Pain in NMOSD and MOGAD: A Systematic Literature Review of Pathophysiology, Symptoms, and Current Treatment Strategies

Neuromyelitis optica spectrum disorders (NMOSDs) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) are autoimmune inflammatory disorders of the central nervous system (CNS). Pain is highly prevalent and debilitating in NMOSD and MOGAD with a severe impact on quality of life, and there is a critical need for further studies to successfully treat and manage pain in these rare disorders. In NMOSD, pain has a prevalence of over 80%, and pain syndromes include neuropathic, nociceptive, and mixed pain, which can emerge in acute relapse or become chronic during the disease course. The impact of pain in MOGAD has only recently received increased attention, with an estimated prevalence of over 70%. These patients typically experience not only severe headache, retrobulbar pain, and/or pain on eye movement in optic neuritis but also neuropathic and nociceptive pain. Given the high relevance of pain in MOGAD and NMOSD, this article provides a systematic review of the current literature pertaining to pain in both disorders, focusing on the etiology of their respective pain syndromes and their pathophysiological background. Acknowledging the challenge and complexity of diagnosing pain, we also provide a mechanism-based classification of NMOSD- and MOGAD-related pain syndromes and summarize current treatment strategies

Practical recognition tools of immunoglobulin G serum antibodies against the myelin oligodendrocyte glycoprotein‐positive optic neuritis and its clinical implications

Myelin oligodendrocyte glycoprotein (MOG)-associated disease is an autoimmune disease of the central nervous system, associated with the presence of immunoglobulin G serum antibodies against MOG. Recent data have allowed characterization of the clinical spectrum of MOG-associated disease, which is now considered a new disease entity, distinct from multiple sclerosis and neuromyelitis optica spectrum disorders. Optic neuritis is the most common clinical presentation of MOG-associated disease in adults, both at disease onset and during the disease course, and has several distinct clinical and paraclinical features. Immunoglobulin G serum antibodies against MOG-positive optic neuritis is often bilateral and associated with optic disc swelling and a longitudinally extensive abnormal magnetic resonance imaging signal involving the retrobulbar portion of the optic nerve. The visual acuity during the acute attack is severely decreased, and the response to corticosteroids is often rapid and prominent. However, early relapses after steroid cessation are common, and a subset of patients is left with a permanent visual disability. In this review, we discuss the clinical and paraclinical features of immunoglobulin G serum antibodies against MOG-positive optic neuritis in adults, and focus on the distinctive features that can enable its early diagnosis. Therapeutical considerations at the acute stage and for relapse prevention are further deliberated

Anti-aquaporin 4 IgG Is Not Associated With Any Clinical Disease Characteristics in Neuromyelitis Optica Spectrum Disorder

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a clinically defined, inflammatory central nervous system (CNS) disease of unknown cause, associated with humoral autoimmune findings such as anti-aquaporin 4 (AQP4)-IgG. Recent clinical trials showed a benefit of anti-B cell and anti-complement-antibodies in NMOSD, suggesting relevance of anti-AQP4-IgG in disease pathogenesis. Objective: AQP4-IgG in NMOSD is clearly defined, yet up to 40% of the patients are negative for AQP4-IgG. This may indicate that AQP4-IgG is not disease-driving in NMOSD or defines a distinct patient endotype. Methods: We established a biobank of 63 clinically well-characterized NMOSD patients with an extensive annotation of 351 symptoms, patient characteristics, laboratory results and clinical scores. We used phylogenetic clustering, heatmaps, principal component and longitudinal causal interference analyses to test for the relevance of anti-AQP4-IgG. Results: Anti-AQP4-IgG was undetectable in 29 (46%) of the 63 NMOSD patients. Within anti-AQP4-IgG-positive patients, anti-AQP4-IgG titers did not correlate with clinical disease activity. Comparing anti-AQP4-IgG-positive vs. -negative patients did not delineate any clinically defined subgroup. However, anti-AQP4-IgG positive patients had a significantly (p = 0.022) higher rate of additional autoimmune diagnoses. Conclusion: Our results challenge the assumption that anti-AQP4-IgG alone plays a disease-driving role in NMOSD. Anti-AQP4-IgG might represent an epiphenomenon associated with NMOSD, may represent one of several immune mechanisms that collectively contribute to the pathogenesis of this disease or indeed, anti-AQP4-IgG might be the relevant factor in only a subgroup of patients

Normative Data and Minimally Detectable Change for Inner Retinal Layer Thicknesses Using a Semi-automated OCT Image Segmentation Pipeline

Neurodegenerative and neuroinflammatory diseases regularly cause optic nerve and retinal damage. Evaluating retinal changes using optical coherence tomography (OCT) in diseases like multiple sclerosis has thus become increasingly relevant. However, intraretinal segmentation, a necessary step for interpreting retinal changes in the context of these diseases, is not standardized and often requires manual correction. Here we present a semi-automatic intraretinal layer segmentation pipeline and establish normative values for retinal layer thicknesses at the macula, including dependencies on age, sex, and refractive error. Spectral domain OCT macular 3D volume scans were obtained from healthy participants using a Heidelberg Engineering Spectralis OCT. A semi-automated segmentation tool (SAMIRIX) based on an interchangeable third-party segmentation algorithm was developed and employed for segmentation, correction, and thickness computation of intraretinal layers. Normative data is reported froma 6mmEarly Treatment Diabetic Retinopathy Study (ETDRS) circle around the fovea. An interactive toolbox for the normative database allows surveying for additional normative data. We cross-sectionally evaluated data from218 healthy volunteers (144 females/74males, age 36.5 ± 12.3 years, range 18–69 years). Average macular thickness (MT) was 313.70 ± 12.02 μm, macular retinal nerve fiber layer thickness (mRNFL) 39.53 ± 3.57 μm, ganglion cell and inner plexiform layer thickness (GCIPL) 70.81 ± 4.87 μm, and inner nuclear layer thickness (INL) 35.93 ± 2.34 μm. All retinal layer thicknesses decreased with age. MT and GCIPL were associated with sex, with males showing higher thicknesses. Layer thicknesses were also positively associated with each other. Repeated-measurement reliability for the manual correction of automatic intraretinal segmentation results was excellent, with an intra-class correlation coefficient >0.99 for all layers. The SAMIRIX toolbox can simplify intraretinal segmentation in research applications, and the normative data application may serve as an expandable reference for studies, in which normative data cannot be otherwise obtained

Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens (β = −0.85, P = 0.021) and caudate nucleus (β = −0.61, P = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures

Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders

Background: Pain is a frequent symptom in aquaporin-4-immunoglobulin-G-positive neuromyelitis optica spectrum disorders (AQP4-IgG-pos. NMOSD). Data on pain in myelin-oligodendrocyteglycoprotein- immunoglobulin-G autoimmunity with a clinical NMOSD phenotype (MOG-IgG-pos. NMOSD) are scarce. Objective: The objective of this paper is to investigate pain in MOG-IgG-pos. NMOSD, AQP4-IgG-pos. NMOSD and NMOSD without AQP4/MOG-IgG detection (AQP4/MOG-IgG-neg. NMOSD). Methods: Forty-nine MOG-IgG-pos. (n=14), AQP4-IgG-pos. (n=29) and AQP4/MOG-IgG-neg. (n=6) NMOSD patients were included in this cross-sectional baseline analysis from an ongoing observational study. We identified spinal cord lesions on magnetic resonance imaging, assessed pain by the painDETECT and McGill Pain questionnaires, quality of life by Short Form Health Survey, and depression by Beck Depression Inventory. Results: Twelve MOG-IgG-pos. NMOSD patients (86%), 24 AQP4-IgG-pos. NMOSD patients (83%), and all AQP4/MOG-IgG-neg. NMOSD patients (100%) suffered from pain. MOG-IgG-pos. NMOSD patients had mostly neuropathic pain and headache; AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD patients had mostly neuropathic pain. A history of myelitis was less frequent in MOG-IgGpos. NMOSD than in AQP4-IgG-pos. NMOSD patients. Pain influenced quality of life in all patients. Thirty-six percent of patients with pain received pain medication; none of them were free of pain. Conclusions: Pain is a frequent symptom of patients with MOG-IgG-pos. NMOSD and is as important as in AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD. Despite its impact on quality of life, pain is insufficiently alleviated by medication

Low-Density Granulocytes Are a Novel Immunopathological Feature in Both Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

Objective: To investigate whether low-density granulocytes (LDGs) are an immunophenotypic feature of patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD). Methods: Blood samples were collected from 20 patients with NMOSD and 17 patients with MS, as well as from 15 patients with Systemic Lupus Erythematosus (SLE) and 23 Healthy Donors (HD). We isolated peripheral blood mononuclear cells (PBMCs) with density gradient separation and stained the cells with antibodies against CD14, CD15, CD16, and CD45, and analyzed the cells by flow cytometry or imaging flow cytometry. We defined LDGs as CD14-CD15(high) and calculated their share in total PBMC leukocytes (CD45+) as well as the share of CD16(hi) LDGs. Clinical data on disease course, medication, and antibody status were obtained. Results: LDGs were significantly more common in MS and NMOSD than in HDs, comparable to SLE samples (median values HD 0.2%, MS 0.9%, NMOSD 2.1%, SLE 4.3%). 0/23 of the HDs, but 17/20 NMOSD and 11/17 MS samples as well as 13/15 SLE samples had at least 0.7 % LDGs. NMOSD patients without continuous immunosuppressive treatment had significantly more LDGs compared to their treated counterparts. LDG nuclear morphology ranged from segmented to rounded, suggesting a heterogeneity within the group. Conclusion: LDGs are a feature of the immunophenotype in some patients with MS and NMOSD

Uncovering convolutional neural network decisions for diagnosing multiple sclerosis on conventional MRI using layer-wise relevance propagation

Machine learning-based imaging diagnostics has recently reached or even superseded the level of clinical experts in several clinical domains. However, classification decisions of a trained machine learning system are typically non-transparent, a major hindrance for clinical integration, error tracking or knowledge discovery. In this study, we present a transparent deep learning framework relying on convolutional neural networks (CNNs) and layer-wise relevance propagation (LRP) for diagnosing multiple sclerosis (MS). MS is commonly diagnosed utilizing a combination of clinical presentation and conventional magnetic resonance imaging (MRI), specifically the occurrence and presentation of white matter lesions in T2-weighted images. We hypothesized that using LRP in a naive predictive model would enable us to uncover relevant image features that a trained CNN uses for decision-making. Since imaging markers in MS are well-established this would enable us to validate the respective CNN model. First, we pre-trained a CNN on MRI data from the Alzheimer's Disease Neuroimaging Initiative (n = 921), afterwards specializing the CNN to discriminate between MS patients and healthy controls (n = 147). Using LRP, we then produced a heatmap for each subject in the holdout set depicting the voxel-wise relevance for a particular classification decision. The resulting CNN model resulted in a balanced accuracy of 87.04% and an area under the curve of 96.08% in a receiver operating characteristic curve. The subsequent LRP visualization revealed that the CNN model focuses indeed on individual lesions, but also incorporates additional information such as lesion location, non-lesional white matter or gray matter areas such as the thalamus, which are established conventional and advanced MRI markers in MS. We conclude that LRP and the proposed framework have the capability to make diagnostic decisions of..

Multi-parameter immune profiling of peripheral blood mononuclear cells by multiplexed single-cell mass cytometry in patients with early multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Studies in rodent models demonstrated an association of CNS-infiltrating monocyte-derived macrophages with disease severity. However, little is known about humans. Here, we performed an exploratory analysis of peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and drug-naïve patients with early MS using multiplexed single-cell mass cytometry and algorithm-based data analysis. Two antibody panels comprising a total of 64 antibodies were designed to comprehensively analyse diverse immune cell populations, with particular emphasis on monocytes. PBMC composition and marker expression were overall similar between the groups. However, an increased abundance of CCR7+ and IL-6+ T cells was detected in early MS-PBMCs, whereas NFAT1hiT-bethiCD4+ T cells were decreased. Similarly, we detected changes in the subset composition of the CCR7+ and MIPβhi HLA-DR+ lymphocyte compartment. Only mild alterations were detected in monocytes/myeloid cells of patients with early MS, namely a decreased abundance of CD141hiIRF8hiCXCR3+CD68- dendritic cells. Unlike in Crohn's disease, no significant differences were found in the monocyte fraction of patients with early MS compared to healthy controls. This study provides a valuable resource for future studies designed to characterise and target diverse PBMC subsets in MS

Standardization of T1w/T2w Ratio Improves Detection of Tissue Damage in Multiple Sclerosis

Normal appearing white matter (NAWM) damage develops early in multiple sclerosis (MS) and continues in the absence of new lesions. The ratio of T1w and T2w (T1w/T2w ratio), a measure of white matter integrity, has previously shown reduced intensity values in MS NAWM. We evaluate the validity of a standardized T1w/T2w ratio (sT1w/T2w ratio) in MS and whether this method is sensitive in detecting MS-related differences in NAWM. T1w and T2w scans were acquired at 3 Tesla in 47 patients with relapsing-remitting MS and 47 matched controls (HC). T1w/T2w and sT1w/T2w ratios were then calculated. We compared between-group variability between T1w/T2w and sT1w/T2w ratio in HC and MS and assessed for group differences. We also evaluated the relationship between the T1w/T2w and sT1w/T2w ratios and clinically relevant variables. Compared to the classic T1w/T2w ratio, the between-subject variability in sT1w/T2w ratio showed a significant reduction in MS patients (0 <. 0.001) and HC < 0.001). However, only sT1w/T2w ratio values were reduced in patients compared to HC (p < 0.001). The sT1w/T2w ratio intensity values were significantly influenced by age, T2 lesion volume and group status (MS vs. HC) (adjusted R-2 = 0.30, p 0.001). We demonstrate the validity of the sT1w/T2w ratio in MS and that it is more sensitive to MS-related differences in NAWM compared to T1w/T2w ratio. The sT1w/T2w ratio shows promise as an easily-implemented measure of NAWM in MS using readily available scans and simple post-processing methods