Is it cost-effective to request IgM oligoclonal bands against lipids in daily practice as a biomarker for poor prognosis in multiple sclerosis?

BACKGROUND: various prognostic factors of multiple sclerosis have been identified, including demographic, clinical, radiological, and laboratory factors. The aim was to analyze whether the presence of IgM oligoclonal bands against lipids is associated with disease progression. METHODS: an individual-based, prospective, observational study was conducted at the Neurology Department of Hospital Universitari i Politècnic la Fe. Clinical, radiological, and laboratory variables were collected. Data analysis was divided into a descriptive phase and a subsequent analytical phase. RESULTS: a total of 116 patients were included. 81.9% of them had IgM oligoclonal bands against lipids, with phosphatidylcholine being the predominant type. A higher proportion of patients with IgM oligoclonal bands against lipids required treatment with a disease-modifying drug, started treatment at an earlier stage, showed poorer results in functional tests, and exhibited a higher increase in lesion burden, although these differences were not statistically significant. CONCLUSIONS: In our study, the presence of IgM oligoclonal bands against lipids was not found to be associated with other poor prognostic variables.

Improving the efficiency of free kappa light chains as diagnostic biomarker of Multiple Sclerosis by using a novel algorithm.

BACKGROUND: Intrathecal immunoglobulin synthesis (ITS) plays a crucial role in the diagnosis of multiple sclerosis (MS). Traditionally, the gold standard method for detecting ITS has been through the analysis of oligoclonal bands (OCB). However, the paradigm has shifted with the introduction of the free kappa light chains (FKLC) method. In fact, a recent consensus recommends evaluating FKLC index (FKLCi) as the primary approach and reserving oligoclonal bands with borderline results. The objective of our study is to investigate the diagnostic efficiency of combining FKLC with other methods to predict ITS while minimizing the reliance on OCB. METHODS: A total of 192 patients were included in the study, consisting of 145 individuals diagnosed with multiple sclerosis (pwMS) and 46 with other neurological diseases (controls). Among the MS cases, 100 patients were assigned to the Training Cohort (TC), while an external Validation Cohort (VC) comprised of 45 MS patients was established. Diagnostic efficiency was assessed for FKLCi, OCB, Link index, and the Reiber formula for IgG and FKLC. Optimal cutoff values for Link index and FKLCi were also determined. The last procedure was developed for diverse algorithms using the parameters mentioned above, which included the optimal cutoffs previously obtained. The calculations were conducted independently for both the TC and the VC, as well as for a composite cohort formed by combining data from all patients (OC) RESULTS: One algorithm, named KRO, was developed based on the determination of FKLCi and Reiber Formula as the primary diagnostic parameters. For cases where the FKLCi result was mildly increased, OCB was utilized as a supplementary test. The KRO algorithm demonstrated superior diagnostic accuracy in the OC (89%), resulting in a reduction of OCB consumption by 91%. DISCUSSION: The KRO algorithm demonstrated superior sensitivity and accuracy although lower specificity and NPV compared to the use of FKLCi and OCB alone. The present research aligns with the new consensus recommendations regarding the diagnostic approach. Our findings indicate that employing a combined marker approach via KRO could prove to be a proficient screening tool for multiple sclerosis. This approach also holds the potential to address inherent limitations associated with each individual marker. However, to further validate and solidify the efficacy of our algorithm, additional studies involving larger cohorts are warranted.

Oligoclonal M bands and cervical spinal cord lesions predict early secondary progressive multiple sclerosis.

Objective: To determine baseline cerebrospinal fluid and magnetic resonance imaging (MRI) variables at the onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) that predict evolution to secondary progressive MS (SPMS). Methods: 276 CIS patients with a minimum follow-up of 10 years were studied. Baseline presence of oligoclonal IgG and IgM bands (OCGB and OCMB respectively); number of brain T2 lesions (B-T2L), brain gadolinium enhancement lesions (brain-GEL), cervical spinal cord T2 lesions (cSC-T2L); and fulfillment of 2017 McDonald criteria among other variables were collected. Results: 14 patients ended up with a non-MS condition. 138/276 CIS patients fulfilled 2017 McDonald criteria. Mean age was 32.4 years, 185 female. 227 received treatment, 95 as CIS. After a mean follow-up of 12 years, 36 patients developed SPMS. Conversion to SPMS was associated with OCGB (p = 0.02), OCMB (p = 0.0001); ≥ 9 B-T2L (p = 0.03), brain-GEL (p = 0.03), and cSC-T2L (p = 0.03). However, after adjusting for sex, age, BT2L, brain-GEL, SC-T2, and OCMB status, only OCMB (HR 4.4, 1.9-10.6) and cSC-T2L (HR 2.2, 1.0-6.2) suggested an independent association with risk of conversion to SPMS. Patients with both risk factors had a HR of 6.12 (2.8-12.9). Discussion: OCMB and SC-T2 lesions are potential independent predictors of conversion to SPMS.

Case Report: Exacerbation of Relapses Following mRNA COVID-19 Vaccination in Multiple Sclerosis: A Case Series.

Introduction: mRNA coronavirus disease 2019 (COVID-19) vaccination has been widely used to arrest the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Rarely, autoimmune events such as relapses in patients with multiple sclerosis (MS) have been reported after vaccination. However, the possible effects of vaccination in a patient already experiencing the symptoms of a relapse represent an unusual scenario that has not been described. Patients and Methods: This is a retrospective case series of four patients from three major tertiary referral centers that received mRNA COVID-19 vaccination after starting with symptoms of acute demyelination of the central nervous system due to non-recognized MS. A detailed description of each case, including MRI studies, serum light-neurofilament levels, and cerebrospinal fluid (CSF) cytokine profile, is provided. Case Description: All patients presented exacerbation of ongoing symptoms after vaccination (range 14-112 days first dose). All patients presented MRI features suggestive of highly active MS and fulfilled McDonald 2017 criteria at the time of presentation. All patients presented high serum light-neurofilament levels and oligoclonal G bands restricted to the CSF. Higher levels of interleukin-6 in the CSF were present in the more severe cases. Discussion: We describe exacerbation of relapses after mRNA COVID-19 vaccination. We hypothesize RNA sensors such as Toll-like receptor 7 may be activated and contribute to amplify the inflammatory response during a relapse. Conclusion: Patients should seek medical attention if experiencing acute neurological symptoms, especially before vaccination. Fast diagnostic procedures and prompt treatment should be performed in these patients. Pharmacovigilance and further study are warranted to confirm causality.

High Levels of Cerebrospinal Fluid Kappa Free Light Chains Relate to IgM Intrathecal Synthesis and Might Have Prognostic Implications in Relapsing Multiple Sclerosis.

Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes (p < 0.0001/p < 0.05) and IgG-oligoclonal bands (OCGBs) (p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index (p = 0.049). KFLC-index was higher in patients with LMCE (p = 0.008) and correlated with CHI3L1 (p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1-147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2-7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course.

Potential Role of CHI3L1+ Astrocytes in Progression in MS.

OBJECTIVE: Neurofilament light protein (NfL) and chitinase 3-like 1 (CHI3L1) are biomarkers for acute neuroaxonal damage and local inflammation, respectively. Thus, we set out to evaluate how these biomarkers were associated with clinical features of demyelinating diseases in parallel with the expression in brain autopsies from patients with similar disease stages, assuming their comparability. METHODS: NfL and CHI3L1 in CSF and serum CHI3L1 were assessed retrospectively in a cross-sectional cohort of controls (n = 17) and patients diagnosed with MS (n = 224), relapsing (n = 163) or progressive (n = 61); neuromyelitis optica (NMO, n = 7); and acute disseminated encephalomyelitis (ADEM, n = 15). Inflammatory activity was evaluated at the time of sampling, and CSF biomarker levels were related to the degree of inflammation in 22 brain autopsy tissues. RESULTS: During a clinical attack, the CSF NfL increased in MS, NMO, and ADEM, whereas CHI3L1 was only elevated in patients with NMO and ADEM and in outlier MS patients with extensive radiologic activity. Outside relapses, CHI3L1 levels only remained elevated in patients with progressive MS. CHI3L1 was detected in macrophages and astrocytes, predominantly in areas of active demyelination, and its expression by astrocytes in chronic lesions was independent of lymphocyte infiltrates and associated with active neurodegeneration. CONCLUSIONS: Both CSF NfL and CHI3L1 augment during acute inflammation in demyelinating diseases. In MS, CHI3L1 may be associated with low-grade nonlymphocytic inflammation and active neurodegeneration and therefore linked to progressive disease. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF NfL and CHI3L1 levels increase in inflammatory brain diseases during acute inflammation.

Epilepsy, status epilepticus, and hemiplegic migraine coexisting with a novel SLC4A4 mutation.

BACKGROUND: Recessive mutations in the SLC4A4 gene cause a syndrome characterised by proximal renal tubular acidosis (pRTA), mental retardation, dental and ocular abnormalities, and hemiplegic migraine. Rare cases involving the development of epilepsy or its severe complication-status epilepticus-have been described. METHODS: The clinical and genetic status of four affected members in a Spanish family was studied. The SLC4A4 gene mutation was detected with a next-generation sequencing (NGS) panel in the proband, and Sanger confirmed the putative mutations in affected relatives. In silico analysis was performed to elucidate the putative effect of mutation on the splicing process. RESULTS: A novel mutation, c.2562+2T>G, was identified in the homozygous state in all diseased members of the family. This mutation affected a canonical splice site and is predicted to abolish the wild-type donor site, which predicts a premature truncated NBCe1 protein with cotransport activity. The resulting protein lacks the 190 amino acids of the carboxyl-terminus, and the effect is likely to be a loss of function. All patients suffered from severe pRTA and ocular abnormalities, and the adults also suffered from neurological complications, such as hemiplegic migraine and/or epilepsy. Two developed life-threatening status epilepticus, although they fully recovered and remained free of seizures with valproate. CONCLUSION: These results expand the clinical and mutational spectra of SLC4A4-related disease and have implications for understanding the potential role of NBCe1 in the pathophysiologic processes of hemiplegic migraine and epilepsy/status epilepticus associated with the mutation.