Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome



Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system leading to physical deterioration and a wide range of neuropsychiatric signs and symptoms including cognitive impairment (CI).

It is well known that CI occurs at all stages of the disease, including patients with clinically isolated syndrome (CIS).

The aims of this study were to investigate the evolution of cognitive function in CIS patients over a period of 24 months and to determine brain MRI structural correlates associated with CI in CIS patients. This study is the first prospective, longitudinal clinical investigation of the association between the global, tissue specific and regional MRI outcomes and cognition in CIS patients on disease-modifying treatment.

220 CIS patients with the following characteristics were enrolled: (1) 18–55 years of age, (2) enrolled within 4 months from the clinical event, (3) demonstrated Expanded Disability Status Scale (EDSS) ≤3.5, and (4) displayed the presence of ≥2 T2-hyperintense lesions on diagnostic MRI and presence of ≥2 oligoclonal bands in cerebrospinal fluid obtained at the screening visit prior to steroid treatment.

Of the 220 CIS patients enrolled in the SET study, 81 consecutive CIS patients entered the NP substudy. All 81 participants were tested at baseline, 6, 12 and 24 months with the Czech-validated version of MACFIMS battery. Of those, four CIS patients at month 6 and one patient at month 12 did not undergo NP assessment.

The MACFIMS battery included the following tests:

•    Controlled Oral Word Association Test (COWAT) for measuring phonemic fluency;
•    Judgment of Line Orientation Test (JLO) for measuring visual–spatial ability;
•    California Verbal Learning Test, second edition (CVLT-II) for measuring verbal learning and memory, with total learning (CVLT-II TL) and delayed recall CVLT-II DR subtests;
•    Brief Visuospatial Memory Test-Revised (BVMT-R) for measuring visuospatial learning and memory, with total learning (BVMT-R TL) and delayed recall BVMT-R DR subtests;
•    Paced Auditory Serial Addition Test 3 (PASAT-3) for measuring rapid information processing, simultaneous allocation of attention to two tasks and reasonably intact calculation;
•    Symbol Digit Modalities Test (SDMT) for measuring rapid information processing, visual scanning, and to a lesser extent, working memory;
•    and the Sorting Test from the Delis–Kaplan executive function system (D-KEFS) for measuring conceptual reasoning that assesses higher executive functions, with Sorting Test (D-KEFS ST) and Description Score (DKEFS DS) subtests.

MRI acquisition and analysis were performed at baseline, 6, 12 and 24 months with a standardized protocol on the same 1.5 T scanner. Axial brain acquisitions included fluid attenuated inversion recovery, three-dimensional T1-weighted images, and post-contrast T1 spin-echo images before and 5 min after a single injection of 0.1 mmol/kg of gadopentetate dimeglumine.

Image analyses included a cumulative number and volume of gadolinium contrast enhanced (CE) and new and enlarging T2 lesions, and analyses of changes in whole brain and tissue-specific and regional GM and WM volumes, as previously reported. Longitudinal percent changes in volumes of whole brain, GM, WM, cortical and lateral ventricles were obtained using direct methods of atrophy measurement. Absolute and percent volume changes for the total subcortical deep GM (SDGM) (defined as the sum of thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens), thalamus and hippocampus at each time point were estimated, as previously reported.

During the 24 months, 36 of 81 patients (44.4 per cent) experienced relapses and developed clinically definite multiple sclerosis (CDMS). At the 24 months follow-up, the median of EDSS score was 2.0 (range 6.0) in the CDMS group and 1.5 (range 3.0) in the stable CIS group. At two years, 42 (51.9 per cent) CIS patients fulfilled the McDonald 2005 criteria and 57 (70.4 per cent) CIS patients fulfilled the McDonald 2010 criteria. Of the 81 patients who started Avonex, 70 (86.4 per cent) patients remained on the assigned treatment during the 24 months follow-up.

The results of the study indicate that CI is present in a detectable proportion of high-risk CIS patients at the time of first event suggestive of MS, a finding which is supported by previous research. The CI prevalence (12 per cent) and two-years incidence (five per cent) in the present study was low. Importantly, 60 per cent of the CI patients at baseline remained with CI after 24 months.

Although the authors observed CI in a proportion of CIS subjects that converted to CDMS, they were not able to show a prognostic role of baseline CI on the conversion to CDMS. In multivariate regression and mixed-effect model analyses, no significant relationship was found between NP and MRI parameters.

The present study has some limitations. The analysis contained insufficient power to evaluate the temporal differences in the examined volumetric and NP parameters in mixed-effect model analyses. To address this issue, future studies would benefit from larger samples, longer follow-up and larger intervals between NP testing.

Authors: Uher T, Blahova-Dusankova J.
Source: J Neurol. 2014 Jun 22. [Epub ahead of print]
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