Myelinoclastic diffuse sclerosis (Schilder’s disease) is immunologically distinct from multiple sclerosis: results from retrospective analysis of 92 lumbar punctures

Jarius et al. Journal of Neuroinflammation https://doi.org/10.1186/s12974-019-1425-4 (2019) 16:51 RESEARCH Open Access Myelinoclastic diffuse sclerosis (Schilder’s disease) is immunologically distinct from multiple sclerosis: results from retrospective analysis of 92 lumbar punctures S. Jarius1*, J. Haas1, F. Paul2,3,4,5 and B. Wildemann1 Abstract Background: Myelinoclastic diffuse sclerosis (MDS; also termed Schilder’s disease) is a rare inflammatory demyelinating disorder of the central nervous system characterised by demyelination of vast areas of the white matter. It is unclear whether MDS is a variant of multiple sclerosis (MS) or a disease entity in its own right. Objective: To compare the cerebrospinal fluid (CSF) features of MDS with those of MS. Methods: Retrospective analysis of the CSF profile of all patients with MDS reported in the medical literature between 1960 and 2018. Results: The most striking finding was a substantial lack of oligoclonal bands (OCBs) in MDS, which were absent in at least 77% (30/39) of all lumbar punctures (LP) in the total cohort and in 86% in the subgroup of patients with normal very long-chain fatty acid serum ratios (VLCFA). Almost all cases published in the past 15 years were negative for OCBs. These findings are in contrast to MS, in which OCBs are present in up to 98% of cases (p < 0.00001 when compared with reference works in MS; both in adult and in pediatric patients). CSF pleocytosis was absent in at least 79% (46/58) of all LP (p < 0.0001 vs. MS) and in 92% (24/26) of LPs in the VLCFA-tested subgroup. CSF total protein levels were elevated in 56% of all LPs (p < 0.0001 vs. MS) and in 63% of LPs in the VLCFA-tested subgroup and were often higher than in typical MS (> 100 mg/dL in 13/22; up to 220 mg/dL). EBV serum antibodies, which are present in virtually all patients with MS, and the so-called MRZ (measles/rubella/zoster) reaction, a highly specific marker of MS, were absent in all of the few patients tested. In addition, we discuss further differences between MS and MDS, taking into account also Schilder’s original comprehensive case description from 1912. Conclusion: In the majority of patients diagnosed with MDS, CSF features differ significantly from those typically found in MS and are more similar to those previously reported in patients with myelin oligodendrocyte glycoproteinimmunoglobulin G (IgG)-positive encephalomyelitis, aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders or Baló’s concentric sclerosis. Our data suggest that MDS and MS are immunopathologically distinct entities in the majority of cases. Keywords: Schilder’s disease, Myelinoclastic diffuse sclerosis, Encephalitis periaxialis Schilder, Multiple sclerosis, Tumefactive, Demyelination, Central nervous system, Neuromyelitis optica, Baló’s concentric sclerosis * Correspondence: 1 Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jarius et al. Journal of Neuroinflammation (2019) 16:51 Background Myelinoclastic diffuse sclerosis (MDS; also termed Schilder’s disease or encephalitis periaxialis diffusa) was first described in 1912 by the Austrian psychiatrist Paul Ferdinand Schilder (1886–1940) [1]. MDS is characterized by one or two extensive, often bilateral and roughly symmetrical demyelinating white matter lesions in the centrum semiovale. However, its exact nosological relationship to multiple sclerosis (MS) has remained elusive. In a number of recent studies, we have demonstrated substantial differences in cerebrospinal fluid (CSF) features between patients with MS and patients with other autoimmune disorders of the central nervous system (CNS). In particular, we have found significantly lower frequencies of CSF-restricted oligoclonal bands (OCBs) and other markers of intrathecal immunoglobulin G (IgG) synthesis in patients with aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica (NMO) spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM), acute demyelinating encephalomyelitis (ADEM) and paraneoplastic neurological disorders (PND) than in MS, as well as significant differences in intrathecal IgG composition and dynamics and in blood–CSF barrier function [2– 13]. This indicates that studying CSF profiles may be helpful in distinguishing clinically related but immunopathogenetically distinct diseases. To address the question of whether MDS is just a very active and tumefactive variant of MS or an immunologically distinct disease entity, we set out to systematically compare the CSF features of MDS with those of MS. Page 2 of 14 fraction (γGF; as % of total CSF protein); measles/rubella/ zoster (MRZ) reaction, as defined by a positive reaction to at least two of the three viral agents; CSF total protein (TP), glucose and lactate concentrations; CSF myelin basic protein (MBP) concentrations; CSF opening pressure; Epstein– Barr virus (EBV) and tuberculosis status; aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody serostatus; VLCFA serum ratio; and adrenal function test results. A CSF white cell count > 5/μl was classified as increased. An age-dependent upper reference range for CSF L-lactate was applied (0–15 years of age, 1.8 mmol/ l; 16–50, 2.1 mmol/l; > 50, 2.6 mmol/l). The upper reference limit for CSF TP was set at 45 mg/dl, for CSF IgG at 6 mg/dL, for IgG index at 0.7, for γGF at 13% [14], for CSF glucose at 50% of serum glucose or 80 mg/dl and for CSF opening pressure at 250 mmH2O. Subgroup analyses were performed for patients ≥ 18 years of age at onset (adult onset subgroup), patients < 18 years of age at onset (non-adult onset subgroup) and patients with available VLCFA results. Data from the MDS cohort were compared to publicly available data from the MSBase registry [15] and to data from reference studies in MS [16–21]. Differences in frequency distributions among groups were studied using Fisher’s exact test. Due to the exploratory nature of this study, no corrections for multiple testing were made. All analyses were performed retrospectively; accordingly, no CSF or serum samples were obtained for this study. Results Patient characteristics Methods We performed a systematic review of all MDS cases published in English, Germa (...truncated)