M. Isabel Leite

Myelin water imaging reflects clinical variability in multiple sclerosis.

Whilst MRI is routinely used for the assessment and diagnosis of multiple sclerosis, there is poor correspondence between clinical disability in primary progressive multiple sclerosis (PPMS) patients and conventional MRI markers of disease activity (e.g., number of enhancing lesions). As PPMS patients show diffuse and global myelin loss, the aim of this study was to evaluate the efficacy of whole-brain myelin water fraction (MWF) imaging in PPMS. Specifically, we sought to use full-brain analysis techniques to: 1) determine the reproducibility of MWF estimates in PPMS brain; 2) compare MWF values in PPMS brain to healthy controls; and 3) establish the relationship between MWF and clinical disability, regionally and globally throughout the brain. Seventeen PPMS patients and seventeen age-matched controls were imaged using a whole-brain multi-component relaxation imaging technique to measure MWF. Analysis of MWF reduction was performed on three spatial levels: 1) histogram; 2) white matter skeleton; and 3) voxel-wise at the single-subject level. From histogram analysis, PPMS patients had significantly reduced global normal appearing white matter MWF (6%, p=0.04) compared to controls. Focal lesions showed lower MWF values than white matter in controls (61%, p<0.001) and patients (59%, p<0.001). Along the white matter skeleton, MWF was diffusely reduced throughout the PPMS brain, with significant correlations between reduced MWF and increased clinical disability (more severe symptoms), as measured by the Expanded Disability Status Scale, within the corpus callosum and frontal, temporal, parietal and occipital white matter. Correlations with the more specific mental and sensory functional system scores were localized to clinically eloquent locations: reduced MWF was significantly associated with increased mental scores in anterior regions (i.e., frontal lobes and genu of the corpus callosum), and increased sensory scores in more posterior regions closer to the sensory cortex. Individual patient MWF maps were also compared to a normative population atlas, which highlighted areas of statistical difference between the individual patient and the population mean. A significant correlation was found between the volume of significantly reduced MWF and clinical disability (p=0.008, R=0.58). Our results show that clinical disability is reflected in particular regions of cerebral white matter that are consistent between subjects, and illustrates a method to examine tissue alteration throughout the brain of individual patients. These results strongly support the use of MWF imaging to evaluate disease activity in PPMS.

Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica

Objective Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Methods Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results Results of tests on 92 controls identified 12assays as highly specific (0–1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5–100%) of all 21 assays. The specificities (85.8–100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. Conclusions The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Catastrophic brain relapse in seronegative NMO after a single dose of natalizumab

Natalizumab, an effective treatment for MS, has been shown to exacerbate neuromyelitis optica (NMO) with aquaporin-4 antibodies, but whether this is the case in antibody negative NMO and atypical MS/NMO spectrum disorder overlap syndromes is unknown. We describe a patient with a relapsing optico-spinal demyelinating syndrome, negative for aquaporin-4 antibodies, who experienced a catastrophic brain relapse shortly after a single dose of natalizumab, highlighting that MS immunomodulatory drugs may worsen demyelination in patients with seronegative NMO and atypical MS/NMO overlap syndromes even if they are aquaporin-4 antibody negative. We summarise the treatments considered safe and effective in NMO, and those with potential to exacerbate disease.

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.

Antibodies identified by cell‐based assays in myasthenia gravis and associated diseases

We have established cell‐based assays for the improved detection of acetylcholine receptor (AChR) and muscle‐specific kinase (MuSK) antibodies in myasthenia gravis. This approach has enabled us to demonstrate antibodies to “clustered” AChRs in patients who were previously AChR antibody negative and can also be used to distinguish between adult and fetal AChR antibodies in mothers of babies with arthrogryposis multiplex congenita. We summarize our recent evidence for the pathogenicity of MuSK and clustered AChR antibodies using in vivo models. Cell‐based assays are now also being used for the detection of other antibodies, such as those directed to components of the VGKC/CASPR2/LGI1 complex in Morvans syndrome, and to AQP4 antibodies in neuromyelitis optica; both of these diseases can be associated with MG and sometimes thymoma. The cell‐based method is time consuming but has many advantages and may provide a gold standard for the future in the detection of pathogenic autoantibodies in patients with immune‐mediated diseases.

Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease

Importance Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are consistently identified in a range of demyelinating disorders in adults and children. Current therapeutic strategies are largely center specific, and no treatments have been formally evaluated. Objective To examine the clinical phenotypes, treatment responses, and outcomes of children with relapsing MOG-Ab–associated disease. Design, Setting, and Participants This study prospectively collected demographic, clinical, and radiologic data from 102 patients from 8 countries of the EU Paediatric Demyelinating Disease Consortium from January 1, 2014, through December 31, 2016. Patients were treated according to local protocols. Main Outcomes and Measures Annualized relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) scores before and during treatment with disease-modifying drugs (DMDs). Results A total of 102 children were identified (median [range] age, 7.0 [1.5-7.9] years; male to female ratio, 1.0:1.8; white to other race/ethnicity ratio, 3.6:1.0). Original diagnoses were neuromyelitis optica spectrum disorder (44 patients [43.1%]), acute disseminated encephalomyelitis followed by optic neuritis (20 [19.6%]), multiphasic disseminated encephalomyelitis (20 [19.6%]), and relapsing optic neuritis (18 [17.6%]). In all, 464 demyelinating events were reported. Treated patients had more relapses (median, 3.0; range, 1.0-17.0) than untreated patients (median, 1.0; range 1.0-7.0) (P = .009) and higher EDSS scores (median, 1.5; interquartile range, 0-2.5) than untreated patients (median, 1.0; interquartile range, 0-1.5) (P < .001). Fifty-two children (51.0%) received DMDs: 28 (53.8%) were treated with 1 DMD, 17 (32.7%) with 2, and 7 (13.5%) with 3 or more sequential DMDs. Patients relapsed during all treatments, with a total of 127 relapses on treatment reported. No changes in median ARR and EDSS score were observed between the preinitiation and postinitiation phases of interferon beta and glatiramer acetate treatment (n = 11). The median ARR was reduced from 1.84 to 1.0 with azathioprine (n = 20, P < .001), 1.79 to 0.52 with mycophenolate mofetil (n = 15, P = .003), and 2.12 to 0.67 with rituximab (n = 9, P < .001), although the median EDSS score remained unchanged. An improvement in ARR (from 2.16 to 0.51, P < .001) and EDSS score (from 2.2 to 1.2, P = .01) was observed in the 12 patients treated with regular intravenous immunoglobulins. Conclusions and Relevance Although commonly used to treat patients with multiple sclerosis, DMDs were not associated with clinical improvement in children with MOG-Ab–associated disease, whereas azathioprine, mycophenolate mofetil, rituximab, and particularly intravenous immunoglobulins were associated with a reduction in relapse frequency. A correct diagnosis of relapsing MOG-Ab–associated disorders is therefore important to optimize immune treatment.

Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability

Summary Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2−/−) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2−/− mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.

N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications.

N‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1‐IgG production and the contribution of germinal center B cells to NR1‐IgG levels are unknown.

Predictive value of MRI parameters in severity and recovery of first-episode myelitis in aquaporin-4 antibody disease

BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) associated with aquaporin-4 antibodies (AQP4-Ab) typically causes longitudinally-extensive transverse myelitis (LETM). Few data exist about the association of MRI features with LETM attack severity and recovery. METHODS AQP4-Ab positive NMOSD patients with a first myelitis attack were retrospectively identified and spinal MRI scans reviewed. Association of MRI features with EDSS scores at attack nadir and recovery was evaluated. RESULTS 22 patients were included. Median nadir EDSS score was 8 (range 1 to 8.5). Nadir EDSS scores correlated with total MRI lesion length (r=0.48, p=0.025), higher scores were seen in those with gadolinium enhancement (p=0.025) and there was a trend towards higher scores with central cord involvement. The median recovery EDSS was 6 (range 0 to 10). Total lesion length correlated with poor recovery (r=0.48, p=0.027) but this was confounded by correlation between nadir and recovery EDSS scores. CONCLUSION We confirm that myelitis in AQP4-Ab disease is severe and show that the severity correlates with lesion length and residual disability. Spinal cord lesions in first myelitis attacks are similar to appearances reported later in the disease course, with propensity to involve the central grey matter and high frequency of cord oedema and T1 hypointensity.

Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica

Aquaporin-4 antibodies are pathogenic in neuromyelitis optica spectrum disorders (NMOSD). Wilson et al. show that circulating memory and naïve B cells from patients can differentiate to produce aquaporin-4 antibodies under conditions chosen to mimic aspects of NMOSD. This platform should direct rationale immunotherapy in NMOSD and other antibody-mediated conditions.