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

In 2017, a revision of the 2010 McDonald criteria for multiple sclerosis (MS) diagnosis in clinically isolated syndrome (CIS) patients has been proposed. However, its validation in a large multicenter cohort of CIS patients is still needed.

Objectives

To compare the performance of 2017 and 2010 revisions of the McDonald criteria with respect to MS development in a large multicentric cohort of CIS suggestive of MS.

Methods

Brain and spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination obtained ≤5 months from CIS onset and a follow-up brain MRI acquired ≤15 months from CIS onset were assessed in 626 CIS patients from 9 European MS centres. The occurrence of a second clinical attack (clinically definite [CD] MS) was recorded. Performances of the 2017 and 2010 revisions of McDonald criteria for dissemination in space (DIS), time (DIT) and DIS plus DIT, also including OCB assessment, were evaluated with a time-dependent receiver operating characteristic curve analysis. Median time to MS diagnosis for the different sets of criteria was estimated through Kaplan-Meier curves.

Results

At the last evaluation (median=61.9 months [IQR=39.1-102.5]), 319 (51%) of 626 patients had CDMS. At 36 months, for DIS, the 2017 MRI criteria had higher sensitivity (0.84 [95% CI=0.79-0.88] vs 0.77 [0.72-0.82]), lower specificity (0.33 [0.28-0.39] vs 0.40 [0.35-0.46]), and similar area under the curve values (AUC, 0.59 [0.55-0.62] for both). The 2017 DIS plus DIT MRI criteria had higher sensitivity (0.68 [0.63-0.74] vs 0.62 [0.56-0.68]), lower specificity (0.55 [0.49-0.61] vs 0.62 [0.56-0.68]), and similar AUC values (0.62 [0.58-0.66] for both). CSF-specific OCB assessment as part of the 2017 criteria revision, increased the sensitivity (0.81 [0.75-0.85]), decreased specificity (0.40 [0.34-0.46]) and preserved AUC values (0.60 [0.56-0.64]). Median time to MS diagnosis was earlier with the 2017 revision compared to the 2010 or CDMS criteria, especially with OCB assessment (2017 revision with OCBs=3.6 months [3.1-4.0], 2017 revision without OCB=11.6 months [7.8-13.5], 2010 revision=13.9 months [12.4-15.3], CDMS=56.3 months [43.8-76.0]).

Conclusions

The 2017 revision of the McDonald criteria showed overall similar accuracy to the 2010 McDonald criteria in predicting CDMS development. The suggested modifications are expected to simplify the clinical use of MRI criteria without reducing accuracy and allow an earlier diagnosis of MS.

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

The main clinical and MRI features driving therapeutic choices are not as clear for pediatric multiple sclerosis (MS) patients as for adults.

Objectives

We aimed at assessing early predictors of long-term clinically-relevant outcomes in a large cohort of pediatric MS patients.

Methods

Clinical and MRI assessment was obtained at disease onset and after 1, 2 and 3 years, in a cohort of 123 pediatric MS patients. The longest clinical follow-up (mean 9.33 +/- 3.45 years) was considered for long-term outcomes. Cox proportional hazards models were used to assess predictors of time to first relapse, while multivariable logistic and linear regression models identified clinical and MRI predictors of long-term outcomes.

Results

Across baseline features, optic nerve involvement predicted a shorter time to first relapse (hazard ratio=1.9, p=0.03). Predictors of annualized relapse rate (ARR) were: at baseline, presence of cerebellar (b=-0.16, p=0.00) and number of cervical cord lesions (b=0.14, p=0.01); considering short-term predictors, the same baseline variables together with time to first relapse (2-year: b=-0.12, p=0.01; 3-year: b=-0.08, p=0.00) and the number of relapses (1-year: b=0.14, p=0.00; 2-year: b=0.06, p=0.02). Baseline predictors of 10-year disability worsening were: at baseline, presence of optic nerve [odds ratio(OR)=6.45, p=0.01] and brainstem lesions (OR=6.17, p=0.04); considering short-term predictors, Expanded Disability Status Scale (EDSS) changes at 1 (OR=26.05, p=0.00) and 2 (OR= 16.38, p=0.02) years and the detection of at least two new T2-lesions in 2 years (2-year: OR=4.91, p=0.02; 3-year: OR=5.49, p=0.09). Predictors of higher 10-year EDSS score were: at baseline, EDSS score (b=0.58, p<0.001), presence of brainstem (b=0.31, p=0.04) and number of cervical cord lesions (b=0.22, p=0.05); considering short-term predictors, EDSS changes (1-year: b=0.82, p<0.001; 2-year: b=0.79, p<0.001, 3-year: b=0.27, p=0.04 ), together with the detection of at least two new T2-lesions at 1 (b=0.28, p=0.03) and 2 (b=0.35, p=0.01) years.

Conclusions

In conclusion, baseline spinal cord, brainstem and optic nerve lesions have a major role in predicting long-term outcomes, both in term of disease activity and of disability worsening. In addition, an accurate clinical and MRI monitoring during the first 2 years of disease has proven to represent a powerful tool for counseling patients about long-term prognosis and personalizing treatment strategies.

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.

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.