Neuromyelitis Optica Spectrum Disorder Lesions Research Articles

Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

T1 hypointense brain lesions in NMOSD and its relevance with disability: a single institution cross-sectional study

BackgroundT1 hypointense lesions are considered a surrogate marker of tissue destruction. Although there is a shortage of evidence about T1 hypointense brain lesions, black holes, in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD), the clinical significance of these lesions is not well determined.ObjectivesThe impact of T1 hypointense brain lesions on the clinical status and the disability level of patients with NMOSD was sought in this study.MethodsA total of 83 patients with the final diagnosis of NMOSD were recruited.Aquaporin-4 measures were collected. The expanded disability status scale (EDSS) and MRI studies were also extracted.T1 hypointense and T2/FLAIR hyperintense lesions were investigated. The correlation of MRI findings, AQP-4, and EDSS was assessed.ResultsT1 hypointense brain lesions were detected in 22 patients. Mean ± SD EDSS was 3.7 ± 1.5 and significantly higher in patients with brain T1 hypointense lesions than those without them (p-value = 0.01). Noticeably, patients with more than four T1 hypointense lesions had EDSS scores ≥ 4. The presence of T2/FLAIR hyperintense brain lesions correlated with EDSS (3.6 ± 1.6 vs 2.3 ± 1.7; p-value = 0.01). EDSS was similar between those with and without positive AQP-4 (2.7 ± 1.6 vs. 3.2 ± 1.7; p-value = 0.17). Also, positive AQP-4 was not more prevalent in patients with T1 hypointense brain lesions than those without them (50.9 vs 45.4%; p-value = 0.8).ConclusionWe demonstrated that the presence of the brain T1-hypointense lesions corresponds to a higher disability level in NMOSD.

Structural disconnection is associated with disability in the neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Accumulating evidence suggests there is a distinct pattern of brain lesions characteristic of NMOSD, and brain MRI has potential prognostic implications. However, the question of how the brain lesions in NMOSD are associated with its distinct clinical course remains incompletely understood. Here, we aimed to investigate the association between neurological impairment and brain lesions via brain structural disconnection. Twenty patients were diagnosed with NMOSD according to the 2015 International Panel for NMO Diagnosis criteria. The white matter lesions were manually drawn section by section. Whole-brain structural disconnection was estimated, and connectome-based predictive modeling (CPM) was used to estimate the patient's Expanded Disability Status Scale score (EDSS) from their disconnection severity matrix. Furthermore, correlational tractography was performed to assess the fractional anisotropy (FA) and axial diffusivity (AD) of white matter fibers, which negatively correlated with the EDSS score. CPM successfully predicted the EDSS using the disconnection severity matrix (r = 0.506, p = 0.028; q2 = 0.274). Among the important edges in the prediction process, the majority of edges connected the motor to the frontoparietal network. Correlational tractography identified a decreased FA and AD value according to EDSS scores in periependymal white matter tracts. Structural disconnection-based predictive modeling and local connectome analysis showed that frontoparietal and periependymal white matter disconnection is predictive and associated with the EDSS score of NMOSD patients.

TREM2 deficiency inhibits microglial activation and aggravates demyelinating injury in neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are activated and play a pivotal role in response to tissue injury. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by microglia and promotes microglial activation, survival and phagocytosis. Here, we identify a critical role for TREM2 in microglial activation and function during AQP4-IgG and complement-induced demyelination. TREM2-deficient mice had more severe tissue damage and neurological impairment, as well as fewer oligodendrocytes with suppressed proliferation and maturation. The number of microglia clustering in NMOSD lesions and their proliferation were reduced in TREM2-deficient mice. Moreover, morphology analysis and expression of classic markers showed compromised activation of microglia in TREM2-deficient mice, which was accompanied by suppressed phagocytosis and degradation of myelin debris by microglia. These results overall indicate that TREM2 is a key regulator of microglial activation and exert neuroprotective effects in NMOSD demyelination.Graphical

χ-Separation Imaging for Diagnosis of Multiple Sclerosis versus Neuromyelitis Optica Spectrum Disorder.

Background Use of χ-separation imaging can provide surrogates for iron and myelin that relate closely to abnormal changes in multiple sclerosis (MS) lesions. Purpose To evaluate the appearances of MS and neuromyelitis optica spectrum disorder (NMOSD) brain lesions on χ-separation maps and explore their diagnostic value in differentiating the two diseases in comparison with previously reported diagnostic criteria. Materials and Methods This prospective study included individuals with MS or NMOSD who underwent χ-separation imaging from October 2017 to October 2020. Positive (χpos) and negative (χneg) susceptibility were estimated separately by using local frequency shifts and calculating R2' (R2' = R2* - R2). R2 mapping was performed with a machine learning approach. For each lesion, presence of the central vein sign (CVS) and paramagnetic rim sign (PRS) and signal characteristics on χneg and χpos maps were assessed and compared. For each participant, the proportion of lesions with CVS, PRS, and hypodiamagnetism was calculated. Diagnostic performances were assessed using receiver operating characteristic (ROC) curve analysis. Results A total of 32 participants with MS (mean age, 34 years ± 10 [SD]; 25 women, seven men) and 15 with NMOSD (mean age, 52 years ± 17; 14 women, one man) were evaluated, with a total of 611 MS and 225 NMOSD brain lesions. On the χneg maps, 80.2% (490 of 611) of MS lesions were categorized as hypodiamagnetic versus 13.8% (31 of 225) of NMOSD lesions (P < .001). Lesion appearances on the χpos maps showed no evidence of a difference between the two diseases. In per-participant analysis, participants with MS showed a higher proportion of hypodiamagnetic lesions (83%; IQR, 72-93) than those with NMOSD (6%; IQR, 0-14; P < .001). The proportion of hypodiamagnetic lesions achieved excellent diagnostic performance (area under the ROC curve, 0.96; 95% CI: 0.91, 1.00). Conclusion On χ-separation maps, multiple sclerosis (MS) lesions tend to be hypodiamagnetic, which can serve as an important hallmark to differentiate MS from neuromyelitis optica spectrum disorder. © RSNA, 2022 Supplemental material is available for this article.

The utility of diffusion-weighted imaging in patients with spinal cord infarction: difference from the findings of neuromyelitis optica spectrum disorder

BackgroundMagnetic resonance imaging (MRI) plays a crucial role in diagnosing spinal cord infarction (SCI). However, the findings are often indistinguishable from those of other intramedullary diseases, such as neuromyelitis optica spectrum disorder (NMOSD). Although diffusion-weighted imaging (DWI) is a promising technique, the utility for discriminating SCI from NMOSD remains unclear because the DWI findings of acute NMOSD lesions have not been investigated in detail.MethodsClinical and MRI findings were retrospectively evaluated in 15 and 12 patients with acute SCI and NMOSD, respectively. First, clinical characteristics were compared between the SCI and NMOSD groups. Second, MRI abnormalities were examined to find differences between these groups. Third, in the SCI group, factors influencing T2 and DWI abnormalities were analyzed using the mixed-effects logistic regression analysis.ResultsThe proportion of female patients was higher in the NMOSD group (92%) than in the SCI (40%). The time from symptom onset to nadir was smaller in the SCI group (median [interquartile range]; 4 [0.1–8.3] hours) than in the NMOSD (252 [162–576]). On T2-weighted images, SCI lesions had smaller length than NMOSD (2 [1–2] and 5 [2–7] vertebral segments, respectively). Focal lesions within the T9–L2 level were found only in patients with SCI. DWI hyperintensity was observed both in the SCI (frequency, 100%) and NMOSD (60%) groups. On apparent diffusion coefficient (ADC) maps, the hyperintensities of SCI had corresponding hypointensities, whereas those of NMOSD were isointense and a large portion of NMOSD lesions had hyperintense signals. Owl’s eyes sign and pencil-like hyperintensity, typically reported as T2 findings suggestive of SCI, were also found on DWI. Posterior linear hyperintensity was frequently detected on DWI in patients with posterior spinal artery infarction. The presence of MRI abnormality revealing SCI was modeled with the time from symptom onset, imaging sequence and plane, and affected vascular territory.ConclusionsDWI and ADC maps help distinguish SCI from NMOSD. The time from symptom onset, imaging sequence, and imaging plane should be considered when MRI findings are interpreted in patients with suspected SCI.

Sick sinus syndrome as the initial manifestation of neuromyelitis optica spectrum disorder: a case report

BackgroundSick sinus syndrome (SSS) is known to occur due to lesions in the medulla oblongata. Although medullary lesions have occurred in patients with neuromyelitis optica spectrum disorder (NMOSD), there are few reports of SSS associated with NMOSD. We report a patient with NMOSD who developed refractory nausea, vomiting and SSS as the initial manifestation.Case presentationA 77-year-old female developed refractory nausea and frequent episodes of syncope. The patient was diagnosed with SSS because sinus pauses lasting five to six seconds were observed, and pacemaker implantation was performed. Two months later, she was referred to our hospital because of limb weakness and sensory impairment that progressed over a month. The patient was confirmed to have muscle weakness; manual muscle testing revealed grade 4 in the upper extremities and grade 3 in the lower extremities. Tendon reflexes were diminished, while no pathological reflexes were present. Thermal and pain sensations were impaired in the upper and lower extremities, and vibration sensation was impaired in both lower extremities. Bladder and rectal disturbances were also noted. Optic neuritis was not detected. T2-weighted magnetic resonance imaging (MRI) showed high-intensity lesions in the dorsal part of the medulla oblongata and C3–6 cervical cord. Her serum was positive for antibodies against aquaporin 4, and a diagnosis of NMOSD was made. She was treated with two courses of an intravenous methylprednisolone pulse and one course of plasma exchange. Then, she was transferred to another hospital for rehabilitation.ConclusionsBecause SSS is a life-threatening complication, clinicians should be aware of the possibility that medullary lesions in NMOSD can cause SSS as the initial manifestation.

Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration.

Approximately 80% of neuromyelitis optica spectrum disorder (NMOSD) patients harbor serum anti-aquaporin-4 autoantibodies targeting astrocytes in the CNS. Crucial for NMOSD lesion initiation is disruption of the blood-brain barrier (BBB), which allows the entrance of Abs and serum complement into the CNS and which is a target for new NMOSD therapies. Astrocytes have important functions in BBB maintenance; however, the influence of their loss and the role of immune cell infiltration on BBB permeability in NMOSD have not yet been investigated. Using an experimental model of targeted NMOSD lesions in rats, we demonstrate that astrocyte destruction coincides with a transient disruption of the BBB and a selective loss of occludin from tight junctions. It is noteworthy that BBB integrity is reestablished before astrocytes repopulate. Rather than persistent astrocyte loss, polymorphonuclear leukocytes (PMNs) are the main mediators of BBB disruption, and their depletion preserves BBB integrity and prevents astrocyte loss. Inhibition of PMN chemoattraction, activation, and proteolytic function reduces lesion size. In summary, our data support a crucial role for PMNs in BBB disruption and NMOSD lesion development, rendering their recruitment and activation promising therapeutic targets.

Longitudinal ultra-high field MRI of brain lesions in neuromyelitis optica spectrum disorders

BackgroundIn neuromyelitis optica spectrum disorder (NMOSD), clinical disability in NMOSD patients is relapse-related and progressive phase is rare. This observation raises the question whether there is any radiographic disease activity. The aim of present study was to determine the longitudinal changes in cerebral lesion number, lesion size, lesion-to-venule relationship, and morphological patterns of lesions in NMOSD using multiparametric 7T MR imaging. We also aimed to assess brain volume changes in NMOSD. MethodsA cohort of 22 patients with NMOSD underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo (GRE-T2*) weighted imaging on 7T MRI of brain at baseline and after ~2.8 years of follow-up. Morphologic imaging characteristics, and signal intensity patterns of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on GRE-T2* images and/or SWI as well as hyperintense signal on quantitative susceptibility mapping (QSM). Lesions were considered "non-iron-laden" if they were hyperintense on GRE-T2*/SWI and isointense or hyperintense on QSM. Additionally, fractional brain parenchymal volume (fBPV) was computed at both time points. ResultsA total of 169 lesions were observed at baseline. At follow-up, 6 new lesions were found in 5 patients. In one patient, a single lesion could not be detected on the follow-up scan. No appreciable change in lesion size and vessel-lesion relationship was observed at follow up. All lesions demonstrated hyperintense signal intensity on GRE-T2* weighted images and isointense signal on QSM at both time points. Therefore, these lesions were considered as non-associated with iron pathology. Additionally, no significant change in brain volume was observed: fBPV 0.78 ± 0.06 at baseline vs. 0.77 ± 0.05 at follow up, p>0.05. ConclusionCerebral lesions in NMOSD patients remain ‘inert’ and do not show any substantial variations in morphological characteristics during a 2–3-year follow-up period.

Rapid myelin water imaging for the assessment of cervical spinal cord myelin damage.

BackgroundRapid myelin water imaging (MWI) using a combined gradient and spin echo (GRASE) sequence can produce myelin specific metrics for the human brain. Spinal cord MWI could be similarly useful, but technical challenges have hindered routine application. GRASE rapid MWI was recently successfully implemented for imaging of healthy cervical spinal cord and may complement other advanced imaging methods, such as diffusion tensor imaging (DTI) and quantitative T1 (qT1).ObjectiveTo demonstrate the feasibility of cervical cord GRASE rapid MWI in multiple sclerosis (MS), primary lateral sclerosis (PLS) and neuromyelitis optica spectrum disorder (NMO), with comparison to DTI and qT1 metrics.MethodsGRASE MWI, DTI and qT1 data were acquired in 2 PLS, 1 relapsing-remitting MS (RRMS), 1 primary-progressive MS (PPMS) and 2 NMO subjects, as well as 6 age (±3 yrs) and sex matched healthy controls (HC). Internal cord structure guided template registrations, used for region of interest (ROI) analysis. Z score maps were calculated for the difference between disease subject and mean HC metric values.ResultsPLS subjects had low myelin water fraction (MWF) in the lateral funiculi compared to HC. RRMS subject MWF was heterogeneous within the cord. The PPMS subject showed no trends in ROI results but had a region of low MWF Z score corresponding to a focal lesion. The NMO subject with a longitudinally extensive transverse myelitis lesion had low values for whole cord mean MWF of 12.8% compared to 24.3% (standard deviation 2.2%) for HC. The NMO subject without lesions also had low MWF compared to HC. DTI and qT1 metrics showed similar trends, corroborating the MWF results and providing complementary information.ConclusionGRASE is sufficiently sensitive to detect decreased myelin within MS spinal cord plaques, NMO lesions, and PLS diffuse spinal cord injury. Decreased MWF in PLS is consistent with demyelination secondary to motor neuron degeneration. GRASE MWI is a feasible method for rapid assessment of myelin content in the cervical spinal cord and provides complementary information to that of DTI and qT1 measures.

Serum anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder presenting as acute eosinophilic encephalomyelitis

We report the case of a 57-year-old man with neuromyelitis optica spectrum disorder (NMOSD) presenting as acute eosinophilic encephalomyelitis. Magnetic resonance imaging revealed central nervous system lesions typical of NMOSD and anti-aquaporin-4 antibodies in the serum were identified; however, eosinophilia was evident in the cerebrospinal fluid (CSF) at the early stage of the disease. The number of eosinophils in the CSF decreased subsequently. Although activation of eosinophils is known to be an important factor in the development of NMOSD lesions, prominent eosinophilia in the CSF at the early stage of the disease has never been reported in patients with NMOSD.

Müller cells and retinal axons can be primary targets in experimental neuromyelitis optica spectrum disorder

Recent work from our laboratory, using different models of experimental neuromyelitis optica spectrum disorder (NMOSD), has led to a number of observations that might be highly relevant for NMOSD patients. For example: (i) in the presence of neuromyelitis optica immunoglobulin G, astrocyte‐destructive lesions can be initiated by CD4+ T cells when these cells recognize aquaporin 4 (AQP4), but also when they recognize other antigens of the central nervous system. The only important prerequisite is that the T cells have to be activated within the central nervous system by “their” specific antigen. Recently activated CD4+ T cells with yet unknown antigen specificity are also found in human NMOSD lesions. (ii) The normal immune repertoire might contain AQP4‐specific T cells, which are highly encephalitogenic on activation. (iii) The retina might be a primary target of AQP4‐specific T cells and neuromyelitis optica immunoglobulin G: AQP4‐specific T cells alone are sufficient to cause retinitis with low‐grade axonal pathology in the retinal nerve fiber/ganglionic cell layer. A thinning of these layers is also observed in NMOSD patients, where it is thought to be a consequence of optic neuritis. Neuromyelitis optica immunoglobulin G might target cellular processes of Müller cells and cause their loss of AQP4 reactivity, when AQP4‐specific T cells open the blood–retina barrier in the outer plexiform layer. Patchy loss of AQP4 reactivity on Müller cells of NMOSD patients has been recently described. Cumulatively, our findings in experimental NMOSD suggest that both CD4+ T cell and antibody responses directed against AQP4 might play an important role in the pathogenesis of tissue destruction seen in NMOSD.

MRI phase changes in multiple sclerosis vs neuromyelitis optica lesions at 7T.

Objective:To characterize paramagnetic MRI phase signal abnormalities in neuromyelitis optica spectrum disorder (NMOSD) vs multiple sclerosis (MS) lesions in a cross-sectional study.Methods:Ten patients with NMOSD and 10 patients with relapsing-remitting MS underwent 7-tesla brain MRI including supratentorial T2*-weighted imaging and supratentorial susceptibility weighted imaging. Next, we analyzed intra- and perilesional paramagnetic phase changes on susceptibility weighted imaging filtered magnetic resonance phase images.Results:We frequently observed paramagnetic rim-like (75 of 232 lesions, 32%) or nodular (32 of 232 lesions, 14%) phase changes in MS lesions, but only rarely in NMOSD lesions (rim-like phase changes: 2 of 112 lesions, 2%, p < 0.001; nodular phase changes: 2 of 112 lesions, 2%, p < 0.001).Conclusions:Rim-like or nodular paramagnetic MRI phase changes are characteristic for MS lesions and not frequently detectable in NMOSD. Future prospective studies should ask whether these imaging findings can be used as a biomarker to distinguish between NMOSD- and MS-related brain lesions.

Comparison of myelin water fraction values in periventricular white matter lesions between multiple sclerosis and neuromyelitis optica spectrum disorder

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory autoimmune diseases of the central nervous system. We hypothesized that the degree of demyelination within lesions in MS and NMOSD would differ as the pathophysiology of the two diseases do. We used myelin water imaging to compare the myelin water fraction (MWF) in 106 periventricular white matter (PVWM) lesions in 27 MS patients and 51 PVWM lesions in 20 NMOSD patients. The MWF was significantly reduced in the MS compared with the NMOSD lesions, suggesting that myelin loss was more severe in MS than in NMOSD.

A longitudinal brain magnetic resonance imaging study of neuromyelitis optica spectrum disorder.

Brain involvement is commonly seen in patients with neuromyelitis optica spectrum disorder (NMOSD). However, little is known about the chronic changes of acute brain lesions on MRI over time. Here, our objective was to evaluate how acute brain MRI lesions in NMOSD changed on follow-up MRI. We reviewed the MRIs of 63 patients with NMOSD who had acute brain lesions and follow-up MRI over an interval of at least 3 months. Of the 211 acute brain lesions, 24% of lesions disappeared completely on T2-weighed images (WI) and a decrease in size ≥50% on T2-WI was observed in 58% of lesions on follow-up MRI. However, 47% of lesions revealed focal T1-hypointensity and, in particular, 18% showed focal cystic changes. Cystic changes were observed most commonly in corticospinal tract and corpus callosal lesions whereas the vast majority of lesions in the cerebellum, basal ganglia and temporal white matter resolved completely. MRI remission on T2-WI occurred in 82% of lesions, while approximately half of the lesions presented foci of T1-hypointensity, which may be considered a severe tissue injury over time. The extent of brain injury following an acute brain lesion in NMOSD may depend on the location of the lesion.

Ultrahigh-Field MR (7 T) Imaging of Brain Lesions in Neuromyelitis Optica

Background. Brain lesions are common in neuromyelitis optica spectrum disorder (NMOsd) and may resemble lesions of multiple sclerosis (MS). Objectives. To describe the imaging characteristics of supratentorial lesions in NMOsd on ultrahigh-field (7 T) MRI with special attention to vessel-lesion relationship. Methods. Ten NMOsd patients, all women and all seropositive for NMO IgG, with mean age of 51.3 ± 15.4 years and disease duration of 9.2 ± 6.4 years, were scanned at a 7 T whole-body human MR system with high-resolution 2D gradient echo sequence optimized to best visualize lesions and venous structures, T2- and T1-weighted imaging. Results. In 10 patients with NMOsd, a total of 92 lesions were observed (mean: 9.2 ± 8.8; range: 2–30), but only 8 lesions (9%) were traversed by a central venule. All lesions were <5 mm in diameter, and 83% were located in subcortical white matter. There were no lesions in the cortex or basal ganglia. Two patients exhibited diffuse periependymal abnormalities on FLAIR. Conclusions. Small, subcortical lesions without a central venule are the most consistent finding of NMOsd on 7 T MRI of the brain. Ultrahigh-field imaging may be useful for differentiating between NMOsd and MS.