Difficulty in identification of patients with active secondary progressive multiple sclerosis by clinical classification tools.

BACKGROUND AND PURPOSE: The transition from relapsing-remitting to secondary progressive multiple sclerosis (SPMS) is not well defined. Different definitions and tools to identify SPMS have been proposed. Meanwhile, early diagnosis of "active" SPMS is getting progressively more important as pharmaceutical treatment options are developed. In this study, we compared different classification methods regarding their accuracy to reliably identify "active SPMS." METHODS: Independent from previous diagnostic classification, we descriptively analyzed the disease course (regarding relapses, progression, and magnetic resonance imaging activity) in 208 consecutive multiple sclerosis (MS) patients treated in our MS outpatient clinic in 2018. Patients were reclassified according to different SPMS criteria and tools. Diagnostic accuracy in identifying patients with "active SPMS" was determined. RESULTS: Comparing the tools to each other, significant variability in the number of patients identified as having SPMS as well as in the proportion of these patients having "active SPMS" was noted. Applying both diagnostic criteria "SPMS" and "active disease" reduced the sensitivity in identifying patients with active progressive disease in all approaches. CONCLUSIONS: We propose lessening the emphasis on the label "SPMS" in favor of the more open term "active progressive disease" to simplify the process of identifying patients who may benefit from immune therapy.

Serum GFAP for stroke diagnosis in regions with limited access to brain imaging (BE FAST India).

INTRODUCTION: Despite a high burden of stroke, access to rapid brain imaging is limited in many middle- and low-income countries. Previous studies have described the astroglial protein GFAP (glial fibrillary acidic protein) as a biomarker of intracerebral hemorrhage. The aim of this study was to test the diagnostic accuracy of GFAP for ruling out intracranial hemorrhage in a prospective cohort of Indian stroke patients. PATIENTS AND METHODS: This study was conducted in an Indian tertiary hospital (Christian Medical College, Ludhiana). Patients with symptoms suggestive of acute stroke admitted within 12 h of symptom onset were enrolled. Blood samples were collected at hospital admission. Single Molecule Array technology was used for determining serum GFAP concentrations. RESULTS: A total number of 155 patients were included (70 intracranial hemorrhage, 75 ischemic stroke, 10 stroke mimics). GFAP serum concentrations were elevated in intracranial hemorrhage patients compared to ischemic stroke patients [median (interquartile range) 2.36 µg/L (0.61-7.16) vs. 0.18 µg/L (0.11-0.38), p < 0.001]. Stroke mimics patients had a median GFAP serum level of 0.14 µg/L (0.09-0.26). GFAP values below the cut-off of 0.33 µg/L (area under the curve 0.871) ruled out intracranial hemorrhage with a negative predictive value of 89.7%, (at a sensitivity for detecting intracranial hemorrhage of 90.0%). DISCUSSION: The high negative predictive value of a GFAP test system allows ruling out patients with intracranial hemorrhage. CONCLUSION: In settings where immediate brain imaging is not available, this would enable to implement secondary prevention (e.g., aspirin) in suspected ischemic stroke patients as soon as possible.

Lateralization bias for autoimmune optic neuritis.

The asymmetrical structure of the human brain is reflected not only by innate interhemispheric differences but also by lateralization in neurological disease. We tested if unilateral autoimmune optic neuritis (aON) manifests more frequently on the left than the right eye in clinical and neuroimaging terms and whether Google searches for aON symptoms reflect this bias, too. We employed a retrospective analysis of a patient cohort from 2009 to 2019 with 552 unilateral aONs and 374 corresponding MRI imaging data sets. Searchmetrics Suite keywords tool was applied for the analysis of Google searches on aON-symptoms in Germany, the US and the UK for the last 12 months. Left eye aON manifestations were more frequent than right aON manifestations (55.3% vs. 44.7%, p = 0.015) and 1.9 times more likely to be associated with a pathological MRI finding in the affected optic nerve (p = 0.013). Keywords describing aON-typical but not other ocular symptoms were more frequently associated with Google searches for the left in comparison to the right eye (p < 0.001). Autoimmune optic neuritis more frequently affects the left than the right eye and people search on the Internet more often for left-sided aON symptoms. Although a reporting bias due to an increased perception of left eye symptoms is one possible explanation, MRI evidence of more frequent optic nerve affection for the left in comparison to the right side suggests a leftward lateralization bias similar to the one previously shown for cerebral neuroinflammatory lesions.

Immune Cell Profiling During Switching from Natalizumab to Fingolimod Reveals Differential Effects on Systemic Immune-Regulatory Networks and on Trafficking of Non-T Cell Populations into the Cerebrospinal Fluid-Results from the ToFingo Successor Study.

Leukocyte sequestration is an established therapeutic concept in multiple sclerosis (MS) as represented by the trafficking drugs natalizumab (NAT) and fingolimod (FTY). However, the precise consequences of targeting immune cell trafficking for immunoregulatory network functions are only incompletely understood. In the present study, we performed an in-depth longitudinal characterization of functional and phenotypic immune signatures in peripheral blood (PB) and cerebrospinal fluid (CSF) of 15 MS patients during switching from long-term NAT to FTY treatment after a defined 8-week washout period within a clinical trial (ToFingo successor study; ClinicalTrials.gov: NCT02325440). Unbiased visualization and analysis of high-dimensional single cell flow-cytometry data revealed that switching resulted in a profound alteration of more than 80% of investigated innate and adaptive immune cell subpopulations in the PB, revealing an unexpectedly broad effect of trafficking drugs on peripheral immune signatures. Longitudinal CSF analysis demonstrated that NAT and FTY both reduced T cell subset counts and proportions in the CSF of MS patients with equal potency; NAT however was superior with regard to sequestering non-T cell populations out of the CSF, including B cells, natural killer cells and inflammatory monocytes, suggesting that disease exacerbation in the context of switching might be driven by non-T cell populations. Finally, correlation of our immunological data with signs of disease exacerbation in this small cohort suggested that both (i) CD49d expression levels under NAT at the time of treatment cessation and (ii) swiftness of FTY-mediated effects on immune cell subsets in the PB together may predict stability during switching later on.

Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis.

OBJECTIVE: To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4(+) and CD8(+) T cell subsets in patients with multiple sclerosis (MS). METHODS: Peripheral lymphocyte subsets, including CD4(+) and CD8(+) memory cells and T helper (TH) cells TH1, TH2, TH17, and peripheral regulatory T cell (pTreg) subpopulations were analyzed before and 6 months after onset of DMF treatment. RESULTS: CD4(+) and CD8(+) memory T cells were preferentially decreased compared to naive CD4(+) and CD8(+) T cell populations. Within the CD4(+) memory T cell population, frequencies of TH1 cells were decreased, whereas those of TH2 cells were increased and those of TH17 cells remained unaltered. Accordingly, we observed decreased production of interferon γ, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-22 by CD4(+) T cells under DMF treatment, whereas the frequency of IL-4- and IL-17A-producing CD4(+) T cells remained unchanged. With regard to regulatory T cells, proportions of pTreg increased following DMF treatment. CONCLUSION: Our data demonstrate that DMF treatment of patients with MS affects predominantly memory T cells accompanied by a shift in TH cell populations, resulting in a shift toward anti-inflammatory responses. These findings indicate that monitoring of memory subsets might enhance vigilance of impaired antiviral immunity and that patients with TH1-driven disease might preferentially benefit from DMF treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that DMF might preferentially reduce CD4(+) and CD8(+) memory T cells in MS.