RISCOP–Cognitive profile in a Portuguese cohort of radiological isolated syndrome patients: A case-control study

Highlights

• This the first study using BICAMS in Radiologically isolated patients (RIS).

• Cognitive impairment is present at the earliest stages of demyelination.

• Verbal memory and learning might be impairment in RIS patients.

Abstract

Introduction

Radiologically isolated syndrome (RIS) refers to the incidental discovery of white matter lesions suggestive of MS, on brain MRI, in asymptomatic patients. Recent studies suggest similar features of cognitive impairment between RIS and MS patients. Also, lower levels of health-related quality of life (QOL) and fatigue are reported in such patients.

Aims

characterize and compare the cognitive profile of a multicentric Portuguese cohort of RIS patients with a control group.

Methods

multicentric comparative study of a cohort of adult patients with RIS, and age and gender-matched controls followed in the headache outpatient clinic with prior MRI not fulfilling criteria for RIS diagnosis. We conducted interviews with participants, collected clinical data and applied the BICAMS battery and self-reported questionnaires (HADS, MFIS, MSQOL-54).

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). Prevalence of cognitive impairment did not differ between groups (16% of the RIS and 10% of the controls, p=0.579). We found no differences between groups on the BICAMS tests, although the results of the California Verbal Learning Test (CVLT-II) score presented a trend to significance, with a lower value on the RIS group (53.9 vs. 59.3, p=0.066). There were no significant differences regarding fatigue, QOL, anxiety/depression scores.

Conclusion

this is the first study on a Portuguese cohort of RIS patients assessing cognitive profile with BICAMS. A non-neglectable part of our cohort presented cognitive impairment. Our findings add to previous studies in suggesting that a more pronounced impairment of verbal memory and learning, evaluated by CVLT-II, may be present in RIS patients compared to controls. BICAMS should be assessed on future studies with larger cohorts.

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.