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.

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.

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.

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.

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.

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.

[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.

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.

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.

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.

[Autoantibody-associated autoimmune encephalitis and cerebellitis : Clinical presentation, diagnostic work-up and treatment]. / Autoantikörperassoziierte autoimmune Enzephalitiden und Zerebellitiden : Klinik, Diagnostik und Therapie.

There is no other field of neurology where clinically relevant serological biomarkers have witnessed a surge in importance over the past decade resembling that in autoimmune encephalitis and cerebellitis. A multitude of newly discovered neuronal autoantibodies facilitate early diagnosis, estimation of prognosis, and therapeutic decision-making. However, this has led to growing uncertainty with regard to meaningful patient selection, the appropriate extent of testing, and management of seronegative cases. This review summarizes the essential aspects of the clinical presentation, diagnostic work-up, pathophysiology, and treatment of autoimmune encephalitis and cerebellitis.

'Medusa-head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII.

Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as 'Medusa-head antibodies' due to their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects and provides a summary and outlook.

'Medusa head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 2: Anti-PKC-gamma, anti-GluR-delta2, anti-Ca/ARHGAP26 and anti-VGCC.

Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as 'Medusa head antibodies' due their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects, and provides a summary and outlook.

'Medusa head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 3: Anti-Yo/CDR2, anti-Nb/AP3B2, PCA-2, anti-Tr/DNER, other antibodies, diagnostic pitfalls, summary and outlook.

Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as 'Medusa head antibodies' due to their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects and provides a summary and outlook.

Neuromyelitis optica: clinical features, immunopathogenesis and treatment.

The term 'neuromyelitis optica' ('Devic's syndrome', NMO) refers to a syndrome characterized by optic neuritis and myelitis. In recent years, the condition has raised enormous interest among scientists and clinical neurologists, fuelled by the detection of a specific serum immunoglobulin (Ig)G reactivity (NMO-IgG) in up to 80% of patients with NMO. These autoantibodies were later shown to target aquaporin-4 (AQP4), the most abundant water channel in the central nervous system (CNS). Here we give an up-to-date overview of the clinical and paraclinical features, immunopathogenesis and treatment of NMO. We discuss the widening clinical spectrum of AQP4-related autoimmunity, the role of magnetic resonance imaging (MRI) and new diagnostic means such as optical coherence tomography in the diagnosis of NMO, the role of NMO-IgG, T cells and granulocytes in the pathophysiology of NMO, and outline prospects for new and emerging therapies for this rare, but often devastating condition.

Contribution of spinal cord biopsy to diagnosis of aquaporin-4 antibody positive neuromyelitis optica spectrum disorder.

Longitudinally extensive transverse myelitis is characteristic but not pathognomonic for neuromyelitis optica spectrum disorders (NMOSDs) and may mimic local tumors. In this retrospective study based on a cohort of 175 NMOSD patients we identified seven patients who initially presented with a longitudinally extensive spinal cord lesion and underwent spinal cord biopsy due to magnetic resonance imaging (MRI)-suspected malignancies. Remarkably, routine neuropathology was inconclusive and did not guide the diagnostic process to anti-aquaporin-4 (AQP4)-seropositive NMOSD. Serious postoperative complications occurred in 5/7 patients and persisted during follow-up in 2/7 patients (29%). Considering these sequelae, AQP4-antibody testing should be mandatory in patients with inconclusive longitudinally extensive spinal cord lesions prior to biopsy.

Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients.

BACKGROUND: Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system characterized by spinal cord and optic nerve involvement. Brainstem manifestations have recently been described. OBJECTIVE: To evaluate the time of occurrence, the frequency and the characteristics of brainstem symptoms in a cohort of patients with NMO according to the ethnic background and the serologic status for anti-aquaporin-4 antibodies (AQP4-abs). METHODS: We performed a multicenter study of 258 patients with NMO according to the 2006 Wingerchuk criteria and we evaluated prospectively the frequency, the date of onset and the duration of various brainstem signs in this population. RESULTS: Brainstem signs were observed in 81 patients (31.4%). The most frequently observed signs were vomiting (33.1%), hiccups (22.3%), oculomotor dysfunction (19.8%), pruritus (12.4%), followed by hearing loss (2.5%), facial palsy (2.5%), vertigo or vestibular ataxia (1.7%), trigeminal neuralgia (2.5%) and other cranial nerve signs (3.3%). They were inaugural in 44 patients (54.3%). The prevalence was higher in the non-Caucasian population (36.6%) than in the Caucasian population (26%) (p<0.05) and was higher in AQP4-ab-seropositive patients (32.7%) than in seronegative patients (26%) (not significant). CONCLUSIONS: This study confirms the high frequency of brainstem symptoms in NMO with a majority of vomiting and hiccups. The prevalence of these manifestations was higher in the non Caucasian population.

Characterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset.

BACKGROUND: Few data are available for patients with a late onset (≥ 50 years) of neuromyelitis optica (LONMO) or neuromyelitis optica spectrum disease (LONMOSD), defined by an optic neuritis/longitudinally extensive transverse myelitis with aquaporin-4 antibodies (AQP4-Ab). OBJECTIVE: To characterize LONMO and LONMOSD, and to analyze their predictive factors of disability and death. METHODS: We identified 430 patients from four cohorts of NMO/NMOSD in France, Germany, Turkey and UK. We extracted the late onset patients and analyzed them for predictive factors of disability and death, using the Cox proportional model. RESULTS: We followed up on 63 patients with LONMO and 45 with LONMOSD during a mean of 4.6 years. This LONMO/LONMOSD cohort was mainly of Caucasian origin (93%), women (80%), seropositive for AQP4-Ab (85%) and from 50 to 82.5 years of age at onset. No progressive course was noted. At last follow-up, the median Expanded Disability Status Scale (EDSS) scores were 5.5 and 6 in the LONMO and LONMOSD groups, respectively. Outcome was mainly characterized by motor disability and relatively good visual function. At last follow-up, 14 patients had died, including seven (50%) due to acute myelitis and six (43%) because of opportunistic infections. The EDSS 4 score was independently predicted by an older age at onset, as a continuous variable after 50 years of age. Death was predicted by two independent factors: an older age at onset and a high annualized relapse rate. CONCLUSION: LONMO/LONMOSD is particularly severe, with a high rate of motor impairment and death.

[Contribution of spinal cord biopsy to the differential diagnosis of longitudinal extensive transverse myelitis]. / Biopsie bei tumorverdächtiger spinaler Raumforderung: Fallstrick Neuromyelitis optica.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are characterized by recurrent optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM) as well as the serological detection of antibodies to aquaporin-4 (AQP4-ab). However, longitudinal extensive spinal cord lesions are not pathognomonic for NMOSD as they can also occur in systemic autoimmune diseases or mimic spinal cord tumors. OBJECTIVES/METHODS: We report a female patient who initially presented with a subacute spinal syndrome and a longitudinal spinal cord lesion on magnetic resonance imaging (MRI). As the brain MRI showed only unspecific white matter lesions and the cerebrospinal fluid was normal, a spinal cord biopsy was performed to exclude malignancies and revealed inflammatory demyelinating changes. In addition, after several deep vein thromboses and the detection of antiphospholipid antibodies, an antiphospholipid syndrome (APS) was diagnosed. Many years after the spinal cord biopsy, AQP4-ab were tested and found to be positive. We discuss the important differential diagnoses of LETM, give an overview of previously reported NMOSD cases in which a spinal cord biopsy was performed and highlight the crucial role of AQP4-ab testing for the differential diagnosis of longitudinal spinal cord lesions. RESULTS/CONCLUSIONS: Considering possible serious sequelae of spinal biopsy procedures, testing for AQP4-ab is mandatory in patients with unclear longitudinally extensive spinal cord lesions and should be performed preoperatively in all cases. In light of the heterogeneity of available assays, different detection methods should be used in doubtful cases. The relationship between NMO and APS needs further clarification; however, AQP4 IgG testing is recommended in patients presenting with APS and myelitis, optic neuritis or brainstem encephalitis.

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.