Examining the relative contribution of slow-burning inflammation and chronic demyelination to axonal damage in chronic multiple sclerosis lesions.

BACKGROUND AND OBJECTIVES: Slow-burning inflammation at the edge, and chronic demyelination at the core, of established multiple sclerosis (MS) lesions are potential mediators of disease progression. However, their relative contribution to progressive axonal damage has not been explored. Therefore, in this study, we investigated the comparative contribution of slow-burning inflammation and chronic demyelination to axonal attrition within MS lesions by measuring progressive tissue rarefaction. In addition, we use the visual system as a model to investigate the effect of chronic demyelination on the acceleration of axonal death in a sub-group of patients with unilateral optic neuritis. METHODS: Pre- and post-gadolinium 3D-T1, 3D FLAIR, diffusion tensor images, Optical Coherence tomography and multifocal visual evoked potentials were acquired from 52 relapsing-remitting MS patients who completed at least 5 years follow-up. Lesion expansion was measured using custom software, and the rate of tissue rarefication inside lesion core was assessed by measuring increase of normalized mean diffusivity (nMD). Axonal loss was also examined in eyes with severe optic nerve demyelination. RESULTS: Among the 361 lesions analyzed, 104 were expanding (a minimum of 4 % expansion per year) and 257 were stable. Expanding lesions showed a significantly higher rate of progressive tissue rarefication inside lesion (1.12 % per year) core compared to stable lesions (0.21 % per year, p = 0.01). The magnitude of nMD change was significantly correlated with the rate of lesion expansion (r = 0.4, p < 0.001). Analysis of retinal ganglion cells in eyes with severe optic nerve demyelination (Inter-eye latency delay of >10 ms) revealed a similar rate of axonal loss (0.19 %) to the degree of tissue rarefaction observed in stable lesions (0.21 %). DISCUSSION: The results of the study suggest that the slow-burning inflammation at the lesion's edge (as measured by lesion expansion), is likely to have a greater impact on tissue damage (as measured by nMD change), when compared to stable chronically demyelinated lesions. The similar modest degree of tissue damage was also observed in chronically demyelinated fibers of the optic nerve.

The clinical relevance of MOG antibody testing in cerebrospinal fluid.

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.

Quantifying chronic lesion expansion in multiple sclerosis: Exploring imaging markers for longitudinal assessment.

OBJECTIVES: Gradual expansion of multiple sclerosis lesions over time is known to have a significant impact on disease progression. However, accurately quantifying the volume changes in chronic lesions presents challenges due to their slow rate of progression and the need for longitudinal segmentation. Our study addresses this by estimating the expansion of chronic lesions using data collected over a 1-2 year period and exploring imaging markers that do not require longitudinal lesion segmentation. METHODS: Pre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 42 patients with MS. Lesion expansion, stratified by the severity of tissue damage as measured by mean diffusivity change, was analysed between baseline and 48 months (Progressive Volume/Severity Index, PVSI). Central brain atrophy (CBA) and the degree of tissue loss inside chronic lesions (measured by the change of T1 intensity and mean diffusivity (MD)) were used as surrogate markers. RESULTS: CBA measured after 2 years of follow-up estimated lesion expansion at 4 years with a high degree of accuracy (r = 0.82, p < 0.001, ROC area under the curve 0.92, sensitivity of 94 %, specificity of 85 %). Increased MD within chronic lesions measured over 2 years was strongly associated with future expansion (r = 0.77, p < 0.001, ROC area under the curve 0.87, sensitivity of 81 % and specificity of 81 %). In contrast, change in lesion T1 hypointensity poorly explained future PVSI (best sensitivity and specificity 60 % and 59 % respectively). INTERPRETATION: CBA and, to a lesser extent, the change in MD within chronic MS lesions, measured over a period of 2 years, can provide a reliable and sensitive estimate of the extent and severity of chronic lesion expansion.

Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients.

BACKGROUND AND OBJECTIVE: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments. METHODS: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up. RESULTS: The volume of CP significantly increased by 1.4% annually. However, the extent of CP enlargement varied considerably among individuals (ranging from -3.6 to 150.8 mm3 or -0.2% to 6.3%). The magnitude of CP enlargement significantly correlated with central (r = 0.70, p < 0.001) and total brain atrophy (r = -0.57, p < 0.001), white (r = -0.61, p < 0.001) and deep grey matter atrophy (r = -0.60, p < 0.001). Progressive CP enlargement was significantly associated with the volume and extent of chronic lesion expansion (r = 0.60, p < 0.001), but not with the number or volume of new lesions. CONCLUSION: This study provides evidence of progressive CP enlargement in patients with RRMS. Our findings also demonstrate that enlargement of the CP volume is linked to the expansion of chronic lesions and neurodegeneration of periventricular white and grey matter in RRMS patients.

Upper and lower limb tremor in inflammatory neuropathies.

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.

Upper and lower limb tremor in Charcot-Marie-Tooth neuropathy type 1A and the implications for standing balance.

BACKGROUND: Neuropathic tremor occurs in Charcot-Marie-Tooth neuropathy type 1A (CMT1A; hereditary motor and sensory neuropathy, HMSN), although the pathophysiological mechanisms remain to be elucidated. Separately, lower limb tremor has not been explored in CMT1A and could be associated with imbalance as in other neuropathies. The present study aimed to determine tremor characteristics in the upper and lower limbs in CMT1A and relate these findings to clinical disability, particularly imbalance. METHODS: Tremor and posturography studies were undertaken in phenotyped and genotyped CMT1A patients. Participants underwent detailed clinical assessment, tremor study recordings, and nerve conduction studies. Tremor stability index was calculated for upper limb tremor and compared to essential tremor. RESULTS: Seventeen patients were enrolled. Postural and kinetic upper limb tremors were evident in 65%, while postural and orthostatic lower limb tremors were seen in 35% of CMT1A patients. Peak upper limb frequencies were lower distally (~ 6 Hz) and higher proximally (~ 9 Hz), were unchanged by weight-loading, and not impacted by fatigue. The tremor stability index was significantly higher in CMT1A than in essential tremor. A 5-6 Hz lower limb tremor was recorded which did not vary along the limb and was unaffected by fatigue. Balance was impaired in patients with postural lower limb tremor. A high frequency peak on posturography was associated with 'good' balance. CONCLUSIONS: Tremor is a common clinical feature in CMT1A, distinct from essential tremor, mediated by a complex interaction between peripheral and central mechanisms. Postural lower limb tremor is associated with imbalance; strategies aimed at tremor modulation could be of therapeutic utility.

Imbalance and lower limb tremor in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND AIMS: Imbalance is a prominent symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although upper limb tremor in CIDP is described, lower limb tremor has not been assessed. The aim of this study was to determine whether lower limb tremor was present in CIDP and assess potential relationships with imbalance. METHODS: This was a cross-sectional observational study of prospectively recruited consecutive patients with typical CIDP (N = 25). Clinical phenotyping, lower limb nerve conduction and tremor studies, and posturography analyses were performed. The Berg Balance Scale (BBS) divided CIDP patients into those with "good" and "poor" balance. RESULTS: Lower limb tremor was evident in 32% of CIDP patients and associated with poor balance (BBSTremor 35 [23-46], BBSNo Tremor 52 [44-55], p = .035). Tremor frequency was 10.2-12.5 Hz with legs outstretched and on standing, apart from four patients with a lower frequency tremor (3.8-4.6 Hz) while standing. Posturography analysis revealed a high-frequency spectral peak in the vertical axis in 44% of CIDP patients (16.0 ± 0.4 Hz). This was more likely in those with "good" balance (40% vs. 4%, p = .013). INTERPRETATION: Lower limb tremor is present in one third of CIDP patients and is associated with poor balance. A high-frequency peak on posturography is associated with better balance in CIDP. Lower limb tremor and posturography assessments could serve as important biomarkers of balance in a clinical setting.

Choroid plexus volume is enlarged in clinically isolated syndrome patients with optic neuritis.

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.

Chronic inflammatory demyelinating polyradiculoneuropathy-associated tremor: Phenotype and pathogenesis.

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.

Progressive Camptocormia With Head Drop and Dysphagia.

A 72-year-old man had mild proximal weakness that developed into progressive camptocormia, head drop, numbness, and significant muscle wasting. What is your diagnosis?

Effect of teriflunomide on Epstein-Barr virus shedding in relapsing-remitting multiple sclerosis patients: Outcomes from a real-world pilot cohort study.

BACKGROUND: Given its potential antiviral activity, we investigated the effect of teriflunomide on EBV in patients with relapsing-remitting MS (RRMS). METHODS: Saliva samples were collected at home and analysed for EBV DNA presence in patients with RRMS treated with teriflunomide for ≥3 months. RESULTS: The proportion of patients with detectable EBV in the teriflunomide cohort was lower than in the reference cohorts. The proportion of samples with EBV DNA or shedding from teriflunomide-treated patients was reduced relative to each reference cohort (P<0.0001; >5.8 virus copies/µL cut-off). CONCLUSION: This pilot study demonstrated the feasibility of at-home saliva sample collection and revealed a possible effect of teriflunomide on EBV shedding.

Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy.

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.

Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis.

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.

Expansion of chronic MS lesions is associated with an increase of radial diffusivity in periplaque white matter.

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.

Posturography as a biomarker of intravenous immunoglobulin efficacy in chronic inflammatory demyelinating polyradiculoneuropathy.

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.

Proximal Median Neuropathy Following Anterior Shoulder Dislocation: The Use of Magnetic Resonance Neurography.

Proximal median nerve injury is an uncommon consequence of anterior shoulder dislocation, especially occurring in isolation of other upper limb peripheral nerve injury. We report the case of an 82-year-old woman with a median nerve injury as detected by clinical and neurophysiological examination following a fall and anterior shoulder dislocation. Magnetic resonance neurography confirmed the diagnosis, but also detected asymptomatic brachial plexus and ulnar nerve involvement. Management was non-operative and there has been some improvement over several months. Our case expands the differential diagnosis for proximal median neuropathy and discusses the utility of neurography in cases of neural injury.

Interferon-ß Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS.

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-ß 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-ß, glatiramer acetate, fingolimod, and natalizumab), interferon-ß 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-ß 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-ß compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss.

Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis.

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.