Karolinska Institute

Author Of 4 Presentations

Imaging Oral Presentation

HT04.03 - Presentation 03 - Cortical atrophy in multiple sclerosis may start at puberty

Speakers
Presentation Number
HT04.03
Presentation Topic
Imaging
Lecture Time
09:39 - 09:51

Abstract

Background

Decreased gray matter (GM) volumes have been shown at the diagnosis of multiple sclerosis (MS), suggestive of early neurodegeneration processes preceding clinical symptoms. The onset and progression rate of atrophy in early stages and across large time spans in MS is still, however, uncertain.

Objectives

To analyze cortical atrophy rates in relation to the patient age vs. disease duration, to find a possible impact of age-at-onset on atrophy progression and to retropolate the time of the brain atrophy onset, based on the progression rate and trajectories.

Methods

Standardized high-resolution brain volumetric imaging was performed in the Stockholm Prospective Assessment of MS (StopMS) study. A total of 1085 MS patients (age: 11-79 years, disease duration: 0-48 years) were included and 3642 brain MRI scans were performed. FSL-SIENAX was used to evaluate the normalized cortical GM volume and further analyzed using R-libraries. Cortical atrophy rates were assessed in relation to age and disease duration respectively and stratified into five age-at-onset subgroups: <20, 20-30, 30-40, 40-50, >50 years. Locally estimated scatterplot smoothing - LOESS and linear regressions were used to calculate atrophy rates for each subgroup for the first, last and all MRI scans performed per patient (range 1-14 scans per person, median 3 scans) between the ages 17 and 60 years, and duration 0-40 years. Demographic and clinical data were available from the Swedish MS Registry.

Results

Cortical atrophy had a clearly linear progression with patient age. At the group level, the normalized cortical GM volume decreased by 3.1 ml/year. The corresponding annual cortical atrophy rates were 0.43% at age 17 and 0.53% at age 60. Patients with later onset started with lower cortical volume, following a similar linear age trajectory as patients with earlier onset. Similar findings were found for both sexes and all MS subtypes. Primary progressive MS patients, older at diagnosis, had the correspondingly lower cortical volume at their time of diagnosis. Retropolation of cortical atrophy trajectory along the linear age-related slopes to normative values suggested that MS atrophy can possibly start as early as at the age of 13 (time of puberty). Similar GM volume analyses vs. disease duration (instead of age) showed separate atrophy trajectories, where each age-at-onset subgroup started with 350 ml difference in volume at the time of onset and followed its own quasi-linear trajectory. Early age-at-onset subgroups had a higher atrophy rate with disease duration and a late age-at-onset subgroups had the lower rates.

Conclusions

Cortical atrophy progresses linearly from around the time of puberty, i.e. typically before the first reported MS symptom and appears largely independent of reported time of MS onset, diagnosis, or a subtype. Assessments of neurodegeneration in MS should preferably be analyzed in relation to the patient's age rather than the disease duration.

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Epidemiology Oral Presentation

PS05.02 - Validation of three Secondary Progressive Multiple Sclerosis classification methods in five registries within the SPMS Research Collaboration Network

Abstract

Background

Assigning Secondary Progressive Multiple Sclerosis (SPMS) course consistently is challenging as it is based on a gradual worsening in neurological disability independent of relapses. Clinical SPMS assignment may therefore vary between registries depending on clinical practice. Consequently, a comparison of SPMS between registries would benefit from an objective definition of SPMS.

Objectives

To validate three different methods for classifying patients into Relapsing Remitting Multiple Sclerosis (RRMS) or SPMS, compared to the clinical assignment, in five European Multiple Sclerosis (MS) registries.

Methods

Data from MS registries in Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients), and the United Kingdom (UK) (5,086 patients) were used. Patients with either RRMS or SPMS, age ≥ 18 years at index date (date with the latest Expanded Disability Status Scale (EDSS) observation) were included. Index period was 01/2017 - 12/2019. Three EDSS centric classification methods were applied; method 1: a modified real world EXPAND criteria (Kappos, L. et al., 2018. The Lancet 391(10127), 2018), method 2: the data-derived definition from Melbourne University but without pyramidal Functional Score (Lorscheider, J. et al., 2016. Brain 139(9)), method 3: the decision tree classifier from Karolinska Institutet (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674). The classifications were compared to the clinical assignment, where sensitivity (SPMS as true positive), specificity (RRMS as true negative) and accuracy were calculated as similarity measurements.

Results

The overall classification performance (sensitivity, specificity, accuracy) among classifiable patients were; method 1: (0.47, 0.85, 0.79), method 2: (0.77, 0.87, 0.85), method 3: (0.84, 0.83, 0.84). The proportions of unclassifiable patients with each method were; method 1: 20.0%, method 2: 32.2%, method 3: 0%. Methods 2 & 3 provided a high sensitivity, specificity and accuracy, while method 1 provided high specificity but low sensitivity. Method 3 was the only method having no unclassifiable patients.

Conclusions

Our findings suggest that these methods can be used to objectively assign SPMS with a fairly high performance in different registries. The method of choice depends on the research question and to what degree unclassifiable patients are tolerable.

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Observational Studies Oral Presentation

PS05.04 - Ongoing disease modifying treatment associated with mis-classification of secondary progressive as relapsing-remitting multiple sclerosis

Abstract

Background

Until recently, disease modifying treatment options for MS patients with a secondary progressive course (SPMS) were limited, leading to the common practice of off-label treatment with drugs approved for relapsing-remitting MS. We previously showed that applying objective algorithms tend to increase the proportion of SPMS in MS registries, suggesting that SPMS is under-diagnosed in clinical practice, possibly related to available treatment options.

Objectives

To compare characteristics of patients clinically assigned an RRMS course that are re-classified when an algorithm-based SPMS assignment method is applied.

Methods

Data from MS registries in the Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (5,086 patients) were used. Inclusion criteria were patients with relapsing remitting (RR)MS or SPMS with age ≥ 18 years at the beginning of the study period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS a data-driven assignment method was applied in the form of a decision tree classifier based on age and last EDSS (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).

Results

Across the five registries 8,372 RRMS patients were re-assigned as SPMS (Denmark: n=1,566, Czech Republic: n=1,958, Germany: n=2,906, Sweden: n=648, United Kingdom: n=1,294) increasing the overall SPMS proportion from 17% to 31%. Re-assigned patients tended be younger, were older at onset and had experienced a quicker progression to SPMS. The overall proportion of clinically assigned SPMS patients on disease modifying treatments (DMTs) was 36% but varied greatly between registries (Czech Republic: 18%, Denmark: 35%, Germany: 50%, Sweden: 40%, and the United Kingdom: 12%) whereas a higher proportion of 69% (OR=4.0, P<0.00004) were on DMTs among RRMS patients re-assigned as SPMS (Czech Republic: 71%, Denmark: 68%, Germany: 78%, Sweden: 80%, and the United Kingdom 40%).

Conclusions

SPMS patients on DMTs may be clinically mis-classified as RRMS, most likely by not being re-assigned to SPMS after conversion has occurred. This challenges the use of time to SPMS conversion as an outcome in comparative effectiveness studies using real world evidence data and argues for the use of objective classification tools in the analysis of MS patient populations.

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COVID-19 Late Breaking Abstracts

SS02.04 - First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes

Abstract

Background

As the COVID-19 pandemic amplifies, efforts to minimise the risk on vulnerable people are essential. People with multiple sclerosis (MS) may be a vulnerable group due to the high proportion taking long-term immunosuppressive disease-modifying therapies (DMTs). Studies from Italy and France suggest older age, higher disability and progressive MS are associated with severe COVID-19, yet there remains uncertainty around the influence of DMTs.

Objectives

Given the many approved MS DMTs and the relatively low frequency of COVID-19 in MS patients per country, international data sharing is desirable to examine the impact of DMTs on COVID-19 severity. Here, we present the first results of the COVID-19 in MS global data sharing initiative of the MS International Federation and MS Data Alliance and many other data partners to inform MS clinical management during the COVID-19 pandemic.

Methods

Clinician-reported data from 21 countries were aggregated into a dataset of 1540 patients. Characteristics of admission to hospital, admission to intensive care unit (ICU), need for artificial ventilation, and death, were assessed in patients with confirmed or suspected COVID-19 infection using log-binomial regression. Adjusted prevalence ratios (aPR) were calculated adjusting for age, sex, MS type, and Expanded Disability Status Scale (EDSS).

Results

Of 1540 patients, 476 (30.9%) with suspected and 776 (50.4%) with confirmed COVID-19 were included in the analysis. Older age, progressive MS and higher EDSS were associated with higher frequencies of severe outcomes. Anti-CD20 DMTs, ocrelizumab and rituximab, were positively associated with hospital admission (aPRs=1.19 & 1.58), ICU admission (aPRs=3.53 & 4.12), and the need for artificial ventilation (aPRs=3.17 & 7.27) compared to dimethyl fumarate. Higher frequencies of all three outcomes were associated with combined anti-CD20 DMT use compared to all other DMTs (hospitalisation aPR=1.49; ICU aPR=2.55; ventilation aPR=3.05) and compared to natalizumab (hospitalisation aPR=1.99; ICU aPR=2.39; ventilation aPR=2.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases and upon exclusion of each contributing data source in turn. No associations were observed between DMTs and death.

Conclusions

This study used the largest federated international cohort of people with MS and COVID19 currently available. We demonstrate a consistent association of anti-CD20 DMTs with hospitalisation, ICU admission and use of artificial ventilation suggesting their use among MS patients at risk for COVID-19 exposure may be a risk factor for more severe COVID-19 disease. To address study limitations, further research incorporating comorbidities, smoking and body mass index is required. Alternative study designs are needed to address questions on COVID-19 susceptibility among people with MS.

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Presenter Of 1 Presentation

Epidemiology Oral Presentation

PS05.02 - Validation of three Secondary Progressive Multiple Sclerosis classification methods in five registries within the SPMS Research Collaboration Network

Abstract

Background

Assigning Secondary Progressive Multiple Sclerosis (SPMS) course consistently is challenging as it is based on a gradual worsening in neurological disability independent of relapses. Clinical SPMS assignment may therefore vary between registries depending on clinical practice. Consequently, a comparison of SPMS between registries would benefit from an objective definition of SPMS.

Objectives

To validate three different methods for classifying patients into Relapsing Remitting Multiple Sclerosis (RRMS) or SPMS, compared to the clinical assignment, in five European Multiple Sclerosis (MS) registries.

Methods

Data from MS registries in Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients), and the United Kingdom (UK) (5,086 patients) were used. Patients with either RRMS or SPMS, age ≥ 18 years at index date (date with the latest Expanded Disability Status Scale (EDSS) observation) were included. Index period was 01/2017 - 12/2019. Three EDSS centric classification methods were applied; method 1: a modified real world EXPAND criteria (Kappos, L. et al., 2018. The Lancet 391(10127), 2018), method 2: the data-derived definition from Melbourne University but without pyramidal Functional Score (Lorscheider, J. et al., 2016. Brain 139(9)), method 3: the decision tree classifier from Karolinska Institutet (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674). The classifications were compared to the clinical assignment, where sensitivity (SPMS as true positive), specificity (RRMS as true negative) and accuracy were calculated as similarity measurements.

Results

The overall classification performance (sensitivity, specificity, accuracy) among classifiable patients were; method 1: (0.47, 0.85, 0.79), method 2: (0.77, 0.87, 0.85), method 3: (0.84, 0.83, 0.84). The proportions of unclassifiable patients with each method were; method 1: 20.0%, method 2: 32.2%, method 3: 0%. Methods 2 & 3 provided a high sensitivity, specificity and accuracy, while method 1 provided high specificity but low sensitivity. Method 3 was the only method having no unclassifiable patients.

Conclusions

Our findings suggest that these methods can be used to objectively assign SPMS with a fairly high performance in different registries. The method of choice depends on the research question and to what degree unclassifiable patients are tolerable.

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Author Of 2 Presentations

Prognostic Factors Poster Presentation

P0420 -  Performance on Symbol Digits Modalities Test preceding conversion to Secondary Progressive Multiple Sclerosis (ID 1254)

Speakers
Presentation Number
P0420
Presentation Topic
Prognostic Factors

Abstract

Background

In an era of emerging new therapies for SPMS, neurologist are searching for robust tools to predict and identify conversion to SPMS. Cognitive impairment is prevalent in 40-75% of MS patients and supposedly more common in SPMS as it increases with age. Symbol Digits Modalities Test (SDMT) is a sensitive, easy administrated test of information processing speed and predicts driving capacity and future income in MS populations.

Objectives

In this pilot study we test if SDMT absolute values could be used to predict SPMS conversion, hypothesizing that SPMS patients prior to conversion have lower scores on SDMT compared to age and gender matched RRMS patients.

Methods

This is a Swedish MS Registry-based study. We extracted first SDMT score and age at testing, available for MS patients included in the registry. Then we selected RRMS patients with first SDMT value at least 4 years (mean ± SD, 6.5 ± 1.98) before SPMS onset n=192 (SPMS converters) and gender matched RRMS patients (n=192) that performed their first SDMT at the same age as SPMS converters. We performed a linear regression analysis using SDMT as dependent variable and age, gender, disease course (SP convert) as independent variables.

Results

RRMS patients that later converted to SPMS, had statistically significant lower SDMT values compared to age and gender matched RRMS patients, p=3.43x10-13. Overall, SDMT decreased with age and was lower for men compared to women (p=0.0002 and p=0.024).

Conclusions

Differences in SDMT absolute values correlate with and precede SPMS conversion at the group level. High variation of inter-individual SDMT performance is likely to limit the usefulness of SDMT to predict SPMS by itself, but SDMT could be an integrated component of a more complex prediction algorithm.

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Epidemiology Poster Presentation

P0482 - Objective classification methods result in an increased proportion of secondary progressive multiple sclerosis in five patient registries (ID 1120)

Abstract

Background

Secondary progressive MS (SPMS) is a research area that is attracting more attention as better treatment options are still needed for this patient group. The assignment of SPMS by clinicians can differ between countries and may be influenced by drug prescription guidelines, reimbursement issues and other societal limitations.

Objectives

To compare the clinically assigned SPMS proportion to three objective SPMS classification methods in five MS registries.

Methods

Data from MS registries in the Czech Republic (CR) (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (UK) (5,086 patients) were used. Inclusion criteria were patients with relapsing remitting (RR)MS or SPMS with age ≥ 18 years at the beginning of the index period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS three different classification methods were applied; method 1: modified real world EXPAND criteria (Kappos et al, Lancet 2018:391; 1263-1273), method 2: the data-derived definition from Melbourne University without the pyramidal Functional Systems Score (Lorscheider et al, Brain 2016:139; 2395-2405) and method 3: the decision tree classifier from Karolinska Institutet (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).

Results

The SPMS proportions per registry, when comparing the clinically assigned SPMS with the results of the three classification methods, were CR: 8.8%, 21.3%, 22.1%, 25.0%; Denmark: 15.5%, 27.5%, 25.4%, 28.0%; Germany: 15.6%, 15.4%, 16.7%, 25.4%; Sweden: 23.7%, 20.8%, 23.2%, 24.6% and UK: 34.3%, 21.7%, 38.4%, 58.3% for clinical SPMS and methods 1, 2 and 3, respectively.

Conclusions

The proportion of clinically assigned SPMS patients varies between MS registries. When applying other classification methods, the SPMS proportion generally increases but remains variable between registries. As some of the classification methods have extensive requirements regarding data density, the number of unclassifiable samples created are considerable for some of the registries, which will influence the results. Providing a classification method that depends on objective information could prove useful when attempting to estimate the proportion of SPMS patients in MS populations but the choice of method may depend on the data characteristics of the individual MS registry.

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