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

Current diagnostic criteria of neuromyelitis optica spectrum disorders (NMOSD) allow the diagnosis of aquaporin-4 (AQP4) seropositive patients with limited manifestations, whereas seronegative patients with limited phenotypes remain unclassified and are usually considered as prodromal phases of multiple sclerosis (MS) or different entities themselves. Nowadays, there is great effort to perform an automatic diagnosis of different neurological diseases using deep-learning-based imaging diagnostics, which is a form of artificial intelligence, allowing predicting or making decisions without a priori human intervention.

Objectives

To provide a deep-learning classification of NMOSD patients with different serological profiles and to compare these results with their clinical evolution.

Methods

228 T2- and T1-weighted brain MRIs were acquired from patients with AQP4-seropositive NMOSD (n=85), early MS (n=95), AQP4-seronegative NMOSD (n=11, 3 with anti-myelin oligodendrocyte glycoprotein antibodies) and unclassified double-seronegative limited phenotypes (n=17 idiopathic recurrent optic neuritis [IRON], n=20 idiopathic recurrent myelitis [IRM]). The latter had a clinical re-evaluation after 4-year follow-up. The neural network architecture was based on four 3D convolutional layers. It was trained and validated on MRI scans (n=180) from AQP4-seropositive NMOSD and MS patients. Then, it was applied to AQP4-seronegative NMOSD and double-seronegative patients with limited phenotypes to evaluate their classification as NMOSD or MS in comparison with their clinical follow-up.

Results

The final algorithm discriminated between AQP-4-seropositive NMOSD and MS with an accuracy of 0.95. Forty-seven/48 (97.9%) seronegative patients were classified as NMOSD (one patient with IRON was classified as MS). Clinical follow-up was available in 27/37 (73%) double-seronegative limited phenotypes: one patient evolved to MS, three developed NMOSD and the others did not change phenotype.

Conclusions

Deep-learning may help in the diagnostic work-up of NMOSD. Our findings support the inclusion of AQP4-seronegative patients to the spectrum of NMO and suggest its enlargement to double-seronegative limited phenotypes.

Background

Cognitive impairment (CI) affects nearly 30% of paediatric patients with Multiple Sclerosis (MS) and has a negative impact on school performance and participation in social activities. This study is a re-appraisal of cognitive functioning and socio-professional attainment in adulthood in an Italian cohort of paediatric MS patients after 10 years from baseline neuropsychological assessment.

Objectives

To re-assess cognitive performance and its impact on socio-professional attainment in our cohort of paediatric MS patients after 10 years from baseline evaluation and to determine predictors of the individual outcomes.

Methods

Sixty-three paediatric patients were assessed at baseline and 48 followed-up after five years. To date, 31 out of these 48 patients (17 females, mean age 27.9±2.5 years, mean EDSS 1.7±1.6) were reassessed on an extensive neuropsychological battery and compared with a matched group of 31 healthy controls. CI was defined as the failure of > 2 tests. Socio-professional attainment was evaluated on the Work and Social Assessment Scale (WSAS). Predictors of CI and WSAS score were assessed through multivariable logistic and linear models.

Results

After a mean follow-up of 12.5±2.3 years, 15 (54%) subjects were classified as cognitively impaired. Patients with CI compared with those cognitively preserved at follow-up had higher Expanded Disability Status Scale (EDSS) score (1.9±1.4 vs 1.0±0.7; p = 0.046), lower baseline intelligence quotient (IQ) (86.2±23.8 vs 103.6±14.7; p = 0.025) and were less frequently treated with disease modifying therapy (DMT) at baseline [6 (35.3%) vs 11 (78.6%); p = 0.016]. In the regression model, CI after 10 years was related to lower IQ (OR 0.93, 95% CI 0.87-0.99, p = 0. 027) and absence of DMT at baseline assessment (OR 17.78 95%; 1.72-183.65, p = 0.017).

Baseline predictors of worse socio-professional attainment on the WSAS in adulthood were CI (B=6.3, p=0.016), higher EDSS (B=2.2, p=0.023) and higher age at onset (B=0.6, p=0.041). As for 10-year correlates, only CI was associated to poor functional outcome (B=5.2, p=0.006).

Conclusions

Complete data collection is ongoing; available findings to date show that in paediatric onset subjects CI remains significant in adulthood, is related to lower cognitive reserve, higher levels of neurological impairment and delay in DMT initiation. Moreover, CI plays a key role in predicting the subject social performance and professional outcome. Early treatment and promotion of strategies aimed at enhancing cognitive reserve are recommended in paediatric patients with MS.

Background

Cladribine significantly reduces disease activity and disability progression in relapsing-remitting multiple sclerosis (RRMS) through a selective but transient depletion of lymphocyte subsets. The SARS-COV-2 outbreak has raised several concerns regarding cladribine use for RRMS patients.

Objectives

To evaluate the prevalence and clinical features of COVID-19 disease among cladribine-treated relapsing-remitting MS patients.

Methods

Fifty-six RRMS patients treated with cladribine in our centre (female=39; mean age=33.8 years [y]; median Expanded Disability Status Scale [EDSS]=1.5, disease duration [DD]=5.2 y, treatment duration=1.15 y) were asked if they had developed manifestations suggestive of SARS-COV-2 infection up to June 30^th 2020. Their detailed characteristics were collected.

Results

At June 30^th 2020, nasal/pharyngeal swabs have been found positive in 0.94% of the Lombardy population. Since the pandemic start, 2/56 (3.6%) cladribine-treated RRMS complained a symptomatology suggestive of COVID-19 disease, with a prevalence similar to that of the whole MS population of our centre (84/2950, 2.8%). The first patient was a 30-year-old male with RRMS (DD=1.2 y, EDSS=1.5) and no comorbidities. He started cladribine on January 10^th 2020. One week later, he developed fever (<37.5°), ageusia, cough, fatigue, sputum production, sore throat, nasal congestion, shortness of breath without desaturation and conjunctivitis.

The second patient is a 39-year-old female with RRMS (DD=13.2 y, EDSS=3.5), and no comorbidities. She started cladribine on February 13^th 2020 and underwent the second week of the first treatment course from March 5^th 2020. On March 30^th, she developed fever (<37.8°), anosmia, ageusia, cough, fatigue, and bone/joint pain. Serology for SARS-COV-2 was positive in May 2020. For both patients, blood examinations performed before and after COVID-19 disease were within normal limits. Both patients were telephone-monitored at home and completely recovered within 15 days.

Conclusions

Only a minority of cladribine-treated RRMS patients developed a mild and self-limiting COVID-19 disease. In our cohort, this occurred in two RRMS patients within a few weeks from treatment course and the possible nadir of selective immunosuppression. Both patients recovered completely. Cladribine administration seems to be safe also in the setting of the COVID-19 pandemic.

Background

in multiple sclerosis (MS), disease-related factors and dysfunctional coping might favour the development of mental distress induced by COVID-19 containment measures.

Objectives

to explore the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown.

Methods

Structural equation modeling (SEM) was applied to information collected via web-survey to identify modifiable factors that could account for mental distress. Information about the following domains was collected: (1) socio-demographic features; (2) general and MS related health status; (3) changes in lifestyle; (4) COVID-19 infection and risk perception; (5) physical disability assessed via the Patient-Determined Disease Steps (PDDS) scale and the Upper Extremity Function – Short Form (UEF) from the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system; (6) cognitive function investigated using the Cognition Function– Short Form from the Neuro-QoL. Abstract reasoning, logical thinking and, in part, sustained attention, were measured using six Raven-like matrices; (7) mental distress: four domains from the Neuro-QoL were explored. Specifically, sleep disturbances, anxiety feelings, depressive symptoms, emotional dyscontrol; (8) coping strategies: individual response to lockdown was assessed using 18 items from the COPE-NVI-25, evaluating five independent coping strategies: avoidance (AV), social support (SS), positive attitude (PA), problem solving (PS) and turning to religion (TR).

Results

845 subjects (497 MS and 348 controls) were included in the study. MS patients showed higher scores than controls for depression (p=0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The SEM explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (β=0.509 and β=0.836, p<0.001); positive attitude and exercise contributed to active attitude (β=0.386 and β=0.297, p<0.001); avoidance, social support and watching TV contributed to passive attitude (β=0.301, β=0.243 and β=0.212, p<0.001). As per the relationship between latent factors and their influence on depression, disability contributed to passive attitude (β=0.855, p<0.001) while both passive and active attitude significantly influenced depression (β=0.729 and β=-0.456, p<0.001).

Conclusions

As practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool for the long term management of COVID-19 related mental distress in MS.

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

Background. Lymphopenia monitoring during treatment with disease modifying drugs for MS is relevant because of the potential increased risk of infections. Lymphopenia is an anticipated effect of cladribine (CLD) treatment, given its mechanism of action.

Objectives

Objectives. We aimed to i) characterize the absolute lymphocyte count (ALC) changes, and ii) evaluate the risk of infections in CLD-treated RRMS patients. ALCs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Methods

Materials and methods. In this observational multicentre study, demographic, clinical and MRI data of the patients included in the Free Of Charge CLD program were collected. ALC was also collected at baseline (before therapy initiation) and at month 3, 7, 12, 15, 19 and 24.

Results

Results. 236 patients were enrolled in 56 Italian MS Centres (71% F; mean age: 39+11.5 years; mean disease duration: 10+8.5 years). The median baseline EDSS was 3.0 (quartiles 1.5-3.5; range 0-6.5). 53 patients (22.5%) were treatment naïve, 107 (45.3%) switched to CLD from first line DMDs (for inefficacy), 76 (32.2%) switched to CLD after a second line therapy (33/76 for safety reason, 43/76 for inefficacy). Mean follow up was 12.2+5 months. At baseline, median ALC was 1615.0 cell/mm³ (quartiles, 1300.0-2200.0). At month 3, ALC was available in 190/236 and 101/190 had lymphopenia: 12 (6.3%) grade 3, 47 (24.7%) grade 2 and 42 (22.1%) grade 1. Among patients presenting grade 3 at month 3, only one had persistent ALC <500 cell/mm³ at month 7. At month 7, ALC was available in 180/236 and 77/180 had lymphopenia: 1 (0.6%) grade 4, 1 (0.6%) grade 3, 43 (23.9%) grade 2 and 32 (17.8%) grade 1. Up to date, 159/236 patients were re-treated. No retreatment was delayed because of grade 4 lymphopenia. No patient presented grade 4 lymphopenia at month 15, 6/89 (6.6%) experienced grade 3, 37/89 (40.7%) grade 2, 17/89 (18.7%) grade 1. At month 19, 1/38 (2.6%) presented grade 3 lymphopenia, 11/38 (29.0%) grade 2 and 9/38 (23.7%) grade 1. At month 24, 1/9 (11.1%) patient presented grade 3 and 1/9 (11.1%) presented grade 4 lymphopenia. During treatment course, 15 patients experienced infections (1 VZV, 3 HSV), none occurring in grade 3 or 4 lymphopenia.

Conclusions

Conclusions. In our study, the risk of grade 3 and 4 lymphopenia was lower compared to that observed in RCT. Moreover, grade 3 lymphopenia was transient in the majority of the patients. Compared to RTC, a more favourable CLD safety profile emerged in our study.

Background

Fingolimod is a highly effective drug, with a significant proportion of subjects showing no evidence of disease activity (NEDA) at 2-years follow-up. However, it is not known whether the previous treatment history may influence clinical outcomes under fingolimod.

Objectives

To assess NEDA status in a Italian cohort of relapsing remitting (RR) MS patients treated with fingolimod (FTY), comparing naïve patients with patients previously treated with first-line and second-line drugs.

Methods

543 RRMS patients, who started fingolimod treatment at San Raffaele Hospital (Milan) between 2011 and 2018 were enrolled in the study. Patients were divided in three categories, according to the previous treatment: naïve patients (group 1, n=74), patients previously treated with first-line drugs (group 2, n=315) and patients previously treated with second-line and immunosuppressive drugs (group 3, n=146). NEDA status was assessed at two-year follow-up. Baseline characteristics were investigated in association with NEDA status, using logistic regression in univariable and multivariable models.

Results

Overall, 45.6% patients were NEDA (n=227) at 2-year follow-up; specifically 62.1% patients belonging to group 1, 47.4% to group 2 and 33.6% to group 3 respectively. In the multivariable analysis we observed that patients treated with a first-line and second-line therapy had an increased risk of being EDA (OR=2.2, p=0.036 and OR=3.9, p<0.001 respectively) compared to naïve patients. Moreover, a higher number of new/active MRI lesions (OR, 1.2, p=0.004), a higher annualized relapse rate in the 2 years before (OR=1.3, p=0.03) and a younger age (OR=0.97, p=0.01) at onset were independently associated with increased risk of being EDA.

Conclusions

We confirmed FTY effectiveness in a large monocentric cohort of Italian RRMS patients. Moreover, patients treated with FTY as first drug had a higher probability of being NEDA after 2 years compared to patients previously treated with second-line but also first-line drugs. These data suggest an early use of FTY in naïve patients with high inflammatory activity, considering the better clinical outcomes observed at short-term follow-up.

Background

Trials leading to Cladribine (CLD) approval for the treatment of Multiple Sclerosis (MS) were conducted over a decade ago: there is a need of proof of CLD efficacy and safety profile in the present MS therapeutic landscape.

Objectives

To evaluate CLD efficacy and safety profile in the current MS population, and to identify early predictors of response.

Methods

Before the drug was marketed under the national healthcare system, in Italy CLD was available through a Free Of Charge (FOC) program. We asked all participating MS centres to contribute to the present study, collecting demographic, clinical and MRI data of the patients who received CLD in the FOC program.

Results

56 MS centres participated to the study, for a total of 236 patients (71% F) (mean age: 39 + 11,5 years; mean disease duration: 10 + 8,5 years). Mean Annualized Relapse Rate (ARR) in the two years before CLD was 0,7 + 0,6; median baseline EDSS was 3 (quartiles 1,5-3,5; range 0-6,5). 53 patients (22,5%) were treatment naïve, 107 (45,3%) switched to CLD from first-line DMDs (for inefficacy), 76 (32,2%) switched to CLD from a second line therapy (33/76 for safety or loss of tolerability, 43/76 for inefficacy). Mean follow up was 12,2 + 5 months. 84,7% of the patients were relapse-free at follow-up. Mean ARR at follow-up was 0,2 + 0,6. Patients taking CLD as first therapy were less likely to experience a relapse (HR 0,6; 95% CI: 0,2-0,8; p = 0,04) while a higher baseline ARR was a predictor of clinical activity (HR 2,7, 95% CI: 1,4-5,6; p = 0,004). Median EDSS at follow up was 2 (quartiles 1-3,5). EDSS was stable in 73.7%, improved of at least 1 point in 21,6% and worsened of at least 1 point in 4,7% of the patients. 157/236 patients completed one year of follow up. Of these 92 (59,7%) reached No Evidence of Disease Activity (NEDA-3); NEDA-3 was achieved more frequently by naive patients (70%) than switchers from a first (57%) or a second line (50%) (HR 2,3; 95% CI: 1,01-5,3; p = 0,04). 33/236 patients reported at least one adverse event (AE), most frequently infections (15 cases); other AEs included gastrointestinal side effects, cutaneous rash, aphthous stomatitis and headache. Two severe AEs were reported (one pneumonia, one melanoma).

Conclusions

Even with the limitations of a retrospective study, our data confirm CLD safety and efficacy profile. Consistently with previous studies on patients with a first demyelinating event, CLD efficacy is maximized when used early in the course of MS.

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.