Deborah Mason

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

To perform a 1‐stage meta‐analysis of genome‐wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.

MS prevalence in New Zealand, an ethnically and latitudinally diverse country

Background: The prevalence of multiple sclerosis (MS) is not uniform, with a latitudinal gradient of prevalence present in most studies. Understanding the drivers of this gradient may allow a better understanding of the environmental factors involved in MS pathogenesis. Method: The New Zealand national MS prevalence study (NZMSPS) is a cross-sectional study of people with definite MS (DMS) (McDonald criteria 2005) resident in New Zealand on census night, 7 March 2006, utilizing multiple sources of notification. Capture—recapture analysis (CRA) was used to estimate missing cases. Results: Of 2917 people with DMS identified, the crude prevalence was 72.4 per 100,000 population, and 73.1 per 100,000 when age-standardized to the European population. CRA estimated that 96.7% of cases were identified. A latitudinal gradient was seen with MS prevalence increasing three-fold from the North (35°S) to the South (48°S). The gradient was non-uniform; females with relapsing—remitting/secondary-progressive (RRMS/SPMS) disease have a gradient 11 times greater than males with primary-progressive MS (p < 1 × 10-7). DMS was significantly less common among those of Māori ethnicity. Conclusions: This study confirms the presence of a robust latitudinal gradient of MS prevalence in New Zealand. This gradient is largely driven by European females with the RRMS/SPMS phenotype. These results indicate that the environmental factors that underlie the latitudinal gradient act differentially by gender, ethnicity and MS phenotype. A better understanding of these factors may allow more targeted MS therapies aimed at modifiable environmental triggers at the population level.

Reduced grey matter perfusion without volume loss in early relapsing-remitting multiple sclerosis

Background Grey matter (GM) pathology in multiple sclerosis (MS) is associated with progressive long-term disability. Detection of GM abnormalities in early MS may therefore be valuable in understanding and predicting the long-term course. However, structural MRI measures such as volume loss have shown only modest abnormalities in early relapsing-remitting MS (RRMS). We therefore investigated for evidence of abnormality in GM perfusion, consistent with metabolic dysfunction, in early RRMS. Methods 25 RRMS patients with ≤5 years disease duration and 25 age-matched healthy controls underwent 3 Tesla MRI with a pseudo-continuous arterial spin labelling sequence to quantify GM perfusion and a volumetric T1-weighted sequence to measure GM volume. Neurological status was assessed in patients and neuropsychological evaluation undertaken in all subjects. Voxel-based analysis was used to compare regional GM perfusion and volume measures in patients and controls. Results There was reduced global GM perfusion in patients versus controls (50.6±5.8 mL/100 g/min vs 54.4±7.6 mL/100 g/min, p=0.04). Voxel-based analysis revealed extensive regions of decreased cortical and deep GM perfusion in MS subjects. Reduced perfusion was associated with impaired memory scores. There was no reduction in global or regional analysis of GM volume in patients versus controls. Conclusions The decrease in GM perfusion in the absence of volume loss is consistent with neuronal metabolic dysfunction in early RRMS. Future studies in larger cohorts and longitudinal follow-up are needed to investigate the functional and prognostic significance of the early GM perfusion deficits observed.

Deep grey matter MRI abnormalities and cognitive function in relapsing-remitting multiple sclerosis.

Although deep grey matter (GM) involvement in multiple sclerosis (MS) is well documented, in-vivo multi-parameter magnetic resonance imaging (MRI) studies and association with detailed cognitive measures are limited. We investigated volumetric, diffusion and perfusion metrics in thalamus, hippocampus, putamen, caudate nucleus and globus pallidum, and neuropsychological measures, spanning 4 cognitive domains, in 60 relapsing-remitting MS patients (RRMS) (mean disease duration of 5.1 years, median EDSS of 1.5) and 30 healthy controls. There was significantly reduced volume of thalamus, hippocampus and putamen in the RRMS patients, but no diffusion or perfusion changes in these structures. Decreased volume in these deep GM volumes in RRMS patients was associated with a modest reduction in cognitive performance, particularly information processing speed, consistent with a subtle disruption of distributed networks, that subserve cognition, in these patients. Future longitudinal studies are needed to elucidate the influence of deep GM changes on the evolution of cognitive deficits in MS.

Assessing possible selection bias in a national voluntary MS longitudinal study in Australia

Background: Surveying volunteer members of a multiple sclerosis registry is a very cost-effective way of assessing the impact of the disease on life outcomes. However, whether the data from such a study can be generalised to the whole population of persons living with MS in a country or region is unclear. Methods: Here we compare the demographic and disease characteristics of participants in one such study, the Australian Multiple Sclerosis Longitudinal Study (AMSLS), with two well-characterised MS prevalence studies with near-complete ascertainment of MS in their study regions. Results: Although some differences were found, these largely represented the effects of geography (sex ratios) and local factors (national immunomodulatory therapy prescribing requirements), and the cohorts were otherwise comparable. Overall, despite comprising only 12–16% of MS cases in Australia, the AMSLS is highly representative of the MS population. Conclusions: Therefore with some minor caveats, the AMSLS data can be generalised to the whole Australasian MS population. Volunteer disease registries such as this can be highly representative and provide an excellent convenience sample when studying rare conditions such as MS.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 2 New and emerging therapies and their efficacy

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

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.

Multiple sclerosis in New Zealand.

New Zealand (NZ) is a high risk country for multiple sclerosis (MS) with an overall age and sex standardised prevalence of 73.1 per 100,000 population. The age and sex standardised prevalence within the Māori population is substantially lower at 24.2 per 100,000 population. A latitudinal gradient exists with MS prevalence increasing threefold from the North (37°S) to the South (48°S) of NZ. Over 1600 (56.8%) persons with MS experience moderate to severe disability. Despite the high prevalence of MS and the significant degree of disability experienced by people with MS, the availability and prescribing guidelines for MS disease modifying treatments are more restrictive in NZ than in other developed nations.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 3 Treatment practicalities and recommendations

In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.

The Increasing Prevalence of Multiple Sclerosis in New Zealand

Background: New Zealand (NZ) has a high prevalence of multiple sclerosis (MS). Worldwide, the prevalence of MS appears to be increasing. Objectives: To review all published prevalence studies undertaken in NZ to determine whether the prevalence of MS in NZ is increasing. Methods: PubMed, Medline, Scopus, Web of Knowledge, EMBASE, AMED and CINAHL were searched to identify studies reporting the prevalence of MS in NZ. Prevalence rates from the National MS Prevalence study in 2006 were compared with earlier prevalence rates for the same regions using Poisson regression. Results: Prevalence rates reported in the earlier regional studies ranged from 23.6 to 68.5/100,000 population; in the same regions in 2006, the range was 47.6-134.2/100,000 population. Prevalence rates were significantly increased in all regions studied except for the Bay of Plenty. The increase in prevalence was seen in both sexes. The sex ratio remained constant over time. Conclusions: In studies spanning almost 40 years (1968-2006), the prevalence of MS within the same regions of NZ has significantly increased whereas the sex ratio and latitudinal gradient have remained stable.