u003ctd\u003eBehring\/N-latex\u003c\/td\u003e\n\u003ctd\u003e6.2\u003c\/td\u003e\n\u003ctd\u003e0.85\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eLeurs et al. 2020*\u003c\/td\u003e\n\u003ctd\u003e526\/219\u003c\/td\u003e\n\u003ctd\u003eOptilite\/Freelight\u003c\/td\u003e\n\u003ctd\u003e6.6\u003c\/td\u003e\n\u003ctd\u003e0.86\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eFerraro et al. 2020\u003c\/td\u003e\n\u003ctd\u003e146\/299\u003c\/td\u003e\n\u003ctd\u003eOptilite\/Freelight\u003c\/td\u003e\n\u003ctd\u003e5.8\u003c\/td\u003e\n\u003ctd\u003e0.73\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eFerraro et al. 2020\u003c\/td\u003e\n\u003ctd\u003e84\/458\u003c\/td\u003e\n\u003ctd\u003eOptilite\/Freelight\u003c\/td\u003e\n\u003ctd\u003e6.2\u003c\/td\u003e\n\u003ctd\u003e0.86\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eSanz Diaz et al. 2021*\u003c\/td\u003e\n\u003ctd\u003e36\/197\u003c\/td\u003e\n\u003ctd\u003eOptilite\/Freelight\u003c\/td\u003e\n\u003ctd\u003e6.6\u003c\/td\u003e\n\u003ctd\u003e0.90\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eRosenstein et al. 2021*\u003c\/td\u003e\n\u003ctd\u003e223\/101\u003c\/td\u003e\n\u003ctd\u003eSiemens\/N-latex\u003c\/td\u003e\n\u003ctd\u003e4.6\u003c\/td\u003e\n\u003ctd\u003e0.90\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eBernardi et al. 2022\u003c\/td\u003e\n\u003ctd\u003e171\/235\u003c\/td\u003e\n\u003ctd\u003eOptilite\/Freelight\u003c\/td\u003e\n\u003ctd\u003e6.4\u003c\/td\u003e\n\u003ctd\u003e0.86\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eLevraut et al. 2022*\u003c\/td\u003e\n\u003ctd\u003e765\/856\u003c\/td\u003e\n\u003ctd\u003eOptilite\/Freelight\u003c\/td\u003e\n\u003ctd\u003e8.9\u003c\/td\u003e\n\u003ctd\u003e0.89\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eZondra Revendova et al. 2024*\u003c\/td\u003e\n\u003ctd\u003e439\/1312\u003c\/td\u003e\n\u003ctd\u003eSPAplus\/Freelight\u003c\/td\u003e\n\u003ctd\u003e8.9\u003c\/td\u003e\n\u003ctd\u003e0.93\u003c\/td\u003e\n\u003c\/tr\u003e\n  \u003c\/tbody\u003e\n\u003c\/table\u003e\n\n\u003cp\u003e\u003cem\u003e*Studies that placed MS and CIS patients in the same group.\u003c\/em\u003e\u003c\/p\u003e\n\n\u003cp\u003eThe kFLC index has also been evaluated in primary progressive MS and in pediatric-onset MS, with results similar to those in relapsing MS. Reported cutoffs for positivity across studies ranged from \u003cstrong\u003e2.4 to 10.6\u003c\/strong\u003e, and the cutoff tended to be higher when patients with other inflammatory neurological diseases served as the control group. A recent meta-analysis suggested that an optimized threshold for clinical practice could be \u003cstrong\u003e6.1\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eWhy so many different cutoffs? Partly because study populations differed, and partly because researchers handled \"undetectable\" spinal fluid values differently. A crucial technical point is that different machines have different detection limits — for example, 0.28 mg\/L for the Optilite analyzer versus 0.09 mg\/L for certain Siemens analyzers. Values below these limits should be treated as negative.\u003c\/p\u003e\n\n\u003cp\u003eThe good news for clinical practice: a recent multicenter study found \u003cstrong\u003e98% concordance\u003c\/strong\u003e when comparing site-specific kFLC index thresholds (ranging from 4.6 to 7.5) with the proposed 6.1 threshold. In plain terms, most reported cutoffs work well. Higher cutoffs give better specificity (fewer false positives), while lower cutoffs give better sensitivity (fewer false negatives). Most people with MS have very high kFLC index values anyway, making the exact threshold choice less critical for them.\u003c\/p\u003e\n\n\u003ch2 id=\"prognosis\"\u003eThe kFLC Index as a Crystal Ball: Predicting Future Disease Activity\u003c\/h2\u003e\n\n\u003cp\u003eBeyond diagnosis, the kFLC index has prognostic value — it helps predict what will happen next. Across studies, people with CIS who later experienced a clinical relapse had higher median kFLC index values at diagnosis than those who remained stable.\u003c\/p\u003e\n\n\u003cp\u003eThree key studies — Arrambide et al. (214 patients), Gaetani et al. (23 patients), and Levraut et al. (146 patients) — all reached the same conclusion: people with CIS and a positive kFLC index are more likely to develop a second clinical attack during follow-up. The increased risk was estimated as \u003cstrong\u003etwofold higher\u003c\/strong\u003e compared with CIS patients with a negative kFLC index.\u003c\/p\u003e\n\n\u003cp\u003eThe kFLC index can even be used as a continuous scale. One study suggested that a kFLC index value above 100 corresponds to a twofold higher risk of a second attack each year. Another (Levraut et al.) found the risk was \u003cstrong\u003e40% higher per year for each increase of 100 in the index\u003c\/strong\u003e. In a separate study of 86 CIS patients, an elevated kFLC index predicted a second relapse better than elevated neurofilament light chains (NfL), a widely studied marker of nerve damage.\u003c\/p\u003e\n\n\u003cp\u003eIn people already diagnosed with MS, a high kFLC index at baseline is associated with more active disease. That means higher disability scores on the Expanded Disability Status Scale (EDSS), more gadolinium-enhancing lesions on MRI, an increased risk of reaching clinical disability during follow-up, confirmed disability worsening independent of relapse activity, and a shorter time until doctors needed to escalate to high-efficacy disease-modifying therapy.\u003c\/p\u003e\n\n\u003cp\u003eThe evidence in RIS is thinner but striking. In the only dedicated study (Levraut et al., 36 people with RIS), the median kFLC index was \u003cstrong\u003e19\u003c\/strong\u003e, and \u003cstrong\u003e61% had a positive index\u003c\/strong\u003e. Those with a positive index had a \u003cstrong\u003e3.5-fold increased risk of MRI activity\u003c\/strong\u003e during follow-up — supporting the idea that kFLC positivity identifies true preclinical MS. The same study found a \u003cstrong\u003e3.6-fold increased risk of dissemination in time (new MRI lesions) \u003c\/strong\u003e in RIS patients with a positive kFLC index compared with those with a negative one.\u003c\/p\u003e\n\n\u003cp\u003eThat study had limited statistical power to detect clinical attacks (only 36 RIS patients, with a median follow-up of 2 years). However, an ongoing international study (trial number NCT06395662) is now working to stratify the risk of clinical conversion in people with RIS using various serum and CSF biomarkers, including the kFLC index. Its results should provide firmer answers.\u003c\/p\u003e\n\n\u003ch2 id=\"ocb\"\u003ekFLC Index vs. Oligoclonal Bands: The Same Story, Two Tests\u003c\/h2\u003e\n\n\u003cp\u003eBecause the kFLC index and OCB detect the same underlying process — intrathecal immunoglobulin synthesis — it is no surprise that they are highly correlated. Studies report an agreement between the two biomarkers of \u003cstrong\u003e85% to 90%\u003c\/strong\u003e. Even the level of the kFLC index correlates with the \u003cem\u003enumber\u003c\/em\u003e of OCB bands present.\u003c\/p\u003e\n\n\u003cp\u003eWhen the two tests disagree, the discrepancy usually favors a positive kFLC index with a negative OCB result. That reflects the kFLC index's higher sensitivity. But the kFLC index is not perfect. It can turn positive with negative OCB testing in certain other conditions, including:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eCentral nervous system infections\u003c\/li\u003e\n  \u003cli\u003eAQP4 IgG-positive neuromyelitis optica spectrum disorder (NMOSD), a different autoimmune disease that also attacks the central nervous system\u003c\/li\u003e\n  \u003cli\u003ePeople living with HIV who have neurological symptoms\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe kFLC index can also add value when OCB results are ambiguous — specifically, the \"pattern V\" isoelectric focusing pattern, which is difficult to interpret.\u003c\/p\u003e\n\n\u003cp\u003eSo which test should come first? The kFLC index is cost-effective, faster, and more sensitive than OCB. Many authors therefore suggest using it as a screening tool, reserving OCB testing for cases with high suspicion of central nervous system inflammation but a negative kFLC index. This two-step approach must rule out intrathecal synthesis definitively, and such algorithms are reported to be very accurate.\u003c\/p\u003e\n\n\u003cp\u003eOn the other hand, using the kFLC index alone could lead to misdiagnosis, given the conditions listed above. The German CSF Society recently suggested a pragmatic solution: since a lumbar puncture is invasive and usually performed only once during the diagnostic work-up, laboratories should consider running \u003cstrong\u003eboth biomarkers at the same time\u003c\/strong\u003e. The final choice — one test or both — depends on what each laboratory is familiar with, weighing cost, procedure time, and the invasiveness of the lumbar puncture.\u003c\/p\u003e\n\n\u003ch2 id=\"laboratory\"\u003eLaboratory Practicalities: How kFLC Testing Works\u003c\/h2\u003e\n\n\u003cp\u003eCalculating the kFLC index requires measuring kappa free light chains and albumin in both serum and cerebrospinal fluid. The recommended measurement techniques are based on \u003cstrong\u003eturbidimetry\u003c\/strong\u003e and \u003cstrong\u003enephelometry\u003c\/strong\u003e — automated methods that measure how much light is scattered or blocked as antibodies bind to the kappa light chains. Both are automated, cost-effective, and provide reproducible results.\u003c\/p\u003e\n\n\u003cp\u003eTwo main platforms dominate MS research. The \u003cstrong\u003eOptilite\u003c\/strong\u003e (from The Binding Site) uses turbidimetry with the Freelight assay. \u003cstrong\u003eSiemens platforms\u003c\/strong\u003e, such as the BN Prospec, use nephelometry with the N-latex assay. Studies using either platform achieved similar diagnostic accuracy, as seen in the table above.\u003c\/p\u003e\n\n\u003cp\u003eSeveral factors can interfere with results and should be considered when interpreting them. Because the index formula divides CSF kFLC by serum kFLC, conditions that raise blood kFLC concentrations can artificially lower the index, potentially causing \u003cstrong\u003efalse negative\u003c\/strong\u003e results. Kidney (renal) failure is a key example, since free light chains are normally cleared by the kidneys. Exposure to highly effective disease-modifying therapies before the lumbar puncture is another factor that must be weighed when interpreting the kFLC index, since treatment can suppress the very inflammation the test detects.\u003c\/p\u003e\n\n\u003ch2 id=\"cvs\"\u003eThe Central Vein Sign: A New MRI Biomarker\u003c\/h2\u003e\n\n\u003cp\u003eThe second new biomarker in the proposed criteria is the \u003cstrong\u003ecentral vein sign (CVS)\u003c\/strong\u003e — a radiological finding visible on specialized MRI scans. In MS, the demyelinating lesions that form in the brain characteristically develop around small veins. When a vein runs through the center of a lesion, that is the \"central vein sign.\"\u003c\/p\u003e\n\n\u003cp\u003eThis feature helps distinguish MS lesions from those caused by other conditions, such as small vessel disease related to aging, high blood pressure, or diabetes — which often look similar on standard MRI but do not form around veins.\u003c\/p\u003e\n\n\u003cp\u003eFor accurate CVS assessment, experts recommend using \u003cstrong\u003emerged 1mm FLAIR and T2*-weighted sequences, or susceptibility-weighted imaging (SWI)\u003c\/strong\u003e. The assessment should be performed on typical MS-suggestive lesions — those that are ovoid (egg-shaped), not confluent (not merging into one another), and larger than 3 mm in diameter.\u003c\/p\u003e\n\n\u003cp\u003eTwo rules have been developed to define a \"CVS-positive\" MRI scan:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eThe Select-6 rule:\u003c\/strong\u003e at least 6 lesions showing the central vein sign.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eThe 40% threshold rule:\u003c\/strong\u003e at least 40% of visible lesions showing the central vein sign (used in patients with a low overall lesion load, where the Select-6 rule cannot be applied).\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBoth rules reach high sensitivity and specificity for MS diagnosis. In the proposed 2024 criteria, the presence of at least six CVS-positive lesions serves as one of the three acceptable diagnostic biomarkers that — combined with dissemination in space — supports a preclinical MS diagnosis.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat These Changes Mean for Patients\u003c\/h2\u003e\n\n\u003cp\u003eIf adopted, the 2024 McDonald criteria will change the conversation in the doctor's office. A person whose brain MRI shows MS-like lesions but who feels perfectly fine could leave that visit with a formal MS diagnosis rather than a vague label like RIS and a \"wait and see\" approach.\u003c\/p\u003e\n\n\u003cp\u003eThat has real consequences — and real benefits. Symptom-free people who meet the new criteria could be offered disease-modifying therapies. In the RIS trials mentioned above, teriflunomide and dimethyl fumarate reduced first clinical events by a factor of 4 to 5 at 96 weeks. Early treatment of MS is associated with less long-term disability. The proposed criteria are designed to prevent both problems of the 2017 rules: too few people treated early and too many people misdiagnosed.\u003c\/p\u003e\n\n\u003cp\u003eFor patients undergoing diagnostic testing, the practical implications include:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eA lumbar puncture remains valuable. The kFLC index can now be measured from the same spinal fluid sample used for OCB testing, and the two tests together provide powerful diagnostic information.\u003c\/li\u003e\n  \u003cli\u003eOCB testing requires a specialized technique (isoelectric focusing) and expert interpretation. The kFLC index is automated, faster, and less subjective — which may mean quicker answers for patients.\u003c\/li\u003e\n  \u003cli\u003eMRI protocols may need updating. Detecting the central vein sign requires specific sequences (FLAIR merged with T2* or SWI) that are not part of every routine MRI scan.\u003c\/li\u003e\n  \u003cli\u003eA positive kFLC index in a person with RIS is not an abstract lab value. It corresponds to a 3.5-fold higher risk of MRI activity and a 3.6-fold higher risk of new lesions — information that can guide decisions about monitoring and treatment.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What the Research Could Not Yet Prove\u003c\/h2\u003e\n\n\u003cp\u003eThe authors are careful to note several limitations. Most importantly, the 2024 McDonald criteria had not been formally published when this review was written; the article relies on the presentation given at the ECTRIMS meeting in September 2024. Final published criteria could differ in details.\u003c\/p\u003e\n\n\u003cp\u003eThe evidence base for the kFLC index in RIS is much thinner than in symptomatic MS. Only one dedicated study has evaluated the kFLC index in people with RIS, and it included just 36 participants with a median follow-up of 2 years. The study could not determine whether a positive kFLC index predicts actual clinical attacks (not just MRI changes) in RIS. Larger, longer studies are needed.\u003c\/p\u003e\n\n\u003cp\u003eThere is also no universally agreed-upon kFLC index cutoff. Reported thresholds range from 2.4 to 10.6, depending on the study population, the analyzer used, and how undetectable values were handled. Different machines have different detection limits, which complicates comparing results across laboratories.\u003c\/p\u003e\n\n\u003cp\u003eMisdiagnosis remains possible. A positive kFLC index occurs in conditions other than MS, including central nervous system infections, AQP4+ neuromyelitis optica spectrum disorder, and HIV with neurological symptoms. The proposed criteria's additional biomarker requirement for patients over 50 or with vascular comorbidities is a safeguard, but its performance in real-world populations still needs validation.\u003c\/p\u003e\n\n\u003cp\u003eThis article is a narrative review by the authors, not a systematic review or meta-analysis of all available literature.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\n\u003cp\u003eFor patients and families navigating these changes, several practical points stand out:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk about both biomarkers.\u003c\/strong\u003e If you are having a lumbar puncture to evaluate possible MS, ask whether the kFLC index will be measured alongside OCB. The German CSF Society suggests running both, since the lumbar puncture is usually a one-time procedure.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eUnderstand the numbers.\u003c\/strong\u003e Of 100 people who have MS, about 88 will have a positive kFLC index (sensitivity), and of 100 people without MS, about 89 will have a negative result (specificity). No test is perfect — a positive result is one piece of the diagnostic puzzle, not the whole picture.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eInterpretation depends on context.\u003c\/strong\u003e A positive kFLC index means something different in a young person with typical MS symptoms than in a 60-year-old with vascular risk factors. The proposed criteria address this by requiring extra confirmation in older patients and those with comorbidities.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIf you have RIS, do not ignore it.\u003c\/strong\u003e The data show that roughly 1 in 3 people with RIS will have a first MS attack within 5 years, and about half within 10 years. Biomarkers like the kFLC index and OCB can refine your personal risk. Discuss monitoring and treatment options with your neurologist.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk about the MRI protocol.\u003c\/strong\u003e If central vein sign assessment is being considered, the MRI must include the appropriate sequences. Not all imaging centers routinely perform them.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThese diagnostic advances do not change the fact that MS is a highly individual disease. A diagnosis — even a preclinical one — should always lead to a personalized discussion with a neurologist about the risks, benefits, and timing of treatment.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is the kappa free light chain (kFLC) index and how is it measured?\u003c\/h3\u003e\n\u003cp\u003eThe kFLC index is a calculated value comparing kappa free light chain and albumin levels in cerebrospinal fluid and serum. It detects immune system activity inside the central nervous system. Measurement uses automated turbidimetry or nephelometry methods, which are cost-effective and reproducible. The index can be measured from the same spinal fluid sample used for oligoclonal band testing.\u003c\/p\u003e\n\u003ch3\u003eHow accurate is the kFLC index for diagnosing multiple sclerosis?\u003c\/h3\u003e\n\u003cp\u003eWhen a positive kFLC index is defined using site-specific thresholds, its overall sensitivity for diagnosing MS is 88% and its overall specificity is 89%, according to pooled data from multiple studies. This is similar to oligoclonal band testing. A positive result means about 88 out of 100 people tested will truly have MS, but it is one piece of the diagnostic puzzle.\u003c\/p\u003e\n\u003ch3\u003eCan the kFLC index predict future MS disease activity?\u003c\/h3\u003e\n\u003cp\u003eYes. In people with clinically isolated syndrome, a positive kFLC index is associated with a twofold higher risk of a second clinical attack compared with a negative index. In people already diagnosed with MS, a high baseline kFLC index is linked to more active disease, including higher disability scores and more gadolinium-enhancing lesions on MRI.\u003c\/p\u003e\n\u003ch3\u003eWhat is the central vein sign and how is it used in MS diagnosis?\u003c\/h3\u003e\n\u003cp\u003eThe central vein sign is an MRI finding where a small vein runs through the center of a demyelinating lesion. It helps distinguish MS lesions from those caused by other conditions like small vessel disease. In the proposed 2024 criteria, at least six lesions showing the central vein sign can serve as one of three acceptable diagnostic biomarkers.\u003c\/p\u003e\n\u003ch3\u003eWhat does it mean if I have radiologically isolated syndrome (RIS)?\u003c\/h3\u003e\n\u003cp\u003eRIS means you have no MS symptoms but your MRI shows white matter lesions that look like MS. Research shows that 34% of people with RIS experience a first clinical event suggestive of MS after 5 years, and 51.2% after 10 years. Biomarkers like the kFLC index and oligoclonal bands can refine your personal risk, so discuss monitoring with your neurologist.\u003c\/p\u003e\n\u003ch3\u003eWhat are the limitations of the kFLC index and the 2024 proposed criteria?\u003c\/h3\u003e\n\u003cp\u003eThe 2024 McDonald criteria had not been formally published when the review was written. Evidence for the kFLC index in RIS is thin, from one study of 36 participants with median 2-year follow-up. No universally agreed cutoff exists, and a positive kFLC index can occur in other conditions like central nervous system infections or AQP4+ neuromyelitis optica spectrum disorder.\u003c\/p\u003e\n\u003ch3\u003eShould I ask for both kFLC index and oligoclonal band testing?\u003c\/h3\u003e\n\u003cp\u003eThe German CSF Society suggests running both biomarkers at the same time, since a lumbar puncture is invasive and usually performed only once. The kFLC index is automated, faster, and less subjective than oligoclonal band testing, which requires specialized isoelectric focusing and expert interpretation. Ask your neurologist whether both will be measured from your spinal fluid sample.\u003c\/p\u003e\n\u003ch3\u003eIf my MRI shows MS-like lesions but I have no symptoms, when should I seek a second opinion about a preclinical MS diagnosis?\u003c\/h3\u003e\n\u003cp\u003eA preclinical MS diagnosis rests on MRI lesions in at least 2 of 5 locations plus one biomarker: dissemination in time, intrathecal immunoglobulin synthesis (oligoclonal bands or a positive kappa free light chain index), or at least 6 central vein sign lesions. Because the 2024 criteria were presented but not yet formally published, and a positive kappa free light chain index also occurs in central nervous system infections, AQP4-positive neuromyelitis optica spectrum disorder, and HIV with neurological symptoms, an independent review of your MRI sequences and spinal fluid results is reasonable before committing to a diagnosis and long-term therapy. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e The Kappa Free Light Chains Index and Central Vein Sign: Two New Biomarkers for Multiple Sclerosis Diagnosis.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Levraut M, Landes-Chateau C, Mondot L, Cohen M, Lebrun-Frenay C.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eJournal:\u003c\/strong\u003e Neurology and Therapy (Neurol Ther), 2025, Volume 14, pages 711–731. Published online April 6, 2025.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e https:\/\/doi.org\/10.1007\/s40120-025-00737-7\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eImportant note:\u003c\/strong\u003e This manuscript focuses on the 2024 McDonald criteria presented by Montalban X. and colleagues at the ECTRIMS meeting held September 17–20, 2024, in Copenhagen, Denmark. The 2024 McDonald criteria had not yet been published at the time of this review.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not replace professional medical advice. Always discuss diagnostic and treatment decisions with your neurologist or healthcare provider.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47738941603996,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/es\/products\/two-new-biomarkers-that-could-transform-multiple-sclerosis-diagnosis-the-kappa-free-light-chain-index-and-the-central-vein-sign","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}