Sebastian Luppe

Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution

Objective: Neuromyelitis optica and its spectrum disorder (NMOSD) can present similarly to relapsing-remitting multiple sclerosis (RRMS). Using a quantitative lesion mapping approach, this research aimed to identify differences in MRI brain lesion distribution between aquaporin-4 antibody–positive NMOSD and RRMS, and to test their diagnostic potential. Methods: Clinical brain MRI sequences for 44 patients with aquaporin-4 antibody–positive NMOSD and 50 patients with RRMS were examined for the distribution and morphology of brain lesions. T2 lesion maps were created for each subject allowing the quantitative comparison of the 2 conditions with lesion probability and voxel-wise analysis. Results: Sixty-three percent of patients with NMOSD had brain lesions and of these 27% were diagnostic of multiple sclerosis. Patients with RRMS were significantly more likely to have lesions adjacent to the body of the lateral ventricle than patients with NMOSD. Direct comparison of the probability distributions and the morphologic attributes of the lesions in each group identified criteria of “at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion; or a Dawsons finger-type lesion,” which could distinguish patients with multiple sclerosis from those with NMOSD with 92% sensitivity, 96% specificity, 98% positive predictive value, and 86% negative predictive value. Conclusion: Careful inspection of the distribution and morphology of MRI brain lesions can distinguish RRMS and NMOSD.

Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK

Background: Azathioprine (AZA) is a common immunosuppressive drug used for relapse prevention in neuromyelitis optica (NMO). Objectives: The objective of this paper is to assess efficacy, tolerability and retention of AZA in a large NMO cohort. Methods: We conducted a retrospective review of medical records of 103 aquaporin-4 antibody-positive NMO and NMO spectrum disorder (NMOSD) patients treated with AZA. Results: This is the largest reported cohort of AQP4-Ab positive patients treated with AZA. Eighty-nine per cent (n = 92) had reduction in median annualised relapse rates from 1.5 (IQR 0.6–4.0) to 0 (IQR 0–0.27, p < 0.00005) with treatment. Sixty-one per cent (n = 63) remained relapse free at a median follow-up of 18 months. Neurological function improved or stabilised in 78%. At last follow-up, treatment was discontinued in 46% (n = 47). Of these, 62% (n = 29) were because of side effects, 19% (n = 9) because of death, 15% (n = 7) because of ongoing disease activity, and 2% (n = 1) because of pregnancy. Using Kaplan-Meyer curves, we estimate that 73%, 58%, 47% and 33% of patients will remain on AZA for longer than one, three, five and 10 years, respectively, after initiation of treatment. Conclusions: AZA is a modestly effective treatment for NMO. However, many patients discontinue AZA over time and this seems to reflect poor tolerability more than lack of efficacy.

Plasma complement biomarkers distinguish multiple sclerosis and neuromyelitis optica spectrum disorder

Background: Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory demyelinating diseases of the central nervous system. Although distinguished by clinicoradiological and demographic features, early manifestations can be similar complicating management. Antibodies against aquaporin-4 support the diagnosis of NMOSD but are negative in some patients. Therefore, there is unmet need for biomarkers that enable early diagnosis and disease-specific intervention. Objective: We investigated whether plasma complement proteins are altered in MS and NMOSD and provide biomarkers that distinguish these diseases. Methods: Plasma from 54 NMOSD, 40 MS and 69 control donors was tested in multiplex assays measuring complement activation products and proteins. Using logistic regression, we tested whether combinations of complement analytes distinguished NMOSD from controls and MS. Results: All activation products were elevated in NMOSD compared to either control or MS. Four complement proteins (C1inh, C1s, C5 and FH) were higher in NMOSD compared to MS or controls. A model comprising C1inh and terminal complement complex (TCC) distinguished NMOSD from MS (area under the curve (AUC): 0.98), while C1inh and C5 distinguished NMOSD from controls (AUC: 0.94). Conclusion: NMOSD is distinguished from MS by plasma complement biomarkers. Selected complement analytes enable differential diagnosis. Findings support trials of anti-complement therapies in NMOSD.

CSF ANALYSIS AND THE DIAGNOSIS OF NEUROMYELITIS OPTICA

Objective Neuromyelitis optica (NMO) is a distinct disorder with recognizable clinical radiological and immune characteristics. Whereas cerebrospinal fluid (CSF) examination has an established role in the diagnosis of other CNS inflammatory disorders including Multiple Sclerosis (MS), data for NMO is scarce and where available frequently predates availability of testing for anti–Aquaporin 4 antibodies (AQP4–IgG) that now form an essential component of the diagnostic process. In this study we have examined disease course and CSF characteristics in a population–based cohort of patients with seropositive NMO. Methods From June 2011 to January 2013, we identified 42 cases of NMO, fulfilling Wingerchuk 2006 revised diagnostic criteria and testing positive for AQP4–IgG. We enrolled these patients into a retrospective case series with longitudinal follow–up and systematically collected clinical and laboratory data through patient visits and review of computer and paper records. CSF analyses were performed as part of routine clinical investigations on these patients in 15 NHS hospitals between December 1987 and February 2012. Results Data on 66 CSF samples from 33 patients were available. Thirteen patients (39%) had a single lumbar puncture and 21 patients 2 or more (range 1–6). 74% of samples showed≥1 abnormality, this increased to 87% for the samples obtained within 30 days of a relapse. White cell pleocytosis (predominantly lymphocytic), of >5 cells/ml (range 6–190) was found in 48%, >15 cells/ml in 27%, and >50 cells/ml in 7% of samples. A CSF Pleocytosis of >5 cells/ml was seen in 54% samples obtained within 30 days of a relapse, compared to only 20% in samples obtained after this time. CSF protein was raised (range 0.46–2.1 mg/dl) in 52%, and was ≥0.7 mg/dl in 28%, and ≥1.0 mg/dl in 11% of samples. CSF protein was raised in 63% samples obtained within 30 days of relapse compared with only 27% obtained at a greater time interval from relapse. CSF glucose (range 2.3–6.0 mmol/l) and matched CSF/serum glucose ratios (0.4–0.9) were within normal range in all samples. Oligoclonal band (OCB) status was positive in 23/56 (41%) of samples (48% neg, 9% paired, 2% equivocal). OCBs were more likely to be positive within the first 12 months of disease onset (48%), than after that time (42%). In addition dynamic change in OCB status over time was observed in 5/14 (36%) but remained unchanged in 9/14 (64%). Conclusion White cell pleocytosis was the most frequent abnormality (48%) followed by raised CSF protein (54%) and positive OCBs (41%) and were most commonly observed within 30 days of relapse. Cell counts of >50/ml and CSF protein of >1.0 g/dl, contrary to popular belief, were unusual. In addition CSF changes in NMO were frequently dynamic and likely to relate to recent disease activity. Whilst these changes may be useful in monitoring some aspects of disease activity OCBs should not be employed to discriminate between NMO and other neuroinflammatory disorders and in particular MS, and also challenge the concept that development of positive OCB status is irreversible.

MOG-IgG in neuromyelitis optica

Up to 90 % of patients with neuromyelitis optica (NMO) and many patients with NMO-like disorders, including isolated recurrent optic neuritis (ON) and longitudinal extensive myelitis, test positive for autoantibodies against aquaporin-4 (AQP4-IgG). Recent studies have shown that some patients with these clinical phenotypes who are seronegative for AQP4-IgG have antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), a protein exclusively expressed in the central nervous system (CNS) on the surface of oligodendrocytes. However, studies using MOG, expressed in Escherichia coli as a recombinant protein in a linear or refolded form, have led to contradictory results, with MOG antibodies being detected both in patients with multiple sclerosis (MS) but also in healthy controls. More recent studies have arguably used more specific cell-based assays (CBAs), expressing human MOG in its native conformation on the surface of live human embryonic kidney (HEK) cells. Using this methodology, MOG-IgG has been detected in the serum of children with demyelinating disorders, in particular acute disseminated encephalomyelitis (ADEM), as well as in paediatric and adult patients with AQP4-IgG seronegative NMO and NMO-like syndromes. Although it remains debatable whether MOG-IgG is truly pathogenic, it is currently unclear whether patients expressing this antibody have a similar disease course and similar requirements for immunosuppressive treatment as AQP4-IgG-positive patients. In this journal club we review three recent publications centred on patients with CNS demyelinating disorders and positive MOG-IgG serology. In addition we discuss whether antibodies against MOG could be employed as a useful biomarker for diagnosis and prognosis across the spectrum of NMO and NMO-like disorders.

THE ROLE OF BRAIN MRI IN THE DIAGNOSIS OF NEUROMYELITIS OPTICA

Objective Relapsing remitting Multiple Sclerosis (RRMS) remains an important differential diagnosis of Neuromyelitis optica (NMO). The recently proposed Oxford 2012 diagnostic imaging criteria suggest that analysis of selected data from brain Magnetic Resonance Imaging (MRI) may usefully contribute to the diagnostic process in NMO. When comparing the distribution of brain MRI lesions in patients with NMO vs. RRMS, these criteria demonstrate that patients with RRMS are significantly more likely to have lesions adjacent to the body of the lateral ventricles and in the inferior aspect of the temporal lobes than patients with NMO. We have tested the Oxford 2012 criteria in analysing MR images of a cohort of well–characterised NMO cases from South Wales and South West England to investigate whether they would improve our ability to differentiate NMO from RRMS. Methods We obtained 27 brain MRI scans from 24 patients with aquaporin–4 antibody positive NMO. Images were acquired on 1.5 Tesla MRI scanners at 11 radiology departments between February 2006 and December 2012. A single neuroradiologist, blinded to the clinical diagnoses, systematically identified T2 hyperintense lesions on the T2–weighted images, which were then classified according to location and morphology. The Barkhof criteria for dissemination of MS lesions in space, as well as the Oxford 2012 criteria for differentiation of RRMS from NMO were then applied to this data. This allowed us to quantify the sensitivity of both sets of criteria for differentiating NMO from RRMS. Results T2 hyperintense lesions were identified in 26/27 (96%) brain scans of patients with NMO (median lesion count 9, range 1–60). The majority of lesions were located within the frontal lobes, mostly juxtacortical (median lesion count 3, range 0–28) and in the deep white matter (median lesion count 2, range 0–27). Periventricular lesions were present in 18/27 (67%) scans (median lesion count 1, range 0–9). Temporal lobe, infratentorial, and cerebellar lesions were observed in 4/27 (15%), 6/27 (23%) and 3/27 (11%) respectively. Application of the Oxford 2012 criteria identified 23/27 (85%) scans which were ‘true negative’ for RRMS compared to 18/27 (67%) using Barkhofs criteria for dissemination of RRMS lesions in space, based on unenhanced brain MRI alone. Of the 9/27 (34%) that fulfilled Barkhofs criteria only 4 were also positive for Oxford 2012 criteria for RRMS. Conclusion Application of the Oxford 2012 diagnostic criteria in a clinical setting resulted in an 85% specificity for differentiating NMO from RRMS, the most common differential diagnosis compared to only 67% for Barkhofs criteria. This data should be considered in the MRI assessment of patients in whom the diagnosis of NMO is being considered. In particular patients fulfilling Barkhofs criteria should also be assessed with the Oxford 2012 criteria to improve the interpretation of brain MR imaging and its diagnostic accuracy.