An In-vivo 1H-MRS short-echo time technique at 7T: Quantification of metabolites in chronic multiple sclerosis and neuromyelitis optica brain lesions and normal appearing brain tissue

Highlights NAAG likely contributes to the total NAA differences between multiple sclerosis lesion and normal appearing brain tissue. myo-Inositol was not shown to be different between chronic AQP4Ab-NMOSD brain lesions and normal appearing brain tissue. An optimised MRS methodology is described, using 7T field strength and correcting for tissue T2 water relaxion differences. 7-tesla MRS profiles of chronic brain lesions and normal appearing white matter are presented for MS and AQP4Ab-NMOSD. Abstract Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS

Open-access quantitative MRI data of the spinal cord and reproducibility across participants, sites and manufacturers

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/. The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord

Generic acquisition protocol for quantitative MRI of the spinal cord

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols. The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition

Long-term safety and efficacy of Eculizumab in Aquaporin-4 IgG-positive NMOSD

Objective During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy. Methods Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis. Results Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use. Interpretation This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088–109

The in-vivo study of pain in neuromyelitis optica

A thesis exploring the aetiology of pain in neuromyelitis optica (NMO). Neuromyelitis optica is a severe autoimmune neuroinflammatory disorder characterised by longitudinally extensive myelitis and severe optic neuritis. An oft-neglected symptom of the condition is severe, intractable chronic pain that can be detrimental to quality of life and is marked out by its severity and prevalence in comparison to the related disorder, multiple sclerosis. The experiments within this thesis make use of both conventional and advanced MRI techniques applied to the spinal cord and brain, and 1H NMR spectroscopy of blood plasma to explore the mechanisms driving chronic pain in NMO. The principle findings are: i. Thoracic lesions are associated with greater pain, irrespective of lesion length or cervical lesion volume. They are associated with spinothalamic tract damage in the cervical cord that correlates with the severity of pain. A possible autonomic aetiology is proposed. ii. Periaqueductal grey (PAG) to dorsolateral prefrontal cortex and to pregenual anterior cingulate cortex functional connectivity is correlated with pain severity, conversely PAG to rostroventromedial medulla connectivity is negatively associated with pain severity. Disruption of descending pain modulatory circuits is considered. iii. PAG glutamate concentration is negatively correlated with pain scores and is higher in low pain patients compared to controls and high pain patients. The discussion includes consideration of pain vulnerability. Chronic pain in NMO can devastate lives. The studies undertaken in this thesis are some of the earliest MRI imaging studies directed at understanding pain in NMO and the association of pain with thoracic lesions and the aberrations in the descending pain modulatory network are novel findings. There is more to be done and my hope is that this body of work will serve as a stepping-stone to a better understanding of chronic pain in NMO and the future development of effective treatments.</p

The in-vivo study of pain in neuromyelitis optica

A thesis exploring the aetiology of pain in neuromyelitis optica (NMO). Neuromyelitis optica is a severe autoimmune neuroinflammatory disorder characterised by longitudinally extensive myelitis and severe optic neuritis. An oft-neglected symptom of the condition is severe, intractable chronic pain that can be detrimental to quality of life and is marked out by its severity and prevalence in comparison to the related disorder, multiple sclerosis. The experiments within this thesis make use of both conventional and advanced MRI techniques applied to the spinal cord and brain, and 1H NMR spectroscopy of blood plasma to explore the mechanisms driving chronic pain in NMO. The principle findings are: i. Thoracic lesions are associated with greater pain, irrespective of lesion length or cervical lesion volume. They are associated with spinothalamic tract damage in the cervical cord that correlates with the severity of pain. A possible autonomic aetiology is proposed. ii. Periaqueductal grey (PAG) to dorsolateral prefrontal cortex and to pregenual anterior cingulate cortex functional connectivity is correlated with pain severity, conversely PAG to rostroventromedial medulla connectivity is negatively associated with pain severity. Disruption of descending pain modulatory circuits is considered. iii. PAG glutamate concentration is negatively correlated with pain scores and is higher in low pain patients compared to controls and high pain patients. The discussion includes consideration of pain vulnerability. Chronic pain in NMO can devastate lives. The studies undertaken in this thesis are some of the earliest MRI imaging studies directed at understanding pain in NMO and the association of pain with thoracic lesions and the aberrations in the descending pain modulatory network are novel findings. There is more to be done and my hope is that this body of work will serve as a stepping-stone to a better understanding of chronic pain in NMO and the future development of effective treatments.</p

Pain in patients with transverse myelitis and its relationship to aquaporin 4 antibody status

Pain in transverse myelitis has been poorly studied. The aim of the study was to investigate the relationship between transverse myelitis related pain and disability, quality of life, anxiety and depression, cognitive-affective states in neuromyelitis optica (NMO) patients and aquaporin4 antibody status (AQP4-Ab +ve as positive and AQP4-Ab −ve as negative). Transverse myelitis patients (44 in total; 29 AQP4-Ab +ve and 15 AQP4-Ab −ve) completed questionnaires including Pain Severity Index (PSI), Pain Catastrophising Scale (PCS), Hospital Anxiety and Depression Scale (HADS), Short Form-36 quality of life (SF-36 QOL). Clinical details such as disability, gender, age and spinal cord lesion type (short or long lesion) were noted. Correlation and multiple linear regression tests were performed using these clinical scores. Pain was found to be correlated strongly with quality of life in both groups but only correlated with disability in the AQP4-Ab +ve group. PCS, HADS and EDMUS were found to be highly correlated with pain severity using partial correlation, however, a stronger relationship between pain severity and PCS was found in the AQP4-Ab −ve group. Multiple regression analysis showed that pain severity was the most important factor for quality of life but not disability or anxiety and depression symptoms in the whole patient group. We confirm that pain is an important symptom of transverse myelitis and has more influence on quality of life than disability despite health services being predominantly focused on the latter. There may be different factors associated with pain between AQP4-Ab +ve and −ve patients

The prevalence of neuromyelitis optica in South East Wales

Background and purpose: Neuromyeltis optica (NMO) is a neuroinflammatory disorder considered rare in Caucasian populations. However, accurate population-based epidemiological data for NMO and NMO spectrum disorder (NMO-SD) from Western populations employing validated diagnostic criteria remain limited. We sought therefore to estimate the prevalence and clinical features of NMO in a north European Caucasian population in South East Wales. Methods: Patients were identified by a comprehensive, multistage ascertainment strategy employing a regional neuroinflammatory disease register, hospital diagnostic databases personal physician referrals and regional requests for anti-aquaporin-4 antibodies (anti-AQP4). Results: Fourteen Caucasian patients (11 patients with NMO and three with NMO-SD) were identified in a population of 712 572 (19.6/million; 95% CIs: 12.2–29.7). There was an excess of females (female:male 12:2), 11/14 were anti-AQP4 positive and 5/14 had disease onset under the age of 20 years. Conclusion: This study suggests that NMO and related spectrum disorders are at least as frequent in Northern European populations as in non-Caucasian populations and that the demographic profile of prevalent patients differs from clinic-based cohorts