Increased CX3CL1 in cerebrospinal fluid and ictal serum t-tau elevations in migraine: results from a cross-sectional exploratory case-control study.

BACKGROUND: To date, migraine is diagnosed exclusively based on clinical criteria, but fluid biomarkers are desirable to gain insight into pathophysiological processes and inform clinical management. We investigated the state-dependent profile of fluid biomarkers for neuroaxonal damage and microglial activation as two potentially relevant aspects in human migraine pathophysiology. METHODS: This exploratory study included serum and cerebrospinal fluid (CSF) samples of patients with migraine during the headache phase (ictally) (n = 23), between attacks (interictally) (n = 16), and age/sex-matched controls (n = 19). Total Tau (t-Tau) protein, glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NfL) were measured with the Neurology 4-plex kit on a Single Molecule Array SR-X Analyzer (Simoa® SR-X, Quanterix Corp., Lexington, MA). Markers of microglial activation, C-X3-C motif chemokine ligand 1 (CX3CL1) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), were assessed using an immunoassay. RESULTS: Concentrations of CX3CL1 but not sTREM2 were significantly increased both ictally and interictally in CSF but not in serum in comparison to the control cohort (p = 0.039). ROC curve analysis provided an AUC of 0.699 (95% CI 0.563 to 0.813, p = 0.007). T-Tau in serum but not in CSF was significantly increased in samples from patients taken during the headache phase, but not interictally (effect size: η2 = 0.121, p = 0.038). ROC analysis of t-Tau protein in serum between ictal and interictal collected samples provided an AUC of 0.729 (95% CI 0.558 to 0.861, p = 0.006). The other determined biomarkers for axonal damage were not significantly different between the cohorts in either serum or CSF. DISCUSSION: CX3CL1 in CSF is a novel potential fluid biomarker of migraine that is unrelated to the headache status. Serum t-Tau is linked to the headache phase but not interictal migraine. These data need to be confirmed in a larger hypothesis-driven prospective study.

Serum tau protein elevation in migraine: a cross-sectional case-control study.

BACKGROUND: Migraine is a disorder associated with neuropeptide release, pain and inflammation. Tau protein has recently been linked to inflammatory diseases and can be influenced by neuropeptides such as CGRP, a key neurotransmitter in migraine. Here, we report serum concentrations of total-tau protein in migraine patients and healthy controls. METHODS: In this cross-sectional study, interictal blood samples from n = 92 patients with episodic migraine (EM), n = 93 patients with chronic migraine (CM), and n = 42 healthy matched controls (HC) were studied. We assessed serum total-tau protein (t-tau) and for comparison neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L (UCH-L1) concentrations using the Neurology 4-plex kit, on a single molecule array HD-X Analyzer (Quanterix Corp Lexington, MA). Matched serum/cerebrospinal fluid (CSF) samples were used for post-hoc evaluations of a central nervous system (CNS) source of relevant findings. We applied non-parametric tests to compare groups and assess correlations. RESULTS: Serum t-tau concentrations were elevated in EM [0.320 (0.204 to 0.466) pg/mL] and CM [0.304 (0.158 to 0.406) pg/mL] patients compared to HC [0.200 (0.114 to 0.288) pg/mL] (p = 0.002 vs. EM; p = 0.025 vs. CM). EM with aura [0.291 (0.184 to 0.486 pg/mL); p = 0.013] and EM without aura [0.332 (0.234 to 0.449) pg/mL; p = 0.008] patients had higher t-tau levels than HC but did not differ between each other. Subgroup analysis of CM with/without preventive treatment revealed elevated t-tau levels compared to HC only in the non-prevention group [0.322 (0.181 to 0.463) pg/mL; p = 0.009]. T-tau was elevated in serum (p = 0.028) but not in cerebrospinal fluid (p = 0.760). In contrast to t-tau, all proteins associated with cell damage (NfL, GFAP, and UCH-L1), did not differ between groups. DISCUSSION: Migraine is associated with t-tau elevation in serum but not in the CSF. Our clinical study identifies t-tau as a new target for migraine research.

Clinical associations and characteristics of the polyspecific intrathecal immune response in elderly patients with non-multiple sclerosis chronic autoimmune-inflammatory neurological diseases - a retrospective cross-sectional study.

Introduction: The polyspecific intrathecal immune response (PSIIR), aka MRZ reaction (M = measles, R = rubella, Z = zoster, optionally Herpes simplex virus, HSV) is defined as intrathecal immunoglobulin synthesis (IIS) for two or more unrelated viruses. Although an established cerebrospinal fluid (CSF) biomarker for multiple sclerosis (MS), a chronic autoimmune-inflammatory neurological disease (CAIND) of the central nervous system (CNS) usually starting in young adulthood, the full spectrum of CAINDs with a positive PSIIR remains ill defined. Methods: In this retrospective, cross-sectional study, patients with CSF-positive oligoclonal bands (OCB) and - to enrich for non-MS diagnoses - aged ≥50 years were enrolled. Results: Of 415 with PSIIR testing results (MRZ, HSV optional), 76 were PSIIR-positive. Of these, 25 (33%) did not meet the diagnostic criteria for MS spectrum diseases (MS-S) comprising clinically or radiologically isolated syndrome (CIS/RIS) or MS. PSIIR-positive non-MS-S phenotypes were heterogenous with CNS, peripheral nerve and motor neuron involvement and often defied unequivocal diagnostic classification. A rating by neuroimmunology experts suggested non-MS CAINDs in 16/25 (64%). Long-term follow-up available in 13 always showed a chronically progressive course. Four of five responded to immunotherapy. Compared to MS-S patients, non-MS CAIND patients showed less frequent CNS regions with demyelination (25% vs. 75%) and quantitative IgG IIS (31% vs. 81%). MRZ-specific IIS did not differ between both groups, while additional HSV-specific IIS was characteristic for non-MS CAIND patients. Discussion: In conclusion, PSIIR positivity occurs frequently in non-MS-S patients ≥50 years. Although sometimes apparently coincidental, the PSIIR seems to represent a suitable biomarker for previously unnoticed chronic neurologic autoimmunities, which require further characterization.

Modulation of cytokine release from peripheral blood mononuclear cells from multiple sclerosis patients by coenzyme A and soraphen A.

By applying the acetyl-CoA-carboxylase inhibitors soraphen A (SorA) and coenzyme A (CoA) ex vivo, we aimed to reduce proinflammatory cytokine release by PBMCs and increase anti-inflammatory cytokine levels, thereby demonstrating a possible application of those pathways in future multiple sclerosis (MS) therapy. In a prospective exploratory monocentric study, we analysed cytokine production by PBMCs treated with SorA (10 or 50 nM) and CoA (600 µM). Thirty-one MS patients were compared to 18 healthy age-matched controls. We demonstrated the immunomodulatory potential of SorA and CoA in targeting the immune function of MS patients, with an overall reduction of cytokines except of IL-2, IL-6 and IL-10.

Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response.

BACKGROUND: Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis. METHODS: All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays. RESULTS: One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome. CONCLUSIONS: Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.

Polypharmacy in patients with multiple sclerosis and the impact on levels of care and therapy units.

Background: The aim of this study was to examine the societal costs of polypharmacy in patients with multiple sclerosis (MS). We therefore focused on the association between the number of medications on the level of care (LOC), the German classification of the need for care, and the number of therapy sessions (TTU). Methods: In addition to demographic information and medication, 101 MS patients performed the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS). Medications were subdivided into a total number of medications (TD), MS-related medication [MSD, i.e., disease-modifying drugs (DMDs) and symptomatic treatment (SD)], and medication for comorbidities (CDs). Multivariate linear regression models were performed to estimate if the amount of each medication type affects LOC or TTU. Results: Polypharmacy appeared in 54 patients at the time of the survey. The relative risk (RR) of LOC 1 increased significantly by 2.46 (p = 0.001) per TD and by 2.55 (p = 0.004) per MSD, but not per CD (RR 1.44; p = 0.092). The effect of RR on MSD was driven by SD (RR 2.2; p = 0.013) but not DMD (RR 2.6; p = 0.4). RR of MSD remained significant for LOC 2 (1.77; p = 0.009) and LOC 3/4 (1.91; p = 0.015), with a strong trend in RR of SD, but not DMD. TTU increased significantly per MSD (p = 0.012), but not per TD (p = 0.081) and CD (p = 0.724). Conclusion: The number of MSDs is related to the likelihood of a higher level of care and the number of therapy sessions and is therefore a good indication of the extent of the societal costs.

A New Laboratory Workflow Integrating the Free Light Chains Kappa Quotient into Routine CSF Analysis.

We performed this cohort study to test whether further analysis of intrathecal inflammation can be omitted if the free light chain kappa (FLCκ) quotient is within the reference range in the corresponding quotient diagram. FLCκ concentrations were measured in serum and cerebrospinal fluid (CSF) samples. The intrathecal fraction (IF) of FLCκ was calculated in relation to the hyperbolic reference range. 679 patient samples were used as a discovery cohort (DC). The sensitivity and negative predictive value (NPV) of the FLCκ-IF for the detection of an intrathecal humoral immune response (CSF-specific OCB and/or IF IgG/A/M > 0%) was determined. Based on these data, a diagnostic algorithm was developed and prospectively validated in an independent validation cohort (VC, n = 278). The sensitivity of the FLCκ-IF was 98% in the DC and 97% in the VC with a corresponding NPV of 99%. The use of the FLCκ-IF as a first line analysis would have reduced the Ig and OCB analysis by 62% in the DC and 74% in the VC. The absence of a FLCκ-IF predicts the absence of a humoral intrathecal immune response with a very high NPV of 99%. Thus, integration of our proposed algorithm into routine CSF laboratory analysis could help to reduce analytical efforts.

Diagnostic Cerebrospinal Fluid Biomarker in Early and Late Onset Multiple Sclerosis.

Background: The intrathecal humoral response is the characteristic diagnostic finding in the cerebrospinal fluid (CSF) analysis of patients with multiple sclerosis (MS). Although the average age of MS patients increases, little is known about the sensitivity of diagnostic markers in elderly MS patients. Methods: In this retrospective two-center study, intrathecal free light chains kappa fraction (FLCk IF) and oligoclonal bands (OCB) were studied in a large cohort of patients with early and late onset relapsing (RMS) and progressive (PMS) MS. Furthermore, the humoral immune profile in CSF was analyzed, including the polyspecific intrathecal immune response measured as the MRZ reaction. Results: While the frequency of CSF-specific OCB did not differ between early and late onset RMS and PMS, the sensitivity of positive FLCk IF and absolute FLCk IF values were lower in PMS. The positivity of the MRZ reaction was equally frequent in early and late onset RMS and PMS. PMS patients had higher local IgA concentrations than RMS patients (p = 0.0123). Conclusions: OCB are slightly superior to FLCk IF in progressive MS in terms of sensitivity for detecting intrathecal immunoglobulin synthesis. The MRZ reaction, as the most specific parameter for MS, is also applicable in patients with late onset and progressive MS.

The Seasonal Fluctuation of Fatigue in Multiple Sclerosis.

Background: Fatigue is a common symptom in patients with multiple sclerosis. Several studies suggest that outdoor temperature can impact fatigue severity, but a systematic study of seasonal variations is lacking. Methods: Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC) in a temperate climatic zone with an average outdoor temperature of 8.8°C. This study included 258 patients with multiple sclerosis from 572 visits temporally distributed over the year. The data were adjusted for age, sex, cognition, depression, disease severity, and follow-up time. Linear regression models were performed to determine whether the temporal course of fatigue was time-independent, linearly time dependent, or non-linearly time dependent. Results: Fatigue was lowest during January (mean FSMC: 49.84) and highest during August (mean FSMC: 53.88). The regression analysis showed the best fit with a model that included months + months2, which was a non-linear time dependency. Mean FSMC per month correlated significantly with the average monthly temperature (ρ = 0.972; p < 0.001). Conclusion: In multiple sclerosis, fatigue showed a natural temporal fluctuation. Fatigue was higher during summer compared to winter, with a significant relationship of fatigue with outdoor temperature. This finding should be carefully taken into account when clinically monitoring patients over time to not interpret higher or lower scores independent of seasonal aspects.

Kappa Free Light Chains in Cerebrospinal Fluid in Inflammatory and Non-Inflammatory Neurological Diseases.

BACKGROUND: Oligoclonal bands represent intrathecal immunoglobulin G (IgG) synthesis and play an important role in the diagnosis of multiple sclerosis (MS). Kappa free light chains (KFLC) are increasingly recognized as an additional biomarker for intrathecal Ig synthesis. However, there are limited data on KFLC in neurological diseases other than MS. METHODS: This study, conducted at two centers, retrospectively enrolled 346 non-MS patients. A total of 182 patients were diagnosed with non-inflammatory and 84 with inflammatory neurological diseases other than MS. A further 80 patients were classified as symptomatic controls. Intrathecal KFLC production was determined using different approaches: KFLC index, Reiber's diagram, Presslauer's exponential curve, and Senel's linear curve. RESULTS: Matching results of oligoclonal bands and KFLC (Reiber's diagram) were frequently observed (93%). The Reiber's diagram for KFLC detected intrathecal KFLC synthesis in an additional 7% of the patient samples investigated (4% non-inflammatory; 3% inflammatory), which was not found by oligoclonal band detection. CONCLUSIONS: The determination of both biomarkers (KFLC and oligoclonal bands) is recommended for routine diagnosis and differentiation of non-inflammatory and inflammatory neurological diseases. Due to the high sensitivity and physiological considerations, the assessment of KFLC in the Reiber's diagram should be preferred to other evaluation methods.

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.

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.

The Influence of Renal Function Impairment on Kappa Free Light Chains in Cerebrospinal Fluid.

BACKGROUND: The determination of kappa free light chains (KFLC) in cerebrospinal fluid (CSF) is an upcoming biomarker for the detection of an intrathecal immunoglobulin synthesis. Since renal function impairment leads to altered serum KFLC and albumin concentrations, interpretation of KFLC in CSF may be influenced by these parameters. METHODS: In this two-center study, the influence of renal function (according to the CKD-EPI creatinine equation) on KFLC and albumin concentrations was investigated in patients with "physiological" (n = 139), "non-inflammatory" (n = 146), and "inflammatory" (n = 172) CSF profiles in respect to the KFLC index and the evaluation in quotient diagrams in reference to the hyperbolic reference range (KFLC IF). RESULTS: All sample groups displayed declining KFLC indices and KFLC IF values with decreasing renal function (P-values between <.0001 and .0209). In "inflammatory" CSF profile samples, 15% of the patients presented a KFLC index <5.9 while 10% showed an intrathecal KFLC fraction below QKappa(lim), suggesting possible false negative KFLC results. CONCLUSIONS: The influence of renal function should be considered while interpreting KFLC results in patients with neuroinflammatory diseases. The interpretation of KFLC in quotient diagrams is less susceptible to renal function impairment than the KFLC index and should be preferentially used.

Informed DEcision for cerebrospinal fluid analysis after epiLeptic seizures- the IDEAL-score: A development and validation study.

BACKGROUND: This observational study was done to develop a score based on clinical predictors that enables a guided decision for the necessity of cerebrospinal fluid (CSF) analysis after first unprovoked epileptic seizures and to validate this score in a retrospective patient cohort. METHODS: Clinical predictors were identified by two panels of epilepsy experts and selected according to content validity ratios. Based on these predictors a score was created and applied to a cohort of patients with first epileptic seizures. RESULTS: The "IDEAL score" consists of 9 items (fever, prolonged disturbance of consciousness, headache, imaging results, cognitive dysfunction, status epilepticus, malignancy, autoimmune encephalitis symptoms) that are collected at two different time points (< 3 h [A-score]; > 3 h [B-score] after hospital admittance). A CSF analysis is recommended, if at least one clinical finding is present, either one of the items evaluated during the acute phase (A-score) or later in the diagnostic process (B-score). In 41 patients (13%) CSF analysis provided essential clues to the cause of the seizure. The combined IDEAL score reached a sensitivity of 98%, a specificity of 53%, a positive predictive value of 24% and a negative predictive value of 99% in this patient cohort. CONCLUSIONS: A CSF analysis after first epileptic seizures provided decisive etiological findings in only 13% of all investigated patients. The IDEAL score offers clinicians a simple and easy-to-implement algorithm to assess the necessity of a CSF analysis, and to prevent unnecessary diagnostic procedures.

Kappa Free Light Chains in the Context of Blood Contamination, and Other IgA- and IgM-Related Cerebrospinal Fluid Disease Pattern.

In this retrospective, monocentric cohort study, we tested if an intrathecal free light chain kappa (FLC-k) synthesis reflects not only an IgG but also IgA and IgM synthesis. We also analysed if FLC-k can help to distinguish between an inflammatory process and a blood contamination of cerebrospinal fluid (CSF). A total of 296 patient samples were identified and acquired from patients of the department of Neurology, University Medicine Greifswald (Germany). FLC-k were analysed in paired CSF and serum samples using the Siemens FLC-k kit. To determine an intrathecal FLC-k and immunoglobulin (Ig) A/-M-synthesis we analysed CSF/serum quotients in quotient diagrams, according to Reiber et al. Patient samples were grouped into three cohorts: cohort I (n = 41), intrathecal IgA and/or IgM synthesis; cohort II (n = 16), artificial blood contamination; and the control group (n = 239), no intrathecal immunoglobulin synthesis. None of the samples had intrathecal IgG synthesis, as evaluated with quotient diagrams or oligoclonal band analysis. In cohort I, 98% of patient samples presented an intrathecal synthesis of FLC-k. In cohort II, all patients lacked intrathecal FLC-k synthesis. In the control group, 6.5% presented an intrathecal synthesis of FLC-k. The data support the concept that an intrathecal FLC-k synthesis is independent of the antibody class produced. In patients with an artificial intrathecal Ig synthesis due to blood contamination, FLC-k synthesis is lacking. Thus, additional determination of FLC-k in quotient diagrams helps to discriminate an inflammatory process from a blood contamination of CSF.

Autoimmune Encephalitis in Late-Onset Seizures: When to Suspect and How to Treat.

Objective: This study was conducted to elucidate prevalence, clinical features, outcomes, and best treatment in patients with late-onset seizures due to autoimmune encephalitis (AE). Methods: This is a single-institution prospective cohort study (2012-2019) conducted at the Epilepsy Center at the University of Greifswald, Germany. A total of 225 patients aged ≥50 years with epileptic seizures were enrolled and underwent an MRI/CT scan, profiling of neural antibodies (AB) in serum and cerebrospinal fluid (CSF), and neuropsychological testing. On the basis of their work-up, patients were categorized into the following three cohorts: definite, suspected, or no AE. Patients with definite and suspected AE were subsequently treated with immunosuppressive therapy (IT) and/or anti-seizure drug (ASD) therapy and were followed up (FU) regarding clinical and seizure outcome. Results: Of the 225 patients, 17 (8%) fulfilled the criteria for definite or suspected AE according to their AB profile and MRI results. Compared with patients with no evidence of AE, those with AE were younger (p = 0.028), had mesial temporal neuropsychological deficits (p = 0.001), frequently had an active or known malignancy (p = 0.006) and/or a pleocytosis (p = 0.0002), and/or had oligoclonal bands in CSF (p = 0.001). All patients with follow-up became seizure-free with at least one ASD. The Modified Rankin scale (mRS) at hospital admission was low for patients with AE (71% with mRS ≤2) and further decreased to 60% with mRS ≤2 at last FU. Significance: AE is an important etiology in late-onset seizures, and seizures may be the first symptom of AE. Outcome in non-paraneoplastic AE was favorable with ASD and IT. AB testing in CSF and sera, cerebral MRI, CSF analysis, and neuropsychological testing for mesial temporal deficits should be part of the diagnostic protocol for AE following late-onset seizures.

Acute disseminated encephalomyelitis following endonasal resection of a craniopharyngioma: illustrative case.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a rare, acquired demyelination syndrome that causes cognitive impairment and focal neurological deficits and may be fatal. The potentially reversible disease mainly affects children, often after vaccination or viral infection, but may be seen rarely in adults. OBSERVATIONS: A 50-year-old woman presented with loss of visual acuity of the left eye. Magnetic resonance imaging (MRI) revealed an intra- and suprasellar mass, which was removed successfully. On postoperative day 1, MRI showed gross total resection of the lesion and no surgery-related complications. On postoperative day 2, the patient presented with a progressive left-sided hemiparesis, hemineglect, and decline of cognitive performance. MRI showed white matter edema in both hemispheres. Cerebrospinal fluid analysis revealed mixed pleocytosis (355/µL) without further evidence of infection. In synopsis of the findings, ADEM was diagnosed and treated with intravenous immunoglobulins. Shortly thereafter, the patient recovered, and no sensorimotor deficits were detected in the follow-up examination. LESSONS: Pituitary gland pathologies are commonly treated by transsphenoidal surgery, with only minor risks for complications. A case of ADEM after craniopharyngioma resection has not been published before and should be considered in case of progressive neurological deterioration with multiple white matter lesions.

Epileptic seizures in multiple sclerosis: prevalence, competing causes and diagnostic accuracy.

BACKGROUND: Multiple sclerosis (MS) is accompanied by an increased risk of epileptic seizures, but data with a detailed description of the competing causes are lacking. METHODS: We aimed to describe a cohort of patients with both MS and epileptic seizures in a retrospective, population-based study. RESULTS: We included 59 out of 2285 MS patients who had at least one epileptic seizure. Out of them, 22 had seizures before the diagnosis of MS, whereas epileptic seizures occurred after MS diagnosis in 37 patients, resulting in a total prevalence of epileptic seizures in MS of 2.6%. Competing causes could be found in 50.8% (30/59) of all patients, with 40.9% (9/22) compared to 56.8% (21/37) of the MS patients with seizures before vs after MS diagnosis. The main alternative causes were traumatic brain injury and cerebral ischemia accounting for more than 30% of the patients, with no difference between the subgroups. 33.3% and 55.6% of MS patients with seizures before/after MS diagnosis had documented pathological EEG alterations. CONCLUSION: A remarkable percentage of MS patients with epileptic seizures do have alternative competing causes at the time of the first seizure. A detailed diagnostic setup including patient history, EEG and MRI is recommended in the evaluation and choice for the best treatment.

Free light chains kappa can differentiate between myelitis and noninflammatory myelopathy.

OBJECTIVE: To test the hypothesis that the intrathecal synthesis of free light chain kappa (FLC-k) can be used as a CSF biomarker to differentiate patients with myelitis due to multiple sclerosis (MS), myelitis due to neuromyelitis optica spectrum disease (NMOSD), and noninflammatory myelopathy, we analyzed FLC-k in 26 patients with MS myelitis, 9 patients with NMOSD myelitis, and 14 patients with myelopathy. METHODS: This is a retrospective monocentric cohort study. FLC-k were analyzed using the nephelometric Siemens FLC-k kit in paired samples of CSF and sera. Intrathecal fraction (IF) of FLC-k was plotted in a FLC-k quotient diagram. RESULTS: Ninety-six percent of patients with MS myelitis had an intrathecal synthesis of FLC-k in comparison with 55.6% for NMOSD and 14.3% of patients with noninflammatory myelopathy. The locally synthesized absolute amount of FLC-k was significantly higher in patients with myelitis due to MS than in patients with NMOSD (p = 0.038) or noninflammatory myelopathy (p < 0.0001). The sensitivity of FLC-k synthesis to detect inflammation in patients with myelitis is 85.7%. Using a receiver operating characteristic analysis, FLC-k IF >78% can discriminate patients with myelitis due to MS and NMOSD with a sensitivity of 88.5% and a specificity of 88.9% CONCLUSIONS: With the hyperbolic reference range in quotient diagrams for FLC-k, it is possible to distinguish inflammatory myelitis from noninflammatory myelopathies. An FLC-k IF >78% can be a hint to suspect myelitis due to MS rather than NMOSD.

Free light chain kappa and the polyspecific immune response in MS and CIS - Application of the hyperbolic reference range for most reliable data interpretation.

OBJECTIVES: Free light chain kappa (FLC-k) in cerebrospinal fluid (CSF) is involved in intrathecal immune responses and is being investigated frequently for its diagnostic sensitivity. The objective of this study was the application and interpretation of FLC-k data in quotient diagrams with a hyperbolic reference range and to confirm the superior evaluation in comparison with another proposed reference method and cut-off values. Secondly, the performance of the FLC-k quotient diagram was analyzed in respect to MS and CIS patients and in relation to the polyspecific immune response. MATERIALS AND METHODS: FLC-k was analyzed in a control cohort (n = 302) and in patients with MS/CIS (n = 98) using a nephelometric FLC-k kit. The intrathecal fraction of FLC-k based on the hyperbolic reference range was calculated in comparison to various linear FLC-k indices and routine CSF parameters [oligoclonal bands (OCB), polyspecific antiviral immune response]. RESULTS: Using the new hyperbolic reference range, intrathecal FLC-k synthesis was found in 20 / 302 OCB negative controls. The sensitivity in the definitive MS cohort was 100%, compared to 93% positive OCB. The linear FLC-k Index interpretation with similar sensitivity for MS, however, bares the risk for the control samples,depending on the reference range, of false positive interpretations (up to 7 at low QAlb) or false negative interpretations (up to 17/20 FLC-k positives at high QAlb). The quantitative mean intrathecal FLC-k synthesis in the CIS cohort (later MS) was even slightly higher than in initially definitive MS questioning a pathophysiological difference. A positive MRZ reaction found in 53% percent of CIS patients with intrathecal FLC-k synthesis could have allowed diagnosis of MS immediately, i.e. earlier than with the Mc Donald criteria. CONCLUSIONS: The evaluation of FLC-k with hyperbolic reference range in quotient diagrams is superior to other analytical methods like the linear FLC-k index. We suggest a sequential CSF testing with FLC-k Reibergram evaluation, potentially followed by isoelectric focusing. With the MRZ reaction we obtain highest specificity for MS diagnosis.