Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome.

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

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.

The latitude gradient for multiple sclerosis prevalence is established in the early life course.

The strongest epidemiological clue that the environment at the population level has a significant impact on the risk of developing multiple sclerosis is the well established, and in many instances, increasing latitudinal gradient of prevalence, incidence and mortality globally, with prevalence increasing by up to 10-fold between the equator and 60° north and south. The drivers of this gradient are thought to be environmental with latitude seen as a proxy for ultraviolet radiation and thus vitamin D production; however, other factors may also play a role. Several important questions remain unanswered, particularly when in the life course is the gradient established, does lifetime migration mitigate or exacerbate previously reported latitude gradients at location of diagnosis, and do factors such as sex or multiple sclerosis disease phenotype influence the timing or significance of the gradient? Utilizing lifetime residence calendars collected as part of the New Zealand National Multiple Sclerosis Prevalence Study, we constructed lifetime latitudinal gradients for multiple sclerosis from birth to prevalence day in 2006 taking into account migration internally and externally and then analysed by sex and multiple sclerosis clinical course phenotype. Of 2917 individuals living in New Zealand on prevalence day, 7 March 2006, with multiple sclerosis, 2127 completed the life course questionnaire and of these, 1587 were born in New Zealand. All cohorts and sub-cohorts were representative of the overall multiple sclerosis population in New Zealand on prevalence day. We found that the prevalence gradient was present at birth and was, in fact, stronger than at census day, and the slope of the gradient persisted until the age of 12 before gradually declining. We found that internal and external migration into New Zealand had little, if any, effect on the gradient except to decrease the significance of the gradient somewhat. Finally, we found as we had reported previously, that the lifetime prevalence gradients were largely driven by females with relapse onset multiple sclerosis. These findings confirm for the first time the importance of early life environmental exposures in the risk of multiple sclerosis indicating strongly that exposures as early as in utero and at birth drive the latitudinal gradient. Consequently, prevention studies should be focused on high-risk individuals and populations from the earliest possible time points especially, when appropriate, on females.

Testing Wearable UV Sensors to Improve Sun Protection in Young Adults at an Outdoor Festival: Field Study.

BACKGROUND: Australia and New Zealand have the highest skin cancer incidence rates worldwide, and sun exposure is the main risk factor for developing skin cancer. Sun exposure during childhood and adolescence is a critical factor in developing skin cancer later in life. OBJECTIVE: This study aims to test the effectiveness of wearable UV sensors to increase sun protection habits (SPH) and prevent sunburn in adolescents. METHODS: During the weeklong school leavers outdoor festival (November 2019) at the Gold Coast, Australia, registered attendees aged 15-19 years were recruited into the field study. Participants were provided with a wearable UV sensor and free sunscreen. The primary outcome was sun exposure practices using the SPH index. Secondary outcomes were self-reported sunburns, sunscreen use, and satisfaction with the wearable UV sensor. RESULTS: A total of 663 participants were enrolled in the study, and complete data were available for 188 participants (188/663, 28.4% response rate). Participants provided with a wearable UV sensor significantly improved their use of sunglasses (P=.004) and sunscreen use both on the face (P<.001) and on other parts of the body (P=.005). However, the use of long-sleeve shirts (P<.001) and the use of a hat (P<.001) decreased. During the study period, 31.4% (59/188) of the participants reported receiving one or more sunburns. Satisfaction with the wearable UV sensor was high, with 73.4% (138/188) of participants reporting the UV sensor was helpful to remind them to use sun protection. CONCLUSIONS: Devices that target health behaviors when outdoors, such as wearable UV sensors, may improve use of sunscreen and sunglasses in adolescents.

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.

Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: a phase I, randomised, blinded, placebo-controlled trial.

OBJECTIVE: Because clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the Clozapine and Risperidone in Progressive Multiple Sclerosis (CRISP) trial was conducted to determine whether clozapine and risperidone are suitable for progressive multiple sclerosis (pMS). METHODS: The CRISP trial (ACTRN12616000178448) was a blinded, randomised, placebo-controlled trial with three parallel arms (n=12/arm). Participants with pMS were randomised to clozapine (100-150 mg/day), risperidone (2.0-3.5 mg/day) or placebo for 6 months. The primary outcome measures were safety (adverse events (AEs)/serious adverse events (SAE)) and acceptability (Treatment Satisfaction Questionnaire for Medication-9). RESULTS: An interim analysis (n=9) revealed significant differences in the time-on-trial between treatment groups and placebo (p=0.030 and 0.025, clozapine and risperidone, respectively) with all participants receiving clozapine being withdrawn during the titration period (mean dose=35±15 mg/day). Participants receiving clozapine or risperidone reported a significantly higher rate of AEs than placebo (p=0.00001) but not SAEs. Specifically, low doses of clozapine appeared to cause an acute and dose-related intoxicant effect in patients with pMS who had fairly severe chronic spastic ataxic gait and worsening over all mobility, which resolved on drug cessation. INTERPRETATION: The CRISP trial results suggest that patients with pMS may experience increased sensitivity to clozapine and risperidone and indicate that the dose and/or titration schedule developed for schizophrenia may not be suitable for pMS. While these findings do not negate the potential of these drugs to reduce multiple sclerosis-associated neuroinflammation, they highlight the need for further research to understand the pharmacodynamic profile and effect of clozapine and risperidone in patients with pMS. TRIAL REGISTRATION NUMBER: ACTRN12616000178448.

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.

Glatiramer acetate treatment normalized the monocyte activation profile in MS patients to that of healthy controls.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, and monocytes contribute to MS-associated neuroinflammation. While classically activated monocytes promote inflammation, type II-activated monocytes improve the course of MS. This study investigated type II activation of monocytes and their two main subsets, namely CD14+ (CD14++CD16- subset) and CD16+ monocytes (CD14+CD16+ subset), by glatiramer acetate (GA) or intravenous immunoglobulin-associated immune complexes (IC), both of which are known MS treatments. Total monocytes and subsets were isolated from peripheral blood mononuclear cells (PBMC) of healthy controls, untreated MS patients (MS) and GA-treated MS patients (GA-MS). In contrast to the more activated ex vivo profile of monocytes from the MS group, monocytes from the GA-MS group resembled those from healthy controls. In vitro type II activation with GA primarily reduced CD40, CD86 and IL-12p40 whereas type II activation with IC consistently reduced CD40 but increased interleukin-10 (IL-10), suggesting that the GA and IC activation pathways are distinct. Moreover, while GA treatment reduced IL-12p40 by both CD14+ and CD16+ subsets, IC treatment only enhanced IL-10 by the CD16+ subset. Further analysis of the CD16+ subset revealed that MS patients had a greatly expanded CD14+CD16int population while both CD14+CD16int and CD14lowCD16high monocyte populations were expanded in GA-MS patients. Finally, a global analysis of the ex vivo monocyte data indicated that GA treatment distinctly altered the monocyte profile of MS patients, further supporting the idea that GA directly targets monocytes.

Disability profile of multiple sclerosis in New Zealand.

New Zealand is a high risk region for multiple sclerosis (MS). The aim of this study was to investigate demographic, clinical and temporal factors associated with disability status in the New Zealand National Multiple Sclerosis Prevalence Study (NZNMSPS) cohort. Data were obtained from the 2006 NZNMSPS with MS diagnosis based on the 2005 McDonald criteria. Disability was assessed using the Expanded Disability Status Scale (EDSS). Disability profiles were generated using multiple linear regression analysis. A total of 2917 persons with MS was identified, of whom disability data were available for 2422 (75% females). The overall disability was EDSS 4.4±standard deviation 2.6. Higher disability was associated with older age, longer disease duration, older and younger ages of onset, spinal cord syndromes with motor involvement at onset, and a progressive onset type. Lower disability was associated with sensory symptoms at onset and a relapsing onset type. Overall, the factors studied explained about one-third of the variation in disability, and of this, about two-thirds was accounted for by age, age of onset and disease duration and one-third by the nature of first symptoms and type of disease onset (progressive or relapsing). Current age, age at onset and disease duration all had independent associations with disability and their effects also interacted in contributing to higher disability levels over the course of the disease.

New Zealand's neurologist workforce: a pragmatic analysis of demand, supply and future projections.

AIMS: To estimate current and future specialist neurologist demand and supply to assist with health sector planning. METHODS: Current demand for the neurology workforce in New Zealand was assessed using neuroepidemiological data. To assess current supply, all New Zealand neurology departments were surveyed to determine current workforce and estimate average neurologist productivity. Projections were made based on current neurologists anticipated retirement rates and addition of new neurologists based on current training positions. We explored several models to address the supply-demand gap. RESULTS: The current supply of neurologists in New Zealand is 36 full-time equivalents (FTE), insufficient to meet current demand of 74 FTE. Demand will grow over time and if status quo is maintained the gap will widen. CONCLUSIONS: Pressures on healthcare dollars are ever increasing and we cannot expect to address the identified service gap by immediately doubling the number of neurologists. Instead we propose a 12-year strategic approach with investments to enhance service productivity, strengthen collaborative efforts between specialists and general service providers, moderately increase the number of neurologists and neurology training positions, and develop highly skilled non-specialists including trained.

Expansion and preferential activation of the CD14(+)CD16(+) monocyte subset during multiple sclerosis.

Multiple sclerosis (MS) is an immune-driven, demyelinating disease of the central nervous system (CNS). Although many types of immune cells are involved in disease progression, activated monocytes are believed to be one of the first to arrive to the brain and initiate inflammation. However, little is known about how the two main monocyte subsets, CD14(++)CD16(-) and CD14(+)CD16(+), are involved in MS. To understand how the phenotype and responses of these monocyte subsets are altered during MS, total monocytes and the purified monocyte subsets from healthy subjects (n=29) and MS patients (n=20) were characterized ex vivo and stimulated in vitro with lipopolysaccharide (LPS). The ex vivo analyses showed that total monocytes from MS patients had significantly elevated levels of CD40, CD86, HLA-DR, CD64 and C-C motif chemokine receptor 2 (CCR2), and this elevation was most marked on CD16(+) monocytes. In vitro stimulation with LPS led to an increase in CD86, HLA-DR, CD64 and IL-6 production by monocytes from MS patients. Furthermore, in purified cultures, CD14(+) monocytes were found to be the main producers of IL-10 while CD16(+) monocytes produced more IL-12. In monocytes from MS patients, both subsets produced substantially more IL-6, and the production of IL-10 by the CD16(+) subset was also significantly elevated compared with healthy monocytes. Together these findings highlight the important contribution of the CD16(+) monocyte subset in driving inflammatory responses during MS.

Hypoventilation in glycine-receptor antibody related progressive encephalomyelitis, rigidity and myoclonus.

Glycine receptor (GlyR) antibodies have been identified in patients with rigidity and hyperekplexia, but the clinical phenotype associated with these antibodies has not been fully elucidated. The clinical features in two additional patients with GlyR antibodies are described. A 55-year-old man presented with stimulus-induced hyperekplexia and rigidity in the lower limbs and trunk. He initially responded to benzodiazepines, but presented after 18 months with severe, painful, prolonged spasms associated with supraventricular and ventricular arrhythmias, hypoventilation and oxygen desaturation requiring intubation. He improved following treatment with clonazepam, baclofen and immunomodulatory therapies. A 58-year-old woman presented with stiffness in the legs and hyperekplexia associated with hypoventilation, at times leading to loss of consciousness. She responded to benzodiazepines and has remained in remission. The clinical picture associated with GlyR antibodies includes autonomic dysfunction, cardiac arrhythmias and hypoventilation. It is important to recognise these serious complications early to limit mortality from this treatable condition.

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.

Carotid endarterectomy: a Southern North Island regional consensus statement.

AIMS: The aim of this project was to employ interdepartmental and cross district health board collaboration to reach a regional consensus on the management of patients who may benefit from carotid endarterectomy. METHODS: All regional stroke physicians, neurologists, and vascular surgeons met to review relevant literature and local audits and to discuss best management strategies suited to the region. RESULTS: A consensus statement was agreed upon and is presented here along with a summary of the supporting scientific evidence. DISCUSSION: Regional interdisciplinary collaboration proved an effective way to reach a carotid endarterectomy management consensus across a wider geographical area that is served by a single vascular surgery department. This approach could serve as a model for other regional initiatives.

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 Maori 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.

A meta-analysis of performance on simple span and more complex working memory tasks in Parkinson's disease.

The working memory (WM) concept has stimulated substantial research since Baddeley and Hitch advanced their model in 1974. There has also been growing interest in WM in Parkinson's disease (PD) where the brain structures considered important for WM are often compromised. However, it remains unclear how and to what degree WM is affected in PD. The authors used meta-analysis to clarify the research findings on WM in PD. The results confirmed that people with PD are impaired on tests of WM. This impairment is small for verbal span but moderate on complex verbal and both simple and complex visuospatial tasks. These data do not support the belief that WM impairment in PD is solely at the level of the central executive. However, our findings support the notion that impairment is more pronounced for visuospatial than verbal WM. A number of different interpretations of these results are discussed. It remains to be established what these statistically significant differences mean in terms of clinically significant levels of impairment in WM. Another important methodological issue that demands greater consideration in this area is that of sampling and the generalizability of results.