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Objective: The mechanisms underlying neuropathic tremor remain incompletely understood and a distinction has not been drawn between proximal and distal neuropathies. Lower limb tremor contributes to imbalance in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but this is unexplored in other neuropathies. We characterized upper and lower limb tremor in chronic immune sensory polyradiculopathy (CISP) and distal acquired demyelinating neuropathy with anti-MAG antibodies (DADS-MAG), contrasted to CIDP., Methods: This was a cross-sectional study of 38 patients (CIDP [n = 25], CISP [n = 7], DADS-MAG [n = 6]). Clinical assessment, tremor study recordings, nerve conduction studies, and somatosensory evoked potentials were performed. Balance was measured by force platform., Results: Upper limb tremor was prevalent (CIDP 66%, CISP 70%, DADS-MAG 100%). Peak frequencies followed a gradient along the upper limb, unchanged by weight-loading. Lower limb tremor was also present (CIDP 32%, CISP 29%, DADS-MAG 66%) and associated with imbalance. Nerve conduction parameters correlated with upper limb tremor in DADS-MAG and CISP, and imbalance in CISP., Conclusions: Upper limb tremor is mediated by peripheral and central mechanisms regardless of distal or proximal pathology. Lower limb tremor correlates with peripheral nerve function and contributes to imbalance., Significance: This study contributes to the understanding of neuropathic tremor. Addressing lower limb tremor may be of therapeutic importance for neuropathy-associated imbalance., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP-related tremor is more variable than other tremor disorders., Methods: Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross-sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t-test was used for comparisons between groups., Results: Twenty-four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high-frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F-wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor., Conclusions: Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat-to-beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor., (© 2023 European Academy of Neurology.)

Objectives: We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs)., Methods: Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison., Results: CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI)., Interpretation: Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.

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: Expansion of chronic multiple sclerosis (MS) lesion is associated with slow-burning inflammation at lesion rim. However, the underlying mechanisms leading to expansion are not fully understood., Objective: To investigate the relationship between diffusivity markers of demyelination and axonal loss in perilesional white matter and lesion expansion in relapsing-remitting MS (RRMS)., Methods: T1, FLAIR and diffusion tensor images were acquired from 30 patients. Novel single-streamline technique was used to estimate diffusivity in lesions, perilesional white matter and normal-appearing white matter (NAWM)., Results: Significant association was found between baseline periplaque radial diffusivity (RD) and subsequent lesion expansion. Conversely, periplaque axial diffusivity (AD) did not correlate with lesion growth. Baseline RD (but not AD) in periplaque white matter of expanding lesions was significantly higher compared with non-expanding lesions. Correlation between increase of both RD and AD in the periplaque area during follow-up period and lesion expansion was noticeably stronger for RD. Increase of RD in periplaque area was also much higher compared to AD. There was significant increase of AD and RD in the periplaque area of expanding, but not in non-expanding, lesions., Conclusion: Periplaque demyelination is likely to be an initial step in a process of lesion expansion and, as such, potentially represents a suitable target for remyelinating therapies.

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.)

Introduction/aims: Imbalance is a common feature of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Intravenous immunoglobulin (IVIg) exerts clinical benefit in CIDP, including improving balance, although objective markers of efficacy are lacking. Posturography is an established objective marker of balance; therefore, this study aimed to determine the utility of posturography as an objective marker of treatment efficacy in CIDP., Methods: Posturography was performed on 18 CIDP patients, established on IVIg infusions, and results were compared to age-matched healthy controls. CIDP patients were assessed just prior to IVIg infusion and at the mid-point of the cycle. Center of pressure (CoP) was measured and the total path traveled by CoP (Sway Path, SP) was calculated for five different conditions: feet placed in parallel 16 cm apart at the medial border with eyes open (16cmEO) and eyes closed (16cmEC); medial borders of the feet touching with eyes open (0cmEO) and eyes closed (0cmEC); and tandem stance., Results: The sway path (SP) was significantly increased in CIDP patients (mean SP 1191 ± 104 mm) when compared to healthy controls (mean SP 724 ± 26 mm, P < .001). The increase was most prominent during eyes closed and tandem stance conditions. Treatment with IVIg significantly reduced SP when assessing 0cmEC (1759 ± 324 mm vs. 1081 ± 134 mm, P = .019) and tandem stance (1775 ± 290 mm vs. 1152 ± 113 mm, P = .027)., Discussion: Posturography detected significant improvements in balance following IVIg in CIDP patients established on maintenance therapy. As such, posturography may be considered an objective marker of treatment response in clinical management and therapeutic trials., (© 2021 Wiley Periodicals LLC.)

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.)

Background: Slow-burning inflammation is putatively associated with lesion expansion and leads to progressive loss of axons and disability worsening., Objective: To investigate the incidence and extent of chronic white matter lesion expansion in relapsing-remitting multiple sclerosis (RRMS) patients and to evaluate its relationship with biomarkers of disease progression., Methods: Pre- and post-gadolinium T1, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 33 patients. Lesional activity were analysed between baseline and 48 months using custom-designed software., Results: A total of 569 lesions were identified as chronic at baseline, of which 261 were expanding, 236 were stable and 72 were shrinking. In addition, 139 new lesions (both confluent and free-standing) were observed. Chronic lesion expansion was associated with patient's age and accounted for the bulk (67.3%) of total brain lesion volume increase, while only 32.7% was attributable to new lesion formation. Change in chronic lesion volume correlated with the rate of brain atrophy ( r  = -0.57, p  = 0.001), change of Expanded Disability Status Scale (EDSS; r  = 0.38, p  = 0.03) and an increase of isotropic diffusivity inside the lesions ( r  = 0.75, p  < 0.001)., Conclusion: Expansion of chronic lesions in RRMS patients is the primary determinant of increased T2 total lesion load. It significantly contributes to disease progression and partially driving axonal loss inside the lesions and brain damage outside of lesional tissue.

Purpose: Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing-remitting multiple sclerosis (RRMS) patients. The potential sample size required for a remyelination-based clinical trial using different treatment effect sizes and the mfVEP latency as an outcome measure was also estimated., Methods: A total of 50 RRMS consecutive patients with no previous history of optic neuritis in at least one eye and 15 normal controls of similar age and gender composition were prospectively enrolled. Fifteen patients had a history of unilateral ON more than 12 months earlier, whereas 41 patients demonstrated optic radiations lesions on MRI at baseline. Most patients were on disease modifying therapy. A mfVEP was recorded at baseline and 12 months later., Results: At baseline, the mfVEP latency in RRMS patients was delayed compared with normal controls in both optic neuritis and nonoptic neuritis eyes. Latency delay was significantly correlated to optic radiation lesion volume (R2 = 0.38, P < 0.001). There was no significant latency change in multiple sclerosis patients' eyes or optic neuritis and nonoptic neuritis eyes over the follow-up period with latency remaining remarkably constant. This was despite the fact that 46 of 50 patients were on disease-modifying therapies, implying current treatments do not affect myelination in chronic RRMS cases. Sample size calculations to evaluate an additional or alternative remyelinating agent, based on a 40% treatment effect, revealed that a relatively small sample size (78 patients) would be required to demonstrate efficacy in future trials of remyelination therapies., Conclusions: Given its known sensitivity for latency changes and the stability found in this RRMS population, the mfVEP represents an ideal biomarker to assess the degree of latency recovery that may be achieved by remyelination in multiple sclerosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

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.)

Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals., Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants., Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003)., Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Purpose: To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS)., Design: Cross-sectional study; biochemical study of human retinas., Participants: A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis., Methods: Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Müller glial distribution were analyzed using Western blotting and immunohistochemistry., Main Outcome Measures: Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions., Results: The b-wave amplitude was significantly reduced in patients with AQP4-IgG+ NMOSD in scotopic ERGs (compared with AQP4-IgG- subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Müller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgG+ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction (P = 0.005∼0.01, fixed-effects model). Western blotting demonstrated that Müller cell-specific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Müller glial distribution in the human macula., Conclusions: This study provides in vivo structural and functional evidence of Müller glial dysfunction in eyes of patients with AQP4-IgG+ NMOSD. Topography of retinal structural change is supported by distribution of Müller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in NMOSD., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess differential patterns of axonal loss and demyelination in the optic nerve in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD)., Design: Cross-sectional study., Participants: One hundred ninety-two participants, including 136 MS patients (272 eyes), 19 NMOSD patients (38 eyes), and 37 healthy control participants (74 eyes)., Methods: All participants underwent spectral-domain OCT scans and multifocal visual evoked potential (mfVEP) recordings. High-resolution magnetic resonance imaging (MRI) with the diffusion protocol also was performed in all patients., Main Outcome Measures: Ganglion cell-inner plexiform layer (GCIPL) thickness and mfVEP amplitude and latency at 5 eccentricities; global and temporal retinal nerve fiber layer thickness., Results: In optic neuritis (ON) eyes, the NMOSD patients had more severe GCIPL loss (P < 0.001) and mfVEP amplitude reduction (P < 0.001) compared with MS patients, whereas in contrast, mfVEP latency delay was more evident in MS patients (P < 0.001). The NMOSD patients showed more morphologic and functional loss at the foveal to parafoveal region, whereas the MS patients showed evenly distributed damage at the macula. Correlation analysis demonstrated a strong structure-function (OCT-mfVEP) association in the NMOSD patients, which was only moderate in the MS patients. In non-ON (NON) eyes, the MS patients showed significantly thinner GCIPL than controls (P < 0.001), whereas no GCIPL loss was observed in NON eyes in NMOSD. In addition, a significant correlation was found between all OCT and mfVEP measures in MS patients, but not in NMOSD patients. MRI demonstrated significant lesional load in the optic radiation in MS compared to NMOSD eyes (P = 0.002), which was related to the above OCT and mfVEP changes in NON eyes., Conclusions: Our study demonstrated different patterns of ON damage in NMOSD and MS. In MS, the ON damage was less severe, with demyelination as the main pathologic component, whereas in NMOSD, axonal loss was more severe compared with myelin loss. The disproportional mfVEP amplitude and latency changes suggested predominant axonal damage within the anterior visual pathway as the main clinical feature of NMOSD, in contrast to MS, where demyelination spreads along the entire visual pathway., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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.

Introduction: This study explored potential diagnostic markers of nerve ultrasound in differentiating amyotrophic lateral sclerosis (ALS) from mimic disorders., Methods: Ultrasound of the median, ulnar, and tibial nerves was conducted in 53 patients with ALS, 32 patients with ALS-mimic disorders, and 30 controls. Nerve cross-sectional area (CSA) and distal-proximal ratios were calculated., Results: The median nerve CSA in the upper arm was decreased (7.9 ± 1.3 mm 2 vs. 9.0 ± 1.4 mm 2 , P < 0.05), and the median nerve wrist-upper arm ratio was increased in ALS patients compared with controls (1.3 ± 0.4 vs. 1.1 ± 0.2; P < 0.01). In differentiating ALS from mimic presentations, assessment of median nerve CSA in the upper arm and comparison of a median and ulnar nerve CSA distal-proximal ratio provide diagnostic potential., Discussion: Assessment of nerve CSA combined with calculation of nerve CSA distal-proximal ratio provides a useful marker to aid in the diagnosis of ALS. Muscle Nerve 58:777-783, 2018., (© 2018 Wiley Periodicals, Inc.)

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.

Objective: To improve understanding of disease pathophysiology in anti-myelin-associated glycoprotein (anti-MAG) neuropathy to guide further treatment approaches., Methods: Anti-MAG neuropathy patients underwent clinical assessments, nerve conduction and excitability studies, and ultrasound assessment., Results: Patients demonstrated a distinctive axonal excitability profile characterised by a reduction in superexcitability [MAG: -14.2 ± 1.6% vs healthy controls (HC): -21.8 ± 1.2%; p < 0.01] without alterations in most other excitability parameters. Mathematical modelling of nerve excitability recordings suggested that changes in axonal function could be explained by a 72.5% increase in juxtaparanodal fast potassium channel activation and an accompanying hyperpolarization of resting membrane potential (by 0.3 mV) resulting in a 94.2% reduction in discrepancy between anti-MAG data and the healthy control model. Superexcitability changes correlated strongly with clinical and neurophysiological parameters. Furthermore, structural assessments demonstrated a proximal pattern of nerve enlargement (C6 nerve root cross-sectional area: 15.9 ± 8.1 mm 2 vs HC: 9.1 ± 2.3 mm 2 ; p < 0.05)., Conclusions: The imaging and neurophysiological results support the pathogenicity of anti-MAG IgM. Widening between adjacent loops of paranodal myelin due to antibodies would expand the pathway from the node to the juxtaparanode, increasing activation of juxtaparanodal fast potassium channels, thereby impairing saltatory conduction., Significance: Potassium channel blockers may prove beneficial in restoring conduction closer to its normal state and improving nerve function in anti-MAG neuropathy., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Introduction: Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor., Methods: From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound., Results: Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal., Discussion: A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018., (© 2017 Wiley Periodicals, Inc.)

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: To estimate the degree of axonal loss in patients diagnosed with multifocal motor neuropathy (MMN) using a novel assessment of motor unit numbers and size., Methods: Automated motor unit number estimation using a compound muscle action potential (CMAP) scan was undertaken in median nerves with conduction block. Results were compared with 30 age-matched healthy controls., Results: Compared with healthy controls, MMN patients had fewer motor units (MMN: 33±11vs HC: 93±36 [mean±SD]; p<0.0001) and larger 'size of the largest unit' (MMN: 1.2±0.5mVvs HC: 0.4±0.1mV; p<0.0001), despite having normal distal CMAP amplitudes (MMN: 7.6±1.8mVvs HC: 8.7±2.5mV; p=0.24)., Conclusions: MMN is associated with marked axonal loss which may be masked by striking re-innervation resulting in preservation of distal CMAP amplitudes., Significance: Assessment of motor unit properties should be incorporated into assessment of disease progression in MMN, given that nerve conduction studies are insensitive to motor unit remodelling., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Introduction: Congenital myasthenic syndromes (CMS) usually present neonatally or in early childhood. When they present later, they may be mistaken for seronegative autoimmune myasthenia, and unnecessary immunosuppressive treatment may be administered., Methods: Patients who met criteria for seronegative generalized myasthenia without congenital or early childhood onset, but with an affected sibling were tested for CMS associated genes using exome and Sanger sequencing., Results: Four sibling pairs from nonconsanguineous families were identified. Three had mutations in the RAPSN gene, and 1 had a mutation in CHRNA1. One sibling of a pair with symptoms of fatigue but no convincing features of neuromuscular dysfunction tested negative on genetic studies. The definite CMS cases comprised 7 of 25 seronegative patients with definite generalized myasthenia in the clinic, and over half had been treated for autoimmune myasthenia., Conclusions: CMS is probably underdiagnosed in seronegative myasthenic disorders and should be considered in the differential diagnosis. Muscle Nerve 54: 721-727, 2016., (© 2016 Wiley Periodicals, Inc.)

Background: Ocular neuromyotonia is a rare, but well-recognized, complication of cranial irradiation., Case Report: Using figures and videos, we report a 52-year-old man with extensive ocular, brainstem, and lower cranial nerve neuromyotonia postradiation therapy for a fourth ventricle glioma who, in the context of an apparently positive edrophonium test, was initially misdiagnosed with myasthenia gravis., Conclusions: This is the first case of postirradiation neuromyotonia to be reported with such extensive cranial nerve and brainstem involvement.

Objective: To assess the sensitivity and specificity of the Awaji and revised El Escorial diagnostic criteria (rEEC) in amyotrophic lateral sclerosis (ALS)., Methods: We conducted a large prospective multicenter study, recruiting 416 patients (253 male, 163 female) between January 1, 2012, and August 31, 2015, to compare the diagnostic accuracy of Awaji and rEEC in accordance with standards of reporting of diagnostic accuracy criteria., Results: The sensitivity of the Awaji criteria (57%, 50.0%-63.3%) was higher when compared to rEEC (45%, 38.7%-51.7%, p < 0.001), translating to a 12% gain in sensitivity. The specificity of the both criteria were identical, 99.5%, indicating the number needed to test in order to diagnose one extra case of ALS was 1.8 (1.5-2) for Awaji criteria and 2.4 (2-2.6) for rEEC. The Awaji criteria exhibited a higher sensitivity across subgroups, including bulbar (p < 0.001) and limb-onset (p < 0.001) patients. The inclusion of the possible diagnostic category as a positive finding enhanced sensitivity of the Awaji criteria and rEEC, particularly in early stages of ALS, while maintaining specificity., Conclusion: The present study established a higher sensitivity of Awaji criteria when compared to rEEC, with diagnostic benefits evident in bulbar and limb-onset disease. Inclusion of possible as a positive finding enhanced sensitivity of both criteria, while maintaining specificity, and should be considered in clinical practice and future therapeutic trials., Classification of Evidence: This study provides Class IV evidence that the Awaji criteria have a higher sensitivity and the same specificity as the rEEC in identifying patients with ALS., (© 2016 American Academy of Neurology.)

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.

Cortical hyperexcitability has been identified as an intrinsic feature of amyotrophic lateral sclerosis (ALS). Consequently, the aim of the present study was to determine whether cortical hyperexcitability formed the pathophysiological basis for the flail leg syndrome (FL), an atypical ALS variant. Cortical excitability studies were undertaken on 18 FL patients, using the threshold tracking transcranial magnetic stimulation (TMS) technique, and results were compared to healthy controls, upper and lower limb-onset ALS as well as bulbar-onset and the flail arm variant ALS. Results showed that cortical hyperexcitability was a feature of FL and was heralded by a significant reduction of short-interval intracortical inhibition (FL 7.2 ± 1.8%; controls 13.2 ± 0.8%, p <0.01) and cortical silent period (CSP) duration (FL 181.7 ± 10.8ms; controls 209.8 ± 3.4ms; p <0.05) along with an increase in motor evoked potential amplitude (FL 29.2 ± 5.1%; controls 18.9 ± 1.2%, p <0.05). The degree of cortical hyperexcitability was comparable between FL and other ALS phenotypes, defined by site of disease onset. In addition, the CSP duration correlated with biomarkers of peripheral neurodegeneration in FL. In conclusion, cortical hyperexcitability is a feature of the flail leg syndrome, being comparable to other ALS phenotypes. Importantly, cortical hyperexcitability correlates with neurodegeneration, and as such may contribute to the underlying pathophysiology in FL.

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.

Objective: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes., Methods: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing., Results: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A > G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy., Conclusion: We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects., (© 2015 American Academy of Neurology.)