Neurología 37 (2022) 557—563 NEUROLOGÍA www.elsevier.es/neurologia ORIGINAL ARTICLE Gadolinium-enhanced brain lesions in multiple sclerosis relapse L. Martín-Aguilar a , S. Presas-Rodriguez b , À. Rovira c , J. Capellades d , A. Massuet-Vilamajó e , L. Ramió-Torrentà f , M. Tintoré g , L. Brieva-Ruiz h , E. Moral i , A. Cano-Orgaz j , Y. Blanco k , J. Batlle-Nadal l , O. Carmona m , M. Gea b , J.V. Hervás-García h , C. Ramo-Tello b,∗ a Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain b Multiple Sclerosis Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain c Neuroradiology Section, Hospital Universitari Vall d’Hebrón, Barcelona, Spain d Neuroradiology Department, Hospital del Mar, Barcelona, Spain e Neuroradiology Section, Diagnostic Imaging Institute, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain f Multiple Sclerosis Unit, Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain g Multiple Sclerosis Unit, Hospital Universitari Vall Hebrón, Barcelona, Spain h Multiple Sclerosis Unit, Hospital Universitari Arnau de Vilanova, Lleida, IRBLLEIDA, Spain i Multiple Sclerosis Unit, Hospital de Sant Joan Despí Moisès Broggi, Barcelona, Spain j Neurology Department, Hospital de Mataró, Mataró, Barcelona, Spain k Multiple Sclerosis Unit, Hospital Clínic, Barcelona, Spain l Hospital de Santa Tecla de Tarragona, Tarragona, Spain m Neurology Department, Hospital de Figueres, Figueres, Girona, Spain Received 10 August 2021; accepted 28 October 2021 Available online 7 December 2021 KEYWORDS Abstract Multiple Sclerosis; Objective: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by ana- Relapse; lyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before MRI; methylprednisolone (MP) treatment. Gadolinium Methods: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter enhancement double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treat- ment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. Abbreviations: DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; GBCAs, gadolinium-based contrast agents; Gd+, gadolinium-enhanced; MP, methylprednisolone; MRI, magnetic resonance imaging; ON, optic neuritis. ∗ Corresponding author. E-mail address: cramot.germanstrias@gencat.cat (C. Ramo-Tello). https://doi.org/10.1016/j.nrl.2021.10.005 0213-4853/© 2021 Sociedad Española de Neurologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). L. Martín-Aguilar, S. Presas-Rodriguez, À. Rovira et al. Results: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0—4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p = 0.002). Conclusion: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario. © 2021 Sociedad Española de Neurologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). PALABRAS CLAVE Lesiones cerebrales captantes de gadolinio en el brote de los pacientes con esclerosis Esclerosis múltiple; múltiple Brote; Resonancia Resumen magnética; Objetivo: Estudiar la paradoja clínico-radiológica en el brote de la esclerosis múltiple (EM) Lesiones captantes de mediante el análisis de lesiones captantes de gadolinio (Gd+) en la RM cerebral antes del gadolinio tratamiento con metilprednisolona (MP). Métodos: Analizamos la RM cerebral basal de 90 pacientes con EM en brote de 2 ensayos clínicos aleatorizados multicéntricos fase IV que demostraron la no inferioridad de diferentes vías y dosis de MP, realizadas antes del tratamiento con MP y en los 15 días siguientes a la aparición de los síntomas. Se analizaron el número y la localización de las lesiones Gd+. Se estudiaron las asociaciones mediante análisis univariado. Resultados: El 62% de los pacientes tenía al menos una lesión Gd+ cerebral y el 41% de los pacientes tenía 2 o más lesiones. La localización más frecuente fue la subcortical (41,4%). Se encontraron lesiones Gd+ cerebrales en el 71,4% de los pacientes con síntomas de tronco cerebral o cerebelo, en el 57,1% con síntomas medulares y en el 55,5% con neuritis óptica. El 30% de los pacientes con síntomas cerebrales no tenían lesiones Gd+ y sólo el 4,.6% de los pacientes tenían lesiones Gd+ sintomáticas. El análisis univariante mostró una correlación negativa entre la edad y el número de lesiones Gd+ (p = 0,002). Conclusiones: La mayoría de los pacientes en brote mostraron varias lesiones Gd+ en la RM cerebral, incluso cuando la manifestación clínica fue medular u óptica. Nuestros hallazgos ilustran la paradoja clínico-radiológica en el brote de la EM y apoyan el valor de la RM cerebral en este escenario. © 2021 Sociedad Española de Neurologı́a. Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by- nc-nd/4.0/). Introduction clinical trials and often being used as the primary outcome in exploratory Phase II studies.7,8 Brain MRI is the most useful tool for multiple sclerosis There are few published studies that evaluate the (MS) diagnosis, helping to determine its dissemination in role of Gd+ lesions in brain MRI at the time of relapse. time and space.1 Gadolinium enhancement (Gd+) is a sensi- We found only two retrospective studies3,9 ; the first tive technique for detecting active MS lesions and confirms study showed that 69% of relapsed patients had Gd+ the inflammatory activity of the disease. The correlation lesions, and almost 50% of them had two or more Gd+ between Gd+ lesions and clinical disease activity is not well lesions.3 The second study found Gd+ lesions in only known.2,3 36.5% of relapsed patients and showed that Gd+ enhance- Previous studies have shown that Gd+ lesions are not a ment depended on age and was correlated with disease good surrogate marker for relapses4 because of the poor duration and Expanded Disability Status Scale (EDSS) correlation between MRI lesions and the clinical disease scores.9 course.5 This ‘‘clinico-radiological paradox’’ was described With the aim of evaluating the existence of the clinico- by Barkhof in 2002.6 Nevertheless, brain MRI has value in radiological paradox in MS relapse, we analyzed the number monitoring treatment effects and disease activity, serving and location of Gd+ lesions on brain MRI before methylpred- as an important secondary outcome measure in Phase III nisolone (MP) treatment. 558 Neurología 37 (2022) 557—563 Figure 1 Flowchart of patient selection. Methods Demographic and clinical variables Study population Demographic characteristics (age and sex) and clinical char- acteristics (disease duration and use of disease-modifying An analysis was performed on the basal data of a subset of therapy (DMT)) were analyzed. Clinical relapse manifesta- 90 relapsed patients from two different Phase IV multicenter tions were classified as brainstem-cerebellum, spinal cord, double-blind randomized clinical trials led by our research optic neuritis (ON) and others. Baseline EDSS scores were team that showed noninferiority of different routes and assessed before starting MP treatment, and previous EDSS doses of MP administration (ClinicalTrials.gov NTC 007537 scores were collected. and NTC 01986998). The clinical trial NTC 007537 showed the A relapse was defined as a new symptom that lasted more noninferiority of the administration of 1 g of intravenous MP than 24 h and that represented an increase of more than 1 compared to 1250 mg of oral MP.10 The recruitment period point in the total EDSS score. Relapses were classified as for this study was from 2008 to 2011. The second clinical mild (EDSS score increased < 1 point), moderate (EDSS score trial NTC 01986998 showed the noninferiority of 1250 mg of increased 1—2.5 points) or severe (EDSS score increased ≥ 3 oral MP compared to 675 mg of oral MP11 ; the recruitment points).10—12 For mild relapses with an increase of <1 point, period for this clinical trial was from 2013 to 2015. The study the involvement of two or more functional systems was included adults who had experienced a relapse and met the mandatory. All patients were evaluated by neurologists spe- 2005 McDonald criteria for RRMS in the first clinical trial and cializing in MS. the 2010 McDonald criteria for RRMS in the second clinical trial. Both studies were approved by the Ethics Committees Radiological variables and MRI protocol of the participating centers, and all patients gave written informed consent to participate. Brain MRI was assessed at the time of relapse diagnosis, The inclusion criteria for the two studies were as follows: within 15 days of symptom onset and before MP treat- (a) an age of 18—59 years; (b) an EDSS score of 0—5.0 prior ment (baseline MRI). The brain MRIs were acquired on a to relapse; (c) recent onset (<15 days) of relapse without 1.5- or 3-T MRI scanner. We obtained an axial proton den- fever; and (d) one month of clinical stability prior to relapse. sity (PD) and T2-weighted turbo spin-echo sequence and The exclusion criteria were as follows: (a) clinically isolated an axial T1-weighted spin-echo sequence before and after syndrome or progressive MS; (b) use of steroids during the the injection of 0.1 mmol/kg of body weight of macrocyclic previous 3 months; (c) ongoing pregnancy or breastfeeding; gadolinium-based contrast agents (GBCAs) (gadoterate meg- and (d) any concomitant disease that could contraindicate lumine; 5-min delay). For each sequence, 44 contiguous, treatment with steroids. 3-mm-thick slices were obtained. The number of Gd+ lesions 559 L. Martín-Aguilar, S. Presas-Rodriguez, À. Rovira et al. was analyzed. The location of the Gd+ lesions on the baseline Table 1 Baseline characteristics. MRI scan (periventricular, subcortical, juxtacortical, brain- stem and cerebellum) and the presence of symptomatic Gd+ Baseline characteristics (n = 90) lesions were analyzed retrospectively. A Gd+ lesion was con- Age (years; mean ± SD) 38.1 ± 8.8 sidered symptomatic when its location matched the clinical Sex (n, % women) 70 (77.8%) topography of the relapse. All brain MRIs were evaluated Baseline EDSS score (median, IQR) 2 [1—2.5] centrally by two neuroradiologists with expertise in MS (AR Disease duration (years; median, IQR) 9 [6—16] and JC). Disease-modifying therapy (n; %) (n = 87) No treatment 44 (50.6%) Interferon 32 (36.8%) Statistical analysis Glatiramer acetate 10 (11.5%) Dimethyl fumarate 1 (1.1%) Descriptive statistics are shown as the mean (± standard deviation) or median (interquartile range (IQR)) for continu- Relapse characteristics ous variables or as frequencies (percentages) for categorical Baseline relapse EDSS score (median, 3 [3—4] variables. Associations were studied using univariate anal- IQR) (n = 87) ysis. Comparisons were performed by Student’s t-test for Severity (n, %) (n = 87) parametric continuous variables, the Mann—Whitney test Mild 24 (27.6%) for nonparametric continuous variables and the chi-squared Moderate 59 (67.8%) test for categorical variables. The Kruskal—Wallis test was Severe 4 (4.6%) used to compare groups. We used Spearman’s coefficient Topography (n, %) (n = 90) to assess the correlation between variables. p values were Optic neuritis (ON) 9 (10%) two-sided, with values less than 0.05 considered statisti- Brainstem-cerebellum 28 (31.1%) cally significant. All statistical analyses were performed with Spinal cord 42 (46.7%) the statistical software IBM SPSS Statistics 23 (Chicago, IL, Others 11 (12.2%) USA). MRI characteristics (n = 90) Patients with Gd+ lesions (n, %) 56 (62.2%) Data availability Number of Gd+ lesions (median, IQR) 1 [0—4] 1 lesion (n, %) 19 (21.1%) 2 lesions (n, %) 11 (12.2%) Anonymized data not published within the article are avail- 3 or more lesions (n, %) 26 (28.9%) able upon request. Symptomatic Gd+ lesions Yes 17 (18.9%) No 22 (24.4%) Results n/a (ON and myelitis without spinal cord 51 (56.7%) MRI) Ninety patients were included in the study (Fig. 1). The SD: standard deviation; EDSS: Expanded Disability Status Scale; mean age was 38 years (± 8.8), and 78% of patients were IQR: interquartile range; ON: optic neuritis; Gd+ lesions: women. The median score of the baseline EDSS was 2.0 (IQR gadolinium-enhanced lesions; n/a: not available. 1—2.5), and the median disease duration was 9 (IQR 6—16) years. Forty-four patients (50.6%) did not receive DMT, and Twenty patients out of 28 with brainstem-cerebellum approximately the other 50% received injectable platform relapse (71.4%), 24 out of 42 patients with myelitis (57.1%) therapies. Regarding the topography of the relapse, 42 and five out of 9 patients with ON (55.6%) had Gd+ lesions on patients (45.6%) were myelitis, 28 (31.1%) were classified brain MRI. Among patients with brain symptoms (n = 39), only as brainstem-cerebellum, 9 (10%) were ON and 11 (12.2%) 17 (43.6%) had a symptomatic Gd+ lesion, and 12 (30.8%) were classified as others. Moderate relapse severity (n = 59, did not have brain Gd+ lesions. The univariate analysis did 65.6%) was the most common. The baseline demographic, not show relationships between clinical topography, relapse clinical, and imaging data are provided in Table 1. severity or disease-modifying treatment and the presence Fifty-six patients (62.2%) had Gd+ brain lesions, the or number of Gd+ brain lesions (Table 2). For the analysis of median number of Gd+ lesions was 1 (IQR 0—4), and 41% symptomatic Gd+ lesions, we excluded patients with clini- of patients had 2 or more Gd+ lesions. The most frequent cal myelitis and no spinal cord MRI, and we also excluded location of Gd+ lesions was the subcortical region (41.4%), patients with optic neuritis because axial brain sequences followed by the juxtacortical region (23.2%), periventricu- are not adequate for the study of the optic nerve. lar region (20.7%), brainstem (8.8%) and cerebellum (5.9%) (Fig. 2). We found a relationship between age and the pres- ence of Gd+ lesions (36.2 vs 41.1 years, p = 0.013), with more Gd+ lesions in patients who were younger (p = 0.002, Discussion Table 2). The disease duration and baseline EDSS were lower in patients with Gd+ lesions (8 vs 13 years; p = 0.26 and 2.0 Our study shows that 62% of relapsed MS patients have Gd+ vs 4.0, p = 0.32), but these differences were not statistically brain lesions, and it provides valuable data regarding the significant. No differences were observed in baseline EDSS number and location of Gd+ lesions. Most relapsed patients (Table 2). showed several Gd+ lesions on brain MRI, even when the 560 Neurología 37 (2022) 557—563 Figure 2 Location of Gd+ lesions. Table 2 Relationship between Gd+ lesions and clinical characteristics. Presence of Gd+ lesions p Number of Gd+ p lesions (n = 90) Gd+ (n = 56) Gd- (n = 34) Age (years; mean ± SD) 41 ± 9.1 36 ± 8.1 0.013 — 0.002 Baseline EDSS (median, IQR) 2 (1.5—2.5) 2 (1—3) 0.41 — 0.98 Disease duration (years; median, IQR) 8 (6—13) 13 (6—18) 0.26 — 0.32 Baseline relapse EDSS (median, IQR) 2 (1.5—2.5) 4 (3—4) 0.32 — 0.92 Severity (n, %) (n = 87) Mild (n = 24) 13 (23.2%) 11 (32.4%) 0.65 1 (0—3) 0.36 Moderate (n = 59) 37 (66.1%) 22 (64.7%) 1 (0—4) Severe (n = 4) 3 (5.4%) 1 (2.9%) 5 (0—48) Topography (n, %) Optic neuritis (ON) (n = 9) 5 (8.9%) 4 (11.8%) 1 (0—2) Brainstem-cerebellum (n = 28) 20 (35.7%) 8 (23.5%) 0.58 1 (0—5) 0.61 Spinal cord (n = 42) 24 (42.9%) 18 (52.9%) 1 (0—3) Others (n = 11) 7 (12.5%) 4 (11.8%) 1 (0—5) Disease-modifying therapy (n, %) (n = 87) Yes (n = 43) 25 (44.6%) 18 (52.9%) 0.38 1 (0—4) 0.63 No (n = 44) 29 (51.8%) 15 (44.1%) 1 (0—4) Gd+ lesion: gadolinium-enhanced lesion; SD: standard deviation; EDSS: Expanded Disability Status Scale; IQR: interquartile range; ON: optic neuritis. clinical manifestation was in the spinal cord or in the optic previously described,9,13,14 and it is well known that the fre- nerve, as more than 50% of patients with spinal cord symp- quency and number of Gd+ lesions were higher in younger toms or ON had silent Gd+ brain lesions. MS patients.15,16 Otherwise, although disease duration and The percentage of patients with brain Gd+ lesions is sim- baseline EDSS were lower in patients with Gd+ lesions, we ilar to that previously reported in one of the retrospective have not found statistically significant associations, unlike studies (69%)3 but differs from the percentage reported by previously published studies.9 the other study (36.5%).9 This difference may have arisen In our study, patients who had a higher presence of because we did not include patients with progressive MS and Gd+ lesions were those with brainstem-cerebellum relapse because the time from symptom onset to the performance of (70%), but we did not find a significant difference regarding baseline MRI was shorter (<15 days vs. more than 1 month). clinical topography because approximately half of our Furthermore, we found a negative correlation between age patients had spinal cord symptoms, and we did not include and the presence of Gd+ lesions. This relationship has been spinal cord MRI in our clinical trial protocols. When we 561 L. Martín-Aguilar, S. Presas-Rodriguez, À. Rovira et al. analyzed only patients with brain symptoms, less than MS relapse did not have brain Gd+ lesions. These results 50% of patients had a symptomatic Gd+ lesion that could highlight the clinico-radiological paradox in MS relapse and explain the symptoms of relapse, and approximately 30% support the value of brain MRI in therapeutic decision mak- of patients with MS relapse did not have brain Gd+ lesions. ing. Further radiological studies in larger cohorts are needed These findings support the use of brain MRI in MS relapse to better understand the pathophysiology of MS relapse. to avoid misdiagnosis, especially in those cases in which relapse involves a therapeutic change. The natural history of Gd+ lesions is highly variable and unpredictable; axonal loss and degeneration are thought Ethics to contribute to clinical worsening and disability,17,18 but we found that most Gd+ lesions are clinically silent. In our NTC 007537 and NTC 01986998 studies were approved by the study, more than 50% of patients with spinal cord symptoms research committee of the institution. or with optic neuritis had silent Gd+ lesions on brain MRI. These findings highlighted the mismatch between clinical and radiological measures in MS. Thus, performing a brain Funding sources MRI in all patients who relapse, even in those patients with spinal cord symptoms, might increase sensitivity in detect- This work was supported in part by the Ministry of Health of ing radiological activity and would help optimize therapeutic Spain (grant numbers EC07/90278 and EC11/132) and per- decisions. sonal grant Rio Hortega CM19/00042 to LMA. Given the evidence regarding the deposition of gadolin- ium in deep gray matter structures, particularly in the dentate nucleus and globus pallidus, which is orders of mag- nitude more evident in patients receiving linear GBCAs than Conflicts of interest macrocyclic GBCAs,19—23 the European Commission decided to suspend the use of linear chelates for CNS MRI exami- Lorena Martín-Aguilar has received speaking honoraria nations and recommended that Gd should be used only if from Roche. Silvia Presas-Rodríguez has received speak- essential and in the lowest dose needed.24 Indications to ing honoraria from Novartis and Merck. Àlex Rovira use GBCAs in clinical practice should be limited, and the serves/served on scientific advisory boards for Bayer, Bio- policy of reducing their use in MS patients is reasonable. gen, Novartis, OLEA Medical, Sanofi-Genzyme, and Synthetic Even so, MS patients need serial MRI to detect silent activ- MR; has received speaker honoraria from Bayer, Biogen, ity, monitor disease activity and detect treatment-related Bracco, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, complications.25 Our study suggests that it could be infor- and Teva Pharmaceutical Industries Ltd.; and has research mative to obtain a postcontrast T1 sequence on brain MRI agreements with Siemens AG. Mar Tintore has received in patients with a clinical suspicion of relapse, as a marker compensation for consulting services and speaking hono- of blood-brain barrier disruption, to predict future disease raria from Almirall, Bayer Schering Pharma, Biogen-Idec, activity and especially in those patients in which the demon- Genzyme, Merck-Serono, Novartis, Roche, Sanofi-Aventis, stration of Gd+ lesions is a requirement to initiate or change Viela Bio and Teva Pharmaceuticals and is a coeditor of a specific disease-modifying treatment immunomodulatory Multiple Sclerosis Journal-ETC. Luis Brieva has received pay- treatment.26 ment as a consultant, as a speaker at scientific meetings, or A major limitation of our study is the lack of spinal cord travel expenses or research grants from Carlos III Institute of and optic nerve MRI at the moment of relapse. Considering Health and Pharmaceutical Industry: Merck, Biogen, Sanofi, that most of our patients had spinal symptoms, the per- Biogen, Roche, Bayer, Teva, Mylan, Almirall and Novartis. centage of patients with symptomatic Gd+ lesions would be Antonio Cano has received speaking honoraria from Novar- higher if a spinal MRI was performed. Another point to study tis, Teva, Sanofi-Genzyme, Merck, Serono and Roche. José would be the formation of new T2 lesions, but most of our Vicente Hervás-García has received speaking honoraria from patients did not have a recent MRI to compare, and the base- Roche and Sanofi. Cristina Ramo-Tello has received compen- line MRI was performed in the first 15 days from symptom sation for being a member of Scientific Advisory Boards as onset. Gd+ enhancement usually persists for 2—6 weeks27 ; well as travel and research support from Almirall Pharma, thus, the possibility of having new T2 lesions without Gd+ Biogen-Idec, Genzyme, Merck-Serono, Novartis and Roche. enhancement is minor. Another point that should be high- The other authors report no conflicts. lighted in our study is the low proportion of patients under disease modifying treatment (DMT). Our clinical trials were conducted between 2008 and 2015, when many of patients were not treated because of the lack of highly effective References and well-tolerated treatments. This can be a reason why we could not find a difference in the percentage or the number 1. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revi- of Gd+ lesions between patients that were receiving or not sions of the McDonald criteria. Lancet Neurol. 2018;17:162—73, a DMT. http://dx.doi.org/10.1016/S1474-4422(17)30470-2. In summary, our results show that most patients with 2. Treabǎ CA, Bǎlaşa R, Podeanu DM, Simu IP, Buruian MM. relapse demonstrate several Gd+ lesions on brain MRI, even Cerebral lesions of multiple sclerosis: is gadolinium always irre- when the clinical manifestation is in the spinal cord or placeable in assessing lesion activity? Diagnostic Interv Radiol. the optic nerve. Otherwise, thirty percent of patients with 2014;20:178—84, http://dx.doi.org/10.5152/dir.2013.13313. 562 Neurología 37 (2022) 557—563 3. Ortiz Salas PA, Bareño Silva J, Cabrera Lopez L, Rueda Vergara frequency decreases with increasing age in relapsing- K, Rovira Cañellas À. Resonancia magnética con gadolinio en la remitting multiple sclerosis. Neurology. 2001;56:422—3, fase aguda de las recaídas en esclerosis múltiple. Rev Neurol. http://dx.doi.org/10.1212/wnl.56.3.422. 2017;64:241, http://dx.doi.org/10.33588/rn.6406.2016310. 17. Miller DH. Multiple sclerosis: use of MRI in evaluat- 4. Petkau J, Reingold SC, Held U, Cutter GR, Fleming TR, Hughes ing new therapies. Semin Neurol. 1998;18:317—25, MD, et al. Magnetic resonance imaging as a surrogate out- http://dx.doi.org/10.1055/s-2008-1040883. come for multiple sclerosis relapses. Mult Scler. 2008;14:770—8, 18. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk http://dx.doi.org/10.1177/1352458507088104. S, Bö L. Axonal transection in the lesions of mul- 5. Chard D, Trip SA. Resolving the clinico-radiological tiple sclerosis. N Engl J Med. 1998;338:278—85, paradox in multiple sclerosis. F1000Research. 2017;6, http://dx.doi.org/10.1056/NEJM199801293380502. http://dx.doi.org/10.12688/f1000esearch.11932.1. 19. Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka 6. Barkhof F. The clinico-radiological paradox in multiple sclerosis D. High signal intensity in the dentate nucleus and revisited. Curr Opin Neurol. 2002;15:239—45. globus pallidus on unenhanced T1-weighted MR images: 7. Sormani MP, Bonzano L, Roccatagliata L, Cutter GR, Man- relationship with increasing cumulative dose of a gadolin- cardi GL, Bruzzi P. Magnetic resonance imaging as a iumbased contrast material. Radiology. 2014;270:834—41, potential surrogate for relapses in multiple sclerosis: a http://dx.doi.org/10.1148/radiol.13131669. meta-analytic approach. Ann Neurol. 2009;65:268—75, 20. Quattrocchi CC, Mallio CA, Errante Y, Cirimele V, Carideo L, Ax http://dx.doi.org/10.1002/ana.21606. A, et al. Gadodiamide and dentate nucleus T1 hyperintensity 8. Sormani MP, Arnold DL, De Stefano N. Treatment effect in patients with meningioma evaluated by multiple follow- on brain atrophy correlates with treatment effect on dis- up contrast-enhanced magnetic resonance examinations with ability in multiple sclerosis. Ann Neurol. 2014;75:43—9, no systemic interval therapy. Invest Radiol. 2015;50:470—2, http://dx.doi.org/10.1002/ana.24018. http://dx.doi.org/10.1097/RLI.0000000000000154. 9. Tortorella C, Bellacosa A, Paolicelli D, Fuiani A, Di Monte E, 21. Radbruch A, Weberling LD, Kieslich PJ, Eidel O, Burth Simone IL, et al. Age-related gadolinium-enhancement of MRI S, Kickingereder P, et al. Gadolinium retention in the brain lesions in multiple sclerosis. J Neurol Sci. 2005;239:95—9, dentate nucleus and globus pallidus is dependent on http://dx.doi.org/10.1016/j.jns.2005.08.006. the class of contrast agent. Radiology. 2015;275:783—91, 10. Ramo-Tello C, Grau-López L, Tintoré M, Rovira A, http://dx.doi.org/10.1148/radiol.2015150337. Ramió I, Torrenta L, Brieva L, et al. A randomized 22. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray clinical trial of oral versus intravenous methylpred- DL, Thielen KR, et al. Intracranial gadolinium deposition after nisolone for relapse of MS. Mult Scler J. 2014;20:717—25, contrast-enhanced MR imaging. Radiology. 2015;275:772—82, http://dx.doi.org/10.1177/1352458513508835. http://dx.doi.org/10.1148/radiol.15150025. 11. Hervás-García JV, Ramió-Torrentà L, Brieva-Ruiz L, Batllé- 23. Ramalho J, Castillo M, AlObaidy M, Nunes RH, Ramalho Nadal J, Moral E, Blanco Y, et al. Comparison of two M, Dale BM, et al. High signal intensity in globus pal- high doses of oral methylprednisolone for multiple scle- lidus and dentate nucleus on unenhanced T1-weighted rosis relapses: a pilot, multicentre, randomized, double- MR images: evaluation of two linear gadolinium- blind, non-inferiority trial. Eur J Neurol. 2019;26:525—32, based contrast agents. Radiology. 2015;276:836—44, http://dx.doi.org/10.1111/ene.13851. http://dx.doi.org/10.1148/radiol.2015150872. 12. Nos C, Sastre-Garriga J, Borràs C, Río J, Tintoré M, Mon- 24. EAM. Gadolinium-containing contrast agents | European talban X. Clinical impact of intravenous methylprednisolone Medicines Agency. Available from: https://www.ema.europa. in attacks of multiple sclerosis. Mult Scler. 2004;10:413—6, eu/en/medicines/human/referrals/gadolinium-containing- http://dx.doi.org/10.1191/1352458504ms1068a. contrast-agents [accessed 11.5.20]. 13. Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, 25. Igra MS, Paling D, Wattjes MP, Connolly DJA, Hoggard N. Multiple et al. Clinical and pathological insights into the dynamic nature sclerosis update: Use of MRI for early diagnosis, disease moni- of the white matter multiple sclerosis plaque. Ann Neurol. toring and assessment of treatment related complications. Br J 2015;78:710—21, http://dx.doi.org/10.1002/ana.24497. Radiol. 2017;90, http://dx.doi.org/10.1259/bjr.20160721. 14. Koch MW, Mostert J, Zhang Y, Wolinsky JS, Lublin FD, Strijbis E, 26. Wattjes MP, Ciccarelli O, Reich DS, Banwell B, de Ste- et al. Association of age with contrast-enhancing lesions across fano N, Enzinger C, et al. 2021 MAGNIMS—CMSC—NAIMS the multiple sclerosis disease spectrum. Neurology. 2021;97, consensus recommendations on the use of MRI in patients http://dx.doi.org/10.1212/wnl.0000000000012603, e1334—42. with multiple sclerosis. Lancet Neurol. 2021;20:653—70, 15. Stone LA, Smith ME, Albert PS, Bash CN, Maloni H, Frank http://dx.doi.org/10.1016/S1474-4422(21)00095-8. JA, et al. Blood-brain barrier disruption on contrast-enhanced 27. Cotton F, Weiner HL, Jolesz FA, Guttmann CRG. MRI mri in patients with mild relapsing-remitting multiple scle- contrast uptake in new lesions in relapsing-remitting MS rosis: relationship to course, gender, and age. Neurology. followed at weekly intervals. Neurology. 2003;60:640—6, 1995;45:1122—6, http://dx.doi.org/10.1212/WNL.45.6.1122. http://dx.doi.org/10.1212/01.WNL.0000046587.83503.1E. 16. Filippi M, Wolinsky JS, Sormani MP, Comi G, Euro- pean/Canadian Glatiramer Acetate Study Group. Enhancement 563