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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., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: Recent studies suggested that the expansion of long-standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus may be linked to chronic inflammation and microglial activation. We investigated the potential association between plexus volume and subsequent lesion expansion in patients with relapsing-remitting MS., Methods: Pre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients. Choroid plexus (CP) volume (normalised by Total Intracranial Volume, TIV) and lesion activity were analysed between baseline and 48 months. In addition, plexus volume was measured in 40 healthy controls of similar age and gender., Results: Baseline CP/TIV ratio was significantly larger in RRMS patients compared to normal controls (p < 0.001). CP/TIV ratio remained stable in RRMS patients during follow-up period. There was a strong correlation between baseline CP/TIV ratio and subsequent rate of chronic lesion expansion (p < 0.001), which was stronger in close proximity to CSF. A cut-off of 98 × 10 -5 CP/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. CP/TIV ratio larger than a cut-off was associated with >8-fold increased risk of chronic lesion expansion. Baseline CP/TIV ratio was also associated with change in Mean Diffusivity (MD) inside of chronic lesions. Furthermore, baseline CP/TIV ratio significantly correlated with central brain atrophy. There was, however, no correlation between CP/TIV ratio and volume of new lesions., Interpretation: Our data demonstrate that baseline CP/TIV ratio predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage within and outside of chronic lesions., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: To investigate the long-term effect of permanent demyelination on axonal attrition by examining an association between intereye asymmetry of the multifocal visual evoked potential (mfVEP) latency delay and subsequent thinning of retinal ganglion cell axons in patients with a long-standing history of unilateral optic neuritis (ON)., Methods: Only patients with a significant degree of chronic demyelination (intereye latency asymmetry >5 ms) were included in this study. The level of optic nerve demyelination was estimated at baseline by the latency delay of mfVEP, while the degree of axonal loss was assessed by thinning of the retinal nerve fiber layer (RNFL) thickness between baseline and follow-up visits. Low-contrast visual acuity (LCVA) was also evaluated at baseline and follow-up. Patients were examined twice with an average interval of 6.1 ± 1.4 years., Results: From 85 examined patients with multiple sclerosis, 28 satisfied inclusion criteria. Latency of the mfVEP was delayed, and RNFL thickness was reduced in ON eyes compared with fellow eyes at both visits. There was significant correlation between latency asymmetry and baseline or follow-up intereye RNFL thickness asymmetry. Intereye asymmetry of LCVA at baseline correlated with baseline latency asymmetry of mfVEP and baseline asymmetry of RNFL thickness. Latency of the mfVEP in ON eyes improved slightly during the follow-up period, whereas latency of the fellow eye remained stable. By contrast, RNFL thickness significantly declined in both ON and fellow eyes during the follow-up period. The rate of RNFL thinning in ON eyes, however, was more than 2 times faster compared with the fellow eyes ( p < 0.001). Furthermore, baseline latency asymmetry significantly correlated with the rate of RNFL thinning in ON eyes during the follow-up ( p < 0.001), explaining almost half of the variability of temporal RNFL progression. For each millisecond of latency delay (i.e., ∼0.5 mm of demyelination along the optic nerve), temporal RNFL thickness was annually reduced by 0.05%., Discussion: Our study provides clear in vivo evidence that chronic demyelination significantly accelerates axonal loss. However, because this process is slow and its effect is mild, long-term monitoring is required to establish and confidently measure the neurodegenerative consequences of demyelination., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Optic neuritis (ON) occurs in immune-mediated disorders including multiple sclerosis (MS), aquaporin-4 antibody-positive (AQP4) neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination (MOGAD). Accurate determination of aetiology is critical for appropriate treatment and prognostication., Objective: To evaluate demyelination and axonal loss in MOG-ON to facilitate differentiation from MS-ON and AQP4-ON., Methods: 15 MOGAD patients with previous ON (25 eyes) underwent multifocal visual evoked potential (mfVEP) recordings and optical coherence tomography scans. Comparison was made to previously reported MS patients ( n  = 67, 69 eyes) and AQP4-NMOSD patients ( n  = 15, 23 eyes) with prior ON and healthy controls ( n  = 37, 74 eyes)., Results: MOG-ON patients had less retinal nerve fibre layer (RNFL) loss than AQP4-ON patients ( p  < 0.05) and less mfVEP latency prolongation than MS-ON patients ( p  < 0.01). Number of ON episodes in MOGAD was associated with reduced RNFL thickness (global, p  = 0.07; temporal, p  < 0.001) and mfVEP amplitude ( p  < 0.001). There was no abnormality in non-ON eyes., Conclusions: Our study demonstrated a distinct pattern of damage in MOG-ON compared to AQP4-ON and MS-ON. ON in MOGAD produces less axonal loss than AQP4-NMOSD. Damage accumulates with relapses, supporting the role of maintenance immunosuppression to induce remission. Compared to MS, MOGAD causes less demyelination., Competing Interests: Declaration of conflicting interests: Dr Stephanie Barnes has accepted travel compensation from Merck and Sanofi Genzyme, and fellowship funding from Allergan. A/Prof Todd Hardy has served on advisory boards for Merck, Biogen, Roche and Bristol Myers Squibb, received personal compensation for speaking engagements from Biogen, Merck, Novartis, Sanofi Genzyme and Teva. He has received research/grant support from Multiple Sclerosis Research Australia and Novartis. He serves as co-editor of Advances in Clinical Neuroscience and Rehabilitation. A/Prof Stephen Reddel reports grants and personal fees from Sanofi Genzyme, personal fees and departmental support from Biogen, CSL, and Baxter; and departmental support from Novartis, outside the subject of the submitted work. A/Prof Fabienne Brilot has received funding from the National Health and Medical Research Council (Australia), Multiple Sclerosis Research Australia, the University of Sydney Research Excellence Initiative grant (Australia). She has received honoraria from Biogen Idec and Merck Serono as an invited speaker. Dr Sudarshini Ramanathan has received research funding from the National Health and Medical Research Council (Australia), the Petre Foundation (Australia), the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She serves as a consultant on an advisory board for UCB, and has been an invited speaker for Biogen and Excemed. Prof Con Yiannikas serves on advisory boards for Lundbeck and Abbvie., (© The Author(s), 2021.)

Objective: To investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS., Methods: One hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration., Results: The annual rates of RNFL and GCIPL thinning were higher in patients treated with "platform" therapies (interferon-β and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = -0.22 μm/y, p = 0.02 for pRNFL; difference = -0.34 μm/y, p = 0.009 for tRNFL; and difference = -0.16 μm/y, p = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-β, glatiramer acetate, fingolimod, and natalizumab), interferon-β was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab., Conclusions: Progressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-β than other DMTs. This finding may have implications for DMT selection in MS., Classification of Evidence: This study provides Class IV evidence that for patients with MS, treatment with interferon-β compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

We describe a new single-streamline based approach to analyse diffusivity within chronic MS lesions. We used the proposed method to examine diffusivity profiles in 30 patients with relapsing multiple sclerosis and observed a significant increase of both RD and AD within the lesion core (0.38+/-0.09 μm2/ms and 0.30+/-0.12 μm2/ms respectively, p<0.0001 for both) that gradually and symmetrically diminished away from the lesion. T1-hypointensity derived axonal loss correlated highly with ΔAD (r = 0.82, p<0.0001), but moderately with ΔRD (r = 0.60, p<0.0001). Furthermore, the trendline of the ΔAD vs axonal loss intersected both axes at zero indicating close agreement between two measures in assessing the degree of axonal loss. Conversely, the trendline of the ΔRD function demonstrated a high positive value at the zero level of axonal loss, suggesting that even lesions with preserved axonal content exhibit a significant increase of RD. There was also a significant negative correlation between the level of preferential RD increase (ΔRD-ΔAD) in the lesion core and the degree of axonal damage (r = -0.62, p<0.001), indicating that ΔRD dominates in cases with milder axonal loss. Modelling diffusivity changes in the core of chronic MS lesions based on the direct proportionality of ΔAD with axonal loss and the proposed dual nature of ΔRD yielded results that were strikingly similar to the experimental data. Evaluation of lesions in a sizable cohort of MS patients using the proposed method supports the use of ΔAD as a marker of axonal loss; and the notion that demyelination and axonal loss independently contribute to the increase of RD in chronic MS lesions. The work highlights the importance of selecting appropriate patient cohorts for clinical trials of pro-remyelinating and neuroprotective therapeutics., Competing Interests: Study was partially funded by Novartis. This funds was used exclusively for MRI data acquisition. None of the authors were employed or recieved consultancy from commercial entity or participated in patents, products development or marketing. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons., Methods: Progressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve., Results: Although both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination., Conclusions: Although the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS). The purpose of the study was to examine the association between the brain-derived neurotrophic factor (BDNF) Val66Met genotype and structural and functional optic nerve damage in the eyes of NMOSD patients. A total of 17 NMOSD subjects (34 eyes) were included in the study and were divided into subgroups based on optic neuritis (ON) history and BDNF Val66Met polymorphisms. The mean (range) age was 47.8 (23-78) years, and the mean (SD) disease duration was 7.4 (2-39) years. All participants had undergone optical coherence tomography (OCT) scans for global retinal nerve fiber layer (gRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness and multifocal visual evoked potential (mfVEP) test for amplitude and latency. BDNF Val66Met polymorphisms were genotyped in all participants. OCT and mfVEP changes were compared between two genotype groups (Met carriers vs. Val homozygotes) by using the generalised estimating equation (GEE) models. The BDNF Val66Met polymorphism was significantly associated with more severe nerve fiber layer damage and axonal loss in ON eyes of NMOSD subjects. Met carriers had more significantly reduced GCIPL ( P = 0.002) and gRNFL ( P < 0.001) thickness as well as more delayed mfVEP latency ( P = 0.008) in ON eyes. No association was found between Val66Met variants and non-ON (NON)-eye of the participants. These findings suggest that the BDNF Val66Met polymorphism may be associated with optic nerve damage caused by acute ON attacks in NMOSD patients., (Copyright © 2019 Shen, Gupta, Yiannikas, Klistorner, Graham and You.)

Objective: The pathophysiological processes underlying amyotrophic lateral sclerosis (ALS) need to be better understood, although cortical dysfunction has been implicated. Previous transcranial magnetic stimulation (TMS) studies have assessed cortical dysfunction from the hand. The aim of the present study was to determine whether cortical dysfunction was evident across representations of three body regions, and to relate these changes to clinical features of ALS., Methods: In this cross-sectional study, threshold tracking TMS was undertaken in 60 sporadic ALS patients, with motor evoked potential (MEP) responses recorded over the hand (abductor pollicis brevis), lower limb (tibialis anterior), and bulbar (trapezius) regions. The cross-sectional findings were compared to 28 age- and gender-matched controls., Results: Cortical dysfunction was evident across the representation of the three body regions, although the degree and nature of the dysfunction varied. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI), was evident in all cortical regions (hand, P < 0.01; leg, P < 0.05; bulbar, P < 0.05) in ALS patients when compared with healthy control subjects. Importantly, features of cortical hyperexcitability seemed more prominent in clinically affected body regions and correlated with functional disability and muscle weakness. Cortical inexcitability was more prominent in the leg (P < 0.001) and bulbar regions (P < 0.01) when compared with controls., Interpretation: The nature of cortical dysfunction varied across the body regions in ALS, with cortical hyperexcitability being more prominent in the upper limbs while cortical inexcitability was more evident in the lower limbs and bulbar regions. The findings suggest a heterogeneity of cortical pathophysiological processes in ALS., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Objective: To evaluate the combined effect of lesion activity and pathologic processes occurring in both chronically demyelinated lesions and normal-appearing white matter (NAWM) on brain atrophy in MS., Methods: Pre- and post-gadolinium T1, fluid attenuation inversion recovery, and diffusion tensor imaging images were acquired from 50 consecutive patients with relapsing-remitting MS (all, but one, on disease-modifying therapy) at baseline and 5 years. Brain atrophy was measured using structural image evaluation, using normalization of atrophy percent brain volume change (PBVC) analysis., Results: During follow-up, brain volume diminished by 2.0% ± 1.1%. PBVC was not associated with patient age, disease duration, sex, or type of treatment. PBVC moderately correlated with baseline lesion load ( r = -0.38, p = 0.016), but demonstrated strong association with new lesion activity ( r = -0.63, p < 0.001). Brain atrophy was also strongly linked to the increase of water diffusion within chronic MS lesions ( r = -0.62, p < 0.001). In normal-appearing white matter (NAWM), PBVC demonstrated a significant correlation with both baseline and longitudinal increase of demyelination as measured by radial diffusivity (RD, r = -0.44, p = 0.005 and r = -0.35, p = 0.026, respectively). Linear regression analysis explained 62% of the variance in PBVC. It confirmed the major role of new lesion activity ( p = 0.002, standardized beta-coefficient -0.42), whereas change in diffusivity inside chronic lesions and NAWM RD at baseline also contributed significantly ( p = 0.04 and 0.02, standardized beta-coefficient -0.31 and -0.29, respectively), increasing predictive power of the model by 55%., Conclusion: In addition to new lesion activity, progressive loss of demyelinated axons in chronic lesions and the degree of demyelination in NAWM significantly contribute to accelerated loss of brain tissue in patients with MS receiving immunomodulatory therapy., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The spread of neurodegeneration through the human brain network is reported as underlying the progression of neurodegenerative disorders. However, the exact mechanisms remain unknown. The human visual pathway is characterized by its unique hierarchical architecture and, therefore, represents an ideal model to study trans-synaptic degeneration, in contrast to the complexity in neural connectivity of the whole brain. Here we show in two specifically selected patient cohorts, including (i) glaucoma patients with symmetrical bilateral hemifield defects respecting the horizontal meridian (n = 25, 14 females, 64.8 ± 10.1 years; versus 13 normal controls with similar age/sex distributions); and (ii) multiple sclerosis patients without optic radiation lesions (to avoid potential effects of lesions on diffusivity measures) (n = 30, 25 females, 37.9 ± 10.8 years; versus 20 controls), that there are measurable topographic changes in the posterior visual pathways corresponding to the primary optic nerve defects. A significant anisotropic increase of water diffusion was detected in both patient cohorts in the optic radiations, characterized by changes in perpendicular (radial) diffusivity (a measure of myelin integrity) that extended more posteriorly than those observed in parallel (axial) diffusivity (reflecting axonal integrity). In glaucoma, which is not considered a demyelinating disease, the observed increase in radial diffusivity within the optic radiations was validated by topographically linked delay of visual evoked potential latency, a functional measure of demyelination. Radial diffusivity change in the optic radiations was also associated with an asymmetrical reduction in the thickness of the calcarine cortex in glaucoma. In addition, 3 years longitudinal observation of the multiple sclerosis patient cohort revealed an anterograde increase of radial diffusivity in the anterior part of optic radiations which again was retinotopically associated with the primary damage caused by optic neuritis. Finally, in an animal model of optic nerve injury, we observed early glial activation and demyelination in the posterior visual projections, evidenced by the presence of myelin-laden macrophages. This occurred prior to the appearance of amyloid precursor protein accumulation, an indicator of disrupted fast axonal transport. This study demonstrated strong topographical spread of neurodegeneration along recognized neural projections and showed that myelin and glial pathology precedes axonal loss in the process, suggesting that the mechanism of trans-synaptic damage may be at least partially mediated by glial components at the cellular level. The findings may have broad biological and therapeutic implications for other neurodegenerative disorders.

Objective: There is currently an urgent need for reliable clinical biomarkers of remyelination to be used in Phase 2 and Phase 3 clinical trials. Low contrast visual acuity (LCVA) has been suggested as a functional measure of the integrity of the visual pathway. Therefore, the aim of this study was to elucidate the potential contribution of axonal loss and demyelination to LCVA loss in MS patients., Method: In this study, 50 consecutive relapsing remitting MS patients with a previous history of unilateral optic neuritis were enrolled. Using the linear regression model, we assessed the relative contribution of multifocal Visual Evoked Potentials (mfVEP) latency and Retinal Nerve Fiber Layer (RNFL) thickness to LCVA deficit., Results: Intereye asymmetry of mfVEP latency and RNFL thickness correlated significantly with intereye asymmetry of LCVA ( P  < 0.001). A linear regression model demonstrated increased predictive power of LCVA when mfVEP latency and RNFL thinning were combined (reaching R 2  = 0.67) and confirmed a higher predictive value of RNFL thinning compared to mfVEP latency delay for both contrast levels. However, elimination of subjects with severe axonal loss dramatically increased the relative contribution of mfVEP latency, with contribution of RNFL thickness losing significance for both 1.25% and 2.5% LCVA., Interpretation: While retinal ganglion cell axonal loss is a superior predictor of LCVA, the degree of demyelination contributes significantly to worsening of LCVA, particularly when patients with severe axonal loss are excluded. These results support the feasibility of using LCVA as a functional biomarker in remyelination therapy trials, providing appropriate patient's selection criteria are implemented.

Background: Diffusion tensor imaging (DTI) has been suggested as a potential biomarker of disease progression, neurodegeneration and de/remyelination in MS. However, the pathological substrates that underpin alterations in brain diffusivity are not yet fully delineated. We propose that in highly cohesive fiber tracts: 1) a relative increase in parallel (axial) diffusivity (AD) may serve as a measure of increased extra-cellular space (ESC) within the core of chronic MS lesions and, as a result, may provide an estimate of the degree of tissue destruction, and 2) the contribution of the increased extra-cellular water to perpendicular (radial) diffusivity (RD) can be eliminated to provide a more accurate assessment of membranal (myelin) loss., Objective: The purpose of this study was to isolate the contribution of extra-cellular water and demyelination to observed DTI indices in the core of chronic MS lesions, using the OR as an anatomically cohesive tract., Method: Pre- and post-gadolinium (Gd) enhanced T1, T2 and DTI images were acquired from 75 consecutive RRMS patients. In addition, 25 age and gender matched normal controls were imaged using an identical MRI protocol (excluding Gd). The optic radiation (OR) was identified in individual patients using probabilistic tractography. The T2 lesions were segmented and intersected with the OR. Average eigenvalues were calculated within the core of OR lesions mask. The proportion of extra-cellular space (ECS) within the lesional core was calculated based on relative increase of AD, which was then used to normalise the perpendicular eigenvalues to eliminate the effect of the expanded ECS. In addition, modelling was implemented to simulate potential effect of various factors on lesional anisotropy., Results: Of 75 patients, 41 (55%) demonstrated sizable T2 lesion volume within the ORs. All lesional eigenvalues were significantly higher compared to NAWM and controls. There was a strong correlation between AD and RD within the core of OR lesions, which was, however, not seen in OR NAWM of MS patients or normal controls. In addition, lesional anisotropy (FA) was predominantly driven by the perpendicular diffusivity, while in NAWM and in OR of normal controls all eigenvectors contributed to variation in FA. Estimated volume of ECS component constituted significant proportion of OR lesional volume and correlated significantly with lesional T1 hypointensity. While perpendicular diffusivity dropped significantly following normalisation, it still remained higher compared with diffusivity in OR NAWM. The "residual" perpendicular diffusivity also showed a substantial reduction of inter-subject variability. Both observed and modelled diffusion data suggested anisotropic nature of water diffusion in ESC. In addition, the simulation procedure offered a possible explanation for the discrepancy in relationship between eigenvalues and anisotropy in lesional tissue and NAWM., Conclusion: This paper presents a potential technique for more reliably quantifying the effects of neurodegeneration (tissue loss) versus demyelination in OR MS lesions. This may provide a simple and effective way for applying single tract diffusion analysis in MS clinical trials, with particular relevance to pro-remyelinating and neuroprotective therapeutics.

To test the hypothesis that latency delay in the fellow eyes of optic neuritis (ON) patients and to compensate for delayed transmission of visual information, latency change of multi-focal visual evoked potential (mfVEP) traces in fellow eyes of 15 ON patients were analyzed. Patients with low risk (LR) for developing multiple sclerosis (MS) were examined separately from MS patients to isolate effect of cortical plasticity from potential pathological changes in disseminated disease. The small increase in latency in fellow eyes of LR group was statistically not significant. In MS patients, the latency was significantly delayed ( P <0.02). The magnitude of the latency change in the fellow eyes did not correlate with the severity of latency delay in the affected eyes ( R 2 <0.02, P =0.3). The differences between ON patients with and without MS, reported here, suggest that the presence of disseminated disease plays critical role in latency delay of the fellow eye.

Objective: To investigate primary retinal functional changes in non-optic neuritis (ON) eyes of patients with MS by full-field electroretinography (ERG)., Methods: Seventy-seven patients with relapsing-remitting MS with no history of clinical ON in at least 1 eye and 30 healthy controls were recruited in the cohort study. Full-field ERGs were recorded, and retinal optical coherence tomography scans were performed to assess the thicknesses of peripapillary retinal nerve fiber layer (RNFL) and retinal ganglion cell layer-inner plexiform layer (GCL-IPL). Annual MRI scans were also carried out to evaluate the disease activity in the brain. Patients were followed up for 3 years., Results: At baseline, a delayed b-wave peak time was observed in the cone response ( p < 0.001), which was associated with the thicknesses of RNFL and GCL-IPL. The peak time of the delayed b-wave also correlated with the Expanded Disability Status Scale, T2 lesion volume, and disease duration. During the 3-year follow-up, progressive ERG amplitude reduction was observed (both a- and b-waves, p < 0.05). There was a correlation between the b-wave amplitude reduction and longitudinal RNFL loss ( p = 0.001). However, no correlation was found between longitudinal ERG changes and disease activity in the brain., Conclusions: This study demonstrated progressive inner nuclear layer dysfunction in MS. The borderline a-wave changes suggested some outer retinal dysfunction as well. The correlation between full-field ERG changes and retinal ganglion cell loss suggested that there might be subclinical retinal pathology in MS affecting both outer and inner retinal layers.

Objective: Using diffusion tensor imaging (DTI), we examined chronic stable MS lesions, peri-lesional white matter (PLWM) and normal appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (RRMS) for evidence of progressive tissue destruction and evaluated whether diffusivity change is associated with conventional MRI parameters and clinical findings., Method: Pre- and post-gadolinium T1, T2 and DTI images were acquired from 55 consecutive RRMS patients at baseline and 42.3 ± 9.7 months later. Chronic stable T2 lesions of sufficient size were identified in 43 patients (total of 134 lesions). Diffusivity parameters such as axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) were compared at baseline and follow-up. MRI was also performed in 20 normal subjects of similar age and gender., Results: Within the core of chronic MS lesions the diffusion of water molecules significantly increased over the follow-up period, while in NAWM all diffusivity indices remained stable. Since increase of AD and RD in lesional core was highly concordant, indicating isotropic nature of diffusivity change, and considering potential effect of crossing fibers on directionally-selective indices, only MD, a directionally-independent measure, was used for further analysis. The significant increase of MD in the lesion core during the follow-up period (1.29 ± 0.19 μm 2 /ms and 1.34 ± 0.20 μm 2 /ms at baseline and follow-up respectively, P  < 0.0001) was independent of age or disease duration, total brain lesion volume or new lesion activity, lesion size or location and baseline tissue damage (T1 hypointensity). Change of MD in the lesion core, however, was associated with progressive brain atrophy ( r  = 0.47, P  = 0.002). A significant gender difference was also observed: the MD change in male patients was almost twice that of female patients (0.030 ± 0.04 μm 2 /ms and 0.058 ± 0.03 μm 2 /ms in female and male respectively, P  = 0.01). Sub-analysis of lesions with lesion-free surrounding revealed the largest MD increase in the lesion core, while MD progression gradually declined towards PLWM. MD in NAWM remained stable over the follow-up period., Conclusion: The significant increase of isotropic water diffusion in the core of chronic stable MS lesions likely reflects gradual, self-sustained tissue destruction in demyelinated white matter that is more aggressive in males.

Objective: The objective of the study was to profile leukocyte markers modulated during intravenous immunoglobulin (IVIg) treatment, and to identify markers and immune pathways associated with clinical efficacy of IVIg for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with potential for monitoring treatment efficacy., Methods: Response to IVIg treatment in newly diagnosed IVIg-naïve and established IVIg-experienced patients was assessed by changes in expression of inflammatory leukocyte markers by flow cytometry. The adjusted INCAT disability and Medical Research Council sum scores defined clinical response., Results: Intravenous immunoglobulin modulated immunopathogenic pathways associated with inflammatory disease in CIDP. Leukocyte markers of clinical efficacy included reduced CD185 + follicular helper T cells, increased regulatory markers (CD23 and CD72) on B cells, and reduction in the circulating inflammatory CD16 + myeloid dendritic cell (mDC) population and concomitant increase in CD62L and CD195 defining a less inflammatory lymphoid homing mDC phenotype. A decline in inflammatory CD16 + dendritic cells was associated with clinical improvement or stability, and correlated with magnitude of improvement in neurological assessment scores, but did not predict relapse. IVIg also induced a nonspecific improvement in regulatory and reduced inflammatory markers not associated with clinical response., Conclusions: Clinically effective IVIg modulated inflammatory and regulatory pathways associated with ongoing control or resolution of CIDP disease. Some of these markers have potential for monitoring outcome.

Background: Radial Diffusivity (RD) has been suggested as a promising biomarker associated with the level of myelination in MS lesions. However, the level of RD within the lesion is affected not only by loss of myelin sheaths, but also by the degree of tissue destruction. This may lead to exaggeration of diffusivity measures, potentially masking the effect of remyelination., Objective: To test the hypothesis that the T2 hyperintense lesion edge that extends beyond the T1 hypointense lesion core is less affected by tissue loss, and therefore a more appropriate target for imaging biomarker development targeting de- and re-myelination., Method: Pre- and post-gadolinium (Gd) enhanced T1, T2 and DTI images were acquired from 75 consecutive RRMS patients. The optic radiation (OR) was identified in individual patients using a template-based method. T2 lesions were segmented into T1-hypointense and T1-isointense areas and lesion masks intersected with the OR. Average Radial, Axial and Mean diffusivity (RD, AD and MD) and fractional anisotropy (FA) were calculated for lesions of the entire brain and the OR. In addition, Gd enhancing lesions were excluded from the analysis., Results: 86% of chronic T2 lesions demonstrated hypointense areas on T1-weighted images, which typically occupied the central part of each T2 lesion, taking about 40% of lesional volume. The T1-isointense component of the T2 lesion was most commonly seen as a peripheral ring of relatively constant thickness ("T2-rim"). While changes of diffusivity between adjacent normal appearing white matter and the "T2-rim" demonstrated a disproportionally high elevation of RD compare to AD, the increase of water diffusion was largely isointense between the "T2-rim" and T1-hypointense parts of the lesion., Conclusion: Distinct patterns of diffusivity within the central and peripheral components of MS lesions suggest that axonal loss dominates in the T1 hypointense core. The effects of de/remyelination may be more readily detected in the "T2-rim", where there is relative preservation of structural integrity. Identifying and separating those patterns has an important implication for clinical trials of both neuroprotective and, in particular, remyelinating agents.

Purpose: To examine the rate of retinal ganglion cell (RGC) layer and retinal nerve fiber layer (RNFL) changes in nonoptic neuritis (NON) eyes of relapsing remitting multiple sclerosis (RRMS) patients, and to find a specific imaging parameter useful for identifying disease progression., Methods: Forty-five consecutive RRMS patients and 20 age- and sex-matched healthy subjects were enrolled. All patients were followed up for 3 years with annual optical coherence tomography (OCT) scans, which included a peripapillary ring scan protocol for RNFL analysis and a macular radial star-like scan to obtain RGC/inner plexiform layer (IPL) thickness measures. Healthy controls were scanned twice, 3 years apart., Results: Retinal ganglion cell/inner plexiform layer and temporal RNFL (tRNFL) demonstrated highly significant thinning (P < 0.01), but all nasal segments and global RNFL (gRNFL) were not significantly different from normal controls. While receiver operating characteristics (ROC) analysis showed no advantage of RGC/IPL over tRNFL in cross-sectional detection of thinning, cut-off point based of fifth percentile in healthy controls demonstrated higher rate of abnormality for RGC/IPL. There was a significant progressive loss of RGC/IPL and tRNFL during the follow-up period. The largest thickness reduction was observed in tRNFL. ROC analysis demonstrated that tRNFL provided better sensitivity/specificity for detecting change over time than RGC/IPL (area under the curve [AUC] 0.78 vs. 0.52), which was confirmed by higher detection rate when 95th percentile of progression in healthy controls was used as a cut-off., Conclusions: This study confirmed significant thinning of RGC/IPL and tRNFL in NON eyes of RRMS patients. Progressive losses were more apparent on tRNFL, while RGC/IPL showed less change over the follow-up period.

Objective: To evaluate the longitudinal integrity of white matter tracts in patients with relapsing remitting multiple sclerosis (RRMS) as determined by changes in diffusivity indices of lesional and non-lesional white matter in the optic radiation over 12 months., Methods: The optic radiation (OR) was identified in sixty RRMS patients using probabilistic tractography. MS lesions were segmented on FLAIR T2 images and a lesion mask was intersected with the co-registered OR. Lesions within the OR were identified in 39 patients. Voxel-based analysis of axial diffusivity (AD) and radial diffusivity (RD) within OR lesions and non-lesional normal appearing white matter (NAWM) was performed at baseline and 12 months in 34 patients (five patients excluded due to new OR lesions)., Results: Both RD and AD demonstrated much higher values within the lesions compared with non-lesional NAWM. There was a significant (p<0.001) increase of lesional AD and RD during the follow-up period. This increase, however, was driven almost entirely by the male cohort, in which a significantly greater change in both AD (M-2.7%, F-0.9%) and RD (M-4.6%, F-0.7%) was observed during the follow-up period. Non-lesional NAWM also demonstrated an increase in both AD and RD, albeit on a much lesser scale (1.0% and 0.6% respectively). In contradistinction to lesions, the diffusivity change in non-lesional NAWM was similar between sexes., Conclusions: The evolution of AD and RD in chronic MS lesions over 12 months suggests ongoing inflammatory demyelinating activity accompanied by axonal loss. In addition, our findings are consistent with the recently observed trend of more rapid clinical progression in males and establish a potential in vivo biomarker of gender dichotomy by demonstrating a significantly faster rate of microstructural change in the chronic lesions of male patients with MS.

Introduction: Visual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON., Methods: Thirty acute ON patients were studied at 1, 3, 6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further., Results: Both latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p = <0.0001) and 12 months (r = 0.75, p < 0.001). Both measures demonstrated a similar trend of recovery. Speed of latency recovery was faster in the early follow-up period while lesion length shortening remained relatively constant. At 1 month, latency delay was worse by 1.76 ms for additional 1mm of lesion length while at 12 months, 1mm of lesion length accounted for 1.94 ms of latency delay., Conclusion: A strong association between two putative measures of demyelination in early and chronic ON was found. Parallel recovery of both measures could reflect optic nerve remyelination.

Objectives: Diffusion tensor imaging (DTI) has been suggested as a new promising tool in MS that may provide greater pathological specificity than conventional MRI, helping, therefore, to elucidate disease pathogenesis and monitor therapeutic efficacy. However, the pathological substrates that underpin alterations in brain tissue diffusivity are not yet fully delineated. Tract-specific DTI analysis has previously been proposed in an attempt to alleviate this problem. Here, we extended this approach by segmenting a single tract into areas bound by seemingly similar pathological processes, which may better delineate the potential association between DTI metrics and underlying tissue damage., Method: Several compartments were segmented in optic radiation (OR) of 50 relapsing-remitting MS patients including T2 lesions, proximal and distal parts of fibers transected by lesion and fibers with no discernable pathology throughout the entire length of the OR., Results: Asymmetry analysis between lesional and non-lesional fibers demonstrated a marked increase in Radial Diffusivity (RD), which was topographically limited to focal T2 lesions and potentially relates to the lesional myelin loss. A relative elevation of Axial Diffusivity (AD) in the distal part of the lesional fibers was observed in a distribution consistent with Wallerian degeneration, while diffusivity in the proximal portion of transected axons remained normal. A moderate, but significant elevation of RD in OR non-lesional fibers was strongly associated with the global (but not local) T2 lesion burden and is probably related to microscopic demyelination undetected by conventional MRI., Conclusion: This study highlights the utility of the compartmentalization approach in elucidating the pathological substrates of diffusivity and demonstrates the presence of tissue-specific patterns of altered diffusivity in MS, providing further evidence that DTI is a sensitive marker of tissue damage in both lesions and NAWM. Our results suggest that, at least within the OR, parallel and perpendicular diffusivities are affected by tissue restructuring related to distinct pathological processes.

Objective: We examined a cohort of adults with aquaporin-4 (AQP4) antibody-negative neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD) for antibodies to myelin oligodendrocyte glycoprotein (MOG)., Methods: We performed a flow cytometry cell-based assay using live human lentivirus-transduced cells expressing full-length surface MOG. Serum was tested in 23 AQP4 antibody-negative NMO/NMOSD patients with bilateral and/or recurrent optic neuritis (BON, n = 11), longitudinally extensive transverse myelitis (LETM, n = 10), and sequential BON and LETM (n = 2), as well as in patients with multiple sclerosis (MS, n = 76) and controls (n = 52)., Results: MOG antibodies were detected in 9/23 AQP4 antibody-negative patients with NMO/NMOSD, compared to 1/76 patients with MS and 0/52 controls (p < 0.001). MOG antibodies were detected in 8/11 patients with BON, 0/10 patients with LETM, and 1/2 patients with sequential BON and LETM. Six of 9 MOG antibody-positive patients had a relapsing course. MOG antibody-positive patients had prominent optic disc swelling and were more likely to have a rapid response to steroid therapy and relapse on steroid cessation than MOG antibody-negative patients (p = 0.034 and p = 0.029, respectively). While 8/9 MOG antibody-positive patients had good follow-up visual acuity, one experienced sustained visual impairment, 3 had retinal nerve fiber layer thinning, and one had residual spinal disability., Conclusions: MOG antibodies have a strong association with BON and may be a useful clinical biomarker. MOG antibody-associated BON is a relapsing disorder that is frequently steroid responsive and often steroid dependent. Failure to recognize the disorder early and institute immunotherapy promptly may be associated with sustained impairment., Classification of Evidence: This study provides Class II evidence that MOG antibodies are associated with AQP4 antibody-negative BON (sensitivity 69%, 95% confidence interval [CI] 42%-87%; specificity 99%, 95% CI 93.7%-99.8%).

Purpose: Loss of retinal ganglion cells in in non-optic neuritis eyes of Multiple Sclerosis patients (MS-NON) has recently been demonstrated. However, the pathological basis of this loss at present is not clear. Therefore, the aim of the current study was to investigate associations of clinical (high and low contrast visual acuity) and electrophysiological (electroretinogram and multifocal Visual Evoked Potentials) measures of the visual pathway with neuronal and axonal loss of RGC in order to better understand the nature of this loss., Methods: Sixty-two patients with relapsing remitting multiple sclerosis with no previous history of optic neuritis in at least one eye were enrolled. All patients underwent a detailed ophthalmological examination in addition to low contrast visual acuity, Optical Coherence Tomography, full field electroretinogram (ERG) and multifocal visual evoked potentials (mfVEP)., Results: There was significant reduction of ganglion cell layer thickness, and total and temporal retinal nerve fibre layer (RNFL) thickness (p<0.0001, 0.002 and 0.0002 respectively). Multifocal VEP also demonstrated significant amplitude reduction and latency delay (p<0.0001 for both). Ganglion cell layer thickness, total and temporal RNFL thickness inversely correlated with mfVEP latency (r = -0.48, p<0.0001 respectively; r = -0.53, p<0.0001 and r = -0.59, p<0.0001 respectively). Ganglion cell layer thickness, total and temporal RNFL thickness also inversely correlated with the photopic b-wave latency (r = -0.35, p = 0.01; r = -0.33, p = 0.025; r = -0.36, p = 0.008 respectively). Multivariate linear regression model demonstrated that while both factors were significantly associated with RGC axonal and neuronal loss, the estimated predictive power of the posterior visual pathway damage was considerably larger compare to retinal dysfunction., Conclusion: The results of our study demonstrated significant association of RGC axonal and neuronal loss in NON-eyes of MS patients with both retinal dysfunction and post-chiasmal damage of the visual pathway.

Purpose: The aim of the study was to test the hypothesis that latency delay of multifocal visual evoked potentials (mfVEP) in nonoptic neuritis (NON) eyes of multiple sclerosis (MS) patients is related to retrochiasmal demyelinating lesions., Methods: A total of 57 MS patients with no history of optic neuritis at least in one eye, and 25 age- and sex-matched healthy controls was enrolled. Probabilistic tractography was used to reconstruct optic radiation (OR) fibers. The MS lesion volume within and outside of OR was calculated. Diffusion tensor imaging (DTI) indices were measured along OR fibers. The relationship of the mfVEP latency with OR lesions and DTI indices was examined., Results: Average mfVEP latency in the MS cohort was significantly delayed compared to controls (P < 0.0001). Of the patients, 77% demonstrated OR lesions. Axial, radial, and mean diffusivity were significantly abnormal in MS patients (P < 0.001). Partial correlation demonstrated significant association between mfVEP latency delay and OR lesion load. There was also significant correlation between MfVEP latency and OR DTI. Subgroup analysis revealed significantly higher correlations in patients without a history of ON in either eye compared to the fellow eye of patients with previous ON., Conclusions: The findings of this study support our hypothesis that latency delay of the mfVEP in eyes of MS patients without previous ON is related to retrogenicular demyelinating lesions. Additionally, this study demonstrated that a previous episode of ON in the fellow eye may be a significant confounding factor, masking the relationship between the latency and OR lesions., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Aim: To examine the relationship between retinal ganglion cell loss and changes in the inner nuclear layer (INL) in optic neuritis (ON)., Methods: 36 multiple sclerosis (MS) patients with a history of ON and 36 age and sex-matched controls underwent Optical Coherence Tomography. The paramacular retinal nerve fiber layer (RNFL), combined ganglion cell and inner plexiform layers (GCL/IPL) and inner nuclear layer (INL) thickness were measured at 36 points around the fovea. To remove inter-subject variability, the difference in thickness of each layer between the ON and fellow eye of each patient was calculated. A topographic analysis was conducted., Results: The INL of the ON patients was thicker than the controls (42.9µm versus 39.6µm, p=0.002). ON patients also had a thinner RNFL (27.8µm versus 32.2µm, p<0.001) and GCL/IPL (69.3µm versus 98.1µm, p<0.001). Among the controls, there was no correlation between RNFL and GCL/IPL as well as RNFL and INL, but a positive correlation was seen between GCL/IPL and INL (r=0.65, p<0.001). In the ON group, there was a positive correlation between RNFL and GCL/IPL (r=0.80, p<0.001) but a negative correlation between RNFL and INL (r=-0.61, p<0.001) as well as GCL/IPL and INL (r=-0.44, p=0.007). The negative correlation between GCL/IPL and INL strengthened in the ON group when inter-subject variability was removed (r=-0.75, p<0.001). Microcysts within the INL were present in 5 ON patients, mainly in the superior and infero-nasal paramacular regions. While patients with microcysts lay at the far end of the correlation curve between GCL/IPL and INL (i.e. larger INL and smaller GCL/IPL compared to other patients), their exclusion did not affect the correlation (r= -0.76, p<0.001)., Conclusions: INL enlargement in MS-related ON is associated with the severity of GCL loss. This is a continuous relationship and patients with INL microcysts may represent the extreme end of the scale.

Purpose: Recently demonstrated neuronal loss in the inner nuclear layer of the retina in multiple sclerosis (MS) and glaucoma raises the question of a primary (possibly immune-mediated) or secondary (transsynaptic) mechanism of retinal damage in these diseases. In the present study we used optical coherence tomography to investigate retrograde retinal transsynaptic degeneration in patients with long-standing and severe loss of ganglion cells due to optic neuropathy., Methods: Fifteen eyes of glaucoma patients with visual field defect limited to upper hemifield and 15 eyes of MS patients with previous episode of optic neuritis (ON) and extensive loss of ganglion cells were imaged using spectral-domain optical coherence tomography and compared with two groups of age-matched controls. Combined retinal ganglion cell layer/inner plexiform layer (GCL/IPL) thickness and inner nuclear layer (INL) thickness were analyzed., Results: In the glaucoma group there was a significant (P = 0.0005) reduction of GCL/IPL thickness in the lower (affected) retina compared with normal controls; however INL thickness was not statistically reduced (P = 0.49). In the MS group reduction of GCL/IPL thickness in both hemifields of ON eyes was also significant (P = 0.0001 and P < 0.0001 for inferior and superior retina respectively). However, similar to the glaucomatous eyes, there was no significant reduction of INL thickness in both hemifields (P = 0.25 and P = 0.45)., Conclusions: This study demonstrates no significant loss of INL thickness in parts of the retina with long-standing and severe loss of retinal ganglion cells.

Objective: To determine clinically related characteristics in patients with pure lower motor neuron (LMN) syndromes, not fulfilling accepted diagnostic criteria, who were likely to respond to intravenous immunoglobulin (IVIg) treatment., Methods: Demographic, clinical, laboratory and neurophysiological characteristics were prospectively collected from patients with undifferentiated isolated LMN syndromes who were then treated with IVIg. Patients were classified as either responders or non-responders to therapy with IVIg based on clinical data and the two groups were compared., Results: From a total cohort of 42 patients (30 males, 12 females, aged 18-83 years), 31 patients responded to IVIg and 11 did not. Compared to patients that developed progressive neurological decline, responders were typically younger (45.8 compared to 56.0 years, P<0.05) and had upper limb (83.9% compared to 63.6%, NS), unilateral (80.6% compared to 45.5%, P<0.05), and isolated distal (54.1% compared to 9.1%, P<0.05) weakness. Patients with predominantly upper limb, asymmetrical, and distal weakness were more likely to respond to IVIg therapy. Of the patients who responded to treatment, only 12.9% had detectable GM(1) antibodies and conduction block (not fulfilling diagnostic criteria) was only identified in 22.6%., Conclusions: More than 70% of patients with pure LMN syndromes from the present series responded to treatment with IVIg therapy, despite a low prevalence of detectable GM(1) antibodies and conduction block. Patients with isolated LMN presentations, not fulfilling accepted diagnostic criteria, may respond to IVIg therapy, irrespective of the presence of conduction block or GM(1) antibodies, and should be given an empirical trial of IVIg to determine treatment responsiveness.

Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 +/- 1.9%; amyotrophic lateral sclerosis 2.6 +/- 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 +/- 3.1%; amyotrophic lateral sclerosis 38.1 +/- 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia -0.9 +/- 1.3%; amyotrophic lateral sclerosis -2.3 +/- 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 +/- 1.6%; amyotrophic lateral sclerosis 57.2 +/- 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 +/- 6.9 ms; amyotrophic lateral sclerosis 181.1 +/- 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity in acquired neuromyotonia, arguing against a contribution of central processes to the development of nerve hyperexcitability in acquired neuromyotonia.

Purpose: Acute optic neuritis (ON) is often followed by recovery of visual function. Although this recovery is mainly attributable to resolution of the acute inflammation, the redistribution of ion channels along the demyelinated membrane, and subsequent remyelination, part of it may be the result of neural plasticity. In the present study, the interrelationship was examined between structural (retinal nerve fiber layer [RNFL] thickness) and functional (amplitude of multifocal visual evoked potentials [mfVEPs]) measures of the integrity of the visual pathway in the postacute stage of ON, to determine whether there was any evidence of ongoing neural reorganization., Methods: Twenty-five subjects with acute unilateral ON underwent serial RNFL thickness measurement and mfVEP recording. The inter-eye asymmetry of both measures was analyzed. In the period between 6 and 12 months, the subjects were considered free of optic disc edema, and that period was used to analyze the structure-function relationship. Twenty control subjects were also examined., Results: There were significant but opposite changes in RNFL thickness and mfVEP amplitude. The average asymmetry of RNFL thickness between affected and fellow eyes increased from 17.5 +/- 11.5 to 21.1 +/- 12.8 microm (P = 0.0003), indicating progressive axonal loss, whereas mfVEP amplitude asymmetry decreased from 46.6 +/- 32.4 to 38.3 +/- 31.1 nV (P = 0.0015), indicating continuous functional recovery. In comparison to the 6-month results, the mfVEP amplitude in the ON eye improved by 17.8%, whereas RNFL thickness decreased by 20.8%. The result remained unchanged regardless of the degree of optic nerve remyelination., Conclusions: The finding of structural-functional discrepancy at the postinflammatory stage may support the concept that neural plasticity contributes to functional recovery after acute ON.

The clinical and neurophysiological findings in six Australian children with generalized tick paralysis are described. Paralysis is usually caused by the mature female of the species Ixodes holocyclus. It most frequently occurs in the spring and summer months but can be seen at any time of year. Children aged 1-5 years are most commonly affected. The tick is usually found in the scalp, often behind the ear. The typical presentation is a prodrome followed by the development of an unsteady gait, and then ascending, symmetrical, flaccid paralysis. Early cranial nerve involvement is a feature, particularly the presence of both internal and external ophthalmoplegia. In contrast to the experience with North American ticks, worsening of paralysis in the 24-48 h following tick removal is common and the child must be carefully observed over this period. Death from respiratory failure was relatively common in the first half of the century and tick paralysis remains a potentially fatal condition. Respiratory support may be required for > 1 week but full recovery occurs. This is slow with several weeks passing before the child can walk unaided. Anti-toxin has a role in the treatment of seriously ill children but there is a high incidence of acute allergy and serum sickness. Neurophysiological studies reveal low-amplitude compound muscle action potentials with normal motor conduction velocities, normal sensory studies and normal response to repetitive stimulation. The biochemical structure of the toxin of I. holocyclus has not been fully characterized but there are many clinical, neurophysiological and experimental similarities to botulinum toxin.