Impact of the McDonald Criteria 2017 on Early Diagnosis of Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis is a chronic immune mediated demyelinating disease leading to neurological disabilities that need to be diagnosed and treated early. Guidelines on multiple sclerosis diagnosis and monitoring experienced comprehensive changes over the last decades. The first McDonald criteria published in 2001 emphasized the importance of MR imaging but also recognized the role of cerebrospinal fluid diagnostics. The demonstration of an intrathecal immunoglobulin G synthesis is a well-established additional component and has a long tradition in the diagnosis of relapsing-remitting multiple sclerosis. However, the role of cerebrospinal fluid for diagnostic purposes was rather diminished in each revision of the McDonald criteria. In the latest revision of the McDonald criteria of 2017, the detection of an intrathecal immunoglobulin G synthesis as oligoclonal bands experienced a revival. Patients with the first clinical event suggesting multiple sclerosis who fulfill the criteria for dissemination in space can be diagnosed with relapsing-remitting multiple sclerosis when oligoclonal bands in cerebrospinal fluid are detected. The diagnostic sensitivity of these novel criteria with a focus on dissemination in time and oligoclonal bands as a substitute for dissemination in time was published in different cohorts in the last year and is of special interest in this review. Recently published data show that by applying the 2017 McDonald criteria, multiple sclerosis can be diagnosed more frequently at the time of first clinical event as compared to the 2010 McDonald criteria. The main effect was due to the implementation of oligoclonal bands as a substitute for dissemination in time. However, careful differential diagnosis is essential in patients with atypical clinical manifestations to avoid misdiagnoses

Investigation of Oligoclonal IgG Bands in Tear Fluid of Multiple Sclerosis Patients

Background: Oligoclonal IgG bands (OCB) in the cerebrospinal fluid (CSF) represent a typical marker for inflammation in multiple sclerosis (MS) patients and have a predictive and diagnostic value in patients with a first suspected demyelinating event. The detection in tears remains controversial but some reports suggested a replacement of CSF analysis by OCB detection in tears. We aimed to investigate the value of OCB detection in tears systematically in patients with MS.Methods: Tears of 59 patients with suspected or diagnosed MS were collected with Schirmer filter paper strips. Tear IgG was purified by affinity chromatography with protein G. After isoelectric focusing in polyacrylamide gels OCB detection was performed with direct silver staining. Paired triplets of CSF, serum, and tears were analyzed. For comparison purposes we additionally used other tear collection methods (flush procedure and plastic capillary tubes) or detection techniques (Immunoblotting). Clinical and paraclinical parameters are provided.Results: IgG collection in tears was most reliable by using Schirmer strips. Thirteen patients had to be excluded due to insufficient sample material. Tear specific proteins that interfered with OCB detection were successfully eliminated by IgG purification. The concordance of OCB in tears and CSF of all investigated MS patients was 39% with a high rate of only marginal pattern in tears. Five patients demonstrated restricted bands in tears, neither detectable in CSF nor serum. Occurrence of OCB in tears was significantly associated with pathological visual evoked potentials (P = 0.0094) and a history of optic neuritis (P = 0.0258).Conclusion: Due to the limited concordance, high rate of samples with insufficient material, and the unknown origin of tear IgG we cannot recommend that tear OCB detection may replace CSF OCB detection in MS patients. The detection of unique OCB in tears might offer new insights in ophthalmological diseases

Towards the Validation of Executive Functioning Assessments: A Clinical Study

Neuropsychological assessment needs a more profound grounding in psychometric theory. Specifically, psychometrically reliable and valid tools are required, both in patient care and in scientific research. The present study examined convergent and discriminant validity of some of the most popular indicators of executive functioning (EF). A sample of 96 neurological inpatients (aged 18–68 years) completed a battery of standardized cognitive tests (Raven’s matrices, vocabulary test, Wisconsin Card Sorting Test, verbal fluency test, figural fluency test). Convergent validity of indicators of intelligence (Raven’s matrices, vocabulary test) and of indicators of EF (Wisconsin Card Sorting Test, verbal fluency test, figural fluency) were calculated. Discriminant validity of indicators of EF against indicators of intelligence was also calculated. Convergent validity of indicators of intelligence (Raven’s matrices, vocabulary test) was good (rxtyt = 0.727; R2 = 0.53). Convergent validity of fluency indicators of EF against executive cognition as indicated by performance on the Wisconsin Card Sorting Test was poor (0.087 ≤ rxtyt ≤ 0.304; 0.008 ≤ R2 ≤ 0.092). Discriminant validity of indicators of EF against indicators of intelligence was good (0.106 ≤ rxtyt ≤ 0.548; 0.011 ≤ R2 ≤ 0.300). Our conclusions from these data are clear-cut: apparently dissimilar indicators of intelligence converge on general intellectual ability. Apparently dissimilar indicators of EF (mental fluency, executive cognition) do not converge on general executive ability. Executive abilities, although non-unitary, can be reasonably well distinguished from intellectual ability. The present data contribute to the hitherto meager evidence base regarding the validity of popular indicators of EF

Reiber’s Diagram for Kappa Free Light Chains: The New Standard for Assessing Intrathecal Synthesis?

Oligoclonal bands are the gold standard for determination of an intrathecal immunoglobulin G synthesis and were recently included in the McDonald criteria of 2017 to diagnose relapsing multiple sclerosis (MS) as a substitute for dissemination in time. Intrathecally produced kappa free light chains (KFLC) are a novel promising biomarker with similar characteristics and the advantage for automated determination. However, different approaches exist to determine the intrathecal KFLC fraction. The most common method is to calculate the CSF/serum KFLC quotient with reference to the albumin CSF/serum quotient (QKappa/QAlb) the so-called KFLC index. Recently, Reiber developed a theoretically and empirically founded hyperbolic function similar to his traditional hyperbolic function for the immunoglobulins A, G, M. Our study included a total of 168 patients with either MS according to the McDonald criteria of 2017, clinically isolated syndrome (CIS) with conversion to MS during follow-up, or stable CIS. Positive oligoclonal bands were compared with the KFLC index, Reiber’s KFLC diagram, Presslauer’s KFLC exponential curve, and Senel’s linear curve for KFLC. Reiber’s diagram detected an intrathecal production of KFLC in 98/100 patients with MS, only one patient fewer than oligoclonal bands positivity (99/100). By using the KFLC index ≥ 5.9, Presslauer’s KFLC exponential function, and Senel’s linear curve two more patients would not have been identified (96/100). For the group of patients who converted from CIS to MS similar results were obtained for both the oligoclonal bands and the Reiber graph (21/24, 88%). The KFLC index ≥ 5.9, Presslauer’s method, and Senel’s linear function each identified two patients fewer (19/24, 79%). In patients with stable CIS, 11/44 patients (25%) displayed oligoclonal bands in contrast to 9/44 patients (20%) with elevated KFLC by using Reiber’s diagram and Presslauer’s method, 8/44 patients (18%) with elevated KFLC as detected by Senel’s linear function, and 7/44 patients (16%) with KFLC index ≥ 5.9. In conclusion, Reiber’s KFLC diagram shows a great diagnostic performance to detect an intrathecal KFLC production in patients with MS

Decreased Intrathecal Concentrations of Free Light Chains Kappa in Multiple Sclerosis Patients Taking Very High Effective Disease-Modifying Treatment

Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the effects of different disease-modifying therapies (DMT) on the humoral intrathecal immune response in the CSF of patients with multiple sclerosis (MS). FLCκ were analyzed in CSF and serum samples from MS patients taking DMT (n = 60) and those in a control cohort of treatment-naïve MS patients (n = 90). DMT was classified as moderately effective (including INFß-1a, INFß-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, triamcinolone); highly effective (including fingolimod, daclizumab) and very highly effective (alemtuzumab, natalizumab, rituximab/ocrelizumab, mitoxantrone). FLCκ were measured using a nephelometric FLCκ kit. Intrathecal FLCκ and IgG concentrations were assessed in relation to the hyperbolic reference range in quotient diagrams. Intrathecal FLCκ concentrations and IgG concentrations were significantly lower in samples from the cohort of MS patients taking very highly effective DMT than in samples from the cohort of MS patients taking highly effective DMT and in the treatment-naïve cohort (FLCκ: p = 0.004, p < 0.0001 respectively/IgG: p = 0.013; p = 0.021). The reduction in FLCκ could contribute to an anti-inflammatory effect in the CNS through this mechanism. There was no difference in the appearance of CSF-specific oligoclonal bands (p = 0.830). Longitudinal analyses are required to confirm these results

McDonald Criteria 2010 and 2005 Compared: Persistence of High Oligoclonal Band Prevalence Despite Almost Doubled Diagnostic Sensitivity

The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral immunoreaction in the form of oligoclonal bands (OCB) is crucial in the diagnostic workup. To date, the impact of the 2010 McDonald criteria on the prevalence of OCB has not been investigated. We retrospectively evaluated data of 325 patients with a clinical relapse suggestive of demyelination that were treated in a German university hospital between 2010 and 2015. One hundred thirty-six patients (42%) were diagnosed with MS and 189 patients with CIS when the criteria of 2010 were applied. The criteria of 2005 allowed only 70 patients (22%) to be designated as MS. In contrast, the prevalence of OCB was marginal affected in MS patients with 96% for the criteria of 2010 and 98.5% for the criteria of 2005. In conclusion, OCB are prevalent in most MS patients and reflect the chronic inflammatory nature of the disease. We recommend CSF examination to exclude alternative diagnoses and reevaluation of the diagnosis MS in patients with negative OCB

The Increasing Role of Kappa Free Light Chains in the Diagnosis of Multiple Sclerosis

Free light chains (FLC) are a promising biomarker to detect intrathecal inflammation in patients with inflammatory central nervous system (CNS) diseases, including multiple sclerosis (MS). The diagnostic use of this biomarker, in particular the kappa isoform of FLC (“KFLC”), has been investigated for more than 40 years. Based on an extensive literature review, we found that an agreement on the correct method for evaluating KFLC concentrations has not yet been reached. KFLC indices with varying cut-off values and blood-CSF-barrier (QAlbumin) related non-linear formulas for KFLC interpretation have been investigated in several studies. All approaches revealed high diagnostic sensitivity and specificity compared with the oligoclonal bands, which are considered the gold standard for the detection of intrathecally synthesized immunoglobulins. Measurement of KFLC is fully automated, rater-independent, and has been shown to be stable against most pre-analytic influencing factors. In conclusion, the determination of KFLC represents a promising diagnostic approach to show intrathecal inflammation in neuroinflammatory diseases. Multicenter studies are needed to show the diagnostic sensitivity and specificity of KFLC in MS by using the latest McDonald criteria and appropriate, as well as standardized, cut-off values for KFLC concentrations, preferably considering non-linear formulas such as Reiber’s diagram

Evidence of Oligoclonal Bands Does Not Exclude Non-Inflammatory Neurological Diseases

Cerebrospinal fluid analysis is an essential part of the diagnostic workup in various neurological disorders. Evidence of an intrathecal immunoglobulin synthesis, as demonstrated by Reiber&rsquo;s diagram or the more sensitive oligoclonal bands (OCB), are typical for neuroinflammatory diseases, and normally not expected in non-inflammatory neurological diseases. Therefore, patients with non-inflammatory neurological diseases are often used in control groups in studies investigating autoimmune diseases of the central nervous system. However, data about the frequency of intrathecal immunoglobulin synthesis in non-inflammatory neurological disease are scarce. The cerebrospinal fluid (CSF) records of a total of 3622 patients were screened and 2114 patients included with presumably non-inflammatory neurological diseases like dementia, idiopathic peripheral neuropathy, motoneuron disease, stroke, and epileptic seizures. Evidence of an intrathecal immunoglobulin synthesis can be found with low frequency also in non-inflammatory neurological diseases. A much higher rate of patients showed intrathecal immunoglobulin synthesis as demonstrated by OCB than by Reiber&rsquo;s diagram. In patients with disorders of the peripheral nervous system the frequency of OCB was much lower than in patients presenting with central nervous system manifestations. Evidence of an intrathecal immunoglobulin synthesis should not automatically lead to exclusion of non-inflammatory neurological diseases but should rather prompt the way to investigate for the origin of the intrathecal immunoglobulin synthesis

Clinically Isolated Syndrome According to McDonald 2010: Intrathecal IgG Synthesis Still Predictive for Conversion to Multiple Sclerosis

While the revised McDonald criteria of 2010 allow for the diagnosis of multiple sclerosis (MS) in an earlier stage, there is still a need to identify the risk factors for conversion to MS in patients with clinically isolated syndrome (CIS). Since the latest McDonald criteria were established, the prognostic role of cerebrospinal fluid (CSF) and visual evoked potentials (VEP) in CIS patients is still poorly defined. We conducted a monocentric investigation including patients with CIS in the time from 2010 to 2015. Follow-ups of 120 patients revealed that 42% converted to MS. CIS patients with positive oligoclonal bands (OCB) were more than twice as likely to convert to MS as OCB negative patients (hazard ratio = 2.6). The probability to develop MS was even higher when a quantitative intrathecal IgG synthesis was detected (hazard ratio = 3.8). In patients with OCB, VEP did not add further information concerning the conversion rate to MS. In patients with optic neuritis and negative OCB, a significantly higher rate converted to MS when VEP were delayed. In conclusion, the detection of an intrathecal IgG synthesis increases the conversion probability to MS. Pathological VEP can help to predict the conversion rate to MS in patients with optic neuritis without an intrathecal IgG synthesis