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.

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.

The influence of smoking on the pattern of disability and relapse risk in AQP4-positive Neuromyelitis Optica Spectrum Disorder, MOG-Ab Disease and Multiple Sclerosis.

BACKGROUND: the role of smoking on clinical outcomes of central nervous system (CNS) inflammatory disorders is unclear. To assess the effect of smoking on relapses and disability in neuromyelitis optica with aquaporin-4-antibodies (NMOSD-AQP4-Ab), Myelin Oligodendrocyte Glycoprotein-antibodies associated disease (MOGAD) and relapsing remitting Multiple Sclerosis (MS) patients. METHODS: in a UK cohort of 101 NMOSD-AQP4-Ab, 70 MOGAD and 159 MS, and a Korean cohort of 97 NMOSD-AQ4-Ab, time to first relapse, annualised relapse rate, onset relapse severity and recovery, time to Expanded Disability Status Score(EDSS)/secondary progressive MS (SPMS) were compared between never-smokers and ever-smokers. All clinical data were collected under the local ethics between January 2017 and January 2019. RESULTS: Smoking did not affect the risk of relapse in any of the diseases. The risk of reaching EDSS 6.0 in the UK NMOSD-AQP4-Ab cohort was higher in ever smokers but this did not achieve significance (HR 2.12, p=0.068). When combining the UK and Korea NMOSD-AQP4-Ab cohorts, poorer recovery from the onset attack was significantly more frequent in the ever-smokers versus the never smokers (55% vs 38%, p=0.04). In the MS cohort the risk of reaching EDSS 6 and SPMS was significantly higher in the ever-smokers (HR=2.67, p=0.01 and HR=3.18, p=0.001). In MOGAD similar patterns were seen without reaching significance. CONCLUSIONS: In NMOSD-AQP4-Ab smoking associates with worse disability not through an increased risk of relapses but through poor relapse recovery. As in MS, smoking cessation should be encouraged in NMOSD-AQP4-Ab.

A clinico-neurophysiological study of urogenital dysfunction in MOG-antibody transverse myelitis.

OBJECTIVE: To assess the clinical, urodynamic, and neurophysiologic features of patients with persisting bladder, bowel, and sexual dysfunction after transverse myelitis in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease. METHODS: Patients with a history of MOG-Ab disease-related transverse myelitis seen prospectively in a tertiary center uro-neurology service between 2017 and 2019 were included. They received cross-sectional clinical assessment; completed standardized questionnaires on bladder, bowel, and sexual symptoms; and underwent urodynamic and pelvic neurophysiologic investigations. RESULTS: Twelve patients (9 male) were included with a total of 17 episodes of transverse myelitis. Mean age at first attack was 26 (SD 9) years, and median follow-up duration was 50 (interquartile range 32-87) months. Acute urinary retention requiring bladder catheterization occurred in 14 episodes and was the first symptom in 10 episodes. Patients with lesions affecting the conus medullaris required catheterization for significantly longer durations than those without a conus lesion (median difference 15.5 days, p = 0.007). At follow-up, all patients had recovered full ambulatory function, but persisting bladder and bowel dysfunction moderately or severely affected quality of life in 55% and 36%, respectively, and 82% had sexual dysfunction. Pelvic neurophysiology demonstrated abnormal residual conus function in 6 patients. Urodynamic findings predominantly showed detrusor overactivity and/or detrusor-sphincter dyssynergia, indicative of a supraconal pattern of lower urinary tract dysfunction. CONCLUSIONS: Persisting urogenital and bowel dysfunction is common despite motor recovery. Although a proportion of patients had neurophysiologic evidence of residual conus abnormalities at follow-up, predominant urodyamic findings suggest that ongoing lower urinary tract dysfunction results from supraconal injury.

Factors associated with fatigue in CNS inflammatory diseases with AQP4 and MOG antibodies.

OBJECTIVE: Fatigue is a common and disabling symptom amongst people with multiple sclerosis, however it has not been compared across the central nervous system (CNS) inflammatory diseases associated with aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). We explored the factors associated with fatigue within and across the two diseases, and compared fatigue levels between them. METHODS: We performed a cross-sectional study of 90 AQP4-Ab and 44 MOG-Ab patients. Fatigue was assessed using the Modified Fatigue Impact Scale (MFIS). Clinical, demographic, and psychometric (anxiety, depression, pain) data were used as independent variables. Multivariable linear regression was used to identify significant independent variables associated with fatigue within and across the two diseases. RESULTS: Within AQP4-Ab patients, age (P = 0.002), disease duration (P = 0.004), number of clinical attacks (P = 0.001), disability (P = 0.007), pain interference (P < 0.001), anxiety (P = 0.026), and depression (P < 0.001) were significant independent variables. Interestingly, disease duration had a negative association with fatigue (P = 0.004). Within MOG-Ab patients, pain interference score (P < 0.001) and anxiety (P = 0.001) were significant independent variables. Although fatigue was worse in AQP4-Ab patients compared to MOG-Ab patients (P = 0.008) in all patients as well as in those who ever had transverse myelitis (P = 0.023), this was driven by the differences in age, disability and pain interference rather than antibody subtype itself. INTERPRETATION: Multiple factors, but not the antibody specificity, appear to contribute to fatigue in antibody positive CNS inflammatory diseases. A multifaceted treatment approach is needed to better manage the physical, cognitive, and psychosocial aspects of fatigue in these patients.

Prodromal headache in MOG-antibody positive optic neuritis.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease is an inflammatory autoimmune condition of the central nervous system, defined by antibodies (Abs) against MOG. Of the various clinical phenotypes optic neuritis (ON) is the commonest. We have observed that some patients with MOG-Ab ON present with a severe associated headache. OBJECTIVE: To highlight the importance of headache in MOG-Ab related optic neuritis. METHODS: Clinical and MRI data from MOG-Ab patients with ON (n = 129) were obtained from observational cohort studies and clinical notes at the NeuroCure Clinical Research Center, Charité Berlin and at the Diagnostic and Advisory Service for Neuromyelitis Optica, John Radcliffe Hospital, Oxford. RESULTS: Sixty-four of 129 MOG-Ab patients (49.6%) reported ≥1 headache-related ON. Headache usually started a few days prior to visual loss and extended from the ocular region to the periorbital and fronto-temporal area, sometimes mimicking migraine. Of those, thirty-two patients (50%) reported severe headache. Two patients did not have headache. No headache history was recorded for 63 patients. MRIs performed acutely during headache-related MOG-Ab ON (n = 15) showed anterior ON with extensive swelling and edema of the optic nerve/s in all patients, either unilaterally (n = 5) or bilaterally (n = 10). Peri-optic cerebro-spinal fluid (CSF) was undetectable due to the inflammatory extension in 12 out of 15 patients. CONCLUSION: Our findings indicate that acute MOG-Ab ON shows florid intra-orbital and peri­optic inflammation, likely to involve meninges and nociceptive fibers around the optic nerve. This may explain the frequent and often severe headache that precedes the visual deficit, sometimes misdiagnosed as migraine.

Clinical presentation and prognosis in MOG-antibody disease: a UK study.

See de Seze (doi:10.1093/brain/awx292) for a scientific commentary on this article. A condition associated with an autoantibody against MOG has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of MOG-antibody disease on a large cohort of patients from the UK. We obtained demographic and clinical data on 252 UK patients positive for serum immunoglobulin G1 MOG antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford Service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44). MOG-antibody disease affects females (57%) slightly more often than males, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months, 47% of patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤6/36 in at least one eye, mobility was limited in 7% (i.e. Expanded Disability Status Scale ≥ 4.0), 5% had Expanded Disability Status Scale ≥ 6.0, 28% had permanent bladder issues, 20% had bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.