Florian Lauda

The Chemokine CXCL13 Is a Prognostic Marker in Clinically Isolated Syndrome (CIS)

Background There is increasing recognition of the importance of B lymphocytes in the immunopathogenesis of multiple sclerosis (MS), encouraging the evaluation of B cell-associated biomarkers in the cerebrospinal fluid (CSF). We aimed to evaluate the relevance of the B cell chemoattractant CXCL13 as a prognostic marker in patients with clinically isolated syndrome (CIS) regarding conversion to MS, and to compare it to Barkhof criteria in magnetic resonance imaging (MRI), oligoclonal bands (OCB) and the polyspecific intrathecal B cell response against measles, rubella and varicella zoster virus (MRZR). Methodology/Principal Findings CXCL13 was determined in a prospective study over 2 years including 46 patients that remained CIS over follow-up (CIS-CIS), 45 patients that developed MS (CIS-RRMS), and 30 controls using ELISA. CSF CXCL13 was significantly elevated in CIS-RRMS as compared to CIS-CIS and controls (p<0.001). It was significantly elevated in CIS with OCB (p<0.001), positive MRZR (p = 0.04), and gadolinium enhancement in MRI (p = 0.02) and showed a significant correlation with CSF leukocyte count (p<0.001) and QIgG (p<0.001). CXCL13 showed the best positive predictive value (PPV) of all parameters investigated (70%, 95%-CI: 53–84%), which could be further increased by combination with Barkhof criteria in MRI (80%). Conclusions/Significance Our data indicate the relevance of CXCL13 in CIS to predict conversion to MS. It furthermore shows CXCL13 to be an important mediator in the inflammatory cascade associated with the polyspecific intrathecal B cell response that manifests itself in OCB and MRZR.

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.

Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy : An autopsy study

In a retrospective study of a consecutive autopsy series of 2060 elderly subjects (mean age 78.5 ± 6.8 SD years), sporadic cerebral amyloid angiopathy (CAA) of various degrees was detected in 73.2% and in 98.5% of autopsy-confirmed cases of typical (plaque and tangle) Alzheimer disease (AD). Spontaneous (non-traumatic) intracerebral hemorrhages (ICH) (excluding microbleeds) were seen in 5.6% of the total cohort and in 7.2% of definite AD cases; CAA was found in 49% of brains without and in 48.7% with ICH which was not significantly different. The latter groups showed a significantly higher frequency of severe degrees of CAA than those without ICH (80.4 vs 30.9%, p < 0.001). Patients with CAA were older than those without CAA, showing a higher frequency of clinical dementia and pathologically confirmed AD, but signs of hypertension (history and/or autopsy) were seen in 41 and 33.6% of these cases, respectively, compared to 70–75% in patients with non-CAA related ICHs. CAA-related ICH much more frequently involved cerebral lobes or hemispheres, while non-CAA related lesions were more often located in basal ganglia and brainstem. The data of a lower prevalence of CAA in cases without than with ICH, but a similar prevalence of ICH with and without CAA do not support the concept that CAA represents the most evident risk factor for ICH in the aged. While severe degrees of CAA were indeed associated with ICH, the general prevalence of large ICH in this autopsy cohort was much higher in cases without CAA, probably due to other risk factors including hypertension, which was documented in around 40% of cases with CAA-related ICH. APOE ε3/4 and ε4/4 were significantly more frequent in AD (n = 163) than in age-matched controls (n = 47) and were associated with more severe degrees of CAA, but no general genotyping in ICHs with and without CAA was performed. Hence, the role of APOE in the pathogenesis of ICH with and without CAA needs further elucidation.

Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage.

The retrospective study of a consecutive autopsy series of 1100 elderly subjects (mean age 78.3 ± 6.8 SD years), revealed sporadic cerebral amyloid angiopathy (CAA) in 50.0% and in 95.7% of autopsy‐confirmed cases of Alzheimer disease (AD). Apolipoprotein (APOE) ɛ 3/4 and ɛ 4/4 were significantly more frequent in AD than in controls, and were associated with more severe degrees of CAA. Spontaneous (non‐traumatic) intracerebral hemorrhages (ICH) (excluding microbleeds and hemorrhagic infarctions) were seen in 5.4% and only in 3.3% of AD cases. CAA was found in 50.6% of brains without and in 42.4% with ICH, the latter showing a significantly higher frequency of severe degrees of CAA. ICH was related to CAA in 42.4%, whilst no such relation was seen in 57.6%. Patients with CAA were older, showed a higher frequency of clinical dementia and pathologically confirmed AD, but signs of hypertension (history and/or autopsy) occurred in 40%, compared with 80% in those with non‐CAA‐related ICHs. CAA‐related ICH more frequently involved in cerebral lobes or hemispheres, whilst non‐CAA‐related ones were more often located in the basal ganglia and brainstem. The data of a lower prevalence of CAA in cases with than without ICH and of ICH with and without CAA do not support the concept that CAA represents the most important risk factor for ICH in the aged, probably because of other risk factors including hypertension.

Lipid‐specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab

Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti–John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid‐specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML.

Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study

We report a newly developed analysis algorithm for optical coherence tomography (OCT) that makes a retinal single-layer analysis with calculation of the average thickness of retinal layers possible. The aim of the study was to examine specific patterns of retinal layer pathology as a potential marker of neurodegeneration in Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Spectral domain OCT with a semiautomatic algorithm to calculate the average thickness of single retinal layers was applied to foveal scans of 65 PD, 16 PSP, and 12 MSA patients as well as 41 matched controls. Demographic and clinical data were collected for correlation analysis. Only PSP and MSA showed a significant reduction of retinal layers in comparison to controls. In PD, there were no significant findings in single retinal layer measurement. Most remarkably, the thickening of the outer nuclear layer in PSP and the outer plexiform layer in MSA was highly specific for these disease entities and allowed differentiating PSP from MSA with high sensitivity and specificity. With this analysis algorithm of OCT data, disease-specific retinal layer changes could be observed. Despite a general tendency to whole retinal and single retinal layer thinning that may reflect neurodegeneration in all Parkinsonian syndromes, the specific findings in MSA and PSP may serve as a highly sensitive and specific differential diagnostic tool and as a progression marker in these disease entities. Upcoming studies with a longitudinal setting will have to prove this assumption.

Cerebrospinal Fluid Immunoglobulin Kappa Light Chain in Clinically Isolated Syndrome and Multiple Sclerosis

Background Oligoclonal bands (OCB) are the most widely used CSF test to support the diagnosis of MS and to predict conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS). Since OCB tests are based on non-quantitative and difficult to standardise techniques, measurement of immunoglobulin kappa free light chains (KFLC) may represent an easier to use quantitative test. Methods KFLC were measured in CSF and serum of 211 patients using ELISA. These include patients without any inflammatory central nervous system reaction (NIND, n = 77), MS (n = 20), viral CNS infections (V-CNS-I, n = 10), neuroborreliosis (NB, n = 17) and other bacterial CNS infections (B-CNS-I, n = 10). Furthermore a cohort of 77 patients with CIS, including 39 patients that remained CIS over follow-up of two years (CIS-CIS) and 38 patients that developed MS over the same follow-up time (CIS-MS). Results CSF-serum ratio of KFLC (Q KFLC) was elevated in all patients with MS, 86.8% of patients with CIS-MS and 61.5% of patients with CIS-CIS. It was significantly elevated in CIS with presence of OCB (p<0.001). Q KFLC significantly correlated with other CSF variables such as CSF leukocyte count (p<0.001, R = 0.46), CSF CXCL13 levels (p<0.001, R = 0.64) and also intrathecal IgG synthesis (p<0.001, R = 0.74) as determined by nephelometry and quotient diagram. OCB were detected in 66.7% of CIS-CIS and in 92.1% of CIS-MS. Conclusions Although the measurement of CSF KFLC is a rapid and quantitative easy to standardize tool, it is almost equal but not superior to OCB with regard to diagnostic sensitivity and specificity in patients with early MS.

Patterns of TH1/TH2 cytokines predict clinical response in multiple sclerosis patients treated with glatiramer acetate.

The patterns of Th1/Th2 cytokines in relapsing-remitting multiple sclerosis were analyzed to evaluate their relevance as biomarkers of therapy response to glatiramer acetate (GA). Serum interferon-γ (IFN-γ), osteopontin and interleukin (IL)-2, IL-4, and IL-10 were measured in 19 relapsing-remitting multiple sclerosis patients treated with GA in a prospective study over 3 years. The quotient (IL-2 + IFN-γ)/(IL-4 + IL-10) was elevated in patients with relapses as compared to relapse-free patients after 12 (p = 0.04), 24 (p = 0.02) and 36 months (p = 0.04). Our study indicates that specific patterns of Th1/Th2 cytokines predict the response to GA therapy.

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response

Objective To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD). Design This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes. Results 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065). Conclusions Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.