Introduction Cladribine Tablets (Mavenclad®) is nucleoside analogue of deoxyadenosine, and an oral treatment for relapsing remitting MS (RRMS). In RRMS clinical trials, Cladribine has been shown to reduce brain atrophy, relapse rates, and new lesions on brain MRI. P2X7R is a purinergic receptor expressed in innate immune cells, and is thought to play a critical role in neuroinflammation. The mechanism of action of Cladribine on peripheral innate immune cells (monocytes), and its effect on P2X7R, is unclear, and forms the basis of this study. Methods This will be a Phase IV, multi-centre, 3 year, translational trial. Patients who are starting Cladribine as part of their routine clinical care will consent to take part in the study. Monocyte numbers and activation states will be measured at various times prior and after commencement of therapy. In addition, and in an in vitro setting the effect of Cladribine on P2X7R expression and function will be assessed, as well as measuring various cytokines/chemokines in serum. The laboratory data will also be correlated with clinical data from another long-term Cladribine study, CLOBAS. Results This study has been approved by Alfred Health Human Research Ethics Committee. The study is to commence in April 2019. Conclusion This study will shed light on whether Cladribine is exerting its beneficial effects via action on peripheral monocytes and alterations of their P2X7Rs. The laboratory and clinical data will be analysed to understand the relationship between innate immune parameters and patient outcome.

Background: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with demyelination inclusive of optic neuritis (ON), acute disseminated encephalomyelitis (ADEM), and transverse myelitis (TM). MOG is thought to be exclusively expressed in the central nervous system. Objectives: We sought to evaluate peripheral nervous system (PNS) involvement in MOG antibody-positive patients. Methods: Using a live cell-based assay analysed by flow cytometry, we diagnosed 250 MOG antibody-positive adults between 2013-2018. We identified 15 patients with significant symptoms attributed to PNS involvement, and reviewed their clinical course. Results: We identified fifteen MOG antibody-positive adults who presented with symptoms consistent with PNS involvement (age of onset 19 to 58 years; follow-up 30-180 months). In addition to their PNS presentations, all patients had a relapsing course, and phenotypes consistent with MOG antibody-associated demyelination [bilateral ON (n=6), unilateral ON (n=7), pontine/brainstem (n=1), short TM (n=1), and longitudinally extensive TM (LETM, n=1)]. PNS presentations included brachial neuritis (n=2), migratory paraesthesia in a Wartenberg pattern (n=2), myeloradicular symptoms (n=3), and recurrent limb paraesthesia (n=7) and/ or pain (n=3). While one patient developed short TM three years after onset of PNS symptoms, and another developed LETM six years later, none of the fifteen patients had TM prior to or concurrent with onset of PNS symptoms. Nerve conduction studies were consistent with brachial neuritis in two patients, but otherwise non-contributory. MRI spine was unremarkable in 10/15 patients, and showed dorsal nerve root enhancement in two. There was documented improvement or resolution of symptoms within 24 to 72 hours of starting high dose prednisone in six patients, and two months after commencing rituximab in one patient. We detail the presentation, clinical course, neurophysiological and radiological investigations, treatment, and outcomes in this series of patients. Conclusions: PNS involvement may occur in patients with MOG antibodies along with the more recognised demyelinating phenotypes of ON, ADEM, and TM. Recognition of these novel associations expands the clinical spectrum of MOG antibody-associated presentations. Further work in identifying possible targets in peripheral myelin in these patients who may have an inflammatory polyradiculoneuropathy is discussed.

Background: The pathophysiology of multiple sclerosis (MS) tremor is uncertain with limited phenotypical studies available.Objective: To investigate whether dystonia contributes to MS tremor and its severity.Methods: MS patients (n = 54) with and without disabling uni- or bilateral upper limb tremor were recruited (39 limbs per group). We rated tremor severity, writing and Archimedes spiral drawing; cerebellar dysfunction (SARA score); the Global Dystonia Scale (GDS) for proximal and distal upper limbs, dystonic posturing, mirror movements, geste antagoniste, and writer's cramp.Results: Geste antagoniste, mirror dystonia, and dystonic posturing were more frequent and severe (p < 0.001) and dystonia scores were correlated with tremor severity in tremor compared to non-tremor patients. A 1-unit increase in distal dystonia predicted a 0.52-Bain unit (95% confidence interval (CI) 0.08-0.97), p = 0.022) increase in tremor severity and a 1-unit (95% CI 0.48-1.6, p = 0.001) increase in drawing scores. A 1-unit increase in proximal dystonia predicted 0.93-Bain unit increase (95% CI 0.45-1.41, p < 0.001) in tremor severity and 1.5-units (95% CI 0.62-2.41, p = 0.002) increase in the drawing score. Cerebellar function in the tremor limb and tremor severity was correlated (p < 0.001).Conclusions: Upper limb dystonia is common in MS tremor suggesting that MS tremor pathophysiology involves cerebello-pallido-thalamo-cortical network dysfunction.

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10-45), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10-7). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

We read with great interest Dr Centonze, et al’s article [1] in which they reported that 7 of 35 consecutively treated patients developed relapses within the 24 hours after the first dose of natalizumab. Our group have also noted very early relapse activity in 6 of 25 of our patients after their first infusion of natalizumab. In four patients, we have observed a clinical relapse within 24 hours of the first dose. In a further two patients, clinical relapses were observed within 72 hours post first dose. Prior to commencing natalizumab, two of the patients were treatment naïve, two had ceased an approved immunomodulatory treatment one month prior to commencing natalizumab, and one had withdrawn from the Fingolimod FTY720 (Transforms) study 5 months prior. The group of six patients with very early post natalizumab relapse activity had an average of 2.5 relapses in the preceding year (range 1–4), whereas the other 19 patients had an average of 1.5 (0–4) relapses in the preceding year. The difference was significant, P = 0.05. However, the observed relapse rate in the six patients with early relapse was still significantly different from the expected monthly rate, P < 0.0001 (chi-squared test). The clinical features of this early relapse activity were varied. In one patient, relapse symptoms consisted of altered sensation in left arm and leg with left lower limb weakness. These symptoms occurred immediately post the infusion and progressed over days. Another patient also experienced progressive left-sided weakness. The other relapses consisted of increased fecal incontinence, fatigue, and recurrence of pre-existing neuropathic pain. The two patients who experienced relapses 72 hours after first injection experienced moderate to severe fatigue the first 2 days post first dose, then occurrence of neurological symptoms including neuropathic pain and altered sensation in one patient and optic neuritis in the other. Three of the patients were treated with 3 days of intravenous methylprednisolone and all patients have since experienced partial or complete recovery. Our experience lends further support to the hypothesis that the first dose of natalizumab may trigger an acute inflammatory response, precipitating a relapse. Additional useful information regarding the occurrence of relapse activity post first-dose natalizumab could be obtained from available clinical postmarketing monitoring databases maintained by Biogen Idec. If there is further evidence to support this first-dose phenomenon, it may be useful for clinicians to consider management strategies such as prophylactic methylprednisolone administration, perhaps targeting patients with high preinfusion relapse activity, patient education, and counseling.

Introduction: There is a great need to develop surrogate measures in Multiple Sclerosis which predict outcome through interrogation of essential components of the pathophysiology of the disease. The potential importance of Diffusion Tensor Imaging (DTI) measures as surrogate markers have been recently established in animal models, with axial diffusivity reflecting axonal loss and radial diffusivity representing demyelination. A recent publication also reported the ability of axial diffusivity to predict visual outcomes at 1 and 3 months following acute optic neuritis in humans (Naismith et al. Neurology 2008). In addition, our group has recently established and applied a 3 Tesla optic nerve DTI protocol to 10 healthy subjects and 16 cases of extant optic neuritis. We showed that our method has good inter-scan reproducibility and is sensitive to optic nerve abnormalities.

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P =0.001, IL2RA (rs2104286) P =0.033, RPL5 (rs6604026) P =0.041 and CD58 (rs12044852) P =0.042. There was no association ( P =0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15 , gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P -values, such as those reported here, can contribute markedly to the posterior probability of ‘true’ association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance ( P =3 × 10 −8 ) evidence of an association between KIAA0350 and risk of disease.