Improving the sensitivity of myelin oligodendrocyte glycoprotein-antibody testing: exclusive or predominant MOG-IgG3 seropositivity-a potential diagnostic pitfall in patients with MOG-EM/MOGAD.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD) is the most important differential diagnosis of both multiple sclerosis and neuromyelitis optica spectrum disorders. A recent proposal for new diagnostic criteria for MOG-EM/MOGAD explicitly recommends the use of immunoglobulin G subclass 1 (IgG1)- or IgG crystallizable fragment (Fc) region-specific assays and allows the use of heavy-and-light-chain-(H+L) specific assays for detecting MOG-IgG. By contrast, the utility of MOG-IgG3-specific testing has not been systematically evaluated. OBJECTIVE: To assess whether the use of MOG-IgG3-specific testing can improve the sensitivity of MOG-IgG testing. METHODS: Re-testing of 22 patients with a definite diagnosis of MOG-EM/MOGAD and clearly positive MOG-IgG status initially but negative or equivocal results in H+L- or Fc-specific routine assays later in the disease course (i.e. patients with spontaneous or treatment-driven seroreversion). RESULTS: In accordance with previous studies that had used MOG-IgG1-specific assays, IgG subclass-specific testing yielded a higher sensitivity than testing by non-subclass-specific assays. Using subclass-specific secondary antibodies, 26/27 supposedly seroreverted samples were still clearly positive for MOG-IgG, with MOG-IgG1 being the most frequently detected subclass (25/27 [93%] samples). However, also MOG-IgG3 was detected in 14/27 (52%) samples (from 12/22 [55%] patients). Most strikingly, MOG-IgG3 was the predominant subclass in 8/27 (30%) samples (from 7/22 [32%] patients), with no unequivocal MOG-IgG1 signal in 2 and only a very weak concomitant MOG-IgG1 signal in the other six samples. By contrast, no significant MOG-IgG3 reactivity was seen in 60 control samples (from 42 healthy individuals and 18 patients with MS). Of note, MOG-IgG3 was also detected in the only patient in our cohort previously diagnosed with MOG-IgA+/IgG- MOG-EM/MOGAD, a recently described new disease subvariant. MOG-IgA and MOG-IgM were negative in all other patients tested. CONCLUSIONS: In some patients with MOG-EM/MOGAD, MOG-IgG is either exclusively or predominantly MOG-IgG3. Thus, the use of IgG1-specific assays might only partly overcome the current limitations of MOG-IgG testing and-just like H+L- and Fcγ-specific testing-might overlook some genuinely seropositive patients. This would have potentially significant consequences for the management of patients with MOG-EM/MOGAD. Given that IgG3 chiefly detects proteins and is a strong activator of complement and other effector mechanisms, MOG-IgG3 may be involved in the immunopathogenesis of MOG-EM/MOGAD. Studies on the frequency and dynamics as well as the clinical and therapeutic significance of MOG-IgG3 seropositivity are warranted.

Newly emerging type B insulin resistance (TBIR) during treatment with eculizumab for AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD): fatal outcome.

BACKGROUND: Aquaporin-4 immunoglobulin G (AQP4-IgG) antibody-positive neuromyelitis optica spectrum disorders (NMOSD) are frequently associated with other autoimmune disorders, including systemic lupus erythematosus (SLE). Eculizumab (ECU) is a highly effective long-term treatment for NMOSD. However, ECU is known to increase significantly the risk of infection with encapsulated bacteria and sepsis. Recently, increased insulin resistance (IR) in patients with NMOSD has been suggested. Type B IR (TBIR) is a rare autoimmune condition often accompanying or preceding SLE. TBIR has not yet been reported in NMOSD. OBJECTIVE: To report an ECU-treated patient with AQP4-IgG-positive NMOSD who developed fatal septic complications after the emergence of TBIR. METHODS: Description of the clinical course over a period of 8 years. RESULTS: A female patient was diagnosed with NMOSD at the age of 16 years. A variety of disease-modifying drugs failed to achieve sufficient disease control, resulting in severe tetraparesis. Treatment with ECU was started 6 years after NMOSD diagnosis and stabilized the disease. The patient developed TBIR 8 months after initiation of ECU therapy. Following high-dose intravenous methylprednisolone therapy for a clinical relapse and three further courses of ECU, the patient was admitted with severe pneumonia caused by the encapsulated bacterium Klebsiella pneumoniae and hypoglycemia. Despite multimodal therapy, the patient died from sepsis-related multiorgan failure 18 months after initiation of ECU. CONCLUSIONS: TBIR should be considered as differential diagnosis in patients with NMOSD presenting with disturbed glucose metabolism, irrespective of the presence of SLE. More real-world data are needed on the risk/benefit ratio of ECU treatment in patients who have co-existing autoimmune comorbidities that may compromise immune function. Strategies to mitigate the risk of serious infection in patients treated with ECU are discussed.

MOG encephalomyelitis after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2): case report and comprehensive review of the literature.

BACKGROUND: In around 20% of cases, myelin oligodendrocyte glycoprotein (MOG) immunoglobulin (IgG)-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD) first occurs in a postinfectious or postvaccinal setting. OBJECTIVE: To report a case of MOG-EM with onset after vaccination with the Pfizer BioNTech COVID-19 mRNA vaccine BNT162b2 (Comirnaty®) and to provide a comprehensive review of the epidemiological, clinical, radiological, electrophysiological and laboratory features as well as treatment outcomes of all published patients with SARS-CoV-2 vaccination-associated new-onset MOG-EM. METHODS: Case report and review of the literature. RESULTS: In our patient, MOG-IgG-positive (serum 1:1000, mainly IgG1 and IgG2; CSF 1:2; MOG-specific antibody index < 4) unilateral optic neuritis (ON) occurred 10 days after booster vaccination with BNT162b2, which had been preceded by two immunizations with the vector-based Oxford AstraZeneca vaccine ChAdOx1-S/ChAdOx1-nCoV-19 (AZD1222). High-dose steroid treatment with oral tapering resulted in complete recovery. Overall, 20 cases of SARS-CoV2 vaccination-associated MOG-EM were analysed (median age at onset 43.5 years, range 28-68; female to male ratio = 1:1.2). All cases occurred in adults and almost all after immunization with ChAdOx1-S/ChAdOx1 nCoV-19 (median interval 13 days, range 7-32), mostly after the first dose. In 70% of patients, more than one CNS region (spinal cord, brainstem, supratentorial brain, optic nerve) was affected at onset, in contrast to a much lower rate in conventional MOG-EM in adults, in which isolated ON is predominant at onset and ADEM-like phenotypes are rare. The cerebrospinal fluid white cell count (WCC) exceeded 100 cells/µl in 5/14 (36%) patients with available data (median peak WCC 58 cells/µl in those with pleocytosis; range 6-720). Severe disease with tetraparesis, paraplegia, functional blindness, brainstem involvement and/or bladder/bowel dysfunction and a high lesion load was common, and treatment escalation with plasma exchange (N = 9) and/or prolonged IVMP therapy was required in 50% of cases. Complete or partial recovery was achieved in the majority of patients, but residual symptoms were significant in some. MOG-IgG remained detectable in 7/7 cases after 3 or 6 months. CONCLUSIONS: MOG-EM with postvaccinal onset was mostly observed after vaccination with ChAdOx1-S/ChAdOx1 nCoV-19. Attack severity was often high at onset. Escalation of immunotherapy was frequently required. MOG-IgG persisted in the long term.

Parvovirus B19 and mumps virus antibodies are major constituents of the intrathecal immune response in European patients with MS and increase the diagnostic sensitivity and discriminatory power of the MRZ reaction.

BACKGROUND: A positive MRZ reaction, as defined by intrathecal IgG production against at least two of its constituents, measles virus (M), rubella virus (R) and varicella zoster virus (Z), is detectable in ~ 63% of patients with multiple sclerosis (MS) and is currently considered the laboratory marker with the highest specificity and positive likelihood ratio for MS. However, M, R and Z are only the most well-established constituents of a broader intrathecal humoral immune response in MS. OBJECTIVE: To identify additional anti-microbial antibodies inclusion of which in the classical MRZ panel may result in increased sensitivity without compromising the marker's high specificity for MS. METHODS: We determined the antibody indices (AIs) for 11 viral and bacterial agents (M, R, Z, herpes simplex virus, Epstein-Barr virus, mumps virus, cytomegalovirus, parvovirus B19, Bordetella pertussis, Corynebacterium diphtheriae, and Clostridium tetani) in paired cerebrospinal fluid and serum samples from patients with MS and disease controls. RESULTS: A positive 'classical' MRZ reaction was found in 17/26 (65.4%) MS patients. The five most frequently positive AIs among patients with MS were M (76.9%), Z (61.5%), R (57.7%), parvovirus B19 (42.3%), and mumps (28%). Addition of parvovirus B19 and mumps virus to the MRZ panel resulted in an increase in sensitivity in the MS group from 65.4% to 73.1%, with 22% of the initially MRZ-negative patients exhibiting a de novo-positive response. The extended MRZ panel ('MRZplus') distinguished sharply between MS (≥ 3 AIs in 90% of all positives) and controls (varying diagnoses, from migraine to vasculitis; 0-1 AIs; p < 0.000001). The highest median AI in the MS group was found for parvovirus B19 (3.97), followed by measles virus (2.79). CONCLUSION: Inclusion of parvovirus B19 and mumps virus in the test panel resulted in an increase in the sensitivity and discriminatory power of MRZ. Our results provide a strong rational for prospective studies investigating the role of extended MRZ panels in the differential diagnosis of MS.

Treatment of MOG antibody associated disorders: results of an international survey.

INTRODUCTION: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. OBJECTIVE: To survey the current global clinical practice of clinicians treating MOGAD. METHOD: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019). RESULTS: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. CONCLUSION: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

The history of neuromyelitis optica. Part 2: 'Spinal amaurosis', or how it all began.

Neuromyelitis optica (NMO) was long considered a clinical variant of multiple sclerosis (MS). However, the discovery of a novel and pathogenic anti-astrocytic serum autoantibody targeting aquaporin-4 (termed NMO-IgG or AQP4-Ab), the most abundant water channel protein in the central nervous system, led to the recognition of NMO as a distinct disease entity in its own right and generated strong and persisting interest in the condition. NMO is now studied as a prototypic autoimmune disorder, which differs from MS in terms of immunopathogenesis, clinicoradiological presentation, optimum treatment, and prognosis. While the history of classic MS has been extensively studied, relatively little is known about the history of NMO. In Part 1 of this series we focused on the late 19th century, when the term 'neuromyelitis optica' was first coined, traced the term's origins and followed its meandering evolution throughout the 20th and into the 21st century. Here, in Part 2, we demonstrate that the peculiar concurrence of acute optic nerve and spinal cord affliction characteristic for NMO caught the attention of physicians much earlier than previously thought by re-presenting a number of very early cases of possible NMO that date back to the late 18th and early 19th century. In addition, we comprehensively discuss the pioneering concept of 'spinal amaurosis', which was introduced into the medical literature by ophthalmologists in the first half of the 19th century.

Devic's index case: A critical reappraisal - AQP4-IgG-mediated neuromyelitis optica spectrum disorder, or rather MOG encephalomyelitis?

In 1894, Eugène Devic (1858-1930) and his doctoral student Fernand Gault (1873-1936) reported on a patient with optic neuritis (ON) and myelitis and proposed the name "neuro-myélite optique" for this syndrome. Subsequently, Devic became the eponym of neuromyelitis optica (NMO), which was then referred to as "Devic's syndrome", "Devic's disease" or "Morbus Devic". Thereby, the case became a historical index case of NMO. For many decades little attention was paid to NMO, which most authors considered a clinical variant of multiple sclerosis. However, the discovery of pathogenic antibodies to aquaporin-4 at the beginning of the 21st century revived interest in the syndrome, and AQP4-IgG-positive NMO spectrum disorders (NMOSD) are now studied as prototypical autoimmune diseases. More recently, antibodies to full-length myelin oligodendrocyte glycoprotein (MOG) have been detected in patients with ON as well as in patients with myelitis, some of whom exhibit a clinical phenotype very similar to that described by Devic. This raises the question of whether Devic's patient might have suffered from MOG encephalomyelitis rather than classic NMOSD. In this article, we summarise and discuss the available evidence for and against that hypothesis. We also discuss differential diagnoses and the question whether Devic's patient, who worked as a hatter and had initially been admitted for nervous hyperexcitability and tremor, might have suffered from co-existing erethism ('mad hatter disease'), which is caused by chronic occupational exposure to mercury.

Cerebrospinal fluid biomarkers for predicting development of multiple sclerosis in acute optic neuritis: a population-based prospective cohort study.

BACKGROUND: Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS. METHODS: Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19-41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2-38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons ("q"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms. RESULTS: CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one ("candidate") and IgG index, OCB, and leukocytes in another ("routine"). Area under the curve was 0.89 [95% CI 0.77-1] and 0.86 [0.74-0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms. CONCLUSIONS: CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.

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

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 glycoprotein-immunoglobulin 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.

The first Japanese report on neuromyelitis optica rediscovered: acute bilateral blindness, tetraparesis and respiratory insufficiency in a 35-year-old man (1891).

The term 'neuromyelitis optica' (NMO, Devic syndrome) is used to refer to a syndrome characterized by optic neuritis and myelitis. For many decades NMO was classified as a clinical variant of multiple sclerosis (MS). Recent research has shown, however, that NMO differs from MS in terms of immunopathogenesis, clinical presentation, and optimum treatment. In most cases, NMO is caused by autoantibodies to aquaporin-4 or myelin oligodendrocyte glycoprotein. While the history of classic MS has been studied extensively, only relatively little is known about the early history of NMO. Although NMO is considered to be much more prevalent among Asian than among European patients with CNS demyelination, all early reports of NMO reviewed by Eugène Devic and Fernand Gault in their seminal 1894 review and all other reports from the 19th century re-discovered by us over the past years related cases of NMO in patients of European descent. Here, we would like to draw the attention to an early report on NMO in a Japanese patient, published by Tanemichi Aoyama (1859-1917), one of the most eminent physicians of the Meiji period, an era characterized by a Western-style revolution in Japanese medicine. The report was published in 1891, i.e. 3 years before Devic and Gault's disease defining study on NMO. To the best of our knowledge, this is the earliest report on an Asian patient with NMO. We give an English translation of the original Japanese report written in bungo (pre-modern Japanese) and discuss the case both in the light of current knowledge on NMO and from a historical perspective.

[MOG encephalomyelitis: international recommendations on diagnosis and antibody testing]. / MOG-Enzephalomyelitis: Internationale Empfehlungen zu Diagnose und Antikörpertestung.

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM ("red flags") that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation, and propose for the first time diagnostic criteria for MOG-EM.

MOG encephalomyelitis: international recommendations on diagnosis and antibody testing.

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM ("red flags") that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.

Autoimmune and immunogenetic profile of patients with optic neuritis in a population-based cohort.

BACKGROUND: Optic neuritis (ON) is an inflammatory optic neuropathy, where the genetic and autoimmune dependency remains poorly characterized. OBJECTIVE: To investigate autoimmune and immunogenetic aspects of ON. METHOD: In a prospective population-based cohort 51 patients with ON were included. At follow up 20 patients had progressed to multiple sclerosis (MS-ON). All patients were screened for neuronal and systemic autoantibodies. HLA genotypes and allele and genotype frequencies of the PTPN22 C1858T and the PD-1.3 single-nucleotide polymorphisms (SNPs) were determined and compared to a cohort of Danish blood donors, acting as healthy controls. RESULTS: Median follow-up was 366 days (301-430) for MS-ON patients and 375 (range 50-436) for isolated ON (ION). Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), were positive in two patients, no patients had anti-aquaporin-4 antibodies. Coexisting neural autoantibodies were detected in two patients and in 12 patients other systemic autoantibodies were found. Four (8%) had other autoimmune disorders. A family history of autoimmunity was observed in 12 (24%) and of demyelinating disease in six patients (12%). In MS-ON patients the frequencies of HLA-DQB1*06:02 and HLA-DRB1*15:01 tended to be higher compared to controls (p = 0.08). Stratification of patients with presence of oligoclonal bands (OCB) showed an association to the HLA-DQB1*06:02-HLA-DRB1*15:01 haplotype in ION (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)), and in MS-ON patients (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)). No significant associations to PTPN22 1858C/T or PD-1.3 G/A were found in any group comparison. CONCLUSIONS: ON patients had a general susceptibility to autoimmunity and two were MOG-IgG positive. HLA-DQB1*06:02 and HLA-DRB1*15:01 were associated with the presence of OCB in ON patients.

MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature.

BACKGROUND: Antibodies to human full-length myelin oligodendrocyte glycoprotein (MOG-IgG) as detected by new-generation cell-based assays have recently been described in patients presenting with acute demyelinating disease of the central nervous system, including patients previously diagnosed with multiple sclerosis (MS). However, only limited data are available on the relevance of MOG-IgG testing in patients with chronic progressive demyelinating disease. It is unclear if patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) should routinely be tested for MOG-IgG. OBJECTIVE: To evaluate the frequency of MOG-IgG among patients classified as having PPMS or SPMS based on current diagnostic criteria. METHODS: For this purpose, we retrospectively tested serum samples of 200 patients with PPMS or SPMS for MOG-IgG using cell-based assays. In addition, we performed a review of the entire English language literature on MOG-IgG published between 2011 and 2017. RESULTS: None of 139 PPMS and 61 SPMS patients tested was positive for MOG-IgG. Based on a review of the literature, we identified 35 further MOG-IgG tests in patients with PPMS and 55 in patients with SPMS; the only reportedly positive sample was positive just at threshold level and was tested in a non-IgG-specific assay. In total, a single borderline positive result was observed among 290 tests. CONCLUSION: Our data suggest that MOG-IgG is absent or extremely rare among patients with PPMS or SPMS. Routine screening of patients with typical PPMS/SPMS for MOG-IgG seems not to be justified.

Baló's concentric sclerosis is immunologically distinct from multiple sclerosis: results from retrospective analysis of almost 150 lumbar punctures.

BACKGROUND: Baló's concentric sclerosis (BCS) is a rare inflammatory demyelinating disorder of the central nervous system characterised by concentric layers of demyelination. It is unclear whether BCS is a variant of multiple sclerosis (MS) or a disease entity in its own right. OBJECTIVE: To compare the cerebrospinal fluid (CSF) features of BCS to those of MS. METHODS: Retrospective analysis of the CSF profile of all patients with BCS reported in the medical literature between 1980 and 2017. RESULTS: In total, the results of 146 lumbar punctures (LP) in 132 patients were analysed. The most striking finding was a lack of CSF-restricted oligoclonal bands (OCB) in 66% (56/85) of all LP in the total BCS group, in 74% (14/19) in the subgroup of patients with both MRI and histological evidence for BCS, and in 82% (18/22) in the subgroup of patients with highest radiological confidence (high MRI quality, ≥ 3 layers of demyelination). OCB disappeared in 1/2 initially OCB-positive patients. These findings are in stark contrast to MS, in which OCB are present in ≥ 95% of patients and are thought to remain stably detectable over the entire course of disease (p < 0.000001). OCB frequency was low both in 'historic' patients (1980-2009; 37%) and in more recent patients (2010-2017; 31%). OCB-positive and OCB-negative patients did not differ significantly with regard to age, sex, disease duration, number of Baló-like lesions on MRI, number of relapses, treatment or final outcome. In accordance with the high rate of OCB negativity, Link's IgG index was negative in 63% of all tested samples (p < 0.000001 vs. MS). CSF pleocytosis was present in 28% (27/96; p < 0.000001 vs. MS) and elevated CSF total protein levels in 41% (31/76) of samples. CONCLUSION: OCB and IgG index frequencies in BCS are much more similar to those reported in neuromyelitis optica or myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis than to those in MS. Our findings suggest that in most cases BCS-like lesions denote the presence of a disease entity immunologically distinct from MS. In addition, we provide data on the demographics, clinical course and radiological features of BCS based on the largest cohort analysed to date.

Magnetic resonance imaging findings at the first episode of acute optic neuritis.

BACKGROUND: Optic neuritis (ON) is a focal demyelinating event, which may evolve into multiple sclerosis (MS). OBJECTIVE: To study MRI characteristics in the acute phase of the first ON episode. METHODS: A prospective population-based study was performed on 31 patients with a first episode of acute ON with a one year follow-up. MRI, clinical evaluation, and detection of aquaporin-4 (AQP4)-IgG and myelin oligodendrocyte glycoprotein (MOG)-IgG was undertaken. For lesion characterization on MRI the optic nerves were divided into three segments: intra-orbital (IO), canalicular (CAN) and chiasmal (CHI). RESULTS: Lesions of the optic nerve were observed in 80.6%(25/31), with IO location in 48%(12/25), CAN in 8% (2/25) and both IO and CAN in 44%(11/25). Patients who converted to MS had lesions located at IO in 77%(10/13), whereas the group with isolated ON had IO and CAN in 73% (8/11), p = 0.003. Brain lesions were observed in 84% (21/25) at onset of ON; 62%(13/25) progressed to MS with more frequent location in brainstem (p = 0.030) and lesions in periventricular areas (p = 0.015). Spinal cord lesions were detected only in patients who progressed to MS (p = 0.002). MOG-IgG was detected in one patient with an optic nerve lesion located at IO and CAN. Serum AQP4-IgG was detected in none. Follow-up MRI showed progression in optic nerve lesions in 55% (11/20) patients. CONCLUSIONS: Specific location of optic nerve and brain lesions and the presence of spinal cord lesions in the acute phase of the first ON episode facilitated an MS diagnosis. The extension of optic nerve lesions following ON suggests a long-term progressive degeneration as an important element of ON pathology.

A population-based prospective study of optic neuritis.

BACKGROUND: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. OBJECTIVE: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. METHOD: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. RESULTS: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16-66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44-4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. CONCLUSION: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

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

BACKGROUND: The 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. OBJECTIVE: The 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. METHODS: Findings 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. RESULTS: Oligoclonal 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). CONCLUSIONS: Patients 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.

Devic's disease before Devic: On the contribution of Friedrich Albin Schanz (1863-1923).

Neuromyelitis optica (NMO, Devic's disease) is an autoimmune disorder of the CNS that mainly affects the optic nerves and spinal cord and, if not treated, can leave patients blind and wheelchair-bound. NMO was long considered a clinical variant of multiple sclerosis (MS). While the history of MS has been studied extensively, relatively little is known about the early history of NMO. A dissertation written by Fernand Gault (1873-1936), a doctoral student to Eugène Devic (1858-1930), a Lyon-based neurologist after whom the disease would later be named, is considered by many the first review of NMO. We would like to draw attention to a forgotten earlier review by the German oculist Friedrich Albin Schanz (1863-1923)-still known to ophthalmologists as one of the inventors of the corneal microscope ("slit lamp")-on which Devic and Gault's work was based and which points to most of the clinical and pathological features nowadays considered characteristic for NMO. The discovery of aquaporin-4 antibodies (NMO-IgG) has revived the interest in NMO, which is now extensively studied as a prototypic autoimmune condition. We believe it is now time to do justice to those who were seminal in describing this rare yet intriguing disease.

Identification of the flotillin-1/2 heterocomplex as a target of autoantibodies in bona fide multiple sclerosis.

BACKGROUND: Autoantibodies, in particular those against aquaporin-4 and myelin-oligodendrocyte glycoprotein (MOG), aid as biomarkers in the differential diagnosis of demyelination. Here, we report on discovery of autoantibodies against flotillin in patients with multiple sclerosis (MS). METHODS: The target antigen was identified by histo-immunoprecipitation using the patients' sera and cryosections of rat or pig cerebellum combined with mass spectrometrical analysis. Correct identification was ascertained by indirect immunofluorescence and neutralization tests using the target antigens recombinantly expressed in HEK293 cells. RESULTS: Serum and CSF of the index patient produced a fine-granular IgG indirect immunofluorescence staining of the hippocampal and cerebellar molecular layers. Flotillin-1 and flotillin-2 were identified as target autoantigens. They also reacted with recombinant human flotillin-1/2 co-expressed in HEK293 cells, but not with the individual flotillins in fixed- and live-cell assays. Moreover, neutralization using flotillin-1/2, but not the single flotillins, abolished the tissue reactivity of patient serum. Screening of 521 patients, for whom anti-aquaporin-4 testing was requested and negative, revealed 8 additional patients with anti-flotillin-1/2 autoantibodies. All eight were negative for anti-MOG. Six patients ex post fulfilled the revised McDonald criteria for MS. Vice versa, screening of 538 MS sera revealed anti-flotillin-1/2 autoantibodies in eight patients. The autoantibodies were not found in a cohort of 67 patients with other neural autoantibody-associated syndromes and in 444 healthy blood donors. CONCLUSIONS: Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, are present in 1-2% of patients with bona fide MS.