Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is one of the most common antibody-mediated CNS disorders. Optimal diagnostic and prognostic biomarkers remain unclear. Our aim was to clarify these biomarkers and therapeutic outcomes internationally. We reviewed articles from 2007 to 2022 and identified 194 unique cohorts encompassing 4699 paediatric and adult patients from 31 countries. Where phenotypes were specified, the most common initial presentation overall was optic neuritis (ON; paediatric 34 %; adults 60 %), during which 71 % had papilloedema on fundoscopy. The most common phenotype at latest follow-up was relapsing ON (20 %). Only 47 % of patients with 6-24 months of follow-up exhibited a relapsing course, while this proportion was much higher (72 %) when follow-up was extended beyond 5 years. Despite a similar relapse rate, the time to first relapse was much shorter in paediatric than adult patients (6 vs 17 months). Adult MRI-Brain scans performed at onset were more frequently normal than in paediatric patients (50 % vs 27 %). Abnormal MRI scans showing involvement of deep grey matter, cortico-subcortical, periventricular lesions, leptomeningeal enhancement, H-shaped spinal cord lesions, and bilateral optic nerve abnormalities were more common in paediatric patients compared to adults. Conversely, adults demonstrated higher frequencies of eccentric spinal cord lesions and intraorbital involvement. CSF analysis demonstrated intrathecally restricted oligoclonal bands in 12 %, elevated protein in 35 %, and pleocytosis in 54 %. Peripapillary retinal nerve fibre layer (pRNFL) thickness, measured acutely, frequently demonstrated swelling (weighted-median 145 mu m; normal 85-110). Most cohorts demonstrated notable pRNFL atrophy at latest follow-up (weighted-median 67 mu m). pRNFL thickness was significantly lower when measured at or after six months following ON onset, compared to measurements taken within the first six months following ON onset (p < 0.001). Therapeutic and outcome data was available for 3031 patients with a weighted-median disease duration of 32 months. Acute immunotherapy was initiated in 97 %, and maintenance immunotherapy in 64 %, with considerable regional variation. Expanded Disability Status Scale (EDSS) scores and visual acuities improved from nadir to latest follow-up in most patients. A negative correlation was noted between follow-up pRNFL thickness and latest follow-up visual acuity (r = -0.56). Based on this unprecedented global aggregation of MOGAD patients, we reveal a higher proportion of relapsing patients than previously recognised. While commonly used measures like EDSS show significant recovery, they underestimate visual disability following optic neuritis, the most frequent clinical presentation. Our findings suggest that RNFL thickness, especially when measured at least 6 months post-ON, may serve as a more sensitive biomarker for long-term visual impairment.

Background Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients.Methods MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated.Results Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%).Conclusions Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is diagnosed by serum MOG-immunoglobulin G (MOG-IgG) in association with typical demyelination. 111/1127 patients with paired CSF/serum samples were seropositive for MOG-IgG. Only 7/1016 (0.7%) seronegative patients had CSF-restricted MOG-IgG. While 3/7 patients had longitudinally extensive transverse myelitis, four had a confirmed alternate diagnosis (three multiple sclerosis, one CNS vasculitis). In a national referral setting, CSF-restricted MOG-IgG had a low sensitivity (2.63%, 95%CI 0.55-7.50%) and low positive predictive value (1.97%, 95%CI 0.45-8.13%). We strongly recommend serum as the preferred diagnostic biospecimen, and urge caution in the interpretation of CSF-restricted MOG-IgG in patients without clinico-radiological features consistent with MOGAD.

BACKGROUND:We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. METHODS:In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy. RESULTS:We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect. CONCLUSIONS:The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

Objectives We evaluated the association of oral corticosteroids (OCS) administered for the initial attack of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with the risk of relapse. Methods We documented clinical presentation of MOGAD, immunotherapy administration, and time to first relapse among patients from the Australasian MOGAD Study Group who had at least 2 sufficiently documented consultations. A Cox proportional hazards model with OCS dose as a time-varying covariate examined the relationship between OCS and the hazard of first relapse, adjusted for IV corticosteroid therapy and age. Results We evaluated 99 patients [(53 female; median age at disease onset 24 years (range 1–69 years); median follow-up duration 69 months (range 5–640 months)]. 67 patients experienced a relapse; median survival time to relapse was 16.4 months. The 57 patients treated with OCS had a median course duration of 47 days (range 5–1242 days ) with a median time from first symptoms to initiation of 12 days (range 0–61 days). Higher dose OCS following the initial attack of MOGAD was associated with a lower cumulative hazard (HR=0.97, 95%CI=0.95–0.998 p=0.03). In this model, no evidence was found to support IV corticosteroid dosage modifying relapse risk (p=0.23). Conclusions Higher doses of OCS following the initial attack of MOGAD are associated with a lower hazard of early relapse. On average, for every 1mg increase in oral prednisolone dose, the cumulative hazard of relapse decreased by 3%. These results have the potential to inform the development of evidence-based treatment strategies for this increasingly recognised CNS autoimmune disorder.

Purpose of review Autoimmune encephalitis (AE) refers to immune-mediated neurological syndromes often characterised by the detection of pathogenic autoantibodies in serum and/or cerebrospinal fluid which target extracellular epitopes of neuroglial antigens. There is increasing evidence these autoantibodies directly modulate function of their antigens in vivo . Early treatment with immunotherapy improves outcomes. Yet, these patients commonly exhibit chronic disability. Importantly, optimal therapeutic strategies at onset and during escalation remain poorly understood. In this review of a rapidly emerging field, we evaluate recent studies on larger cohorts, registries, and meta-analyses to highlight existing evidence for contemporary therapeutic approaches in AE. Recent findings We highlight acute and long-term treatments used in specific AE syndromes, exemplify how understanding disease pathogenesis can inform precision therapy and outline challenges of defining disability outcomes in AE. Summary Early first-line immunotherapies, including corticosteroids and plasma exchange, improve outcomes, with emerging evidence showing second-line immunotherapies (especially rituximab) reduce relapse rates. Optimal timing of immunotherapy escalation remains unclear. Routine reporting of outcome measures which incorporate cognitive impairment, fatigue, pain, and mental health will permit more accurate quantification of residual disability and comprehensive comparisons between international multicentre cohorts, and enable future meta-analyses with the aim of developing evidence-based therapeutic guidelines.

Transaldolase (TAL) is an enzyme of the non-oxidative part of the pentose phosphate pathway which produces reductive potential in the form of NADPH as well as ribose 5-phosphate for incorporation into nucleotides. Developmental analysis via reverse transcriptase-polymerase chain reaction, immunoblots, enzymatic activity, in situ hybridization and immunocytochemistry demonstrate that TAL is expressed during all developmental stages in Drosophila. The tal locus is unique and contains two small introns. The first two introns in the human gene are situated at the same locations in the coding sequence as in Drosophila. Analysis of TAL protein levels and expression patterns reveals that it is also expressed in all larval tissues examined with particularly high levels in the fat body. Interestingly, we describe specific TAL expression only in non-neuronal cells in the larval brain.

OBJECTIVE:We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome.METHODS:The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes.RESULTS:Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss.CONCLUSIONS:Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.

BACKGROUND:B-cell depleting treatments are widely used to modify the course of neuromyelitis optica spectrum disorder (NMOSD). Despite recent successful Phase 3 trials of several novel NMOSD therapies, limited availability and high cost constrains their clinical use, and rituximab (RTX) remains a core treatment in many centres. Since 2013, the Royal Prince Alfred Hospital Neuroimmunology Clinic (NIC) has regularly measured class-switched memory B-cells (SMB-cells) in the peripheral blood of patients with NMOSD, who have been treated with RTX, in order to guide retreatment intervals.OBJECTIVE:To assess the management and outcomes of the treated patients, and to determine the effect of SMB-cell monitoring in guiding retreatment intervals.METHODS:A retrospective analysis of hospital records, clinic letters and laboratory data was performed.RESULTS:Sixteen patients with NMOSD received individualised rituximab dosing at NIC between 2013 and 2018. Fourteen (87.5%) were aquaporin-4 antibody (AQP4-Ab) positive; 1 (6.25%) was myelin oligodendrocyte glycoprotein antibody (MOG-Ab) positive and 1 (6.25%) was seronegative. After commencement of RTX, individually dosed according to regular measurements of serum SMB-cells, there was a 77.5% reduction in annualised relapse rate over a mean follow-up time of 46.1 months in our recently active NMOSD patients. Their mean retreatment interval was 50.9 weeks.CONCLUSIONS:This study provides real-world evidence supporting individualised rituximab dosing in the treatment of NMOSD.

IntroductionWe report a rare case of early-onset dementia with leukoencephalopathy in which the diagnosis was unclear until autopsy. As previously seen in case reports of this condition, there were a number of working diagnoses made, prefixed with ‘atypical’, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Huntington disease.1CaseA sixty-one-year old Caucasian female initially presented with 2 years of progressive chorea of her right upper limb, anxiety and memory difficulties. These symptoms steadily progressed over the next 5 years as she developed dementia and a progressive gait disturbance with pyramidal weakness. In the terminal stages of her illness, at sixty-six years of age, she had recurrent hospital admissions for pyrexia of unknown origin and finally refractory seizures and death. Her serum investigations were non-diagnostic; she was negative for both CADASIL and Huntington disease mutations. Her MRI demonstrated diffuse confluent white matter changes involving the corpus callosum and the vermis. She also had an abnormal electroencephalogram late in the course of her disease, with lateralised periodic discharges recorded during episodes of non-convulsive status epilepticus. Her autopsy revealed a leukoencephalopathy with pathognomonic histologic features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Post-mortem genetic testing is currently underway.ConclusionOur case demonstrates the possibility of establishing an accurate diagnosis with pathology and genetic testing in cases of early-onset dementia with white matter changes. Recently elucidated entities offer diagnostic closure to patients, families and clinicians and can inform prognosis and genetic counselling. Furthermore, potential therapeutic options for leukodystrophies appear to be on the horizon.2 Our case report is the first to our knowledge to present with chorea and to exhibit vermian hyperintensity on T2-weighted MRI.References. Meyer-Ohlendorf M, Braczynski A, Al-Qaisi O, et al. Comprehensive diagnostics in a case of hereditary diffuse leukodystrophy with spheroids. BMC Neurology2015;15:103.. van der Knaap MS, Wolf NI, Heine VM. Leukodystrophies: Five new things. Neurol Clin Pract2016;6:506–514.

IntroductionCerebral amyloid angiopathy (CAA) is a common age-related condition characterised by amyloid beta-peptide deposition affecting the medium sized cortical and leptomeningeal arteries, arterioles and capillaries. CAA-related Inflammation (CAA-I) is an increasingly recognised variant of CAA, which is thought to be due to perivascular auto-inflammation in response to amyloid deposition. We describe the clinical course of two cases of probable CAA-I.CasesA 71 year old man presented with new-onset seizures, headaches and subacute cognitive decline. MRI of the brain demonstrated confluent subcortical T2 white matter hyperintensities and cerebral oedema, with predominantly superimposed widespread cortico-subcortical micro-haemorrhages, in keeping with the diagnosis of CAA-I. A course of immunosuppresive therapy was commenced with five days of intravenous methylprednisolone, resulting in marked radiological and clinical improvement within two weeks.A 76 year old female presented with subacute cognitive dysfunction and apraxia, and transient left-sided weakness. MRI scan of the brain initially demonstrated a right temporo-occipital infarct, leading to primary treatment for stroke, but subsequently evolved to reveal diffuse multi-lobar T2 white matter hyperintensities with leptomeningeal involvement. A provisional diagnosis of CAA-I was made and following a poor clinical response to a trial of corticosteroid therapy, treatment with intravenous cyclophosphamide was commenced.ConclusionThese cases emphasise the importance of CAA-I as part of the differential diagnosis in patients presenting with symptoms of subacute cognitive decline, seizures, headaches and focal neurological deficits, given the potential for dramatic improvement with readily accessible immunosuppressive therapies.

Temporal arteritis, also known as giant cell arteritis, is a chronic vasculitis of large and medium arteries. We audited all the temporal artery biopsies over a 12-year timeframe at a major tertiary hospital in Australia. There were 307 temporal artery biopsies (TABs) in this time frame, of which 59(19.2%) were reportedasbeing positive. We found increased positivity of pathological confirmation of temporal arteritis with longer biopsy specimens. The average length of positive biopsy was 19.2 mm, and negative 16.6 mm (p < 0.05). The average age of all TAB patients was 73.5 years (range 40–94), while the average ageofpositive TAB was 76.4 years. The female to male ratio amongst all biopsied individuals was 2.29, whilst the female to male ratio in positive biopsies was 2.69. Temporal arteritis, also known as giant cell arteritis, is a chronic vasculitis of large and medium arteries. We audited all the temporal artery biopsies over a 12-year timeframe at a major tertiary hospital in Australia. There were 307 temporal artery biopsies (TABs) in this time frame, of which 59(19.2%) were reportedasbeing positive. We found increased positivity of pathological confirmation of temporal arteritis with longer biopsy specimens. The average length of positive biopsy was 19.2 mm, and negative 16.6 mm (p < 0.05). The average age of all TAB patients was 73.5 years (range 40–94), while the average ageofpositive TAB was 76.4 years. The female to male ratio amongst all biopsied individuals was 2.29, whilst the female to male ratio in positive biopsies was 2.69.