The World Federation of Neurology and the challenges in Environment Neurology.

Since its establishment the World Federation of Neurology (WFN) has manifested a keen interest in the environment and its relation to neurological diseases. Thus, in 2007 the WFN renamed the "Neurotoxicological Research Group" to "Environmental Neurology Research Group". In this short article, we review some recent events which illustrate the WFN involvement in Environmental Neurology as well its concerns about global health matters involving environmental issues.

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.

Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme.

Background: Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. Objective: To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Methods: Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Results: Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47-59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5-3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3-3.7]). Conclusions: Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support.

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.

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.

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. METHODS: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. RESULTS: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. CONCLUSION: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5-6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

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.

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS.

BACKGROUND: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. OBJECTIVE: The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. METHODS: Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. RESULTS: CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. CONCLUSION: This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients.

An investigation into the effect of surface roughness of stainless steel on human umbilical vein endothelial cell gene expression.

The surface properties of vascular devices dictate the initial postimplantation reactions that occur and thus the efficacy of the implantation procedure. Over the last number of years, a number of different stent designs have emerged and stents are generally polished to a mirror finish during the manufacturing procedure. This study sought to investigate the effect of stainless steel surface roughness on endothelial cell gene expression using an appropriate cell culture in vitro assay system. Stainless steel discs were roughened by shot blasting or polished by mechanical polishing. The surface roughness of the treated and untreated discs was determined by atomic force microscopy (AFM). Cells were seeded on collagen type 1 gels and left to attach for 24 h. Stainless steel discs of varying roughness were then placed in contact with the cells and incubated for 24 h. RNA extractions and quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was then performed to determine the expression levels of candidate genes in the treated cells compared to suitable control cells. E-selectin and vascular cellular adhesion molecule (VCAM-1) were found to be significantly up-regulated in cells incubated with polished and roughened samples, indicating endothelial cell activation and inflammation. This study indicates that the surface roughness of stainless steel is an important surface property in the development of vascular stents.

Global gene expression analysis of the effects of vinblastine on endothelial cells, when eluted from a thermo-responsive polymer.

In-stent restenosis remains a significant problem associated with bare metal stents. This drawback has prompted research into improving stent design and the development of novel coatings, including drug-eluting stents. A number of drug-eluting stents are currently on the market; however, the success rate of these stents in complex situations has been found to be quite low. Thus, there remains potential for the development of more suitable drug-eluting stents. The aims of this study were to use a thermoresponsive polymer to develop a system to locally deliver vinblastine, an antimitotic agent currently used as an anticancer drug, and in addition, assess the effects of this drug at the gene expression level in vitro. An N-isopropylacrylamide/N-tert-butylacrylamide (NiPAAm/NtBAAm) copolymer solution in the ratio 65:35 was prepared and appropriate volumes of vinblastine were added to generate two final drug concentrations of 22 nanomoles/film or 0.022 nanomoles/film. Stainless steel discs (316) were coated with the copolymer solution or this solution containing drug. Human endothelial cells were cultured on collagen type 1 gels and then incubated with the coated discs for 24 h. Gene expression studies using oligonucleotide microarray analysis and quantitative RT-PCR were then performed. Microarray analysis revealed that vinblastine causes the differential expression of a range of genes involved in a variety of different functions, including cell cycle and apoptosis. The changes in expression of some of these genes culminate in cell cycle arrest and apoptotic pathways.

'Locked-in coma' in postinfective polyneuropathy.

A patient with postinfective cranial and peripheral polyneuropathy exhibited the electroencephalographic and behavioral features of "alpha coma". The relation of this form of extensive peripheral disconnection to those cases with central disconnection due to pontomesencephalic lesions is discussed. We conclude that in both situations further evaluation of brain stem and cortical function is necessary to determine whether or not consciousness is preserved, rather than relying solely on the presence of ocular movements and reactivity of the electroencephalogram.

Optic neuropathy and ophthalmoplegia in herpes zoster oticus.

A 55-year-old man with herpes zoster oticus and minimal cutaneous involvement developed reversible optic neuropathy, and ocular motor and cerebellar abnormalities. Serologic changes confirmed infection with herpes zoster. A demyelinating process seems likely to have been responsible for these lesions. It is suggested that herpes zoster antibody titers should be measured whenever the syndrome of polyneuritis cranialis of acute onset is being investigated.

Passivation of nitinol wire for vascular implants--a demonstration of the benefits.

This study investigated a passivation process for polished nitinol wires and vascular stent components, after being given a typical shape setting heat treatment. Heat treated samples were passivated in a nitric acid solution and a series of corrosion tests, surface analysis and chemical analysis was performed. Potentiodynamic polarization tests demonstrated a significant increase in breakdown potential for passivated samples, compared to heat treated surfaces. Surface analysis indicated that the passivation reduces Ni and NiO content in the oxide and increases TiO2 content. Chemical analysis of passivation solutions suggests that the improvement in corrosion resistance is proportional to the quantity of nickel removed. Long term immersion tests demonstrate that nickel release from the surface of the material decreases with time and the quantity of nickel released is lower for passivated samples. The improved corrosion resistance is maintained after extended periods of immersion in saline solution.

Reactive glial cells in CNS demyelination contain both GC and GFAP.

The glial cell response to anti-galactocerebroside (GC) induced demyelination of the cat optic nerve was studied using electron microscopy and immunocytochemistry. Oligodendrocytes, which are a primary target for anti-GC, were depleted in the early lesions but astrocytes survived and showed reactive changes. Astrocytic processes exhibited dual staining for both GC and glialfibrillary acidic protein, a feature not seen in astrocytes outside the lesion or in normal optic nerve. These reactive astrocytes did not stain for anti-myelin basic protein, nor did they contain myelin debris, making it unlikely that the GC immunoreactivity was due to phagocytosis of myelin. Rather, it is postulated that the presence of GC in these cells represents a process of dedifferentiation to a more primitive state in which both astrocytic and oligodendrocytic determinants are synthesised, and that these reactive glial cells may be precursors of a new population of remyelinating oligodendrocytes.

Saccade onset and offset lambda waves: relation to pattern movement visually evoked potentials.

The lambda (lambda) wave is an occipital EEG potential which occurs when saccadic eye movements are made against an illuminated contrast background. There is some disagreement concerning the presence of sub-components to the lambda-wave, and its relationship to visually evoked potentials. In the present study, lambda-waves were recorded with saccades of different durations (30-110 ms) and compared to VEPs associated with pattern movements of similar durations and velocity. It was found that the lambda-wave consisted of a saccade onset component with positive sub-components at 59 and 100 ms after saccade onset, and a saccade offset component with a positive potential at 74 ms after saccade offset. With small saccades of 30 ms duration or less, these components superimposed to form a single lambda-wave. In the case of pattern movement VEPs, a movement onset component of latency 110 ms following movement onset, and a movement offset component at 89 ms after movement offset, were identified. The similar behaviour of the lambda-wave and VEP under these conditions supports the view that the lambda-wave is a visually evoked potential resulting from movement of the visual field across the retina during a saccadic eye movement.

Galactocerebroside antiserum causes demyelination of cat optic nerve.

A model of immune-mediated optic nerve demyelination is described. Micro-injection of small volumes (less than 5 microliter) of high titer polyclonal anti-Gal-C serum into the cat optic nerve resulted in a focal, highly selective demyelinative lesion followed by remyelination. Demyelination appears to be due to a dual effect on myelin and on oligodendrocytes. The numbers of these cells within the lesion were initially reduced but subsequently increased as remyelination occurred.

Experimental demyelinating optic neuropathy induced by intra-neural injection of galactocerebroside antiserum.

The morphological changes induced by microinjection of galactocerebroside (Gal-C) antiserum into the rat optic nerve are described. Light and electron microscopic observations were made 2-20 days post-injection. The severity and extent of the lesion varied according to the volume of antiserum injected and the depth of penetration into the nerve. With small volumes of antiserum (1-3 microliters), primary demyelination was the principal change found from 2 days onwards and by 10 days there was evidence of remyelination by oligodendroglia. Some fibres undergoing Wallerian-type degeneration were also found. The injection of larger volumes of antiserum (5-10 microliters) produced a more extensive lesion with marked axonal degeneration in addition to demyelination at the periphery of the lesion. These findings show that Gal-C antiserum can cause demyelination of central nerve fibres when the blood-brain barrier is bypassed.

Visual evoked potential abnormalities in Charcot-Marie-Tooth disease and comparison with Friedreich's ataxia.

Pattern-reversal visual evoked potentials (VEPs), recorded in 15 visually asymptomatic patients fulfilling the clinical and electrophysiological criteria of Charcot-Marie-Tooth disease (CMTD), were abnormal in 5 and possibly abnormal in another 3. Five patients showed a prolongation of P100 latency, one a reduction of amplitude and one a possibly abnormal "scotomatous" waveform. In 9 cases abnormalities were detected on neuro-ophthalmological examination. These were poorly correlated with VEP abnormalities, except for patients with 2 or more clinical eye signs. Relative central scotomata were found in the patient with an abnormal waveform. VEP abnormalities, where present, were usually fairly comparable in the 2 eyes. In comparison with a group of Friedrich's ataxia cases there was a lower overall incidence of VEP abnormalities in CMTD, but little to suggest a qualitative difference in the nature of the visual pathway pathology. All 4 patients with unequivocally abnormal VEPs had experienced atypical symptoms suggestive of CNS involvement. In none of these was it possible to sustain an alternative diagnosis. It is concluded that a minor degree of visual pathway involvement may be present in many CMTD cases, in spite of the fact that optic atrophy is only rarely reported, and that the VEP latency may reflect the degree to which other parts of the CNS are involved.

Peripheral and central sensory nerve conduction in Charcot-Marie-Tooth disease and comparison with Friedreich's ataxia.

Somatosensory evoked potentials were recorded in response to stimulation of the median nerve at the wrist and the elbow in 14 cases of Charcot-Marie-Tooth disease (CMTD). Cervical and cortical latencies were used to derive conduction times and velocities over peripheral and central segments of the pathway. Sensory conduction velocities between the wrist and the elbow were distributed bimodally (12-27 m/s and 36-70 m/s), but did not correspond with the bimodality of motor conduction velocity values in 4 cases. Three patients had severely slowed sensory conduction in one arm but only moderate slowing in the other. In the majority of cases sensory conduction was considerably faster from the elbow to the spinal cord than from the wrist to the elbow. This was most apparent in 2 young patients, suggesting that demyelination secondary to axonal degeneration may gradually progress from distal to proximal segments. Compared with a group of Friedreich's ataxia (FA) patients, almost all CMTD cases could be distinguished by a greater degree of peripheral conduction slowing (not significant in FA). In FA there was a much higher incidence of impaired conduction over central segments of the somatosensory pathway, although evidence of this was also seen in 5 CMTD cases. Three of the latter had presented with atypical symptoms suggestive of CNS involvement, and also had delayed visual evoked potentials.

Pattern evoked potentials in human albinism. Evidence of two different topographical asymmetries reflecting abnormal retino-cortical projections.

In fifteen subjects with oculo-cutaneous or ocular albinism pattern-reversal visual evoked potentials (VEP) were recorded to monocular whole-field (16 degrees radius) and right and left vertical half-field (16 degrees radius) stimulation from an array of occipital electrodes. In all 15 subjects the VEP was of low amplitude and the monocular response to whole-field stimulation showed abnormal asymmetry in scalp topography. This asymmetry was similar to that produced by stimulation of the temporal half-field in the same eye. Two distinct types of VEP asymmetry were readily identified in different subjects. In 5 the major positivity of the response (P100) was distributed in the channels ipsilateral to the stimulated eye or temporal half-field, being similar in distribution to the P100 from the temporal hemifield or normal individuals. In 9 other subjects the converse occurred; the P100 was distributed contralaterally. The remaining subject was unique in that the responses from each eye had a distribution that resembled one of the two main groups. The nasal half-field responses also differentiated the two groups. On stimulation of the nasal field in the first group the P100 was usually absent or attenuated and when present it had the same topography as the temporal half-field P100. In contrast the nasal half-field P100 from the second group was always present and, although almost invariably smaller than the temporal half-field P100, it had an identical distribution. There was no correlation between these two patterns of VEP asymmetry and clinical or known genetic features. The findings confirm that in human albinos each hemisphere receives a predominantly monocular input from the contralateral eye; i.e. in addition to the temporal, half-field, approximately 20 degrees of the nasal half-field is projected to the hemisphere contralateral to each eye and not, as in normal subjects, to the ipsilateral hemisphere. Furthermore, the findings of two distinct and in some respects opposite types of VEP topographical asymmetry raises the possibility of two variants of the geniculo-cortical projection patterns existing in human albinos similar to those described in the Siamese cat.