Background

Optic neuritis (ON) is a frequent manifestation in aquaporin-4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (NMOSD). Due to limited samples, existing optical coherence tomography (OCT) studies are inconsistent regarding retinal changes in eyes with a history of ON (NMO-ON) and without a history of ON (NMO-NON), and their functional relevance.

Objectives

The CROCTINO (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica) project aims to reveal correlates of retinal pathology and to generate hypotheses for prospective OCT studies in NMOSD. The objective of this study was to analyze retinal changes of AQP4-IgG seropositive NMO-ON and NMO-NON eyes in an international cross-sectional OCT dataset.

Methods

Of 656 subjects, we enrolled 283 AQP4-IgG seropositive NMOSD patients and 72 healthy controls (HC) from 22 international expert centers. OCT data was acquired with Spectralis SD-OCT, Cirrus HD-OCT and Topcon 3D OCT-1. Mean thickness for the combined ganglion cell and inner plexiform layer (GCIP) and inner nuclear layer (INL) were calculated from macular volume scans. Clinical, functional and laboratory testing were performed at discretion of each center.

Results

We compared NMO-ON eyes (N = 260), NMO-NON eyes (N = 241) and HC eyes (N = 136). GCIP was reduced in NMO-ON (57.4 ± 12.2 µm) compared with NMO-NON (75.9 ± 7.7 µm; p < 0.001) and HC (81.4 ± 5.7 µm; p < 0.001). NMO-NON had thinner GCIP (p < 0.001) compared with HC. INL was thicker in NMO-ON (40.3 ± 3.9 µm) compared with NMO-NON (38.6 ± 3.9µm; p < 0.001), but not HC (39.4 ± 2.6 µm). Microcystic macular edema were visible in 6.6 % of NMOSD eyes.

Conclusions

AQP4-IgG seropositive NMOSD is characterized by a functionally relevant loss of retinal neuroaxonal content and a - probably inflammatory - increase of INL after ON. Our study further supports the existence of attack-independent damage in the visual system of patients with AQP4-IgG seropositive NMOSD.

Background

The visual pathway has emerged as an elective platform to study the interaction between demyelination and neurodegeneration in multiple sclerosis (MS)

Objectives

We specifically assessed neural damage at this level in progressive MS (PMS), also exploring the evolution over time of functional (trough visual evoked potentials - VEPs) and structural (trough optical coherence tomography - OCT) parameters, as well as their relations with disease course and clinical disability.

Methods

We performed a prospective longitudinal study enrolling 350 PMS patients (228 secondary progressive MS - SPMS, 122 primary progressive MS - PPMS) who underwent a cross-sectional evaluation comprehensive of Expanded Disability Statur Scale (EDSS) assessment, high (HCVA)- and low-contrast (LCLA) visual acuity test, full-field (ff-VEPs) as well as multifocal (mf-VEPs) VEPs, and OCT. We performed a follow-up assessment (mean interval 2.0±0.9 years) in 147 patients (52 PPMS and 95 SPMS); a parallel collection of clinical records (including reports MRI scans, performed as per clinical practice) has been also obtained.

Results

Independently from previous optic neuritis (ON), we found visual conduction to be slower among SPMS compared to PPMS patients, particularly for mf-VEPs: mean latency 168.9 ms (95% CI 166.2-171.1) vs 163.8 ms (95% CI 160.7-166.9) respectively, p=0.019. Retinal Nerve Fiber Layer (RNFL) was also found to be thinner among SPMS in comparison to PPMS patients: mean 83.4 μm (95% CI 81.4-85.4) vs 87.0 μm (95% CI 84.4-89.6), p=0.040, with similar results for Ganglion Cell-Inner Plexiform Layer (GCIPL). Considering the evolution over time of functional and structural parameters, we found no significant differences comparing PPMS and SPMS patients. Reclassifying our cohort according to EDSS status (“stable” vs “worsened”) we found a significant between-groups difference in terms of RNFL evolution: mean annualized percent change -0.163 %/year (95% CI -0.467 - -0.141) vs -0.854 %/year (95% CI -1.188 - -0.521) respectively, p=0.003. Similar findings were obtained for GCIPL change. In both cases, these observations were independent from the evidence of MRI activity during follow-up.

Conclusions

our results suggest the presence of a greater functional and structural involvement of the visual system among SPMS compared to PPMS patients, independently from previous ON history; follow-up data suggest however neurodegeneration accrual over time to be similar between these two clinical subgroups. The longitudinal relation between RNFL - GCIPL thinning and EDSS worsening, even in the absence of overt MRI activity and/or clinical relapses, suggests OCT to represent a useful tool to monitor disease progression and to assess neuroprotection in PMS.

Background

Optical coherence tomography is gaining increasing relevance in the assessment of people with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS.

Objectives

The present study aims at exploring the usefulness of optical coherence tomography as a marker of inflammation and disease burden in the earliest phases of the disease.

Methods

a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder. For the present study, patients also received a visual pathway assessment - including OCT, VEP, visual acuity testing –, measurement of CSF inflammatory markers – a set of 17 cytokines-chemokines and, count of extracellular vesicles of myeloid origin –, and dosage of serum neurofilaments.

Results

19.2% of clinically isolated syndromes had abnormal visual evoked potentials in eyes without optic neuritis. Similarly, optical coherence tomography identified neuro-retinal thinning in 17.8% of patients without prior visual symptoms. The presence of asymptomatic involvement of the anterior optic pathway tested with either techniques was associated with a greater disease burden.

A thinner ganglion cell layer in eyes without prior optic neuritis or instrumental evidences of it was correlated with higher EDSS, lower low contrast visual acuity, longer disease duration, higher brain lesion load, presence of gadolinium enhancing lesions, more severe abnormalities along motor and somatosensory evoked potentials, and higher frequency of CSF-specific oligoclonal bands.

We also found that inner nuclear layer thickens in a post-acute (1.1 – 3.7 months) phase after a relapse, particularly in those who did not receive steroid treatment. Likewise, a longitudinal analysis on 65 patients, showed that this swelling is transient and returns to normal values after one year of follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study were strictly associated with one-another but none of them was associated with inner nuclear layer volume.

Conclusions

The present findings suggest that instrumental evidence of asymptomatic optic nerve involvement is associated with a greater disease burden in early MS and clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.

Background

There is a growing body of literature highlighting the role that wearable and mobile remote monitoring technology (RMT) can play in the assessment of Multiple Sclerosis (MS) and how it could improve clinical care and improve efficiency of research.

The Remote Assessment of Disease and Relapse in the Central Nervous System (RADAR-CNS) study is a pan-European consortium aimed to improve the management of different CNS disorders such as MS, Epilepsy or Major Depression using smartphones and wearable devices.

Most of the available data are based in small monocentric studies, however the full validation of these digital devices requires multicenter, well designed studies providing information on feasibility and acceptability.

Objectives

We aimed to describe the outcomes of the recruitment process in the Multiple Sclerosis (MS) RADAR-CNS disability and fatigue study (D&F).

Methods

The study was run in three European centers. Main eligibility criteria for D&F study were patients with relapsing-reminting or secondary progressive MS with an EDSS score between 2.0 and 6.0. Passive and active data were continuously collected through wearables (FitBit) and mobile phones (Android) and compared to the on-site visit every 3 months. The study duration is 2 years. The study sample size was 400 patients.

Results

The enrolment of the D&F study extended for a period of 18 months. We identified 4094 potential candidates (min-max 885-1789). At the end of the recruitment period, 678 (16.6%; min-max 0-24.2%) remained in the pre-screening phase. 3416 (min-max 885-1454) patients were assessed for eligibility. Out of those, 2372 (69.4%; min-max 53.3-87.1%) were excluded for not fulfilling the eligibility criteria: 1520 (64.1%; 15.0-87.1%) did not meet the EDSS score, 254 (10.7%; 0.2-49.6%) would not be suitable in the investigators opinion and 598 (25.2%; 3.0-60.3) did not have an Android. Out of the 1044 (30.6%; 12.9-46.7) eligible candidates, 644 (61.7%; 13.8-79.7%) declined to participate. A total of 400 (90-162) patients, 9.8% of the potential candidates, were enrolled into the study.

Conclusions

Our study illustrates the primary challenges in recruiting MS patients in RMT studies related to eligibility, both clinical and technological criteria, followed by reasons related to patients preferences. There is variability in the recruitment approach between centers. In future studies, developing technology for all types of phones and more attractive assessment for patients should be considered.

Background

Hand dexterity dysfunction is a key feature of disability in people with progressive multiple sclerosis (PMS). It underlies corticospinal tract (CST) and cerebellar integrity but also disruption of cortical networks, which are hardly assessed by standard techniques. Transcranial magnetic stimulation is a promising tool for evaluating the integrity of intracortical motor pathways.

Objectives

to investigate neurophysiological correlates of motor hand impairment in PMS and assess intracortical motor conduction through the use of a innovative TMS protocol.

Methods

Antero-posterior (AP) stimulation of the primary motor cortex activates the CST indirectly through polysynaptic pathways, while a direct CST activation occurs with latero-medial (LM) directed current. 30 PMS and 15 healthy controls underwent dominant hand motor evoked potentials (MEP) using AP and LM-directed stimulation, and a clinical assessment of dexterity (nine-hole peg test) and strength (MRC scale, grip and pinch).

Results

PMS with AP-LM latency difference 2.5 standard deviation above the mean of controls (33%) showed worse dexterity but no difference in upper limb strength. Accordingly, AP-LM latency shortening predicted dexterity (R² 0.538, p<0.001), but not strength impairment. On the contrary, absolute MEP latencies only correlated with strength (grip: R² 0.381, p=0.014; MRC: R² 0.184, p=0.041).

Conclusions

AP-LM latency shortening may be used to assess the integrity polysynaptic intracortical networks implicated in dexterity impairment.

Background

The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.

Objectives

To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.

Methods

MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.

Results

The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).

Conclusions

MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.

Background

Neurodegeneration of multiple sclerosis (MS) can be measured with optic coherence tomography (OCT), as thinning of peripapillary retinal nerve fiber layer (pRNFL), or as reduced total macula volume (TMV). The macula scan can be further segmented into the ganglion cell layer (GCL), inner plexiform layer (IPL), and inner nuclear layer (INL), which are plausible markers for neuronal loss, dendritic loss, or ongoing inflammation. Unlike traditional method yields only several averaged values of the whole image, voxel-based morphometry (VBM) can visualize and compare the whole macula map, therefore it can be more sensitive in detecting focal lesions.

Objectives

Here we applied VBM to macula OCT in different types of MS and compare the results with traditional parameters such as pRNFL or TMV.

Methods

Three groups of patients with CIS (N=12, 2 male, age=32±12 years, disease duration = 0.9±1.3 years), RRMS (N=9, 6 male, age=32±8 years, disease duration = 1.2±1.2 years), PPMS (N=14, 11 male, age=44±9 years, disease duration = 2.5±1.3 years) and eighteen healthy subjects (4M, age = 29±5 y) were enrolled. Eyes with histories of optic neuritis were excluded. Peripapillary and Macula volume scans were performed and segmented with Heidelberg Spectralis OCT. The segmented thickness maps of RNFL, GCL, IPL, and INL were registered to generate group maps with VBM. total macula volume(TMV) and peripapillary thickness (pRNFL) were compared with healthy with independent t-test, while voxel-wise t-tests were performed between patients and healthy maps with correction of false discovery rate(FDR).

Results

No group difference was found in pRNFL, while the PPMS group showed significantly lower TMV of RNFL, GCL, and IPL. On the other hand, the voxel-wise comparison showed significant differences in all patients’ groups compared with healthy, while the lesion loads in RNFL and GCL showed a gradient increases from CIS to RRMS to PPMS. In the MS groups, the significant atrophy of IPL and thickening in INL co-localized at parafovea, while in CIS group the IPL atrophy located in nasal macula while the INL thickening still located at parafovea.

Conclusions

Our results suggest that applying VBM in macula OCT can increase the detection sensitivity of neurodegeneration in MS patients than traditional measures such as pRNFL or TMV. Also, Common neurodegenerative patterns were found in RNFL and GCL and the lesion load increases with disability, while the difference of IPL and INL differs between MS and CIS cohort and can be a potential biomarker for predicting converters.

Background

Optic neuritis is an immune-mediated disease of the optic nerve, strongly associated with multiple sclerosis (MS). Although the visual prognosis of optic neuritis is generally favourable, the degree of remission varies considerably. The degree of clinical remission is associated with the degree of optic nerve axonal loss, that can be quantified accurately by Optic Coeherence Tomography (OCT). Neurofilament light chain (NfL) is part of the axonal cytoskeletal neurofilaments and is released upon immune-mediated axonal damage during optic neuritis and MS.

Objectives

We aimed to investigate if NfL levels sampled close after symptom onset would predict the outcome after optic neuritis.

Methods

We included 31 patients with optic neuritis as a first demyelinating episode. Patients underwent visual tests, OCT, magnetic resonance imaging (MRI) and lumbar puncture. NfL levels were measured through use of a Simoa HD-1 instrument (Quanterix). Longitudinal changes in inter-ocular difference in visual acuity and OCT parameters were chosen as primary outcome measures of visual loss to account for their inter-individual variability. Multilevel mixed effect models have been used to assess the prognostic factor of baseline NfL levels on longitudinal changes in visual outcomes.

Results

Results: patients (mean age 37.3 years, SD 8.7, 71% females) had a mean follow-up of 27.6 months (SD 12.3). The mean inter-ocular visual acuity difference decreased with the follow-up (baseline 2.8 SD 1.2, follow up 2.1 SD 1.5, p <0.05), while mean inter-ocular RNFL thickness difference significantly increased with time (3.2 SD 10.2 at baseline, 12.7 SD 15.2 at follow-up). Basel NfL levels above 75°ile were significantly associated with an increase in inter-ocular visual acuity difference (B 0.05 SE 0.02, p <0.01) and inter-ocular RNFL thickness difference (B 0.64 SE 0.20, p <0.01).

Conclusions

Conclusion: NfL is a promising biomarker of visual outcome after optic neuritis. This could aid neuroprotective/regenerative medical advancements.

Background

In the cuprizone murine model of demyelination neurotoxin cuprizone is fed to mice, inducing death of oligodendrocytes and consequent central nervous system (CNS) demyelination, which leads to demyelination-associated behavioral impairments, occurring within 5-7 weeks, with spontaneous remyelination after 4 weeks of diet suspension. In vitro experiments have demonstrated that neuronal electrical activity, which can be modulated in vivo through transcranial direct current stimulation (tDCS), is able to promote axonal remyelination. Moreover, anodal tDCS ameliorated motor and cognitive impairments in several experimental models of neurological disorders, including stroke, Parkinson’s disease and Alzheimer’s disease.

Objectives

To explore the usefulness of tDCS to promote recovery of demyelination-associated behavioral impairments during the remyelinization phase.

Methods

Male wild-type C57BL/6 (n = 31) were fed cuprizone (n = 19) or control regular diet (n = 12) for 7 weeks, followed by regular diet for one more week. At cuprizone suspension, anodal (n = 10) or sham (n = 9) tDCS (350 microA, 20 min) was performed under sevoflurane anesthesia through epicranial electrodes for 5 consecutive days. Motor performance was assessed through rotarod and spatial working memory through spontaneous alternation T-maze on the last two days of cuprizone diet and on the two days after the last tDCS treatment.

Results

At the end of cuprizone diet, a significant worsening of rotarod motor performance was observed in cuprizone mice vs controls (p = 0.0005). No significant effects were found on T-maze. After neurostimulation, anodal tDCS led to a significant rescue of motor performance in cuprizone mice (post-tDCS vs pre-tDCS: p < 0.0001). After tDCS, motor performance of anodal-stimulated mice was significantly higher than the one of sham-stimulated mice (p = 0.004). While sham-stimulated mice were significantly impaired in comparison with healthy control mice (p = 0.030), anodal-stimulated mice were comparable to healthy mice (p = 0.326). Anodal, but not sham, tDCS rescued motor impairment of cuprizone mice (healthy: 231.8 sec; sham: 138 sec; anodal: 271.6 sec).

Conclusions

These findings reveal a promising role of anodal tDCS in promoting remyelination in the cuprizone model and prompt further experiments exploring the potential of this technique. Indeed, tDCS could represent an innovative, non invasive and easy to use remyelination-boosting treatment.

Supported by: Fondazione Italiana Sclerosi Multipla (FISM 2018/B/3).

Background

It is known that a single-nucleotide polymorphism mapping to the Brain-Derived Neurotrophic Factor (BDNF) gene and resulting in the valine to methionine change (Val66Met or V66M), impacts memory, cognition and motor learning. Previous studies have shown that V66M polymorphism may exert a protective effect on grey matter atrophy in multiple sclerosis (MS) patients; however, its influence on motor recovery after rehabilitation is not known.

Objectives

To explore the possible influence of BDNF V66M polymorphism on motor recovery after rehabilitation in progressive MS subjects and to investigate the effect of two SNPs (rs2289656 and rs1212171) in NTRK2 gene, which encodes for BDNF receptor.

Methods

We retrospectively included in the study patients with primary progressive (PP) and secondary progressive (SP) MS, who were admitted to the Neurorehabilitation Unit and who had already available genetic data. The results of tests for gait (Six-minutes Walking Test, 6MWT; 10-Meters Test, 10MT) and hand dexterity (Nine-Hole Peg Test, 9HPT) were collected at baseline and after a 4-week inpatient rehabilitation program. We used ANCOVA models to explore the effects of the selected SNPs on the change of such clinical outcomes after rehabilitation, expressed as ratio values.

Results

100 patients (79 SP, 21 PP) with available clinical and genetic data were included in the study. Female:Male ratio was 1.27, mean age was 51±10 years and median EDSS score was 6.0 (range: 5.5-6.5). Sixty-eight patients were carriers of the more common genotype (GG), while the remaining were heterozygote (n=28) or homozygote (n=4) carriers of the V66M polymorphism (Met-carriers). Among 89 subjects with available data on 6MWT, Met-carriers showed greater improvement after rehabilitation if compared to GG patients (p=0.024; mean variation=0.16 [CI: 0.02-0.29]). SNPs in NTRK2 did not show any association with 6MWT change after rehabilitation neither alone, nor in interaction with V66M. As regards data on 10MT (n=42) and 9HPT (n=45), no associations were found for V66M or SNPs in NTRK2.

Conclusions

In the present pilot study, progressive MS patients carrying V66M polymorphism seem to have a greater improvement in walking performance at 6MWT after rehabilitation. These data need to be confirmed in larger and independent datasets, in order to better explore the effect of this polymorphism in MS patients undergoing intense rehabilitation program.

Background

Global proprioceptive resonance (GPR) mechanically induces multifocal vibration at specific frequency among various cutaneous mechanoreceptors. Preliminary results suggest that GPR can modulate neuromuscular and neuroendocrine systems, therefore it may improve muscle strength and facilitate Lactose metabolism. Therefore, GPR could be beneficial for patients with multiple sclerosis (PwMS) since muscle weakness is an important factor of their gait impairment.

Objectives

Here we evaluated the acute effects of a single GPR session on gait pattern in patients with MS using wearable sensors to quantitatively measure surface electromyography (sEMG) and body acceleration during walking.

Methods

Ten patients with MS(PwMS, 8 males; mean age: 48±9.1 years; mean EDSS: 5.9±0.74), in a randomized order, underwent 15 minutes GPR and sham session(Keope GPR, ANDROMEDA, Italy) with a week interval. Nine Hole Peg Test(9HPT) and 6-meter-walking-test(SMWT) were performed pre- and immediately after the sessions. During SMWT, surface EMG and body acceleration were recorded with a wearable accelerator and surface electrodes(BTS Bioengineering, Italy). The SMWT were performed with spontaneous(Vp) and maximum velocity(Vmax). Time of 9HPT, velocity, cadence, step length and Coactivation index(CoI) of MWT of pre- and post-GPR were calculated for further statistics.

Results

Compared with sham stimulus, significant improvement was found in 9HPT(p=.02) of the dominant hand after the active GPR session. For SMWT, increased velocity(p = .05) and cadence(p =.03) after active stimulus was found under Vp condition only, but not in the Vmax condition. No significant difference was found in other parameters.

Conclusions

Our preliminary results suggest that a single active GPR session can improve the motor performance in both upper and lower limbs. Our results suggest that GPR could boost muscle recovery and can be beneficial to be incorporated into rehabilitation protocols to ameliorate the fatigue level for PwMS.