Author Of 2 Presentations
LB01.06 - Interrupting disease modifying treatment for pregnancy in multiple sclerosis – effect on disease activity and serum neurofilament light chain
Abstract
Background
Pregnancy in MS typically goes along with reduced disease activity in the third trimester, followed by an increase in relapse frequency postpartum. Neurofilament light chain levels in serum (NfL) is a specific biomarker of neuroaxonal injury. Increased NfL levels are associated with relapses and MRI activity, while disease modifying treatment (DMT) response is reflected by a decrease of NfL.
Objectives
The objective of this study was to evaluate whether interrupting DMT due to pregnancy leads to increased NfL levels in MS.
Methods
We investigated prospectively documented pregnancies in the Swiss MS Cohort Study. Serum samples were collected 6- or 12-monthly and were analyzed by Simoa NF-light® assay. Uni- and multivariable mixed effect models were used to investigate associations between clinical characteristics and longitudinal NfL levels.
Results
We investigated 72 pregnancies in 63 relapsing MS patients (median age 31.4; disease duration 7.1 years; EDSS 1.5 at last visit before birth). In total, 433 samples were included: 92 during pregnancy or up to initiation of DMT but max. 9 months postpartum (pregnancy/post-partum period, pp), 167 prior to pp and 174 after the pp. Four patients had no DMT before, during and after pregnancy. DMT was continued in 13/72 pregnancies (>6 months during pregnancy: 6 rituximab/ocrelizumab, 4 natalizumab, 1 interferon-beta 1a i.m., 1 fingolimod and 1 glatiramer acetate). In univariable analysis, NfL levels were on average 22% higher during vs. outside the pp (β: 1.22, 95%CI: 1.10-1.35; p<0.001). We observed 29 relapses during the pp. In a multivariable analysis, relapses (within 120 days before serum sampling) were associated with 98% higher NfL (β: 1.98, 95%CI: 1.75-2.25; p<0.001); NfL was 7% higher per EDSS step increase (β: 1.07, 95%CI: 1.01-1.12; p=0.013) and on average 13% higher during vs. outside the pp (β: 1.13, 95%CI: 1.03-1.24; p=0.009). The effect of the pp on NfL disappeared after including DMT exposure (yes/no) at the sampling timepoint to the model (β:1.07, 95%CI: 0.97-1.18; p=0.178). Patients sampled during DMT had on average 12% lower NfL levels compared to patients without (β:0.88, 95%CI: 0.79-0.98; p=0.019).
Conclusions
Higher NfL levels were found during pp. This increase was independent of relapses suggesting increased subclinical disease activity during this time span. After including DMT into the model the effect of pregnancy on NfL disappeared: strategies allowing to continue DMT during pregnancy may be warranted.
PS09.05 - Value of serum neurofilament light chain levels as a biomarker of suboptimal treatment response in MS clinical practice
- Ö. Yaldizli
- P. Benkert
- A. Maceski
- M. Barakovic
- R. Todea
- A. Cagol
- S. Schaedelin
- G. Disanto
- J. Oechtering
- A. Orleth
- D. Rey
- T. Sinnecker
- R. Rahmanzadeh
- S. Zadic
- R. Galbusera
- L. Achtnichts
- S. Aeschbacher
- A. Chan
- D. Conen
- T. Derfuss
- O. Findling
- B. Fischer-Barnicol
- K. Hrusovsky
- H. Kropshofer
- P. Lalive
- J. Lieb
- J. Lorscheider
- P. Maggi
- C. Müller
- S. Müller
- Y. Naegelin
- J. Müller
- J. Oksenberg
- C. Pot
- R. Du Pasquier
- E. Radue
- A. Salmen
- J. Vehoff
- E. Waubant
- S. Wellmann
- H. Wiendl
- J. Wuerfel
- C. Zecca
- K. Berger
- C. Gobbi
- L. Kappos
- D. Leppert
- C. Granziera
- J. Kuhle
Abstract
Background
Serum neurofilament light chain (sNfL) reflects neuro-axonal damage and may qualify as a biomarker of suboptimal response to disease modifying therapy (DMT).
Objectives
To investigate the predictive value of sNfL in clinically isolated syndrome (CIS) and relapsing-remitting (RR) MS patients with established DMT for future MS disease activity in the Swiss MS Cohort Study.
Methods
All patients were on DMT for at least 3 months. sNfL was measured 6 or 12-monthly with the NF-light®assay. The association between sNfL and age was modeled using a generalized additive model for location scale and shape. Z-scores (sNfLz) were derived thereof, reflecting the deviation of a patient sNfL value from the mean value of same age healthy controls (n=8865 samples). We used univariable mixed logistic regression models to investigate the association between sNfLz and the occurrence of clinical events (relapses, EDSS worsening [≥1.5 steps if EDSS 0; ≥1.0 if 1.0-5.5 or ≥0.5 if >5.5] in the following year in all patients, and in those fulfilling NEDA-3 criteria (no relapses, EDSS worsening, contrast enhancing or new/enlarging T2 lesions in brain MRI, based on previous year). We combined sNfLz with clinical and MRI measures of MS disease activity in the previous year (EDA-3) in a multivariable mixed logistic regression model for predicting clinical events in the following year.
Results
sNfL was measured in 1062 patients with 5192 longitudinal samples (median age 39.7 yrs; EDSS 2.0; 4.1% CIS, 95.9% RRMS; median follow-up 5 yrs). sNfLz predicted clinical events in the following year (OR 1.21 [95%CI 1.11-1.36], p<0.001, n=4624). This effect increased in magnitude with increasing sNfLz (sNfLz >1: OR 1.41 [95%CI 1.15-1.73], p=0.001; >1.5: OR 1.80 [95%CI 1.43-2.28], p<0.001; >2: OR 2.33 [95%CI 1.74-3.14], p<0.001). Similar results were found for the prediction of future new/enlarging T2 lesions and brain volume loss. In the multivariable model, new/enlarging T2 lesions (OR 1.88 [95%CI 1.13-3.12], p=0.016) and sNfLz>1.5 (OR 2.18 [95%CI 1.21-3.90], p=0.009) predicted future clinical events (n=853), while previous EDSS worsening, previous relapses and current contrast enhancement did not. In NEDA-3 patients, change of sNfLz (per standard deviation) was associated with a 37% increased risk of clinical events in the subsequent year (OR 1.37 [95%CI 1.04-1.78], p=0.025, n=587).
Conclusions
Our data support the value of sNfL levels, beyond the NEDA3 concept, for treatment monitoring in MS clinical practice.
Author Of 8 Presentations
P0092 - Incidence of recurrence of disease activity after fingolimod discontinuation in older patients (ID 264)
Abstract
Background
Discontinuing fingolimod (FTY) in older patient is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal.
Objectives
We investigate the incidence of RDA and rebound in MS patients who discontinued fingolimod for any reason, and looked for risk factors influencing this risk. Of particular interest was the subgroup of older patients who discontinued FTY for other reasons than disease progression. Our hypothesis was that these patients, older at treatment discontinuation, previously stable on treatment, would have a statistically lower risk of recurrence of activity given their age.
Methods
Retrospective analysis of 288 MS patients on FTY. Recurrence of disease activity (RDA) was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal; among these patients with RDA, we considered rebound when the levels of disease activity surpassed pretreatment activity. We defined a subgroup of patients older than ≥ 50 years at FTY discontinuation and with NEDA-3 status during FTY treatment.
Results
128 patients discontinued FTY from 2011 to 2019 mainly for estimated high PML risk (3.6%), inefficacy (26.6%) or pregnancy planning (18%). RDA occurred in 45 patients (35.2 %) within 3.4 months (SD 2). Younger age at disease onset (p=0.008), highly active disease at baseline (p=0.037) and previous treatment with natalizumab (p=0.050) increased the risk of RDA at FTY discontinuation. Sixteen patients (12.5%) experienced rebound with a mean of 9 Gd enhancing lesions. Baseline MRI activity (p=0.008) and longer wash-out period (p=0.001) correlated with rebound. Twenty-two patients were older than 50 years at FTY withdrawal and discontinued FTY for other reasons than disease progression. The incidence of RDA was lower, yet not statistically significant, from younger patients (18.2 % RDA, p=0.068).
Conclusions
RDA occurred in 35.2% of our patients including 12.5% with rebound. Older age at FTY discontinuation may be associated with a lower risk of disease reactivation, although the incidence of RDA remains high, as 1/5 of the older patients, previously stable on treatment, experienced RDA.
P0096 - Intrathecal immunoglobulin M synthesis is associated with higher disease activity and severity in Multiple Sclerosis (ID 1101)
- J. Oechtering
- S. Schaedelin
- P. Benkert
- S. Müller
- L. Achtnichts
- J. Vehoff
- G. Disanto
- O. Findling
- B. Fischer-Barnicol
- A. Orleth
- A. Chan
- A. Salmen
- C. Pot
- C. Granziera
- I. Heijnen
- P. Lalive
- J. Wuerfel
- T. Lincke
- J. Lieb
- Ö. Yaldizli
- T. Sinnecker
- T. Derfuss
- A. Regeniter
- C. Zecca
- C. Gobbi
- L. Kappos
- D. Leppert
- J. Kuhle
Abstract
Background
Additional biomarkers reflecting disease activity and predicting severity of multiple sclerosis (MS) are urgently needed.
Objectives
To explore whether intrathecal immunoglobulin (Ig) M synthesis is associated with time from disease onset to first relapse, MS Severity Score (MSSS) and time to first initiation of high efficacy disease modifying treatments (DMT) in patients with relapsing MS in the Swiss Multiple Sclerosis Cohort study.
Methods
487patients were categorized by presence of CSF oligoclonal IgG bands (OCGB) and quantitative intrathecal IgG and IgM production (Intrathecal Fraction, IF). Treatments were classified according to "no therapy", "platform", "oral" and "high efficacy". Multivariable Cox proportional hazard models or a multivariable linear model, adjusted for relevant covariables, were used to assess time from disease onset to described endpoints and associations with the MSSS.
Results
OCGB were present in 89.3%, IgGIF in 66.3%, IgMIF in 26.9% and IgAIF in 11.9% of patients. Patients with IgMIF had a shorter interval from disease onset to first relapse (HR 1.887 [CI 1.181, 3.014], p<0.01) compared to those without OCGB and IgGIF and IgMIF. Quantitatively, patients with IgMIF above versus below the median had a 1.75- fold increased hazard of occurrence of a first relapse (HR 1.746 [CI 1.097, 2.781]; p=0.019). IgMIF positive patients had on average a 1.24 steps higher MSSS compared with those without any intrathecal Ig synthesis (estimate: 1.243 [CI 0.501,1.986], p<0.01), followed by patients with OCGB and quantitative production of IgGIF (estimate: 0.966 [CI 0.283, 1.650], p<0.01) and patients with only OCGB (estimate: 0.716 [CI -0.030, 1.461], p=0.060). Accordingly, patients with IgMIF production had a shorter interval to initiation of high efficacy DMT (HR 2.788 [CI 1.306, 5.951], p<0.01). Quantitatively, above versus below median IgMIF was associated with a 2.36-fold risk of escalation to a high efficacy DMT (HR 2.361 [CI 1.304, 4.277]; p<0.01).
Conclusions
In relapsing MS, presence of intrathecally produced IgM is associated with higher disease activity, more severe disease course and earlier use of high efficacy treatments. Intrathecally produced IgM may qualify as useful prognostic biomarker for therapeutic decision making in early stage of disease.
P0097 - Intrathecal immunoglobulin M synthesis is associated with higher serum neurofilament light chain levels and increased MRI disease activity in MS (ID 1089)
- J. Oechtering
- S. Schaedelin
- P. Benkert
- M. Barakovic
- A. Maceski
- A. Orleth
- D. Rey
- T. Sinnecker
- R. Rahmanzadeh
- S. Zadic
- R. Galbusera
- R. Todea
- A. Cagol
- L. Achtnichts
- S. Aeschbacher
- K. Berger
- A. Chan
- D. Conen
- T. Derfuss
- G. Disanto
- O. Findling
- B. Fischer-Barnicol
- I. Heijnen
- K. Hrusovsky
- H. Kropshofer
- P. Lalive
- J. Lieb
- T. Lincke
- J. Lorscheider
- P. Maggi
- C. Müller
- S. Müller
- Y. Naegelin
- J. Oksenberg
- C. Pot
- R. Du Pasquier
- E. Radue
- A. Regeniter
- A. Salmen
- J. Vehoff
- E. Waubant
- S. Wellmann
- H. Wiendl
- J. Würfel
- Ö. Yaldizli
- C. Zecca
- D. Leppert
- C. Gobbi
- L. Kappos
- C. Granziera
- J. Kuhle
Abstract
Background
Intrathecal IgM synthesis was reported to be associated with higher clinical disease activity and severity. We found an association also with earlier use of high efficacy treatments in relapsing MS (RMS).
Objectives
To explore whether patients with intrathecal IgM synthesis show a) higher serum neurofilament light chain levels (sNfL) as a reflection of neuronal damage, or b) signs of increased disease severity in cerebral MRI, in patients with RMS followed in the Swiss MS Cohort Study.
Methods
487 patients were categorized by presence of oligoclonal IgG bands (OCGB) and intrathecally produced IgG/M:
1) OCGB-/IgG-/IgM- (reference [ref]);
2) OCGB+/IgG-/IgM-;
3) OCGB+/IgG+/IgM- and
4) OCGB+/IgG+/IgM+.
sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modelled in 8865 healthy control samples to reflect the deviation of a patient sNfL value compared to mean values observed in same age healthy controls. Yearly T2 lesion number and occurrence of new/enlarging T2 lesions were automatically assessed in cerebral MRIs and checked manually. Contrast enhancing lesions (CEL) were manually quantified. Linear or negative binomial mixed models were used to investigate the associations between the four CSF Ig patterns and longitudinal sNfLz and MRI measures, adjusted for DMT and other covariates.
Results
IgM+ patients had higher sNfLz vs reference (estimate 0.50 [CI 0.12, 0.89], p=0.011), whereas those with only OCGB+ (0.11 [-0.28, 0.50], p=0.582) or with OCGB+/IgG+ (0.20 [-0.16, 0.56], p=0.270) did not (n=2970 observations). This was confirmed when analyzing only untreated patients adjusting for T2 and CEL numbers (1.16 [0.47, 1.86], p<0.01 vs 0.58 [-0.11, 1.27], p=0.1022 vs 0.51 [-0.11, 1.13], p=0.108 vs ref, respectively) (n=234).
IgM+ patients had 2.28-fold more T2 lesions ([1.51, 3.44], p<0.01) vs ref; for patients with only OCGB+ (1.61 [1.07, 2.43], p=0.0237) or OCGB+/IgG+ (1.58 [CI 1.08, 2.32], p=0.0179) (n=1580) this association was weaker.
IgM+ was associated with a 2.47-fold risk for new/enlarging T2 lesions on yearly follow-up MRIs vs ref (2.47 [1.28, 4.78], p<0.01) but not the two other patient groups (1.84 [CI 0.93; 3.65], p=0.0799 and 1.61 [CI 0.87; 2.95], p=0.1280) (n=861).
Conclusions
Intrathecal IgM synthesis was consistently associated with quantitative measures of neuro-axonal injury and disease severity in RMS. Our findings strongly support the clinical utiliy of this biomarker.
P0099 - Is disease activity prior to fingolimod initiation in treatment-naive patients predictive of response? (ID 323)
Abstract
Background
Randomized controled trials, post-hoc analysis and real-world post-marketing studies have confirmed fingolimod (FTY) efficacy over placebo as second-line therapy in case of persistent disease activity and in treatment-naive patients with rapidly evolving highly active RR-MS. In countries where fingolimod is available as first-line therapy without restrictions, we have an opportunity to observe long-term efficacy profile of this drug in treatment-naive patients according to their initial disease activity.
Objectives
To evaluate and compare the incidence of NEDA-3 status at last follow up according to the baseline MS disease activity.
Methods
Retrospective analysis of clinical and radiological data of 54 RR-MS patients treated with FTY. The patients were divided into highly active patients (HΑ) if ≥ 2 relapses in the year before treatment initiation and ≥1 Gd-enhancing T1 lesion or “not highly active” (NHA). NEDA-3 status at endpoint was defined as no relapses, no EDSS progression and no new T2 or Gd-enhancing lesions during the follow-up.
Results
Mean follow-up duration was 48.2, SD 18.4 months. FTY efficiently reduced relapses (NHA 90.3% reduction, p<0.001, HA 84.9%, p<0.001), and new Gd enhancing lesions (NHA 85.4% reduction, p=0.019, HA 92.3%, p=0.043). 53.7% reached NEDA-3 status at endpoint, although the distribution was different in the two subgroups with 62.2%, (n=23/37) of the NHA patients reaching NEDA 3 status compared to 35.3% (n=6/17) of the HA. The proportion of patients reaching NEDA-3 status decreased over time (first line : 80% at 2 years and 66% at 4 years, HA : 58% at 2 years and 38% at 4 years, p=0.042). 63% of patients were still on FTY at last follow-up (n=34/54). Main reason for discontinuation was lack of efficacy (75%, n=15/20).
Conclusions
Chances of reaching NEDA-3 status reduce over time with the highest relative benefit from FTY treatment observed when prescribed as a first line disease-modifying drug in treatment-naïve MS patients, which may favour its indication in that context rather than for HA patients only.
P0160 - Serum NfL z-scores derived from a large healthy control group reflect different levels of treatment effect in a real-world setting (ID 916)
- P. Benkert
- S. Schaedelin
- A. Maceski
- G. Disanto
- J. Oechtering
- M. Barakovic
- A. Orleth
- D. Rey
- T. Sinnecker
- Ö. Yaldizli
- R. Rahmanzadeh
- S. Zadic
- R. Galbusera
- R. Todea
- A. Cagol
- L. Achtnichts
- S. Aeschbacher
- A. Chan
- D. Conen
- T. Derfuss
- O. Findling
- B. Fischer-Barnicol
- K. Hrusovsky
- H. Kropshofer
- P. Lalive
- J. Lieb
- J. Lorscheider
- P. Maggi
- C. Müller
- S. Müller
- Y. Naegelin
- J. Oksenberg
- C. Pot
- R. Du Pasquier
- E. Radue
- A. Salmen
- J. Vehoff
- E. Waubant
- S. Wellmann
- H. Wiendl
- J. Wuerfel
- C. Zecca
- C. Gobbi
- L. Kappos
- K. Berger
- C. Granziera
- D. Leppert
- J. Kuhle
Abstract
Background
Serum neurofilament light chain (sNfL) levels reflect neuroaxonal damage and relate to disease activity in MS. sNfL may qualify as well as a biomarker of suboptimal treatment response to disease modifying therapies (DMT). Establishment of age-dependent reference ranges in healthy controls is a prerequisite for developing this biomarker for clinical use.
Objectives
To compare on-treatment sNfL levels with values from a healthy control cohort and to investigate the effect of DMTs on sNfL levels in patients from the Swiss MS Cohort Study.
Methods
sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modeled in healthy controls using a generalized additive model for location scale and shape to reflect the deviation of a patient sNfL value from the mean value of same age healthy controls. Linear mixed models were used to investigate the associations between clinical characteristics, DMT and longitudinal sNfLz. Interaction terms and splines were used to model sNfLz and for comparison log(NfL), and their dynamics under treatment.
Results
sNfL was measured in 1368 patients with 7550 longitudinal samples (baseline: median age: 41.9 yrs; 5.4% CIS, 83.2% RRMS, 5.6% SPMS, 5.8% PPMS; median EDSS: 2.0; median follow-up: 4.6 yrs) and 4133 healthy controls with 8865 samples (median age: 44.8 yrs). In the multivariable model, sNfLz increased with EDSS (0.131/step, [95% CI 0.101;0.161]), recent (<120 days) relapse (0.739 [0.643;0.835]) decreased with age (-0.014/year [-0.02;-0.009]), and time on DMT (-0.040/year [-0.054;-0.027]); sNfLz were lower when sampled while on more effective DMT (oral versus platform injectables: -0.229 [-0.344;-0.144]; monoclonal antibodies (mAB) versus platform injectables: -0.349 [-0.475;-0.224]), (p<0.001 for all associations). sNfLz were inversely associated with the hierarchy in efficacy of mAB over orals and orals over platform therapies with regard to slope and extent of decrease (interaction between time under DMT and DMT class: p<0.001). sNfLz, but not log(NfL) showed normalization of sNfL levels by mAB to healthy control levels.
Conclusions
The dynamic change of sNfLz on DMT reflects closely their relative clinical efficacy and is more meaningful than log(sNfL) by excluding age as a confounding factor. Use of sNfLz based on a large normative database as an age-independent sNfL measure improves the accuracy of the sNfL signal and hence their clinical utility.
P0261 - Paramagnetic rim lesions are specific to multiple sclerosis: an international multicenter 3T MRI study (ID 1025)
Abstract
Background
In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on MRI by their paramagnetic rims, and increasing evidence supports their association with clinical disease severity.
Objectives
To assess the prevalence and MS-specificity of paramagnetic rim lesions (PRL) on 3-tesla susceptibility-based MR brain images in MS vs non-MS cases in a multicenter sample drawn from 5 academic research hospitals at sites in Europe (Brussels, Lausanne, Milan) and the United States (NIH and JHU).
Methods
On submillimetric 3D T2*-segmented EPI brain MRI, the presence of PRL and central vein sign (CVS) were evaluated in the supratentorial brain of adults with MS (n=329) and non-MS neurological conditions (n=83). Non-MS cases were grouped as follows: (1) other-inflammatory neurological diseases (n=41); (2) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=10); (3) HIV-infected (n=10); (4) non-inflammatory neurological diseases (n=22).
ROC curve analysis, with diagnosis as dependent variable (MS vs non-MS), was applied to examine the diagnostic accuracy for each biomarker (PRL and CVS). Youden’s index method was used to obtain the optimal cutoff value for each biomarker.
Results
PRL were detected in 172/329 (52%) of MS cases vs. 6/83 non-MS cases (7%).
In MS, 58% of progressive cases had at least one PRL, compared to 50% of relapsing cases. MS cases with more than 4 PRL were more likely to have higher disability scores (EDSS, MSSS and ARMSS), but not significantly longer disease duration or older age.
In non-MS cases, PRL were seen exclusively in only a few inflammatory/infectious neurological conditions, including Susac syndrome (3 cases), neuromyelitis optica spectrum disorder (1 case), Sjögren disease (1 case) and HAM/TSP (1 case). Unlike in MS, PRL in non-MS cases were not associated with a high frequency of CVS+ lesions.
The identification of at least one PRL (optimal cutoff) was associated with high diagnostic specificity (93%), but relatively low sensitivity (52%) and accuracy (area under ROC curve=0.77), whereas CVS detection alone (optimal cutoff 35.5-38%) could better discriminate MS from non-MS cases with high specificity (96%), sensitivity (99%), and accuracy (area under ROC curve=0.99). The combination of the two biomarkers further improved the specificity (99%), but sensitivity remained low (59%).
Conclusions
PRL yielded high specificity for MS lesions. Future prospective multicenter studies should further validate its role as a diagnostic biomarker.
P0580 - Focal inflammatory activity and lesion repair are associated with brain atrophy rates in MS patients (ID 1092)
- A. Cagol
- M. Barakovic
- P. Benkert
- R. Todea
- R. Rahmanzadeh
- R. Galbusera
- S. Schaedelin
- P. Lu
- M. Weigel
- E. Radue
- Ö. Yaldizli
- J. Lorscheider
- T. Sinnecker
- M. Fartaria
- S. Müller
- L. Achtnichts
- J. Vehoff
- G. Disanto
- O. Findling
- A. Chan
- A. Salmen
- C. Pot
- P. Lalive
- C. Zecca
- T. Derfuss
- J. Lieb
- L. Remonda
- F. Wagner
- M. Vargas
- P. Maeder
- E. Pravata
- J. Weber
- C. Gobbi
- D. Leppert
- V. Silani
- J. Wuerfel
- L. Kappos
- J. Kuhle
- C. Granziera
Abstract
Background
The pathogenesis of neurodegeneration in multiple sclerosis (MS) is multifactorial and the determinants of brain atrophy rates are not completely understood.
Objectives
To investigate the association between annualized atrophy rate (AAR) of multiple brain measures (regional cortical thickness (CTh), volumes of basal ganglia, thalamus, white matter, gray matter, brain and brain parenchymal fraction (BPF)) and: (1) annualized rate of new and enlarging white matter lesions (WMLs); (2) annualized rate of resolved WMLs; (3) occurrence of progression independent of relapse activity (PIRA) during follow-up.
Methods
We included 1573 1.5T or 3T brain MRI scans from 378 patients of the Swiss MS Cohort Study (331 relapsing-remitting MS (RRMS), 27 clinically isolated syndrome (CIS), 11 secondary-progressive MS (SPMS), 9 primary-progressive MS (PPMS); 70% female; median age: 41.9 yrs; disease duration: 8.3 yrs; EDSS: 2.0; follow-up time: 4.0 yrs). Longitudinal changes in WMLs were obtained using an automated prototype (LeMan-PV). Brain volumes and CTh AARs were obtained using FreeSurfer longitudinal pipeline (v6.0) after WMLs filling. In patients fulfilling PIRA an EDSS progression had to be confirmed ≥6 months after the index event. Multivariable generalized linear models were used to model the association between AAR (dependent variable) and independent variables (1-3), correcting for age, sex, disease duration and baseline EDSS. p-values were adjusted for Bonferroni multiple comparison correction; for vertex-wise CTh analysis, Monte Carlo Z simulation was performed (cluster threshold p<0.05).
Results
We found positive associations between annualized rate of new and enlarging WMLs and (i) CTh AAR of 8 extensive clusters (bilateral frontal, temporal and occipital regions and right insula, all p<0.01) and (ii) AAR of: caudate bilaterally (p=0.02), white matter volume, brain volume and BPF (p<0.001 for all).
We also found a negative association between annualized rate of resolved WMLs and CTh AAR in 3 cortical clusters (right insula, precentral area and anterior cingulate region, all p<0.05); no associations with AAR of volumes emerged.
57 patients fulfilled PIRA whereas 295 experienced no EDSS progression events: no significant differences in AAR measures were found between these two groups.
Conclusions
In a large cohort of MS patients, with a median follow-up of 4 years, local radiological inflammatory and reparative activity were associated with AAR in multiple brain regions. PIRA did not seem to be related to increased AAR in any of the regions studied.
P0638 - Role of Gadolinium-based contrast agents to detect subclinical disease activity in clinically stable patients in the Swiss MS Cohort Study (ID 821)
- E. Ruberte
- Ö. Yaldizli
- R. Rahmanzadeh
- R. Galbusera
- R. Todea
- A. Cagol
- S. Subramaniam
- P. Benkert
- S. Müller
- L. Achtnichts
- J. Vehoff
- G. Disanto
- O. Findling
- A. Chan
- A. Salmen
- C. Pot
- P. Lalive
- C. Zecca
- T. Derfuss
- J. Lieb
- E. Radue
- L. Remonda
- F. Wagner
- M. Vargas
- P. Maeder
- E. Pravata
- J. Weber
- D. Leppert
- L. Kappos
- C. Gobbi
- C. Granziera
- J. Würfel
- J. Kuhle
Abstract
Background
Gadolinium (Gd)-based contrast agents are widely used to assess disease activity and treatment response by MRI in multiple sclerosis (MS). There is, however, increasing concern about their safety as their repeated administration may lead to brain parenchymal accumulation, while preclinical models suggest that they induce mitochondrial toxicity and neuronal cell death. Moreover, recent reports have demonstrated that three-dimensional (3D) T2-weighted Fluid-Attenuated-Inversion-Recovery (FLAIR) is highly sensitive in detecting new or enlarging MS lesions.
Objectives
To explore whether the presence of contrast enhancing lesions (CEL) based on Gd injection is more sensitive in detecting lesional activity in clinically stable MS patients in comparison to the analysis of new or enlarging MS lesions by 3D FLAIR.
Methods
MS patients being part of the observational, multicenter Swiss Multiple Sclerosis Cohort Study (SMSC) with contrast enhanced T1-weighted (T1w) images were included. Clinical stability was defined as no relapse and no Expanded Disability Status Scale (EDSS) increase during at least twelve months prior to MRI. Presence of CEL was assessed on contrast enhanced T1w images. Presence of new or enlarging T2w lesions was assessed manually on 3D FLAIR in an independent analysis by a different investigator in clinically stable MS patients presenting with CEL.
Results
3930 MRI scans (3.0 Tesla n=1497 (38%)) in 1057 participants (685 women, median age 42.0 years, 941 with relapsing MS, 116 with progressive MS, median EDSS 2.0 (range 1.5-3.5), median disease duration 7.4 years) were included.
Of 2620 MRI scans (66.7%) acquired in clinically stable conditions 46 (1.8%) demonstrated CEL. In all of these, new or enlarging T2w lesions were detectable by 3D FLAIR when a previous MRI was available for comparison (previous MRI available in 29/46; median number of new or enlarging T2w lesions: 3 (range 1-41, total number 176); median number of CEL: 1 (range 1-4, total number 47)).
Conclusions
In our large cohort from clinical practice, the assessment of new or enlarging lesions by 3D FLAIR was equally sensitive as the quantification of CEL to detect disease activity in clinically stable MS patients, challenging current practice of the use of Gd-enhanced MRI for monitoring of MS in clinical routine.