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.
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Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated autoimmune disease of the central nervous system (CNS) in which the primary target is aquaporin 4 (AQP4), a water channel found in high density on the end-feet of astrocytes, particularly those in close proximity to the blood–brain barrier.1 Difficulties in identifying NMOSD and distinguishing it from multiple sclerosis were dramatically reduced by the discovery of AQP4 antibodies in 2004.2 Since the identification of these seemingly specific and pathogenic antibodies,3 the phenotype of this autoimmune astrocytopathy has broadened.4 It has been noted that the relative frequency of NMOSD is higher in populations of Asian ancestry (50% of CNS demyelinating disease)5 compared with populations of predominantly European ancestry (1% of CNS demyelinating disease).6
A number of studies have attempted to estimate the population prevalence and incidence of NMOSD in various parts of the world. However, many of these studies have been based on AQP4 antibody positivity from laboratory testing. As a result, few population-based clinical surveys of the frequency of NMOSD exist.7 Australia and New Zealand have a population of 27–28 million people with predominantly European ancestry. Both have comprehensive healthcare systems, with a network of adult and paediatric neurologists who have a subspecialty interest in CNS demyelinating disease. We have undertaken a clinic-based survey of NMOSD, using a clinical method of case ascertainment with the aim of estimating the population incidence and prevalence of NMOSD. As secondary aims, we wished to explore the geographical and ethnical distribution of NMOSD.
Possible cases of NMOSD were identified using a network of 36 adult and paediatric neurologists at 23 clinics specialising in demyelinating diseases of the CNS (ICD-10 G35–G37) across Australia and New Zealand. These centres covered every capital and major city of each state or region, as well as several smaller urban centres. Australia and New Zealand have comprehensive state healthcare systems in which most patients with demyelinating diseases of the CNS are cared for in specialist clinics. Participating neurologists and paediatric neurologists were requested to notify the coordinating centre in Queensland of patients with features identified in earlier diagnostic criteria8 that are highly suggestive of NMOSD. To be included as a suspected NMOSD case one of the following ‘high risk’ clinical and laboratory features had to be met: (1) optic neuritis that was either severe with poor recovery (residual visual acuity in better eye worse or equal to 6/36), bilateral (simultaneous or sequential within 3 months) or recurrent (more than two attacks) as the sole clinical manifestation of demyelinating disease; (2) severe transverse myelitis with a central cord syndrome (symmetrical, motor, sensory and bladder involvement) and poor recovery (residual expanded disability status scale (EDSS) greater than 5.0) or a longitudinally extensive lesion of the spinal cord spanning three or more vertebral segments on MRI; or (3) demyelinating disease clinically confined to the optic nerve and spinal cord with at least one of the following: normal or atypical MRI of the brain (fewer than two periventricular lesions),9 negative oligoclonal bands in cerebrospinal fluid, raised cerebrospinal fluid (CSF) protein or a CSF pleocytosis (more than 10 cells per microlitre). Cases were excluded if no serum sample was supplied and clinical criteria for NMOSD were not met, insufficient clinical data were supplied, inclusion criteria for suspected NMOSD were not met, an alternate diagnosis became apparent or subject declined to provide written informed consent. The period of data collection was from 1 January 2011 to 31 December 2013. Informed written consent was obtained for all cases and institutional human research ethics committee approval was obtained for all participating sites.
To facilitate a capture–recapture methodology, the four laboratories in Australia that offer routine AQP4-antibody (Ab) testing provided details of positive cases detected in their laboratories for the same time period. Details on these cases included date of birth, initials, age, gender, state/country and ethnicity (Asian or Other), thereby ensuring the avoidance of double counting and facilitating a whole of population analysis by age, gender, region and ethnicity.
Demographic details (age, gender and ethnicity), relapse history, findings on clinical examination and results of CSF analysis and any prior AQP4-Ab testing were collected using a standard questionnaire in all cases. Serum samples were obtained and tested for AQP4-Ab using immunofluorescence staining techniques on mouse, rat or monkey brain tissue and rat or mouse kidney sections. A subset of samples was also tested using an ELISA kit, as well as M23 AQP4 transfected human embyonic kidney (HEK) cells in a fixed cell assay (Euroimmun, Germany) and a live cell-based assay.10 MRI of brain, orbits and spinal cord were obtained where available. Cases were defined as having NMOSD (ICD-10 G36) and included in the analysis if they met the 2015 Wingerchuk criteria.11
Estimation of incidence and prevalence
Crude incidence rates with 95% CI were calculated, using the normal approximation to the binomial distribution, from the mean number of cases with disease onset (date of first symptoms) occurring from 2009 to 2012 inclusive. The inevitable lag between symptom onset and clinical assessment means that new cases would typically be identified and referred to the study sometime after the onset of their symptoms. Therefore incident cases for the collection year 2013 were not included. Crude point prevalence rates were calculated for the prevalence date of 1 July 2013. To be included in the prevalence estimate cases were required to have disease onset on or before 1 July 2013 and be alive on this date. Gender and age adjustment was performed using the WHO Standard World Population Distribution for 2005 to 2025.12
The Lincoln-Peterson capture–recapture method13 was used to adjust prevalence and incidence rates in light of laboratory identified cases that had been missed in the clinical survey. Standard methods were used to estimate a 95% CI for this adjusted prevalence rate.14 All analyses were conducted on a state and country basis, to allow for regional variations in referral practice, before being combined. Prevalence rates were also estimated for cases with Asian ancestry separately using the same capture–recapture methodology. The definition of Asian ancestry was self-determined but indicated to include those whose genealogical ancestry arose in the continent of Asia.
Population estimates for Australian states and New Zealand were obtained from the Australian Bureau of Statistics and Statistics New Zealand websites.15 16 For incidence, population estimates for 2011 were used (the midpoint of the study years). For prevalence, population estimates for 2013 were used (the year of the prevalence date). Latitudinal variation in prevalence was analysed using the latitude of the centre of population for each region.15–17 The relationship between latitude and prevalence was explored using a regression analysis weighted by the reciprocal variance using StataV.14.0 software.
Incidence and prevalence of NMOSD
A total of 177 cases of suspected NMOSD were referred to the study centre. Of these, 7/177 (4%) were excluded (no serum sample received in one, inclusion criteria not met in two, incomplete clinical data in three and alternative diagnosis in one). The one case excluded because of no serum sample being supplied did not meet the clinical criteria for NMOSD. Clinical information, results of testing for AQP4 antibodies and MRI results were available for all of the remaining 170 suspected cases of NMOSD permitting application of the 2015 Wingerchuk criteria. A cell-based assay was used in 79/177 (46%) of suspected cases, immunofluorescence tissue assay was performed in all. NMOSD was confirmed in 81/170 (48%) cases and 73/81 (90%) were seropositive for AQP4 antibodies. The laboratory survey identified 117 AQP4 antibody positive cases of which 70 were not identified in the clinical survey, giving a total of 151 cases of NMOSD. There were 34 incident cases over the period 2010 to 2012, giving a crude incidence of 0.33 (95% CI 0.11 to 0.55) per million per year. Two cases died prior to the prevalence date and two cases had disease onset after the prevalence date leaving 147 prevalent cases, giving a crude point prevalence of 0.53 (95% CI 0.45 to 0.62) per 100 000. Standardising to the WHO 2005–2025 world population gave a gender and age-adjusted prevalence figure of 0.44 (95% CI 0.36 to 0.52) per 100 000. There were 126/147 (86%) female cases, giving a female to male ratio of 6:1. The frequency distribution by age is shown in figure 1. The peak prevalence age range for women was 40–59 years and for men was 60–69 years.
Capture–recapture analysis and lifetime risk of NMOSD
There were 47/73 (64%) cases from the clinical survey that were recaptured in the laboratory survey. For the capture–recapture analysis, we have extrapolated the total number of seronegative cases assuming the same proportion of missed cases as seen with the seropositive cases. An additional eight ‘seronegative’ cases were added according to the observed regional distribution. Capture–recapture gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and gave an estimated total number of NMOSD cases of 193 and prevalence of 0.70 (95% CI 0.66 to 0.74) per 100 000. The results for prevalence estimates by state, ancestry and overall are shown in table 1. The prevalence of NMOSD in the population of Australia and New Zealand with Asian ancestry was 1.57 (95% CI 1.15 to 1.98) per 100 000 compared with 0.57 (95% CI 0.50 to 0.65) per 100 000 in the remainder of the population. The lifetime risk of developing NMOSD was calculated using the cumulative age of onset for the clinical survey cases (data not shown) as 1.26 (95% CI 1.13 to 1.39) per 100 000.
Latitudinal variation in NMOSD prevalence
The prevalence estimates by region are illustrated in figure 2 and show no increase in prevalence with increasing latitude. In fact, there is a reverse relationship which is statistically significant (p=0.044). Exclusion of cases and state populations with Asian ancestry did not significantly alter this finding.
This is the first incidence and prevalence survey of NMOSD in the Oceania region. We have utilised a clinical survey method combined with a laboratory-based capture–recapture methodology to estimate the incidence and prevalence of NMOSD in Australia and New Zealand and have results that are similar to those previously recorded for both European and Asian populations. The estimates of incidence and prevalence reported here are at the lower end of previous study results (table 2). There are two studies with significantly higher estimates of prevalence18 19 and one of these also has a significantly higher estimate of incidence.19 These studies included methodologies likely to have a high pick up rate for cases of NMOSD through multiple healthcare sources and national databases19 or systematic serological testing of all possible cases.18 Relatively small sample sizes mean that these higher prevalence figures could represent statistical random variation (the number of affected cases in the recent USA study was only six).18 Conversely, it is likely the results presented here are an underestimate. There are a number of limitations with the present study. First, only a proportion of our suspected cases had testing for AQP4 antibodies with a cell-based assay. Second, we have not tested every patient with demyelinating disease of the CNS for AQP4 antibodies. These limitations are, however, only likely to have a relatively small impact on the overall prevalence. A third and more significant limitation is that only currently or recently active cases who have been seen in clinics or undergone AQP4 antibody testing will have been identified. Against this is the fact that the age-specific rates of NMOSD in the present series were very consistent for the higher age groups. Finally, we have used the 2015 Wingerchuk criteria,11 which are more stringent with regard to seronegative NMOSD. Confirmation of seronegative cases was also constrained by the availability of relevant MRI having ever been performed. There is certainly also a potential for the referral of these cases to have been reduced compared with seropositive cases, despite the clinically based mechanism of referral for the initial capture.
The overall estimated number of cases of NMOSD (193) represents less than 1% of the 26 600 people with multiple sclerosis estimated to be living in Australia20 and New Zealand.21 This is a similar proportion to that seen in other European populations. The increased frequency of NMOSD in women is consistent with previous studies. In a survey using the same methodology across a defined geographical region, we have demonstrated a higher prevalence of NMOSD in people with Asian ancestry (threefold increase compared with the remaining population of predominantly European ancestry).
The present data do not support a latitudinal gradient in NMOSD as compared with MS for this region.22 23 In fact, the data suggest a possible weak inverse relationship, with prevalence increasing at lower latitudes. This does not appear to be explained by regional variations in the proportion with Asian ancestry in each region as the trend remained when these populations were removed. Another possible explanation could be ease of access to serological testing, as the two states with the highest prevalence of NMOSD have the two laboratories with the highest throughput of AQP4 antibody testing. The proportions of new cases identified through the laboratory survey certainly suggest that this may have been a factor with the two most distant regions (South Australia/Northern Territory) and New Zealand having the lowest proportions of cases detected through the laboratory survey. We have demonstrated an increased frequency of NMOSD in women compared with men consistent with previous studies (table 3).
In conclusion, the Australia and New Zealand region has incidence and prevalence estimates for NMOSD which are within the ranges seen in other populations around the world, with the possible exception of populations with African ancestry.18 The prevalence of NMOSD is higher in people with Asian ancestry compared with the remaining predominantly European ancestry population of Australia and New Zealand and NMOSD does not share the latitudinal gradient seen with MS across this region. It therefore seems likely that the epidemiology of NMOSD is different to MS and that susceptibility factors thought to be important in MS (eg, vitamin D and sunlight) may not play a significant role in NMOSD.
We are grateful to the study participants and would like to thank the support of the members of the Australian and New Zealand Association of Neurologists and Multiple Sclerosis Nurses Australia who assisted with data collection.
Contributors DA, MHB, SBh, SBl, MBo, KB, BJB, SAB, MBr, WBr, HB, WMC, CC, AC, RCD, CD, KD, DG, SHa, RH, APDH, SHo, AGK, TJK, JK, CK, JL-S, CL, RALM, MPMa, DFM, PAMcC, CO’G, JPa, JPe, JDP, KMP, SWR, CS, MS, JSp, JSt, IS, BVT, AV, SV, MWa, PW, EW, RJW and RCW conceived and designed the study. SAB, WBu, CSB, LC, KD, MJF-P, DG, SHe, SJ-S, M-WL, KMP, RS, JSt, BVT, PW, RJW, MWo and EMY conducted the analyses. SAB prepared the initial draft and MHB, BJB, WBu, WMC, RCD, KD, MJF-P, DF, APDH, SHo, AJK, JL-S, M-WL, MPMa, PAMcC, MPMe, KMP, RS, MS, BVT, AV, SV, MWa, PW, EW, RJW, RCW, MWo and EMY contributed to revisions. All authors approved the final draft.
Funding This project was undertaken by the Australia and New Zealand Neuromyelitis Optica (ANZ NMO) Collaboration and was supported by funding from Multiple Sclerosis Research Australia, the Brain Foundation, Griffith University and the Gold Coast Hospital Foundation. The work in Oxford was supported by the National Health Service National Specialised Commissioning Group for Neuromyelitis Optica and the National Institute for Health Research Oxford Biomedical Research Centre.
Competing interests MHB has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. MBo has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, BiogenIdec and Roche. BJB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, AbbVie and Biogen Idec, has received travel sponsorship from Abbott and ViiV Healthcare and has received research support funding from EIi Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, BiogenIdec, Merck Serono, Novartis and Sanofi-Genzyme, has received speaker honoraria from Biogen Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme and was the recipient of an unencumbered research grant from Biogen Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organised by Novartis, Biogen Idec, Medscape and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi and CSL Biopharma and has received research support form Merck Serono. WMC has been the recipient of travel sponsorship from, and provided advice to, Bayer Schering Pharma, BiogenIdec, Novartis, Genzyme, Sanofi-Aventis, BioCSL and Merck Serono. RCD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney and the Petre Foundation and has received honoraria from Biogen Idec and Bristol-Myers Squibb as an invited speaker. MjF-P has received travel sponsorship from Biogen Australia and New Zealand. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, BiogenIdec, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva. TJK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono and BiogenIdec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer Schering Pharma and Merck Serono and has received scientific consulting fees from GlaxoSmithKline China, Biogen Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer,Genzyme, Novartis and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi-Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia and Teva. RALM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, Biogen Idec, CSL, Merck Serono, Novartis and Sanofi-Genzyme. MPMa has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis and Sanofi-Aventis Genzyme. DFM has received honoraria for attendance at advisory boards from Biogen Idec and Novartis, and travel sponsorship from Bayer Schering Pharma, Biogen Idec and Sanofi-Genzyme. PAMcC has received honoraria or travel sponsorship from Novartis, Sanofi-Aventis and Biogen Idec. JAP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi-Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme and Teva. SWR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi-Aventis Genzyme and Servier, and is a director of Medical Safety Systems Pty Ltd. CPS has received travel sponsorship from Biogen Idec, Novartis and Bayer Schering Pharma. IS has received remuneration for Advisory Board activities from Biogen, CSL and Bayer Schering Pharma and educational activities with Biogen, CSL and travel sponsorship from Biogen, Novartis and Bayer Schering Pharma. MS has received research support from Novartis, Biogen Idec and BioCSL. JSp has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. BVT has received travel sponsorship from Novartis and Bayer Schering Pharma. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received speaker honoraria from Biogen Idec and Euroimmun AG and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen Idec and Novartis, travel sponsorship from Biogen Idec, Bayer Schering Pharma and Teva and is an investigator in clinical trials funded by Biogen Idec and Teva. DA, SBh, SBl, KB, MBr, WBr, WBu, CSB, CCM, LC, AC, CD, KD, DF, DG, SHa, APDH, SHe, SHo, SJ-S, AJK, M-WL, CL, CO’G, MPM, CS, RS, JSt, AV, SV, MWa, RJW, RCW, MWo and EMY report no disclosures.
Patient consent This HREC-approved study involved written informed consent from all participants. No patient-identifying information or patient-specific images are included in the submitted documents.
Ethics approval Griffith University Human Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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