Abstract
Objective: Although in benign multiple sclerosis (BMS) locomotor disability is absent or only minimal, subclinical cognitive impairment seems to occur in many cases. Diffusion tensor (DT) MRI enables us to quantify the extent of “actual” tissue damage, which goes undetected when using conventional MRI. Against this background, we investigated the extent of structural brain damage underlying cognitive dysfunction in BMS, with the ultimate aim to move a first step toward a more reliable definition of this disease phenotype.
Methods: Conventional and DT MRI scans of the brain were acquired from 62 BMS patients. Thirty-six secondary progressive multiple sclerosis (SPMS) patients and 19 healthy subjects served as controls. In BMS patients, neuropsychological tests exploring memory, attention, and frontal lobe functions were administered. Normalized brain volume (NBV), mean diffusivity (MD), and fractional anisotropy (FA) of the normal-appearing white matter (NAWM) and MD of the gray matter (GM) were computed.
Results: Twelve BMS patients (19%) fulfilled predefined criteria for cognitive impairment. BMS patients had abnormal MD and FA values from both NAWM and GM. Whereas BMS patients without cognitive impairment had lower T2 LV (p = 0.03), higher NBV (p = 0.006), and lower average GM MD (p = 0.03) than SPMS patients, BMS patients with cognitive impairment did not significantly differ from SPMS patients for any MRI-derived metric.
Conclusions: In benign multiple sclerosis (BMS), cognitive dysfunction is associated with severe structural brain damage, which resembles that of patients with a much more disabling disease course. A reliable definition of BMS should, therefore, include the preservation of cognitive functioning as an additional requisite.
GLOSSARY: BMS = benign multiple sclerosis; DT = diffusion tensor; EDSS = Expanded Disability Status Scale; FA = fractional anisotropy; FDR = false discovery rate; FOV = field of view; GM = gray matter; LV = lesion volume; MD = mean diffusivity; MP-RAGE = magnetization-prepared rapid-acquisition gradient echo; MS = multiple sclerosis; NAWM = normal-appearing white matter; NBV = normalized volume; PASAT = Paced Auditory Serial Attention Test–3" Version; PGSE = pulsed-gradient echo-planar; ROCF = Rey–Osterrieth Complex Figure; SPMS = secondary progressive multiple sclerosis; TE = echo time; TR = repetition time; WM = white matter.
Multiple sclerosis (MS) patients with absent or mild neurologic impairment, defined as an Expanded Disability Status Scale (EDSS)1 score of 3.0 or less after at least 15 years from the clinical onset, are classified as having “benign” MS (BMS).2 Several clinical features of the early clinical phases of MS, such as onset with optic neuritis, female sex, age at onset lower than 40 years, absence of pyramidal signs at presentation, and low frequency of relapses during the first 5 years, have been associated with a subsequent evolution to BMS.3,4 Nevertheless, two prospective studies have shown that BMS may often be just a temporary condition because, 10 years after a baseline evaluation, 50% to 70% of BMS patients did show a significant EDSS worsening or a shift to secondary progressive MS (SPMS).5,6 In both these studies,5,6 lower EDSS scores at baseline were associated with an increased probability of remaining BMS at follow-up. However, when considering EDSS as a prognostic factor, one should bear in mind that this scale has a relatively low reliability and responsiveness to disease-related changes, because it is heavily weighted toward locomotor disability and is almost not influenced by the presence and severity of cognitive impairment, which are known to occur in a significant proportion of patients with BMS.7 It can, therefore, be hypothesized that BMS patients with cognitive disturbances may represent cases of phenotypic misclassification.
MR-based techniques are extensively used for the assessment of brain damage in patients with MS. Nevertheless, both conventional8–11 and quantitative12–18 MRI studies of BMS patients were inconclusive because they did not provide a clear picture of the factors associated with the mild or absent neurologic impairment of these patients. Diffusion tensor (DT) MRI is sensitive to MS damage and able to detect its evolution over relatively short periods of time, leading to improved correlations with clinical findings.19 DT MRI–derived metrics were also found to predict the medium-term evolution of MS.20
Against this background, we performed the present study to evaluate the neuropsychological profile and to investigate the conventional and DT MRI correlates of cognitive impairment in a large sample of BMS patients. The working hypothesis behind this study was that cognitively impaired BMS patients may have MRI features similar to those of patients with a more severe disease status and, therefore, might not to have a benign disease at all.
METHODS
Subjects.
During the period from January 31, 2006, to January 1, 2007, patients were selected consecutively from the outpatient MS clinic populations in the participating centers. To be included, they had to be relapse- and steroid-free for at least 1 month before study entry. All patients underwent a complete neurologic examination, with rating of the EDSS score.1 This was done by a single observer, who was unaware of MRI results, on the same day of the MRI session. Criteria for a diagnosis of BMS were an EDSS score equal to or less than 3.0 and a disease duration equal to or longer than 15 years. Patients with clinically definite MS, an SPMS course,2 and persistent walking limitations (i.e., an EDSS score of 4.0 or higher, confirmed at two consecutive visits separated by a 3-month interval) were enrolled to serve as controls. Nineteen healthy volunteers (9 women, 10 men; mean age: 42.0 [range: 32–56] years) were also studied. None of the healthy volunteers had had previous episodes of neurologic dysfunction, none had hypertension, diabetes, or other disorders potentially affecting the CNS, and all had a completely normal neurologic exam. All subjects signed a written informed consent before study entry, and the study was approved by the local ethics committees.
Neuropsychological assessment.
Within 48 hours from clinical assessment, all BMS patients underwent a neuropsychological evaluation, exploring the following cognitive domains: a) attention and information processing (Paced Auditory Serial Attention Test–3" Version [PASAT],21 Trail Making Test,22 and Attentive Matrices Test23); b) verbal and visual–spatial memory (Corsi Span Test, Short Story Test, Digit Span Test, Word List Test, and Rey–Osterrieth Complex Figure [ROCF] Test–Recall Task24); c) abstract reasoning (Raven Test25); d) executive functions (Token Test,26 Verbal Fluency Test,27 and Wisconsin Card Sorting Test28); and e) spatial cognition (ROCF Test–Copy Task).24 These tests were administered by a neuropsychologist who was unaware of the clinical and MRI data. For each patient, the results from all tests were scored using a standardized method based on a comparison with the percentile distribution of values from normal controls.23 The individual test scores ranged from 0 to 4, where grade 4 means a normal performance. Only those patients with scores of 0 in at least three tests were considered affected by cognitive impairment.29 Individual test scores were also summed up to provide a composite cognitive score for each patient.29
MR data acquisition.
Brain MRI scans were obtained using a scanner operating at 1.5 T (Vision; Siemens, Erlangen, Germany). During a single session, the following sequences were collected, without moving the subject from the scanner: 1) dual-echo turbo spin echo (repetition time [TR] = 3300 ms, echo time [TE] = 16/98 ms, echo train length = 5); 2) pulsed-gradient echo-planar (PGSE) (interecho spacing = 0.8 ms, TE = 123 ms), with diffusion gradients applied in eight noncollinear directions; the maximum b factor in each direction was 1044 s/mm2; and 3) T1-weighted three-dimensional magnetization-prepared rapid-acquisition gradient echo (MP-RAGE) (TR = 970 ms, TE = 40 ms, inversion time = 300 ms; slab orientation = sagittal; number of partitions = 128, matrix size = 256 × 256, field of view [FOV] = 210 × 210 mm, voxel size = 0.82 × 0.82 × 1.50 mm). Twenty-four contiguous, 5-mm-thick, axial slices with 256 × 256 matrix size and a 250 × 250-mm FOV were obtained for dual-echo scans. For PGSE scans, 10 contiguous, 5-mm-thick axial sections with 128 × 128 matrix and a 250 × 250-mm FOV were acquired, with the second to last caudal section positioned to match exactly the central slices of the dual-echo image sets. A complete brain coverage would have required the acquisition of an additional image slab and, as a consequence, a more prolonged scanning time. We therefore chose to cover those brain areas (which are known to be a preferential location of MS damage) and the image slab always included the thalamic region.
MR data postprocessing.
All postprocessing was performed by an observer who was blinded to subjects’ identity. Total T2-hyperintense lesion volume (LV) measurement was assessed using a semiautomated segmentation technique.30 Using MP-RAGE images, normalized volumes (NBV) of the whole-brain parenchyma were measured using the cross-sectional version of the Structural Image Evaluation of Normalized Atrophy software.31 PGSE images were first corrected for geometric distortion induced by eddy currents. Then, the DT was calculated, and mean diffusivity (MD) and fractional anisotropy (FA) were derived for each voxel. The diffusion images were interpolated to the same image matrix size as the dual echo, and then the b = 0 step of the PGSE scans was coregistered with the dual-echo T2-weighted images using a three-dimensional rigid-body coregistration algorithm based on mutual information. The subsequent step consisted of automatic transfer of lesion outlines onto the MD and FA maps. Using SPM2 software and maximum image in-homogeneity correction,32 brain gray matter (GM), white matter (WM), and CSF were then automatically segmented from proton density and T2-weighted images. Each pixel was classified as GM, WM, or CSF, depending on which mask had at least a 75% likelihood at that location. The resulting masks were superimposed onto the MD and FA maps, on which hyperintense lesions were masked out previously, thus obtaining normal-appearing WM (NAWM) and GM maps. Then, the average MD and FA values of the NAWM and GM were calculated. FA was derived only from the NAWM because no preferential direction of water molecular motion is expected to occur in the GM, because of the absence of a microstructural anisotropic organization of this tissue compartment.
Statistical analysis.
An analysis of variance model was used to test between-group comparisons; a log transform was applied to T2 LV values before the analysis to normalize their distribution. Three comparisons were decided a priori (a priori contrasts): BMS patients vs healthy controls, BMS patients without cognitive impairment vs SPMS patients, and BMS patients with cognitive impairment vs SPMS patients. Univariate correlations were assessed using the Spearman rank correlation coefficient. False discovery rate (FDR)33 was used to correct the p value according to the number of tests performed. In this study, the FDR was set as equal to 0.05.
RESULTS
Sixty-two patients with BMS (37 women, 25 men; mean age [range]: 46.4 [35–63] years) and 36 patients with SPMS (18 women, 18 men; mean age [range]: 44.4 [32–68] years) were studied. There was no age heterogeneity between healthy control subjects, BMS, and SPMS patients (p = 0.151). The gender distribution also did not differ among the three groups of subjects (χ2 test; p = 0.508). The median disease duration was 21.5 (range: 15–40) years for BMS patients and 15.0 (range: 3–41) years for SPMS patients. The median EDSS score was 1.5 (range: 0.0–3.0) for BMS patients and 6.0 (range: 4.0–8.0) for SPMS patients. Forty-two BMS patients were not receiving any disease-modifying treatment, 13 were being treated with interferon beta-1a, and 7 were being treated with glatiramer acetate. Sixteen SPMS patients were not receiving any disease-modifying treatment, 10 were being treated with interferon beta-1b, 6 were being treated with mitoxantrone, and 4 were being treated with azathioprine.
Table 1 summarizes the results of the neuropsychological tests administered to BMS patients. The highest frequencies of abnormal performances were observed for the PASAT and the Wisconsin Card Sorting Test. Executive functions were the domain with the highest number of patients having at least one abnormal test. The median value of the composite cognitive score was 45 (range: 16–58). Twelve BMS patients (19%) were considered as having cognitive impairment.
Table 1 Neuropsychological test results in 62 benign multiple sclerosis patients
The mean NBV did not differ between BMS patients and healthy controls (p = 0.103). The average NAWM and GM MD values were higher, and the average NAWM FA was lower in the former than in the latter group (p values: 0.007, 0.002, and <0.001). In table 2, the MRI characteristics of BMS patients with and without cognitive impairment and those of SPMS patients are presented. BMS patients without cognitive impairment had lower T2 LV (p = 0.03), higher NBV (p = 0.006), and lower average GM MD (p = 0.03) than SPMS patients. Conversely, no significant differences were found between BMS patients with cognitive impairment and SPMS patients.
Table 2 MRI characteristics of BMS (without and with cognitive impairment) and SPMS patients
In BMS patients, the composite cognitive score was correlated with average NAWM MD (r = −0.38, p = 0.008), average NAWM FA (r = 0.40, p = 0.007), and average GM MD (r = −0.31, p = 0.03), but it was not correlated with T2 LV (r = −0.16, p = 0.30) or NBV (r = 0.25, p = 0.09). T2 LV was correlated with all DT MRI–derived metrics (absolute r values ranged from 0.47 to 0.59; p values were all <0.001).
DISCUSSION
The current definition of BMS2 sufficiently reflects the concept that these patients have to have a low disability after a long disease duration, but it suffers from being retrospective. As a matter of fact, studies with prolonged follow-up periods have shown that a significant proportion of BMS patients can enter a disabling disease course after reaching a 15-year disease duration.5,6 In a recent, large-scale study conducted in 163 patients with BMS, cognitive dysfunctions have been found to occur in 45% of these subjects.7 These findings indicate that the definition of BMS, which is mainly based on the absence of locomotor disability, may actually overestimate the prevalence of this condition and fail to capture relevant MS-related cognitive problems. Against this background, we performed the present DT MRI study to assess whether, in BMS patients, cognitive impairment is associated with a severe brain damage and may, therefore, be considered a feature of a potential “nonbenign” condition. To this aim, we chose SPMS patients with persistent walking limitations as a control group because their clinical profile is in sharp contrast with the present requisites of BMS and also because their structural MRI features are known to be associated with the presence of fixed disability. Even though we did not assess the cognitive functioning of our SPMS patients, previous studies34,35 indicate that cognitive impairment is present in 50% to 70% of subjects with such a disease phenotype, thereby suggesting that this feature can be considered an important part of the irreversible neurologic disability characterizing SPMS.
We studied a relatively large cohort of patients with BMS who, in comparison with those recently investigated by another research group,7 had a lower average EDSS score despite a similar disease duration. This difference may be a potential explanation for the lower prevalence of cognitive impairment in our cohort. It is also worth noting that, in our sample of patients, the pattern of cognitive dysfunctions showed a predominant involvement of memory and executive skills, which is highly suggestive of MS-related cognitive impairment.36
In contrast with previous studies13,14,16 indicating that the structural features of the normal-appearing brain of BMS patients may not significantly differ from those of healthy subjects, we found that BMS patients have abnormal water diffusivity and anisotropy in both NAWM and GM. This discrepancy may have different explanations. First, our sample of BMS patients is larger than in most previous studies.14,16 Second, DT MRI may have a different, if not higher, sensitivity to NAWM and GM damage in comparison with other quantitative MR-based techniques.37 It is worth noting that even though two seminal diffusion MRI studies of BMS15,17 suffer from evident technical limitations, in one of them a significant NAWM diffusivity increase was found in BMS patients compared with healthy subjects.
When BMS patients without cognitive impairment were compared with the control group of SPMS patients, a higher lesion load and a more pronounced brain atrophy were found in the latter patients, in contrast to previous findings from other studies.10–12 This is consistent with the hypothesis that only those patients with preserved cognitive functions may represent those with “truly” benign MS. In terms of DT MRI features, the only significant difference between BMS and SPMS patients was the higher average GM MD value found in the latter group. This finding is consistent with that reported by a previous MT MRI study comparing BMS and early RRMS patients,13 thereby suggesting that the paucity of GM damage may be a hallmark of BMS. Admittedly, we studied a cohort of SPMS patients with a disease duration shorter than that of BMS cases. However, such a difference is expected to reduce the magnitude of GM abnormalities we observed in the SPMS group.38 This underpins that our findings in BMS without cognitive impairment vs SPMS patients are most probably related to an absent vs marked disabling disease evolution and were not influenced by the effect of the time elapsed since the onset of MS.
When BMS patients with cognitive impairment were considered in isolation, no significant differences were found between them and those with SPMS. Because BMS patients with cognitive impairment (still) have a limited accrual of disability, it is tempting to speculate that, at this stage, the presence of severe structural brain damage might be counterbalanced by effective compensatory mechanisms, such as cortical reorganization, with the potential to limit the clinical impact of MS pathology.39 Conversely, in BMS patients with cognitive impairment, tissue damage may be located in regions that affect cognition rather than locomotion. At any rate, these findings suggest that the definition of BMS should be changed to include a measure of cognitive functioning, because BMS patients with cognitive impairment do not seem to have structural MRI features of a benign disease at all.
The severity of cognitive disturbances in individual BMS patients, as expressed by the composite score we computed,29 was correlated with increased water diffusion abnormalities in both NAWM and GM, but not with T2 LV and brain atrophy. These findings are consistent with those of MRI studies conducted in patients with other MS phenotypes,40 and they confirm the pivotal role played by normal-appearing brain damage in the pathogenesis of MS-related cognitive dysfunction.33,40 They also indicate that, independently of the criterion used for a binary classification of patients into cognitively impaired and unimpaired, clinically silent neuropsychological dysfunctions occur in BMS in association with an increased severity of structural brain damage. Because MRI is known to be more objective and reproducible than any clinical assessment, the finding of MRI features suggestive of pronounced tissue damage should, therefore, raise the suspicion of undetected disease-related problems in BMS patients.
AUTHOR CONTRIBUTIONS
Statistical analysis was conducted by G.R.
ACKNOWLEDGMENT
The authors thank Dr. Maria Pia Sormani (DISSAL, Biostatistics Unit, University of Genoa, Genoa, Italy), who supervised the data statistical analysis.
Footnotes
-
filippi.massimo{at}hsr.it
e-Pub ahead of print on September 24, 2008, at www.neurology.org.
Supported by a grant from the Fondazione Italiana Sclerosi Multipla (FISM; contract no. 2005/R/18).
Disclosure: The authors report no disclosures.
Received December 17, 2007. Accepted in final form April 2, 2008.
REFERENCES
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