Abstract
Up until now, no information has existed regarding a comparison of the pattern and frequency of cognitive deficits between radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS) patients. Within this objective, Rao’s Brief Repeatable Battery and Stroop test were administered to 28 RIS patients, 25 CIS patients, and 22 healthy controls.
Conclusions:
The prevalence of cognitive deficits in RIS was similar to that of CIS. Cognitive deficits seem to be present in RIS patients regardless of the presence of risk factors for a future symptomatic demyelinating event.
Keywords
Introduction
The current research on the cognitive profile of radiologically isolated syndrome (RIS) patients suggests that there is a cognitive impairment pattern of RIS similar to that observed in multiple sclerosis (MS) itself.1,2 Nevertheless, most RIS patients included in previous reports were at high risk of developing MS and thus, they certainly could not be considered representative of the entire spectrum of RIS. Furthermore, there are no previous studies that have compared the cognitive profile in RIS with that found in clinically isolated syndrome (CIS). Based on this background, the present study was designed to compare for the first time the pattern of cognitive deficits between RIS and CIS patients and, in contrast to previous RIS research, the current investigation incorporates RIS individuals regardless of their risk of MS.
Methods
Study design and participants
CIS patients were recruited consecutively from September 2013 to June 2014 at four MS clinics in Madrid (Spain). RIS patients were searched from already existing MS databases of those MS clinics. Age at RIS diagnosis was between 18 and 55 years and the inclusion criteria were based on the diagnostic criteria for RIS by Okuda et al. 3 The inclusion criteria for CIS patients were as follows: 1) age between 18 and 55; and 2) baseline MRI with at least two T2-hyperintense lesions according to Swanton criteria. 4
Measurement instruments
Cognitive functioning was performed through the Rao Brief Repeatable Battery. 5 The Stroop test was administered to evaluate executive functions. 6 Depression severity was measured by the original 17-item version of the Hamilton Depression Rating Scale (HDRS), 7 and the Fatigue Impact Scale for Daily Use (D-FIS) was administered to measure subjective experience of fatigue.8,9
Procedures
RIS patients came to our attention after undergoing conventional brain magnetic resonance imaging (MRI) (1.5 Tesla) for various medical events not suggestive of MS. MRI examinations, including spinal cord imaging, were originated from non-uniform protocols from differing MS centers. Nevertheless, all examinations included axial fluid-attenuated inversion recovery, fast spin echo, T2- and T1-weighted sequences, without and with gadolinium in axial, coronal and sagittal planes of view. Cervical cord imaging included T1- and T2-weighted fast spin echo sequences in axial and sagittal planes.
Brain white matter abnormalities had initially been identified by a neuroradiologist and subsequently examined and verified by an MS specialist at each clinical site to guarantee dissemination-in-space Barkhof’s criteria were met. MRI scans were performed in each RIS patient on a 12-month basis. Although the frequency of follow-up MRI examinations in CIS patients was variable within participating centers, all CIS patients underwent MRI examination at three and 12 months after the first symptom.
All RIS patients underwent cervical MR, but only a subgroup (66.6%) agreed to undergo lumbar puncture for cerebrospinal fluid analysis.
Statistical analyses
The data were analyzed using SPSS version 21.0 (IBM Corp, 2012). Failure of any of the tests was defined as a Z score ⩽ 2.0 standard deviations (SD) compared to healthy controls and cognitive impairment as failure on at least two tests. One-way analysis of variance (ANOVA) was used to analyze group differences on all cognitive measures. Post-hoc comparisons were made using the Tukey test. Next, analysis of covariance (ANCOVA) (for continuous factors) or two-way univariate analysis of variance (for categorical factors) was used to elucidate which factors could underlie the differences in cognitive performance between groups. Logistic regression analyses were next performed to assess whether RIS patients with potentially high risk for a future symptomatic demyelinating event (as defined at the foot of Table 1) were more frequently cognitive impaired than those RIS patients with non-high risk of developing MS.
Demographic, clinical characteristics and cognitive performance from the entire clinical sample (N = 75).
Mean ± standard deviation (median) and frequency (%) are reported.
F-statistic for ANOVA continuous variables or H-statistic for Kruskal-Wallis test on categorical variables.
p value for test of significance on group differences (for ANOVA p < 0.05; for Kruskal-Wallis test p < 0.05/3 = 0.0167).
Superscripts (1,2,3) reflect p < 0.05 for pairwise between-categories post hoc comparisons.
Six of 28 (25 %) did not agree to undergo lumbar puncture.
F test became nonsignificant after adjusting for the effects of covariates (age, HDRS, fatigue total score) in a series of ANCOVAs or after adjusting for the effects of categorical variables (education level; depression level) in a series of two-way univariate analysis of variance.
RIS were considered as “RIS with high risk of developing MS group” if they had any of the following characteristics: a) presence of lesions within the spinal cord (nine of 28 RIS patients were included based on this criteria or b) no lesions of the spinal cord, but presence of at least two of the following characteristics: abnormal cerebrospinal fluid (positive oligoclonal bands or elevated immunoglobulin G index), gadolinium enhancing lesions or dissemination in time (two RIS patients were included according to these criteria).
Positive oligoclonal bands or an elevated immunoglobulin G index.
Percentage of patients with abnormalities on cognitive tests.
MS: multiple sclerosis; ANCOVA: analysis of covariance; CIS: clinically isolated syndrome; DIS: dissemination in space; EDSS: Expanded Disability Status Scale; HDRS: Hamilton Depression Rating Scale; RIS: Radiologically isolated syndrome; SDMT: Symbol Digit Modalities Test; PASAT: Paced Auditory Serial Addition Test.
Results
The data regarding the demographic and clinical characteristics of the sample are presented in Table 1. The three subgroups were similar for most characteristics although it should be noted that a near significant difference was found between the groups in terms of age (F = 2.74, p = 0.07), largely because the CIS group was slightly younger than both RIS and control subgroups. The median Expanded Disability Status Scale (EDSS) score was 0 (range: 0–4) in CIS patients and myelitis was the most common CIS initial symptom (32%), followed by optic neuritis (28%).
The means and SD for RIS/CIS patients and healthy controls on all cognitive tests are presented in Table 1. Fourteen of 28 (50%) RIS patients failed in at least one cognitive test, a proportion that did not differ from the CIS group (48%). A total of six (21.4 %) RIS patients fulfilled our criterion for cognitive impairment, virtually identical to that observed in CIS patients (20%). Notably, tests most frequently failed by both groups were those assessing information processing speed (Table 1).
The F test on processing speed and Stroop tests remained significant once we took into account the effects of the covariates in a series of ANCOVAs (data not shown).
Neither the failure of one cognitive test (odds ratio (OR) = 0.41; 95% confidence interval (CI) = 0.05–3.42) nor the failure of at least two cognitive measures (OR = 2.07; 95% CI = 0.11–20.21) were most frequent in those RIS patients with cervical cord lesions or with the presence of multiple known risk factors for a future demyelinating event.
Discussion
A novel and important finding of this study is that cognitive impairment in RIS patients was not significantly associated with the presence of the most important known markers of evolution to MS. Although based on a limited number of RIS patients, this observation is intriguing as it suggests that, in contrast to results that have been reported in CIS patients, 10 the presence of cognitive impairment in RIS patients may not herald reliably the conversion to relapsing–remitting MS patients. We acknowledge, however, that our sample of RIS patients is too small to draw conclusions and further longitudinal observation is required.
The study had several limitations. First, the sample size was relatively small. The literature, however, includes several studies with the same objectives with similar sample sizes.1,2 Second, there was a trend of higher inflammatory disease activity in the RIS group (contrast-enhancing lesions and dissemination-in-time criteria), which could have influenced the results. Third, the spinal cord MRI protocol was limited to the cervical spinal cord, and therefore there is a possibility that asymptomatic lesions within the thoracic region were unnoticed or unidentified. Fourth, the representativeness of our CIS sample could arguably be questioned (the number of spinal cord CIS patients is rather high as compared to other CIS cohorts). Fourth, our RIS group was slightly older when compared with both CIS and control groups and hence it might lead to worse information processing results. Finally, MRI assessment was not standardized across all participating centers.
In closing, our data suggest that cognitive deficits develop largely independently of focal and inflammatory disease activity. Future longitudinal and non-conventional imaging studies are warranted to clarify the pathological underpinnings of such cognitive impairment.
Footnotes
Conflict of interest
None declared.
Funding
Dr Benito-León is supported by the National Institutes of Health, Bethesda, MD, USA (NINDS #R01 NS39422), the Commission of the European Union (grant ICT-2011-287739, NeuroTREMOR), and the Spanish Health Research Agency (grant FIS PI12/01602).