Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis

S Jarius,W Brück,F.B König,K Ruprecht,I Metz,B Wildemann,F Paul

doi:10.1186/s12974-017-0929-z

Abstract

BackgroundThe diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity.ObjectiveThe aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis.MethodsFindings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work-up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively.ResultsOligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (P < 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so-called MRZ reaction) was previously reported in 60–80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood–CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (P < 0.005, P < 0.009 and P < 0.006, respectively).ConclusionsPatients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and blood–CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS.

Highlights

The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features
Available serum samples were retrospectively tested for aquaporin 4 (AQP4)-Immunoglobulin G (IgG) and myelin oligodendrocyte glycoprotein (MOG)-IgG using a cell-based assay (CBA) employing formalin HEK293 cells transfected with full-length human M1-AQP4 and M23-AQP4 [15, 16] or full-length human MOG [17, 18], respectively
If only persisting Oligoclonal bands (OCBs) are taken into account, only 22.7% (5/22) patients with pattern II or III MS were positive for OCB (P < 0.006) (Table 2)

Summary

Introduction

The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. Histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity. A fourth pattern, defined by oligodendrocyte degeneration in the periplaque white matter, has been described in few autopsy cases of primary-progressive MS, but is rare. These findings raise the possibility that MS, a diagnosis currently based mainly on phenotypical, namely clinical and radiological features [3], may be a pathologically heterogeneous syndrome rather than a single disease entity. Two recent studies demonstrated intraindividual homogeneity and persistence of pattern I, II and III lesions over time [4, 5], further corroborating the notion that lesion pathology may rather define pathogenetically distinct entities than reflect stagedependent processes in the development of lesions

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