Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.

Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.

BACKGROUND: Recognizing the cause of optic neuritis (ON) affects treatment decisions and visual outcomes. OBJECTIVE: We aimed to define radiological features of first-episode demyelinating ON. METHODS: We performed blinded radiological assessment of 50 patients presenting with first-episode myelin oligodendrocyte glycoprotein (MOG) antibody-associated ON (MOG-ON; n=19), aquaporin-4 (AQP4) antibody-associated ON (AQP4-ON; n=11), multiple sclerosis (MS)-associated ON (MS-ON; n=13), and unclassified ON (n=7). RESULTS: Bilateral involvement was more common in MOG-ON and AQP4-ON than MS-ON (84% vs. 82% vs. 23%), optic nerve head swelling was more common in MOG-ON (53% vs. 9% vs. 0%), chiasmal involvement was more common in AQP4-ON (5% vs. 64% vs. 15%), and bilateral optic tract involvement was more common in AQP4-ON (0% vs. 45% vs. 0%). Retrobulbar involvement was more common in MOG-ON, whereas intracranial involvement was more common in AQP4-ON. MOG-ON and AQP4-ON had longer lesion lengths than MS-ON. The combination of two predictors, the absence of magnetic resonance imaging brain abnormalities and a higher lesion extent score, showed a good ability to discriminate between an autoantibody-associated ON (MOG or AQP4) and MS. AQP4-ON more frequently had severe and sustained visual impairment. CONCLUSION: MOG-ON and AQP4-ON are more commonly bilateral and longitudinally extensive. MOG-ON tends to involve the anterior optic pathway, whereas AQP4-ON the posterior optic pathway.

Early factors associated with axonal loss after optic neuritis.

OBJECTIVE: Acute optic neuritis due to an inflammatory demyelinating lesion of the optic nerve is often seen in association with multiple sclerosis. Although functional recovery usually follows the acute episode of visual loss, persistent visual deficits are common and are probably due to axonal loss. The mechanisms of axonal loss and early features that predict it are not well defined. We investigated clinical, electrophysiological, and imaging measures at presentation and after 3 months as potential markers of axonal loss following optic neuritis. METHODS: We followed 21 patients after their first attack of acute unilateral optic neuritis for up to 18 months. Axonal loss was inferred from optical coherence tomography measures of retinal nerve fiber layer (RNFL) thickness at least 6 months following the episode. Visual function, visual evoked potential, and optic nerve magnetic resonance imaging measures obtained during the acute episode and 3 months later were investigated for their association with later axonal loss. RESULTS: After multivariate analysis, prolonged visual evoked potential latency and impaired color vision, at baseline and after 3 months, were significantly and independently associated with RNFL thinning. Low-contrast acuity measures exhibited significant univariate associations with RNFL thinning. INTERPRETATION: The association of RNFL loss with a prolonged visual evoked potential (VEP) latency suggests that acute and persistent demyelination is associated with increased vulnerability of axons. VEP latency and visual function tests that capture optic nerve function, such as color and contrast, may help identify subjects with a higher risk for axonal loss who are thus more suitable for experimental neuroprotection trials.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

A serial study of retinal changes following optic neuritis with sample size estimates for acute neuroprotection trials.

Following an episode of optic neuritis, thinning of the retinal nerve fibre layer, which indicates axonal loss, is observed using optical coherence tomography. The longitudinal course of the retinal changes has not been well characterized. We performed a serial optical coherence tomography study in patients presenting with optic neuritis in order to define the temporal evolution of retinal nerve fibre layer changes and to estimate sample sizes for proof-of-concept trials of neuroprotection using retinal nerve fibre layer loss as the outcome measure. Twenty-three patients (7 male, 16 female, mean age 31 years) with acute clinically isolated unilateral optic neuritis were recruited to undergo optical coherence tomography, visual assessments and visual evoked potentials at presentation (median 16 days from onset of visual loss) and after 3, 6, 12 and 18 months. Compared with the clinically unaffected fellow eye, the retinal nerve fibre layer thickness of the affected eye was significantly increased at presentation and significantly reduced at all later time points. The evolution of retinal nerve fibre layer changes in the affected eye fitted well with an exponential model, with thinning appearing a mean of 1.6 months from symptom onset and the rate of ongoing retinal nerve fibre layer loss decreasing thereafter. At presentation, increased retinal nerve fibre layer thickness was associated with impaired visual acuity and prolonged visual evoked potential latency. Visual function after 12 months was not related to the extent of acute retinal nerve fibre layer swelling but was significantly associated with the extent of concurrent retinal nerve fibre layer loss. Sample size calculations for placebo-controlled trials of acute neuroprotection indicated that the numbers needed after 6 months of follow up are smaller than those after 3 months and similar to those after 12 months of follow-up. Study power was greater when investigating differences between clinically unaffected and affected eyes rather than retinal nerve fibre layer thickness of the affected eye alone. Inflammation in the optic nerve and impaired axonal transport (implied by retinal nerve fibre layer swelling) are associated with visual dysfunction and demyelination (long visual evoked potential latency) during acute optic neuritis. Retinal nerve fibre layer thinning is usually evident within 3 months. Optical coherence tomography-measured retinal nerve fibre layer loss after 6 months is a suitable outcome measure for proof-of-concept trials of acute neuroprotection in optic neuritis.

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Multiple sclerosis: distribution of inflammatory cells in newly forming lesions.

OBJECTIVE: CD4 T-cell-dependent macrophage activation directed against a myelin or oligodendrocyte antigen is generally thought to be the mechanism causing myelin destruction in multiple sclerosis (MS). However, areas within expanding MS lesions may exhibit prominent oligodendrocyte loss and apoptosis in the absence of infiltrating lymphocytes. The present study was designed to further investigate the inflammatory profile of different regions within rapidly expanding MS lesions. METHODS: Twenty-six active lesions from 11 patients with early MS were serially sectioned and immunostained for T and B cells, plasma cells, ramified microglia, macrophages, monocytes, and CD209-positive dendritic cells. Cell counts were compared in prephagocytic, phagocytic, and immediately postphagocytic areas. RESULTS: Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes. In contrast, trailing areas of complete demyelination packed with lipid macrophages, and, in some lesions, regenerating oligodendrocytes, showed large numbers of T cells, B cells, and immunoglobulin G (IgG)-positive plasma cells. Lesions in 2 exceptionally early cases contained relatively few T and B cells, and no IgG-positive plasma cells. INTERPRETATION: Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions. Macrophage activity is largely an innate scavenging response to the presence of degenerate and dead myelin. Adaptive immune activity involving T and B cells is conspicuous chiefly in recently demyelinated tissue, which may show signs of oligodendrocyte regeneration. The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte antigen.

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

The clinical profile of NMOSD in Australia and New Zealand.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography.

Axonal loss is thought to be the predominant cause of disability in progressive multiple sclerosis (MS). The retinal nerve fibre layer (RNFL) is composed largely of unmyelinated axons of retinal ganglion cells, and is accessible to study with optical coherence tomography (OCT), giving a measure of axonal loss. OCT measures of the RNFL thickness (RNFLT) and macular volume were studied in 23 patients with primary progressive multiple sclerosis (primary progressive MS) (13 male; 10 female; mean age 52 years; median EDSS 6.0; mean disease duration 11 years), and 27 patients with secondary progressive multiple sclerosis (secondary progressive MS) (8 male; 19 female; mean age 50 years; median EDSS 6; mean disease duration 22 years). Of the patients with secondary progressive MS, 14 had clinical history of optic neuritis (ON) in a single eye; the remaining patients had not had ON. Twenty healthy controls (11 male; 9 female; mean age 46 years) had RNFLT and macular volume studied. Of the patients' eyes not previously affected by ON, both the mean RNFL thickness and macular volume were reduced when compared with control values. The mean RNFL thickness and macular volume were significantly reduced in secondary progressive MS, but not in primary progressive MS when compared with control RNFL thickness and macular volume. RNFL loss was most evident in the temporal quadrant, where significant reduction was seen in primary progressive MS versus controls and in secondary versus primary progressive MS. There were significant correlations of decreased RNFLT and macular volume with measures of visual acuity, low contrast visual acuity and visual field mean deviation in the MS patients. There are significant global reductions in RNFLT and macular volume in the eyes of secondary progressive MS patients not previously affected by ON, but not in primary progressive MS patients, compared with controls. This may indicate a difference in the extent of the pathological processes that cause axonal loss in the retina, and by inference the optic nerve, in secondary progressive MS and primary progressive MS.

Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.

A preliminary longitudinal study of the retinal nerve fiber layer in progressive multiple sclerosis.

Thinning of the retinal nerve fiber layer (RNFL) of clinically unaffected eyes is seen in patients with multiple sclerosis (MS). It is uncertain when this thinning occurs, and whether ongoing RNFL loss can be measured over time with optical coherence tomography (OCT). Using time-domain OCT, we studied 34 patients with progressive MS (16 primary progressive MS, 18 secondary progressive; 14 male; 20 female; mean age at study entry 51 years; median EDSS 6; mean disease duration at study entry 12 years) on two occasions with a median interval of 575 (range 411-895) days apart. Eighteen healthy controls (10 male; eight female; mean age at study entry 46 years) were also studied twice, with a median interval of 656 days (range 398-890). Compared to controls, the patients had significant decreases in the RNFL thickness and macular volume of their clinically unaffected eyes at study entry. No significant decrease in RNFL thickness was observed between baseline and follow-up in either patients or controls. Macular volume declined significantly in patients and controls, but there was no difference in this change between the two groups. The study findings suggest that time domain OCT detects little disease-related ongoing loss of retinal axons in progressive forms of MS and has limited use for monitoring potential neuroprotective therapies at this stage of disease. Further studies are needed using higher-resolution OCT systems and in larger groups of patients, to elucidate the timing and mechanism of RNFL loss that is observed in clinically unaffected nerves in MS.

Assessing structure and function of the afferent visual pathway in multiple sclerosis and associated optic neuritis.

The afferent visual pathway is commonly affected in MS. Assessment of the afferent visual pathway using clinical, imaging and electrophysiological methods not only provides insights into the pathophysiology of MS, but also provides a method of investigating potential therapeutic measures in MS. This review summarises the various assessment methods, in particular imaging techniques of the visual pathway. Retinal nerve fibre layer (RNFL) thickness is usually reduced following an episode of optic neuritis. Techniques such as optical coherence tomography, scanning laser polarimetry, and confocal scanning laser ophthalmoscopy are used to quantify RNFL thickness. MRI of the optic nerve is not routinely used in the diagnosis of MS or optic neuritis, but is valuable in atypical cases and in research. T2- weighted images of the optic nerve usually show the hyperintense lesion in optic neuritis and gadolinium enhancement is seen in the acute attack. Quantifying atrophy of the optic nerve using MRI gives an indication of the degree of axonal loss. Magnetization transfer ratio (MTR) of the optic nerve provides an indication of myelination. Diffusion tensor imaging (DTI) of the optic nerve and optic radiation provide information about the integrity of the visual white matter tracts. Functional MRI following visual stimulation is used to assess the contribution of cortical reorganisation to functional recovery following optic neuritis. Investigations including logMAR visual acuity, Sloan contrast acuity, Farnsworth- Munsell 100-hue colour vision tests and Humphrey perimetry provide detailed quantitative information on different aspects of visual function. Visual evoked potentials identify conduction block or delay reflecting demyelination. These collective investigative methods have advanced knowledge of pathophysiological mechanisms in MS and optic neuritis. Relevant ongoing studies and future directions are discussed.