Introduction: MRI activity is less frequent among secondary progressive multiple sclerosis (SPMS) patients. In the current study, we aimed to identify SPMS patients with higher radiological disease activity (RDA) and determine their clinical characteristics. Methods: We evaluated the occurrence of RDA in SPMS patients followed at the Sheba Multiple Sclerosis Center between January 1, 2015, and December 31, 2020. All patients underwent brain and spinal cord MRI examinations as a routine follow-up unrelated to clinical disease activity. Patients were subdivided into RDA and non-RDA MRI groups based on the presence of active gadolinium-enhancing T1 lesions and/or new/enlarging T2 lesions. Demographic variables and disease-related data were compared. Results: One hundred consecutive SPMS patients, 74 females, median age of 50 years, disease duration of 19.5 years, and neurological disability by the Expanded Disability Status Scale (EDSS) score of 6.0, were included in the study. The RDA group comprised 35 patients (35%), of them 65.7% (n = 23) exhibited only brain MRI activity, 22.8% (n = 8) only spinal cord MRI activity, and 11.4% (n = 4) had both. Patients in the RDA group were diagnosed at a younger mean (SD) age of 28.2 (8.9) versus 33.7 (10.1) years and were younger with a mean (SD) age of 47.8 (9.9) versus 53.4 (10.1) years, as compared with the non-RDA group. No significant differences were found in relation to disease duration, EDSS, exposure to immunomodulatory treatments, and duration of immunomodulatory treatments. Conclusions: RDA unrelated to clinical symptomatology was more frequent in a subgroup of young SPMS patients.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Over 50% of relapsing-remitting multiple sclerosis (MS) patients evolve overtime into the secondary progressive (SPMS) disease course [1] characterized by gradual worsening and irreversible neurological deficits [2]. The time frame of conversion to SPMS is frequently obscure and in many patients defined retrospectively [3]. No standardized definition for SPMS existed till 2016, when an objective universal definition was established [4]. In accordance, SPMS is regarded as neurological deterioration, reaching a score of 4.0 or more by the Expanded Disability Status Scale (EDSS) that is confirmed within a period of 3 months in the absence of relapses [4, 5].

Despite the new criteria, it is still challenging to assess SPMS patients in relation to disease activity. Neurological deterioration by the EDSS is mainly based on lower extremities dysfunction; hence, worsening in the upper extremities, urinary control, or cognitive function may not always be reflected [6]. MRI, however, can provide an objective measurement of disease activity [7]. About third of SPMS patients experience either clinical or radiological disease activity (RDA), defined as active SPMS [7, 8]. Identification of patients with active SPMS is of importance since nowadays, several immunomodulatory treatments are available for these patients including siponimod, mitoxantrone, cladribine, and interferon beta 1-b [9-13]. Other high-efficacy therapies such as natalizumab, alemtuzumab, ocrelizumab, rituximab, and fingolimod were suggested for active SPMS, yet their effectiveness is under question [11, 14-17]. In the current study, we retrospectively evaluated the rate of RDA in SPMS patients in both brain and spinal cord MRI examinations and analyzed the related clinical variables associated with neuroaxis ongoing inflammation.

MethodsStudy Design

We conducted a retrospective observational study to evaluate RDA in SPMS patients followed at the Sheba Multiple Sclerosis Center between January 1, 2015, and December 31, 2020. Data were obtained from the Sheba Medical Center Multiple Sclerosis Data Registry that was established to collect long-term health-related variables of subjects diagnosed with MS from referral areas around the country and captures approximately 80% of MS cases in Israel. The Sheba Medical Center Multiple Sclerosis registry is certified by the Israeli Ministry of Justice (Registry number 597247) and is increasingly being used in research [18-20]. Demographics and disease-related data including EDSS score, disease duration, the usage of immunomodulatory treatments, and duration of treatments were collected. Patients were considered treated if they received immunomodulatory treatment for at least 3 consecutive months before performance of brain MRI; patients who received ocrelizumab, almetuzumab, or cladribine were considered treated if they received the last dose within 6- or 12-month intervals, respectively, before the MRI examination.

Inclusion criteria were (1) diagnosis of SPMS [4]; (2) disease duration ≥10 years; (3) EDSS score ≥4.0 in two consecutive neurological exams, at least 3 months apart; (4) brain and spinal cord MRI examinations performed within the study period as a part of routine follow-up; (5) no clinical worsening within 6 months of the MRI examinations. Exclusion criteria were (1) acute clinical relapse; (2) steroid treatment within the 3 months prior to the MRI examinations; (3) any systemic disease that impairs or worsens ambulation.

MRI Data Acquisition

MRI examinations were conducted with a magnet of 1.5 or 3.0 T scanners (Signa Excite; GE Medical Systems, USA) by means of a single-shot, spin echo, diffusion-weighted, echo-planar imaging sequence (∼60 axial, 2.6 mm thick slices, no gap; FOV = 256 mm × 256 mm, matrix size = 256 × 256, providing a voxel size of 1 mm × 1 mm × 2.6 mm), with standardized head or spinal positioning. High-resolution T1-weighted images were acquired before and after the administration of gadolinium (GD) using 3D MPRAGE sequence with 1 mm thick slices. Axial 2-dimensional T2 spin echo and 3-dimensional T2 FLAIR images were also acquired. The number and volume of GD-enhancing lesions and/or new or enlarged T2 lesions were quantified using semi-automated segmentation analysis software (MSET-1.9, Matlab-12). Patients that demonstrated active brain lesions were examined to exclude a possible relapse. Patients were classified into RDA and non-RDA MRI groups in accordance with the occurrence or absence of at least one GD-enhancing T1 lesion or new or enlarging T2 lesion on either brain, cervical, or thoracic spinal cord exams. The results are based on a single brain MRI scan for each patient. For patients with more than one exam during the study period, the most recent one was included in the analysis, excluding predilection of a more active scan.

Statistical Analysis

Descriptive statistics are reported for the overall study sample and for each study group. For categorical variables, frequencies and percentages were used, and for continuous variables, mean, median, standard deviation, and interquartile range were reported. Statistical significance between groups was examined by the χ2 test for categorical variables and t test for continuous variables. The significance level was p value <0.05. All statistical analyses were performed by SAS (version 9.4).

Results

One hundred SPMS patients, 74 females, median age of 50 years, disease duration of 19.5 years and EDSS score 6.0, were included in the study. The time frame between the performance of brain MRI scan to spinal cord MRI scans was mean 1.26 (SD ± 1.6 years). Demographic and clinical characteristics are presented in Table 1.

Table 1.

Demographic and clinical data of study participants

Patients were divided into two groups based on the existence of RDA. The RDA group comprised 35 (35%) patients; 65.7% (n = 23) exhibited only brain MRI activity, 22.8% (n = 8) had only active spinal cord lesions, and 11.4% (n = 4) had both brain and spinal cord active lesions. The majority, 54.2% (n = 19), had new T2 lesions, and 45.7% (n = 16) had GD-enhancing lesions. The non-RDA group comprised 65 (65%) patients; all had stable MRI without evidence of active brain or spinal cord lesions. Patients in the RDA group were younger and also at younger age at the time of disease onset as compared to non-RDA group. There were no significant differences between the groups in relation to the percent of patients treated with immunomodulatory treatments or the duration of treatment. Similarly, there were no differences between the groups in relation to gender distribution, disease duration, and neurological disability. In relation to immunomodulatory treatment, 22/68 (32.4%) of treated SPMS patients had RDA as compared to 13/32 (40.6%) with RDA in untreated patients.

Discussion

In the current study, we found that 35% of SPMS patients demonstrate active MRI lesions in either the brain or spinal cord, unrelated to clinical worsening during routine follow-up. These findings reflect the existence of neuroinflammation in a subgroup of SPMS patients and support the clinical rationale to continue immunomodulatory treatments in these patients. The strength of our study is that we examined MRI activity in the brain, cervical, and thoracic spinal cord. To the best of our knowledge, this is the first study to evaluate RDA along the neuroaxis in patients with SPMS. It is well known that the major process of neurodegeneration is responsible for the neurological deterioration during the SPMS phase [21]. As noted in earlier studies, the main MRI features of this neurodegenerative process are slowly expanding lesions associated with cortical volume loss and subpial demyelination [22]. Once progression has developed, it is assumed that immunomodulatory treatments have limited effects in halting cumulative disability [23]. However, the existence of an ongoing silent inflammatory activity, mainly in younger patients, implies that the processes of active demyelination associated with axonal injury are still operating in this group of patients [24].

In our study, 35 of 100 SPMS patients had RDA. This finding is in line with the results of a large multicenter cohort study that reported disease activity in about third of SPMS patients [8]. Yet, unlike our study, that cohort found isolated RDA only in 20% (291/1414) of patients, though only brain activity was evaluated, while in our study, the spinal cord exams demonstrated additional RDA. In another study that included 26 SPMS patients, a higher rate of 58% of patients showed contrast-enhancing lesions on brain MRI without associated clinical worsening [25]. Similar to our findings, no significant differences were found for disease duration and gender [8]. We showed that RDA is associated with young age and younger age at MS onset, which can both be related to higher level of neuroinflammation that predominates in younger patients, whereas the occurrence of neurodegenerative changes increases with age [24, 26].

In relation to immunomodulatory treatment, we found that treatment was associated with a lower rate of RDA, implying efficacy of the treatments to reduce it. In accordance, a radiological follow-up of SPMS patients after discontinuation of immunomodulatory treatment showed the appearance of RDA, specifically contrast-enhancing lesions, in 21% of patients [27]. Our study assessed both brain and spinal cord RDA, and the distribution of RDA was mainly in the brain. Brain RDA was present in the majority (77.1%) of patients, while spinal cord RDA occurred in 34.2%, while 11.4% had both brain and spinal cord active lesions. These findings are in accordance with the known absent correlation of cord MRI metrics with concomitant brain damage and disability. MS cord pathology was reported to be independent of associated brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual [28].

Taken together, our findings highlight the importance of MRI as a tool for monitoring disease activity in SPMS patients. We demonstrated that RDA exists in SPMS patients unrelated to clinical disease activity, and therefore we suggest following SPMS patients by annual imaging assessment to enable relevant therapeutic decisions.

Statement of Ethics

The study was approved by the Institutional Review Board at Sheba Medical Center (protocol 5596-08). Each patient record was coded anonymously to ensure confidentiality during statistical analyses, and the need for informed consent was waived.

Conflict of Interest Statement

D.N. Zohar, S. Dreyer-Alster, C. Hoffmann, and G. Harari have no conflicts of interest to declare. D. Magalashvili has received honoraria or consulting fees from Bayer, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, and Sanofi, and research support from Biogen, Merck, Roche, and Sanofi. M. Dolev has received honoraria or consulting fees from Bayer, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, and Sanofi and research support from Biogen, Merck, Roche, and Sanofi. A. Achiron has received honoraria or consulting fees from Bayer, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, and Sanofi and research support from Biogen, Merck, Roche, and Sanofi.

Funding Sources

No funding source had a role in the preparation of this article.

Author Contributions

Daniela Noa Zohar: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept; and analysis or interpretation of data. David Magalashvili, Mark Dolev: major role in the acquisition of data and drafting/revision of the manuscript for content. Sapir Dreyer-Alster, Chen Hoffmann, and Gil Harari: analysis and interpretation of data and drafting/revision of the manuscript for content. Anat Achiron: study concept and design; major role in acquisition of data; analysis or interpretation of data; and drafting/revision of the manuscript for content, including medical writing for content.

Data Availability Statement

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available by request to any qualified investigator from the corresponding author (DN.Z).

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