Shared imaging markers of fatigue across multiple sclerosis, aquaporin-4 antibody neuromyelitis optica spectrum disorder and MOG antibody disease.

Fatigue is frequently reported by patients with multiple sclerosis, aquaporin-4-antibody neuromyelitis optica spectrum disorder and myelin-oligodendrocyte-glycoprotein antibody disease; thus they could share a similar pathophysiological mechanism. In this cross-sectional cohort study, we assessed the association of fatigue with resting-state functional MRI, diffusion and structural imaging measures across these three disorders. Sixteen patients with multiple sclerosis, 17 with aquaporin-4-antibody neuromyelitis optica spectrum disorder and 17 with myelin-oligodendrocyte-glycoprotein antibody disease assessed, outside of relapses, at the Oxford Neuromyelitis Optica Service underwent Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale and Expanded Disability Status Scale scoring. A 3T brain and spinal cord MRI was used to derive cortical, deep grey and white matter volumetrics, lesions volume, fractional anisotropy, brain functional connectivity metrics, cervical spinal cord cross-sectional area, spinal cord magnetic transfer ratio and average functional connectivity between the ventral and the dorsal horns of the cervical cord. Linear relationships between MRI measures and total-, cognitive- and physical-fatigue scores were assessed. All analyses were adjusted for correlated clinical regressors. No significant differences in baseline clinical characteristics, fatigue, depression and anxiety questionnaires and disability measures were seen across the three diseases, except for older age in patients with aquaporin-4-antibody neuromyelitis optica spectrum disorder (P = 0.0005). In the total cohort, median total-fatigue score was 35.5 (range 3-72), and 42% of patients were clinically fatigued. A positive correlation existed between the total-fatigue score and functional connectivity of the executive/fronto-temporal network in the in left middle temporal gyrus (P = 0.033) and between the physical-fatigue score and functional connectivity of the sensory-motor network (P = 0.032) in both pre- and post-central gyri. A negative relationship was found between the total-fatigue score and functional connectivity of the salience network (P = 0.023) and of the left fronto-parietal network (P = 0.026) in the right supramarginal gyrus and left superior parietal lobe. No clear relationship between fatigue subscores and the average functional connectivity of the spinal cord was found. Cognitive-fatigue scores were positively associated with white matter lesion volume (P = 0.018) and negatively associated with white matter fractional anisotropy (P = 0.032). Structural, diffusion and functional connectivity alterations were not influenced by the disease group. Functional and structural imaging metrics associated with fatigue relate to brain rather than spinal cord abnormalities. Salience and sensory-motor networks alterations in relation to fatigue might indicate a disconnection between the perception of the interior body state and activity and the actual behavioural responses and performances (reversible or irreversible). Future research should focus on functional rehabilitative strategies.

Quantitative spinal cord MRI in MOG-antibody disease, neuromyelitis optica and multiple sclerosis.

Spinal cord involvement is a hallmark feature of multiple sclerosis, neuromyelitis optica with AQP4 antibodies and MOG-antibody disease. In this cross-sectional study we use quantitative spinal cord MRI to better understand these conditions, differentiate them and associate with relevant clinical outcomes. Eighty participants (20 in each disease group and 20 matched healthy volunteers) underwent spinal cord MRI (cervical cord: 3D T1, 3D T2, diffusion tensor imaging and magnetization transfer ratio; thoracic cord: 3D T2), together with disability, pain and fatigue scoring. All participants had documented spinal cord involvement and were at least 6 months post an acute event. MRI scans were analysed using publicly available software. Those with AQP4-antibody disease showed a significant reduction in cervical cord cross-sectional area (P = 0.038), thoracic cord cross-sectional area (P = 0.043), cervical cord grey matter (P = 0.011), magnetization transfer ratio (P ≤ 0.001), fractional anisotropy (P = 0.004) and increased mean diffusivity (P = 0.008). Those with multiple sclerosis showed significantly increased mean diffusivity (P = 0.001) and reduced fractional anisotropy (P = 0.013), grey matter volume (P = 0.002) and magnetization transfer ratio (P = 0.011). In AQP4-antibody disease the damage was localized to areas of the cord involved in the acute attack. In multiple sclerosis this relationship with lesions was absent. MOG-antibody disease did not show significant differences to healthy volunteers in any modality. However, when considering only areas involved at the time of the acute attack, a reduction in grey matter volume was found (P = 0.023). This suggests a predominant central grey matter component to MOG-antibody myelitis, which we hypothesize could be partially responsible for the significant residual sphincter dysfunction. Those with relapsing MOG-antibody disease showed a reduction in cord cross-sectional area compared to those with monophasic disease, even when relapses occurred elsewhere (P = 0.012). This suggests that relapsing MOG-antibody disease is a more severe phenotype. We then applied a principal component analysis, followed by an orthogonal partial least squares analysis. MOG-antibody disease was discriminated from both AQP4-antibody disease and multiple sclerosis with moderate predictive values. Finally, we assessed the clinical relevance of these metrics using a multiple regression model. Cervical cord cross-sectional area associated with disability scores (B = -0.07, P = 0.0440, R2 = 0.20) and cervical cord spinothalamic tract fractional anisotropy associated with pain scores (B = -19.57, P = 0.016, R2 = 0.55). No spinal cord metric captured fatigue. This work contributes to our understanding of myelitis in these conditions and highlights the clinical relevance of quantitative spinal cord MRI.

Opportunistic infections of the retina in patients with aquaporin-4 antibody disease.

IMPORTANCE: Patients with neuromyelitis optica who have aquaporin-4 antibodies are being identified and receiving immunosuppressant treatment earlier and more aggressively as a result of increasing awareness of the importance of preventing relapses responsible for the high morbidity and mortality associated with the disease. To our knowledge, opportunistic retinal infection in patients with aquaporin-4 antibodies who are receiving immunosuppressants has not been reported to date. OBSERVATIONS: We describe 2 patients with aquaporin-4 antibodies who were receiving conventional doses of first-line immunosuppressive therapy. Both patients presented with vision loss that was initially thought to be optic neuritis attacks. The subsequent diagnoses were ocular toxoplasmosis and cytomegalovirus retinitis. CONCLUSIONS AND RELEVANCE: Retinal opportunistic infections can occur in patients with aquaporin-4 antibodies who are receiving relatively low levels of immunosuppression, may mimic optic neuritis, and are a potentially reversible cause of vision loss when treated promptly.

The role of imaging in diagnosing neuromyelitis optica spectrum disorder.

Early identification of neuromyelitis optica allows aggressive acute and prophylactic relapse management aimed at preventing disability. Since the discovery of pathogenic aquaporin-4 antibodies the neuromyelitis optica spectrum has widened significantly: brain lesions no longer preclude the diagnosis and there are reports of symptoms of cerebral origin presenting as the first manifestation of the condition, prior to optic nerve or spinal cord disease. Defining antibody negative neuromyelitis optica, and distinguishing it from other inflammatory disorders such as multiple sclerosis can therefore be a challenge. In this review we discuss the role of conventional imaging in the diagnosis of neuromyelitis optica, and the scope of quantitative MRI modalities to identify more specific pathophysiological features to aid in the differentiation from other conditions and assess treatment response.

A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology.

Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a 'tract-specific' pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.