Myelin oligodendrocyte glycoprotein antibody-associated demyelination: comparison between onset phenotypes.

BACKGROUND AND PURPOSE: The aim of this study was to analyse the clinical and prognostic features of myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination with different onset phenotypes. METHODS: A total of 52 MOG-IgG-seropositive patients were divided into four groups: (i) optic neuritis (ON) at onset (MOG-ON+ , n = 23), (ii) transverse myelitis (TM) at onset (MOG-TM+ , n = 12), (iii) pure brain symptoms at onset (MOG-ON- -TM- , n = 14) and (iv) both ON and TM at onset (n = 3). This final group was not included in further analyses. Data were collected through medical records and regular follow-up. RESULTS: Median age at presentation was 24 (range, 3-63) years in the whole cohort (50% female). MOG-ON- -TM- patients had the youngest age of onset across the three groups. Patients with MOG-TM+ tended to relapse more frequently and had a longer interval to first relapse than was observed in MOG-ON+ and MOG-ON- -TM- patients. High MOG-IgG titres were associated with increased cerebrospinal fluid leukocytes. The likelihood of harbouring transient, low MOG-IgG titres was higher in the MOG-TM+ group than in the other groups. After a median disease duration of 20 months, most but not all cases had a favourable outcome, with 8% developing severe visual deficit, 2% becoming wheelchair-dependent and 6% developing cognitive impairment. The onset phenotype appeared to be an important predictor of disability type. Having high MOG-IgG titres (odds ratio, 0.168, P = 0.027) or female gender (odds ratio, 0.270, P = 0.067) was associated with a lower likelihood of complete recovery. CONCLUSIONS: Onset phenotype may influence long-term presentation, MOG-IgG status as well as outcome. Further large and prospective studies are needed to better clarify the clinical implications of the first demyelinating event.

Association of serum Cystatin C with neuromyelitis optica spectrum disorders.

BACKGROUND AND PURPOSE: The relationship between Cystatin C (CysC) and neuromyelitis optica spectrum disorders (NMOSD) is unknown. METHODS: Serum CysC levels were measured in 105 Chinese patients with NMOSD (53 in relapse, 52 in remission) and 109 healthy controls (HCs). The association of CysC with NMOSD and its clinical and magnetic resonance imaging parameters were evaluated. RESULTS: Cystatin C levels were significantly lower in patients with relapsing NMOSD than in those in remission (P < 0.001) or HCs (P < 0.05). CysC levels in NMOSD remission were higher than in HCs (P = 0.002). CysC levels were positively associated with age and negatively associated with brain lesion numbers in relapsing NMOSD (r = -0.252, P = 0.069). CONCLUSION: Our results indicate a reduced serum level of CysC in patients with relapsing NMOSD and an increased level in remission. Further studies on the role of CysC in NMOSD are warranted.

Circulating immune cells in multiple sclerosis.

Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS-associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research.

Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study.

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-ß treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-ß-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5).

The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis.

Multiple Sclerosis (MS) is a neurological condition driven in part by immune cells from the peripheral circulation, the targets for current successful therapies. The autoimmune and MS risk gene ZMIZ1 is underexpressed in blood in people with MS. We show that, from three independent sets of transcriptomic data, expression of ZMIZ1 is tightly correlated with that of hundreds of other genes. Further we show expression is partially heritable (heritability 0.26), relatively stable over time, predominantly in plasmacytoid dendritic cells and non-classical monocytes, and that levels of ZMIZ1 protein expression are reduced in MS. ZMIZ1 gene expression is increased in response to calcipotriol (1,25 Vitamin D3) (p < 0.0003) and associated with Epstein Barr Virus (EBV) EBNA-1 antibody titre (p < 0.004). MS therapies fingolimod and dimethyl fumarate altered blood ZMIZ1 gene expression compared to untreated MS. The phenotype indicates susceptibility to MS, and may correspond with clinical response and represent a novel clinical target.

A guide to facilitate the early treatment of patients with idiopathic demyelinating disease (multiple sclerosis and neuromyelitis optica).

Definite diagnosis of inflammatory demyelinating disease (multiple sclerosis (MS) and neuromyelitis optica (NMO)) may require time, but early treatment offers the opportunity to maximize patient outcomes. The purpose of this report is to provide guidance to facilitate early treatment decisions for patients with inflammatory demyelinating disease, before definitive diagnosis. Neurology experts reviewed the existing literature and clinical evidence. A treatment decision pathway was developed, defining patients for whom first-line MS disease-modifying therapies (a) are unlikely to be effective, (b) may be effective but require careful monitoring and (c) are likely to provide benefit. This algorithm seeks to ensure that patients, particularly those in Asia, receive appropriate treatment early in inflammatory demyelinating disease.

Zero retinal vein pulsation amplitude extrapolated model in non-invasive intracranial pressure estimation.

Intracranial pressure (ICP) includes the brain, optic nerve, and spinal cord pressures; it influences blood flow to those structures. Pathological elevation in ICP results in structural damage through various mechanisms, which adversely affects outcomes in traumatic brain injury and stroke. Currently, invasive procedures which tap directly into the cerebrospinal fluid are required to measure this pressure. Recent fluidic engineering modelling analogous to the ocular vascular flow suggests that retinal venous pulse amplitudes are predictably influenced by downstream pressures, suggesting that ICP could be estimated by analysing this pulse signal. We used this modelling theory and our photoplethysmographic (PPG) retinal venous pulse amplitude measurement system to measure amplitudes in 30 subjects undergoing invasive ICP measurements by lumbar puncture (LP) or external ventricular drain (EVD). We estimated ICP from these amplitudes using this modelling and found it to be accurate with a mean absolute error of 3.0 mmHg and a slope of 1.00 (r = 0.91). Ninety-four percent of differences between the PPG and invasive method were between - 5.5 and + 4.0 mmHg, which compares favourably to comparisons between LP and EVD. This type of modelling may be useful for understanding retinal vessel pulsatile fluid dynamics and may provide a method for non-invasive ICP measurement.

The effect of the Australian bushfires and the COVID-19 pandemic on health behaviours in people with multiple sclerosis.

BACKGROUND: Crises and disasters disproportionally impact people with chronic health conditions such as multiple sclerosis (MS). OBJECTIVE: To assess the impact of the COVID-19 pandemic and the Australian Black Summer Bushfires on health behaviours in people with MS. METHODS: People with MS, carers, healthcare and advocacy professionals were recruited online between May-July 2020 for an online survey and telephone interviews. RESULTS: Survey items relating to health behaviours were completed by 113 people with MS, and 18 people with MS, 4 MS advocates, 5 healthcare professionals, and 2 carers were interviewed. The bushfires affected 34.5% and the pandemic affected 74.3% of survey participants with MS. The pandemic and bushfires caused a decrease in physical activity in 53.8% and 55.3% of participants respectively, as well as increases in unhealthy eating (43.6% and 24.3% respectively) and alcohol consumption (35.4% and 10.5% respectively), and a decrease in typical sleeping patterns (40.5% and 39.5% respectively). Conversely, 27.5% of participants reported an increase in physical activity during the pandemic. Interview data detailed the circumstances and motivations for changes in health behaviours, as well as consequences, including reduced mobility, fitness, mood disturbances, and weight gain. CONCLUSION: There is a need to increase support and health promotion for people with MS to maintain or initiate positive health behaviours, especially in times of adversity.

Longitudinally extensive myelopathy in Caucasians: a West Australian study of 26 cases from the Perth Demyelinating Diseases Database.

OBJECTIVES: To characterise West Australian cases of longitudinally extensive myelopathy (LEM). METHODS: Twenty six patients with LEM were identified from a cohort of 983 patients with demyelinating disease. Clinical and MRI data and AQP4-IgG results were reviewed. RESULTS: LEM cases were classified as conventional MS (CMS) 13, neuromyelitis optica (NMO) 7, and isolated LEM 6. LEM was the initial presentation in 13/26 cases. In CMS cases lesions were mainly in the lower cervical cord (C4-C7) whereas in NMO and isolated LEM they were more often thoracic and were longer. The severity of disability was highly variable but was greater in the NMO than the CMS group. Only one of 20 patients tested was seropositive for AQP4-IgG. CONCLUSION: LEM occurred as part of CMS or NMO or in isolation. Patients with LEM had highly heterogeneous clinical characteristics and a low rate of AQP4-IgG seropositivity.

Characterisation of the spectrum of demyelinating disease in Western Australia.

BACKGROUND: The diversity of multiple sclerosis (MS) and the nosology of the conventional form of MS (CMS), optic-spinal MS (OSMS) and neuromyelitis optica (NMO) have been subject to controversy. AIMS: The purpose of this study was to investigate whether the current Asian optic-spinal multiple sclerosis (OSMS) criteria could also apply in Western countries, and whether or not cerebrospinal fluid (CSF) and imaging features in the Western Australian patient population of demyelinating disease was similar to that found in Asia. METHODS: This study retrospectively reviewed 915 individual case notes with central nervous system demyelinating disease seen by two neurologists in Western Australia (WA). 842 cases had sufficient data to be included in the analysis. The patient population was predominantly Caucasian, representing approximately two-thirds of MS cases in WA. The mean duration of follow-up for the whole studied cohort was 12.5 years, with 136 patients (16.2%) being followed-up for more than 20 years. RESULTS: The study confirmed the relatively low frequency of OSMS as a proportion of total demyelinating disease occurring in western countries, with 31 OSMS (3.7%) cases in contrast to 703 CMS cases (83.5%). It is likely, however, that our retrospective classification significantly underestimated the proportion of OSMS cases when compared with prospectively classified Asian cohorts. There were 11 OSMS cases that could also be classified as NMO according to published diagnostic criteria. The remainder of the spectrum comprised clinically isolated syndromes such as 50 acute myelitis (AM, 5.9%), 42 optic neuritis (ON, 5%) and 16 "atypical" cases such as tumefactive MS and acute disseminated encephalomyelitis (1.9%). The clinical characteristics of OSMS in our study were compatible with so-called Asian MS in many respects: oligoclonal bands (OCBs) were less frequent in OSMS (29.4%) than in CMS (66.4%, p = 0.003); visual evoked potentials and spinal MRI abnormalities were more prevalent in OSMS (85% and 92.6%) than in CMS (71.4% and 85%); as were long spinal cord lesions in OSMS (22.2%) versus CMS (3.4%, p,0.001). Brain abnormalities were seen in 48.4% of OSMS patients and 96.2% of CMS patients (p = 0.001). OCBs were identified in 7% of acute myelitis, 14.3% of optic neuritis and 73.4% of primary progressive MS patients. CONCLUSIONS: This cross-sectional study presents the full spectrum of demyelinating disease in WA, which has a stable population representing 10% of the total Australian population and suggests that the current classifications of MS, OSMS or NMO, ON and AM share many clinical and laboratory features, such as female predominance, age at onset, duration of disease and CSF investigations (including OCBs and MRI). Moreover, characteristics of the WA population were similar to those reported in Asian patients.

Intravascular lymphoma presenting as progressive paraparesis.

We present a patient with subacute progressive paraparesis secondary to intravascular lymphoma restricted to the spinal cord where initial laboratory and imaging studies were inconclusive. We emphasise the importance of a systematic approach to the diagnosis and highlight the utility of spinal cord biopsy to establish the definitive diagnosis of this rare but treatable illness.

Leflunomide-induced peripheral neuropathy.

Two cases of leflunomide-induced peripheral neuropathy are described; in a 60-year-old woman with sero-negative polyarthralgia-myalgia syndrome and a 65-year-old man with sero-negative rheumatoid arthritis, both treated with leflunomide at 20mg/day. Nerve conduction studies and electromyogram showed sensorimotor axonal neuropathy in both cases. An alternative cause for the axonal neuropathy was excluded by extensive investigations, including cerebrospinal fluid examination and nerve biopsy in the second patient. Both patients stabilized symptomatically and electrophysiologically upon cessation of leflunomide. It is possible that leflunomide-induced peripheral neuropathy has been under-reported and under-recognized.

Data characterizing the ZMIZ1 molecular phenotype of multiple sclerosis.

The data presented in this article are related to the research article entitled "The autoimmune risk gene ZMIZ1 is a vitamin D responsived marker of a molecular phenotype of multiple sclerosis" Fewings et al. (2017) [1]. Here we identify the set of genes correlated with ZMIZ1 in multiple cohorts, provide phenotypic details on those cohorts, and identify the genes negatively correlated with ZMIZ1 and the cells predominantly expressing those genes. We identify the metabolic pathways in which the molecular phenotype genes are over-represented. Finally, we present the flow cytometry gating strategy we have used to identify the immune cells from blood which are producing ZMIZ1 and RPS6.

Cerebral amyloid angiopathy presenting with vasculitic pathology.

We present an elderly patient with an unusual extensive multifocal central nervous system mass lesion, with dramatic imaging changes but only minor disturbance of cerebral function. Cerebral biopsy revealed an unexpected finding of severe cerebral amyloid angiopathy with secondary florid vasculitic appearances, which is a very rare but recognised association. Immunosuppression has produced significant sustained clinical and radiological remission.

Murray valley encephalitis mimicking herpes simplex encephalitis.

We describe a patient with serologically proven Murray Valley encephalitis (MVE), whose presentation was clinically and radiologically characteristic of Herpes simplex encephalitis (HSE). The reports of MRI abnormalities in MVE, and the closely related Japanese Encephalitis and West Nile virusii are mostly of bilateral thalamic or grey matter involvement. The MRI scan findings in this case instead showed the typical temporal lobe changes of HSE. Our case report highlights that MVE can mimic HSE, both clinically and radiologically. Therefore it is important to collect an accurate and detailed travel history from patients where there is a risk of exposure to MVE virus. If suspected, antibody testing of serum and CSF, and CSF for MVE-RNA if available, should be undertaken. This case also highlights the potential under-diagnosis of Murray Valley encephalitis.

Symptomatic retrochiasmal lesions in multiple sclerosis: clinical features, visual evoked potentials, and magnetic resonance imaging.

We have studied 18 patients with relapsing-remitting multiple sclerosis (MS) who had symptomatic visual field defects due to retrochiasmal lesions. In 17, the lesion responsible was identified by magnetic resonance imaging (MRI), computed x-ray tomography (CT), or both. The lesion responsible involved the posterior optic radiations in eight cases, the optic tract and lateral geniculate nucleus in six, and the posterior limb of the internal capsule in three. The prognosis for recovery of the field defect was good; complete recovery occurred in 14 patients, and only two showed no recovery at all. The striking characteristic of the lesions was that most were unusually large; indeed, many were detectable on CT as well as MRI. Half-field asymmetries of either amplitude or latency of the visual evoked potentials (VEPs), consistent with a postchiasmal lesion, were present in only five out of 13 patients acutely. In only three of these did the abnormality persist at follow-up. We conclude that only large postchiasmal lesions are likely to cause symptomatic homonymous field defects in MS, usually characterized by rapid recovery. Hemifield VEPs have a low sensitivity for the detection of postchiasmal as compared with prechiasmal abnormalities.

Behçet's disease with slowly enlarging midbrain mass on MRI: resolution following steroid therapy.

We describe a case of Behçet's disease with a slowly enlarging midbrain mass on magnetic resonance imaging, which resolved after 4 months of oral steroids.

Heterogeneity of blood-brain barrier changes in multiple sclerosis: an MRI study with gadolinium-DTPA enhancement.

We performed 15 dynamic gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with relapsing and remitting multiple sclerosis; 7 were follow-up studies. We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement. We observed both uniformly enhancing and ring enhancing lesions. The enhancing regions were often less extensive than the corresponding high signal on T2-weighted images. Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1 was seen on unenhanced scans 10 days later, suggesting that blood-brain barrier disturbance may precede other MRI signs of MS lesions. Three months later, some high-signal areas on T2-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the pathogenesis and behavior of MS lesions.

Cerebral lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LG) is an uncommon lymphoproliferative disease characterised by angiocentric and angioinvasive cellular infiltrates. The lung is the usual primary site with secondary central nervous system (CNS) involvement in 20% of cases. Primary cerebral LG is a rare but potentially treatable disease with protean manifestations. Diagnosis is problematical and may be delayed when extracerebral disease is absent or occult. Six cases of cerebral LG are presented, and the clinical features, laboratory investigations, neuroimaging and pathological findings are reviewed.

Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study.

OBJECTIVE: To compare the abnormalities shown by magnetic resonance imaging of the brain in three clinically distinct groups of patients with multiple sclerosis, and to correlate the extent of abnormality with the degree of clinical disability in the three groups. DESIGN: All patients underwent magnetic resonance imaging and full neurological examination, and their disability was scored according to the expanded Kurtzke disability state scale. SETTING: National Hospital for Nervous Diseases (Multiple Sclerosis NMR Research Group). PATIENTS: Three groups of patients with confirmed multiple sclerosis were studied: 12 patients with minimal disability despite a long (greater than 10 years) duration of illness (benign multiple sclerosis), 16 who had developed progressive disability after a relapsing and remitting course (secondary progressive multiple sclerosis), and 13 who had had progressive disability from the onset of the disease (primary progressive multiple sclerosis). MAIN OUTCOME MEASURES: Number and size of lesions in 17 anatomically defined sites; total lesion load, estimated with an arbitrary scoring system weighted for the size of lesions; and disability score. RESULTS: Magnetic resonance imaging showed that all 41 patients had abnormalities. These were extensive in the groups with secondary progressive and benign disease compared with the group with primary progressive disease. The lesions in the patients with secondary progressive disease were larger and more confluent than those in the two other groups (p = 0.007). Most lesions (85%) in the patients with primary progressive disease were under 5 mm in diameter; this percentage was higher than that in the two other groups (p = 0.032). Consequently the patients with primary progressive disease had the lowest mean lesion load (36.7); that in the patients with benign disease was 52.7 and that in the patients with secondary progressive disease 64.6 (p = 0.05). No correlation existed between disability and total lesion load. The distribution of brain lesions and of detectable lesions of the spinal cord, and the frequency of cortical atrophy, were similar in all groups. CONCLUSIONS: No relation was found between the degree of clinical disability and the extent of abnormality shown by magnetic resonance imaging: patients with clinically benign disease often had extensive abnormalities and those with primary progressive disease had surprisingly few lesions. Though magnetic resonance imaging increases knowledge of the disease process in multiple sclerosis and is invaluable in diagnosis, it is not helpful in predicting disability in individual patients.