Original articleRISCOP–Cognitive profile in a Portuguese cohort of radiological isolated syndrome patients: A case-control study
Introduction
The radiologically isolated syndrome (RIS), first described by Okuda in 2009, consists on the incidental discovery of white matter lesions suggestive of multiple sclerosis (MS) on brain magnetic resonance imaging (MRI) scans demonstrating dissemination in space, in the absence of prior neurological dysfunction suggestive of demyelinating events or other identifiable reason for the imagiological findings (Okuda et al., 2009). Okuda criteria consider ovoid and well-circumscribed lesions with or without corpus callosum involvement, measuring >3 mm and fulfilling Barkhof criteria (at least 3 out of 4) for dissemination in space. In 2016, the MAGNIMS study group reviewed RIS criteria, focused on lesion location, suggesting that the description of radiological evidence of dissemination in space and time, as proposed in the most recent 2017 revision of McDonald criteria for the diagnosis of MS should be also applied in subjects with RIS (Thompson et al., 2018; Filippi et al., 2016).
A large multicenter retrospective study evaluating 451 RIS patients showed that clinical events were identified in 34% of individuals within a 5-year period from the first brain MRI. In this study, younger age (<37 years), male gender and spinal cord lesions were the most significant predictors for a first clinical event (Okuda et al., 2014).
Besides clinical factors, other biomarkers have been identified as potential risk factors for subclinical MS, as they are associated with clinically defined MS (CDMS). These include abnormal visual evoked potentials, cerebrospinal fluid (CSF) neurofilament light chain elevated levels and the presence of oligoclonal bands (OCB) in CSF (Lebrun et al., 2009; Matute-Blanch et al., 2018). On 3D quantitative volumetric studies, normalized whole-brain volume, normalized cerebral cortical volume, and normalized cerebellar white matter volume have been found to be significantly lower in patients with RIS compared with healthy individuals (Rojas et al., 2015; George et al., 2021; Hosseiny et al., 2020).
RIS patients manifest lower levels of health-related quality of life (QOL) and fatigue, alterations that can be reported since diagnosis. (Lebrun et al., 2016) Also, the occurrence of cognitive deficits in RIS subjects has also been a matter of study. In fact, over the last years, many studies revealed cognitive impairment is frequently observed at an early stage of MS, with predominantly involvement of information processing speed (IPS), working memory, attention and executive functions (Lebrun et al., 2016; Deloire et al., 2006). Few studies showed that similar cognitive domains appear to be most consistently impaired in RIS and MS patients compared with healthy subjects. Indeed, cognitive impairment is a common feature in MS, affecting up to 70% of patients and could predict the conversion to CDMS among CIS patients. Likewise, cognitive deficits seem to be a risk factor for RIS conversion to CDMS, regardless of the presence of other risk factors for a future symptomatic demyelinating event (Lebrun et al., 2010; Amato et al., 2012; Labiano-Fontcuberta et al., 2016; Zipoli et al., 2010).
Data from clinical trials establishing the benefit of disease modifying treatment (DMT) in RIS is lacking and therefore the most recent recommendations do not support treatment in this condition, even when the findings suggest subclinical MS (Makhani, 2020); it is proposed only active monitoring of patients with periodical clinical and radiological follow-up (De Stefano et al., 2018). In fact, autopsy studies suggest that some individuals with incidental demyelination may never have experienced clinical symptoms in their lifetime, so careful consideration needs to be given to whether the potential benefits of treatment outweigh medication-related side effects (Makhani, 2020; Alshamrani et al., 2017). Therefore, RIS patients could have some subclinical evidence of disease activity and the decision to treat, especially those who present risk factors for subsequent MS, is probably a question of time.
In our study, the main goal was to characterize the cognitive profile of a multicentric Portuguese cohort of RIS patients, compared to a control group. Additionally, we also intended to compare fatigue, health-related QOL, anxiety and depression levels, as well as the clinical and demographic data between RIS and control groups.
Section snippets
Methods
This is a multicentric cross-sectional comparative study involving a cohort of RIS patients from 5 Portuguese tertiary centers and 2 secondary centers. The study protocol was approved by the Local Ethics Committees.
Results
We evaluated 31 patients with RIS (median age 46 years, IQR [(Dusankova et al., 2012-52], 72% women) and 19 control individuals (median age 32 years, IQR [(O'Jile et al., 2005-48], 71% women). Due to dropouts prior to the cognitive evaluation from restrictions in the context of COVID-19 pandemic, we were unable to obtain controls for the previously planned 1:1 age and gender match; however, the study groups did not differ statistically regarding baseline demographics, namely age, gender,
Discussion
In the current study, we analyzed a cohort of 31 RIS patients and 19 controls from 7 different Portuguese centers using BICAMS. This battery is a brief, reliable and valid tool that can be applied by non-neuropsychologists, and is recommended by an international expert consensus committee for cognitive evaluation in MS, which the main goal was to obtain standardized measures, particularly focused on international use to facilitate comparison across settings (Benedict et al., 2012;
Conclusions
To our knowledge, this is the first study on a Portuguese cohort of RIS patients assessing cognitive profile with BICAMS. BICAMS is an internationally recognized tool for brief and practical assessment for cognitive impairment in individuals with MS and applicable by non-neuropsychologists in clinical practice, particularly important in smaller centers with lower access to neuropsychological assessment. A non-neglectable part of our cohort (16% RIS and 10% controls) presented cognitive
Statement
The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. The corresponding author attests that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted.
Funding
This study received no funding.
Ethics
This study was carried out with the approval of the ethics committee of each participating hospital and in accordance with the Declaration of Helsinki.
Author statement
Category 1.
A. Conception and design of study
B. Acquisition of data
C. Analysis and/or interpretation of data
Category 2
A. Drafting the manuscript.
B. Revising the manuscript critically for important intellectual content
Category 3
A. Approval of the version of the manuscript to be published
Vanessa Carvalho: 1A, 1B, 1C, 2A, 2B, 3A
Carolina Soares: 1A, 1B, 1C, 2A, 2B, 3A
Inês Gomes: 1A, 1B, 1C, 2A, 2B, 3A
Andreia Carvalho: 1A, 1B, 1C, 2A, 2B, 3A
Filipa Serrazina: 1A, 1B, 1C, 2A, 2B, 3A
Sofia Grenho
Declaration of Competing Interest
The authors declare no conflicts of interest related to this publication.
Acknowledgments
The authors thank Biogen for the formative sessions on Multiple Sclerosis and for the support on the delineation of this multicentric project.
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These authors contributed equally to the manuscript