San Raffaele Hospital

Author Of 2 Presentations

Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

PS15.03 - Optical coherence tomography in aquaporin-4-IgG positive neuromyelitis optica spectrum disorders: a collaborative multi-center study

Abstract

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.

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Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

PS16.05 - Application of deep-learning to NMOSD and unclassified seronegative patients

Speakers
Presentation Number
PS16.05
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
13:39 - 13:51

Abstract

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.

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Author Of 4 Presentations

Clinical Outcome Measures Poster Presentation

P0085 - Harmonization of real-world studies in multiple sclerosis: retrospective analysis from the RIReMS group (ID 687)

Abstract

Background

Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies.

Objectives

In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods

RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ2).

Results

Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ2=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ2=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ2=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ2=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ2=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p=0.02; τ2=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p=0.02; τ2=1.00).

Conclusions

We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0286 - Alemtuzumab following natalizumab: a multicentric Italian real-world experience (ID 993)

Speakers
Presentation Number
P0286
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab was approved by EMA in 2013 for active relapsing-remitting multiple sclerosis patients (RRMS). The ideal candidate is an active patient in early phase of disease. iIn real world alemtuzumab is also used when many treatments before have failed. Patients with long-term natalizumab exposure and anti JCV seropositivity who stop natalizumab for the risk of PML are a category of patients for whom no specific therapeutic strategy has been established.

At present, neurologists have may highly active drugs but there are no head to head studies directly comparing the efficacy of alemtuzumab with other efficacious therapies and the decision to chose the most suitable medication depends on different factors, such as the potential side effects. In patients who stop natalizumab alemtuzumab can represent a choice.

Objectives

The aim ot this observational study was to evaluate the efficacy and safety of alemtuzumab when used in patients previously treated with natalizumab.

Methods

This is a multicentric retrospective observational study.

Study population is composed by 50 RRMS patients (18 male and 32 female) with a median EDSS of 2 (range 1-7) from five Italian Multiple Sclerosis Centres who stopped natalizumab treatment after a median number of 22 infusions (range 3-114).

Five out of 50 patients were JCV seronegative and in these patients decision to stop natalizumab was due to radiological activity during natalizumab (2 patients), hypertransaminasemia (2 patients), patient request (1 patient). 45 out of patients were JCV seropositive and for these patients reason for stopping was the risk of PML.

Switch to alemtuzumab was made after a median wash out period of 2 months (range 0,7-5 months).

Patients underwent brain MRI at the end of natalizumab treatment, at 6 and 12 months after alemtuzumab infusion.

Results

Brain MRI at six months after alemtuzumab was available for 48 out of 50 patients and in 43 of them neither signs of disease activity nor new lesions were present; 3 patients showed new lesions and 1 patient had radiological activity. No patient showed clinical activity.

Brin MRI at 12 months after alemtuzumab was available in 46 out of 50 patients and in 42 out of 46 there was no sign of disease activity. In 4 patients brain MRI showed disease activity (1 pt) or new lesions (2 pts ) or both (1 pt).

Clinical relapse after alemtuzumab therapy occurred in 1 out of 50 patients; this patient underwent the third infusion of drug.

No patient developed PML.

Conclusions

Alemtuzumab started shortly after natalizumab interruption was highly efficacious in controlling disease course, as 87% of patients showed no evidence of clinical and radiological activity one year after treatment starting.

The choice of alemtuzumab use in JCV seropositive patients must take in consideration the necessity to treat a very severe disease and the safety profile of the drug to which switching.

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Comorbidities Poster Presentation

P0421 -  SARS-CoV-2 infection in multiple sclerosis patients: a single center experience in the province of Bergamo, Italy (ID 1461)

Speakers
Presentation Number
P0421
Presentation Topic
Comorbidities

Abstract

Background

In Europe, the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was reported in Lombardy region; the highest number of cases identified was in Eastern Lombardy , in particular in Bergamo’s province with 11,313 confirmed COVID19 patients up to April 30th 2020. The pandemic represents a challenge for neurologists treating Multiple Sclerosis (MS) because of the higher risk of infections of this population and for disease modifyng treatment (DMT) used. We report the experience of the MS center of Papa Giovanni XXIII Hospital in Bergamo, Italy.

Objectives

To evaluate the risk of SARS-CoV-2 infection and the outcome of the disease in MS patients treated with first and second line DMT.

Methods

We retrospectively and prospectively collected all MS patients who reported symptoms suggestive of SARS-CoV-2 infection since the beginning of February 2020. We considered for the analysis patients with a diagnosis confirmed by real-time reverse-trascriptase polymerase-chain-reaction (RT-PCR) on nasopharyngeal specimens as well as patients with suggestive symptoms and signs of SARS-CoV-2 infection who did not performed swab test and/or serological test. Since the begnning of pandemic , according to Italian reccomandation, we postponed the majority of treatment with depleting therapies whereas all the other drugs were usually continued.

Results

Between February 1st and and June 30, 153 patients with suspected SARS-CoV-2 infection were identified, which represent the 18% of the whole population regoularly followed at our MS center. The mean age was 45 years (range 20-71) and the mean EDSS was 2,5 ( range 1-8,5). The 81% of patients were female. A first line DMT was used in 92 patients (60%) while 51 patients (33%) were treated with second line DMT. Overall only 11 patients performed a nasopharyngeal swab during the symptomatic phase and a positivity was found in 7 patients. In an additional patient the diagnosis was confirmed on bronchoalveolar lavage fluid obtained by bronchoscopy. Only 3 patients (2%) presented a severe distress respiratory syndrome and were hospitalized in Intensive Care Unit. Two of these patients were female of 43 and 46 years old treated with Natalizumab and Ocrelizumab respectively both with mild disability (EDSS 2,5). The third patient was a disabled male of 56 years with a progressive form of MS (EDSS of 6.5). None of these patients had additional comorbidities and they all showed a complete recovery without sequaele.

Conclusions

In our experience the course of infection was mild in the large majority of patients independently of the ongoing DMT and no deaths were reported . The good outcome observed in our cohort might support a possible protective role of immunomodulation during SARS-CoV-2 infection. However, the diagnosis was confirmed only in a minority of our patients, therefore we cannot draw definitive conclusion and more data are needed to confirm our results.

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Pathogenesis – the Blood-Brain Barrier Poster Presentation

P0982 - MR T2-relaxation time as an indirect measure of brain water accumulation in Neuromyelitis Optica Spectrum Disorders (ID 1077)

Speakers
Presentation Number
P0982
Presentation Topic
Pathogenesis – the Blood-Brain Barrier

Abstract

Background

One of the main unsolved issues in the clinical management of neuromyelitis optica spectrum disorders (NMOSD) is the lack of biomarkers predicting short-term relapses. In physiological conditions, the blood brain barrier (BBB) protects the CNS from water unbalance, with aquaporin-4 (AQP4) water channels on astrocytes podocytes being the main regulator of water influx and efflux. In NMOSD, BBB integrity might be threatened by the presence of antibodies targeting AQP4 water channels and triggering complement-mediated astrocytes damage. In line with this, increased T2-signal in acute lesions (“bright spotty lesions”) is considered specific for NMOSD. However, it remains unexplored whether these patients present a chronic water unbalance.

Objectives

To provide an indirect estimation of brain water content in NMOSD by measuring T2-relaxation time (T2rt) and to assess whether it differs in patients having a short-term relapse.

Methods

In this multicenter MR study, T2rt was calculated from brain dual echo turbo spin echo images assuming a mono exponential decay. T2rt maps of normal appearing white matter (NAWM), gray matter (GM) and basal ganglia were obtained from 77 AQP4-positive NMOSD and 84 HC. Short-term relapses were defined as those occurring within one month before or after MRI scan. Differences between NMOSD and HC were assessed with age-, sex- and site-adjusted linear models. ROC analyses were run to identify discriminators between stable and short-term relapsing patients.

Results

NMOSD patients and HC had similar ages. Compared to HC, T2rt was increased in the GM (103 vs 97 ms), NAWM (88 vs 84 ms) and putamen (75 vs 72 ms) of NMOSD patients (p<0.001 for all). Short-term relapses occurred in 20/77 (26%) of patients. According to ROC analysis, T2rt cut-offs of 87 ms in the NAWM, 87 ms in the thalamus and 88 ms in the caudatus were able to discriminate between short-term relapsing and stable patients with good accuracy (AUC=0.70, 0.76 and 0.79 respectively, p≤ 0.027).

Conclusions

NMOSD patients had increased T2rt values, in line with the hypothesis of subclinical water accumulation in this disorder. The burden of T2rt alterations might be useful for identifying those patients with incipient or recent relapses.

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Presenter Of 1 Presentation

Comorbidities Poster Presentation

P0421 -  SARS-CoV-2 infection in multiple sclerosis patients: a single center experience in the province of Bergamo, Italy (ID 1461)

Speakers
Presentation Number
P0421
Presentation Topic
Comorbidities

Abstract

Background

In Europe, the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was reported in Lombardy region; the highest number of cases identified was in Eastern Lombardy , in particular in Bergamo’s province with 11,313 confirmed COVID19 patients up to April 30th 2020. The pandemic represents a challenge for neurologists treating Multiple Sclerosis (MS) because of the higher risk of infections of this population and for disease modifyng treatment (DMT) used. We report the experience of the MS center of Papa Giovanni XXIII Hospital in Bergamo, Italy.

Objectives

To evaluate the risk of SARS-CoV-2 infection and the outcome of the disease in MS patients treated with first and second line DMT.

Methods

We retrospectively and prospectively collected all MS patients who reported symptoms suggestive of SARS-CoV-2 infection since the beginning of February 2020. We considered for the analysis patients with a diagnosis confirmed by real-time reverse-trascriptase polymerase-chain-reaction (RT-PCR) on nasopharyngeal specimens as well as patients with suggestive symptoms and signs of SARS-CoV-2 infection who did not performed swab test and/or serological test. Since the begnning of pandemic , according to Italian reccomandation, we postponed the majority of treatment with depleting therapies whereas all the other drugs were usually continued.

Results

Between February 1st and and June 30, 153 patients with suspected SARS-CoV-2 infection were identified, which represent the 18% of the whole population regoularly followed at our MS center. The mean age was 45 years (range 20-71) and the mean EDSS was 2,5 ( range 1-8,5). The 81% of patients were female. A first line DMT was used in 92 patients (60%) while 51 patients (33%) were treated with second line DMT. Overall only 11 patients performed a nasopharyngeal swab during the symptomatic phase and a positivity was found in 7 patients. In an additional patient the diagnosis was confirmed on bronchoalveolar lavage fluid obtained by bronchoscopy. Only 3 patients (2%) presented a severe distress respiratory syndrome and were hospitalized in Intensive Care Unit. Two of these patients were female of 43 and 46 years old treated with Natalizumab and Ocrelizumab respectively both with mild disability (EDSS 2,5). The third patient was a disabled male of 56 years with a progressive form of MS (EDSS of 6.5). None of these patients had additional comorbidities and they all showed a complete recovery without sequaele.

Conclusions

In our experience the course of infection was mild in the large majority of patients independently of the ongoing DMT and no deaths were reported . The good outcome observed in our cohort might support a possible protective role of immunomodulation during SARS-CoV-2 infection. However, the diagnosis was confirmed only in a minority of our patients, therefore we cannot draw definitive conclusion and more data are needed to confirm our results.

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