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Cognitive Dysfunction in Early-Onset Multiple Sclerosis
A Reappraisal After 10 Years
Maria Pia Amato, MD;
Giuseppina Ponziani, MD;
Gianfranco Siracusa, MD;
Sandro Sorbi, MD
Arch Neurol. 2001;58:1602-1606.
ABSTRACT
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Objective To reassess, in a cohort of patients with early-onset multiple sclerosis,
the long-term evolution of cognitive deficits, their relationship to the disease's
clinical progression, and their effects on daily life.
Design Ten years after our baseline assessment, we again compared the cognitive
performance of patients and control subjects on a neuropsychological test
battery. Clinical and demographic correlates of cognitive impairment and their
effects on everyday functioning were determined by multiple linear regression
analysis.
Setting The research clinic of a university department of neurology.
Participants Forty-five inpatients and outpatients with multiple sclerosis and 65
demographically matched healthy controls from the original sample.
Main Outcome Measures Mean scores of both groups on the neuropsychological test battery in
initial and 2 follow-up evaluations (about 4 and 10 years, respectively);
number of cognitively impaired subjects, defined by the number of subtests
failed; regression coefficients measuring the relationship between clinical
variables and cognitive outcome and between mental decline and everyday functioning
assessed by the Environmental and the Incapacity Status Scales.
Results Previously detected cognitive defects in verbal memory, abstract reasoning,
and linguistic processes were confirmed on the third testing, at which time
deficits in attention/short-term spatial memory also emerged. Only 20 of 37
patients who were cognitively unimpaired on initial testing remained so by
the end of the follow-up, when the proportion of subjects who were cognitively
impaired reached 56%. Degree of physical disability, progressive disease course,
and increasing age predicted the extent of cognitive decline. Disability level
and degree of cognitive impairment were independent predictors of a patient's
handicap in the workplace and in social settings.
Conclusions In the course of a sufficiently long follow-up, cognitive dysfunction
is likely to emerge and progress in a sizable proportion of patients. As multiple
sclerosis advances, neurological and cognitive involvement tend to converge.
Limitations in a patient's work and social activities are correlated with
the extent of cognitive decline, independent of degree of physical disability.
INTRODUCTION
IT IS NOW recognized that cognitive impairment in multiple sclerosis
(MS), occurs in an estimated 30% to 70% of cases.1
Studies of correlations between cognitive deficits and clinical variables
have provided conflicting evidence.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
It is probable that cognitive function is more vulnerable in chronic progressive
disease than in the relapsing-remitting form,5, 8, 9, 10
although this has not been a constant finding.7
In most surveys, the degree of neurological disability has been found either
not to correlate with mental changes6 or to
have only a minor influence.7 With few exceptions,11, 12 the duration of disease has not emerged
as a contributory factor.2, 7 However,
most studies on cognitive impairment in MS are cross-sectional in nature.
So far, only a few authors have undertaken longitudinal investigations of
the evolution of these disturbances and their relation to the clinical course
of the illness. Moreover, the follow-up intervals in these studies have tended
to be relatively short, not exceeding 3 to 4 years.10, 13, 14, 15, 16, 17, 18
Furthermore, the effect of cognitive dysfunction on the social and working
life of patients is still underestimated since MS is widely viewed as producing
neurological defects primarily in the motor sphere.
In an earlier prospective study with a mean follow-up of about 4 years,13 we analyzed the development of cognitive deficits
in a homogeneous cohort of patients in the initial stages of their disorder.
Compared with healthy controls, even subjects whose illnesses were of recent
onset and whose levels of neurological disability were still low showed significant
losses in verbal memory and abstract reasoning on initial testing; these deficits
remained substantially unchanged 4 years later, by which time the pattern
of cognitive disturbances had expanded to include linguistic functions as
well. In this very early stage of MS, the main clinical variables, such as
duration, course, and impairment level were poorly correlated with cognitive
outcome. On the other hand, the extent of cognitive decline, over and above
the degree of physical impairment, proved to be a significant and independent
predictor of handicap in a patient's work and social activity.
In this study, we retested the same sample of subjects after another
5 years had elapsed, for a longer-term assessment of the pattern and evolution
of cognitive deficits, their relationship to the clinical progression of MS,
and their effect on a patient's everyday life.
PATIENTS AND METHODS
Our initial sample consisted of 50 subjects with early-onset MS and
70 healthy controls: we selected controls from the patients' relatives and
friends who agreed to participate in the study and used group matching to
obtain comparable distributions of sex, age, and educational level.13 At the time of the current follow-up, 2 of the patients
and 5 of the controls had dropped out of the study and 3 patients had died. Table 1 presents the main characteristics
of the case and control groups during the entire course of our study.
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Table 1. Characteristics of the Study Sample*
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Subjects were excluded if they were receiving psychoactive or steroid
treatments or were in an acute relapsing phase. Subjects in the study were
assumed not to be receiving any treatment or substance (licit and illicit)
that would be expected to interfere with performance on cognitive tests. During
the follow-up period, 5 relapsing-remitting patients were treated with a daily
dose of 2 mg of azathioprine sodium per kilogram of body weight (mean ±
SD duration, 2.61 ± 1.98 years) and 7 with interferon ß-1a or
interferon ß-1b (mean ± SD duration, 2.62 ± 1.89 years).
We used an extensive neuropsychological battery composed of the following
subtests: the Blessed Information-Memory-Concentration Test,20
Digit Forward,21 Five Items and Paired Words
from Randt's Memory Battery (acquisition and recall after 10 minutes and 24
hours),22 Corsi Block Tapping,23
Set Test,24 Token Test,25
and Raven's Progressive Matrices.26 Mood disturbances
were assessed by the Hamilton Rating Scale for Depression.27
Raw scores were corrected for age and education on the basis of a previous
validation study of the test battery.28 In
that study, analysis of variance was used to examine statistical differences
between various age and education subgroups, and analysis of covariance was
used to derive the regression coefficient for correcting scores.28
Interrater and test-retest reliability on the neuropsychological battery were
substantial (weighted  >0.80), as were content and concurrent validity.28 Alternative versions of the verbal memory tasks were
used in each follow-up session to minimize possible learning effects owing
to repeated exposure.
Mean scores of the MS and control groups were compared by the 2-tailed t test for independent samples. The fifth percentile of
the control performance on each evaluation was taken as the cutoff point for
calculating the number of failed tests; in other words, we considered patients
with MS whose scores fell below the fifth percentile of the control group
during the same testing period to have cognitive impairment.
We used multiple linear regression analysis29
to test whether different demographic and clinical characteristics can predict
a patient's cognitive outcome. Since scores on individual neuropsychological
battery subtests were significantly correlated with one another as well as
with the total number of subtests failed by the subject
(r>-.50; P<.001), we selected the number
of failed subtests as the variable representing the extent of cognitive decline.
Likely predictors identified on the basis of the literature were age, sex,
educational level, disease course (relapsing-remitting vs primary or secondary
progressive), disease duration, and level of neurological impairment measured
on the Expanded Disability Status Scale (EDSS).30
To reduce these potential variables to a more manageable number for the multiple
linear regression, we carried out a preliminary univariate linear regression
analysis. The resulting predictors included in the model were age (ß
= .50; P<.001); disease duration (ß = .30; P = .04); disease course (ß = .50; P<.001); and EDSS score (ß = .60; P<.001),
all significantly correlated with the number of failed subtests while sex
(ß = .14, P = .38) and educational level (ß
= -.16; P = .28) did not. We again used multiple
linear regression analysis to see whether cognitive impairment—expressed
in terms of the total number of subtests failed—and other characteristics
can predict the extent of a patient's handicap and disability in everyday
life. Handicap was assessed by the Environmental Status Scale (ESS), a 7-item
scale focusing on, among other factors, work, social life, and need for personal
assistance.31 Disability was assessed by the
Incapacity Status Scale (ISS), a 16-item scale measuring a subject's capacities
in self-care and other daily living activities.32
In this phase of the study, the variables entered into the model were the
number of subtests failed, age, disease duration, disease course, and EDSS
score, which the preliminary univariate analysis had shown to be significantly
correlated with ESS and ISS scores (P .006).
RESULTS
Mean scores of patients and controls on the subtests of the neuropsychological
battery on this third testing are presented in Table 2. The patients' deficits on the Blessed Information-Memory-Concentration
test, Paired Word Acquisition, Five Items and Paired Words recall tests (both
after 10 minutes and 24 hours), Set and Token tests, and on the Raven's Progressive
Matrices followed the same pattern as those reported in our previous study.13 In addition, disturbances in short-term verbal memory
assessed by the Digit Forward test, and in attention/short-term spatial memory
as measured by the Corsi Block Tapping test, also emerged. Moreover, subjects
with MS failed a significantly greater number of subtests. Finally, the MS
group's mean score on the Hamilton Rating Scale for Depression was significantly
higher. When a score of 16 on this scale was taken as a cutoff,33
22 patients and 12 control subjects were classified as depressed.
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Table 2. Scores of MS and Control Groups on Final Testing*
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To better trace the evolution of cognitive dysfunction, we divided the
patients into 3 subgroups based on the number of tests failed: unimpaired
(0-2 failed tests), mildly impaired (3-5 failed tests), and moderately impaired
(>5 failed tests). The percentage of patients who were cognitively unimpaired
decreased in the course of the follow-up, from 74% during the initial evaluation
to 51% in the 4-year follow-up to 44% on this most recent retest. Correspondingly,
the percentage with mild or moderate impairment tended to increase, reaching
34% and 22%, respectively, by the end of the study (Table 3). We also analyzed the cognitive outcome of every patient
within each of the subgroups. On the whole, the likelihood that patients would
display cognitive deficits tended to increase during the course of our observations.
For instance, of the 37 patients classified as cognitively unimpaired on initial
testing, 25 remained so on the second test while 12 had become mildly impaired
(2 of these were reclassified as unimpaired on the final assessment). By the
final testing, 18 of the 25 were still unimpaired, 3 had become mildly impaired,
and 3 were moderately impaired (1 patient was lost to follow-up). Similarly,
of the 4 patients classified as mildly impaired on initial testing, only 1
remained so and 3 had become moderately impaired by the end of the follow-up.
Patients initially classified as moderately impaired were still in this subgroup
on the final testing (1 subject was reclassified as mildly impaired).
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Table 3. Evolution of Cognitive Dysfunction in Patients With MS*
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The results of the multiple linear regression analysis are presented
in Table 4. A higher EDSS score
and a progressive disease course (primary or secondary), followed by increasing
age, proved to be positively correlated with the severity of cognitive deterioration,
defined as the number of tests failed.
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Table 4. Multiple Linear Regression Analysis: Predictors of Cognitive
Dysfunction and Handicap in Social Life and Daily Living Activities in the
Group With MS
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The best predictor of the extent of a patient's handicap in social and
workplace activities as measured by the ESS score at the end of the follow-up
period was the EDSS score followed by the number of tests failed (Table 4). When we focused on specific ESS
items, we found that of the 25 patients with mild or moderate cognitive impairment,
17 had to modify or stop their work activity by the last examination. Moreover,
18 of these patients required substantial help in their personal lives ( 3
hours daily) and the social contacts of 18 were severely limited. Only 2 patients
in the unimpaired group showed these limitations. Finally, the only predictor
of disability in everyday functioning to emerge from the ISS was the degree
of neurological impairment on the EDSS (Table 4). In this analysis the R2 values expressed a
high accuracy of prediction.
COMMENT
There is a marked lack of information on the natural history of cognitive
dysfunction in MS, starting with the earliest phases of the illness. Results
obtained from the few studies that have examined the evolution of cognitive
functioning in MS have been controversial. Both cognitive preservation15, 16, 17, 18 and
progressive deterioration10, 14
have been reported, and remarkable fluctuations have been noted during very
brief follow-up periods.11 Yet while the duration
of follow-up has been short, the length of the observation period has been
crucial for understanding whether these deficits are likely to progress or
to remain stable.
Our findings are based on a relatively small sample of selected patients
reporting to a specialized center, which may have led us to overestimate the
occurrence of cognitive dysfunction in the MS population as a whole. Nevertheless,
by extending the observations of our original cohort to about 10 years, this
study has enabled us to expand our knowledge of the natural history of cognitive
impairment in this disorder.
As already described,34, 35, 36
we confirmed that cognitive dysfunction can be detected in some patients even
in the incipient phase of MS.13 As the disease
progresses, the number of patients with cognitive defects tends to increase.
The proportion of patients who were cognitively impaired at the end of our
study was 56%, a finding consistent with results of previous cross-sectional
surveys.1 With time, the likelihood increases
that subjects who do not have cognitive impairment may deteriorate; only 20
of the 37 patients in our sample who did not have cognitive impairment on
initial testing remained unchanged by the end of this follow-up. Kujala et
al14 reported that patients who initially did
not have cognitive impairment were still unaffected 3 years later, whereas
incipient cognitive decline seemed to be widespread and progressive in nature.
The difference may be owing to the shorter follow-up in that study, since
the appearance and progression of symptoms may require relatively long periods
to manifest themselves. In any event, it seems reasonable to assume that,
with the progressive buildup of pathological changes within the cerebral white
matter, both neurological and cognitive deficits are bound to increase. Magnetic
resonance studies, both cross-sectional and longitudinal,17, 37, 38, 39
show a correlation between increased cerebral lesion load and the extent of
cognitive deterioration; this relationship is generally stronger than that
between cerebral lesion load and degree of physical incapacity. Cognitive
defects may thus arise from apparently silent cerebral lesions not detectable
by the standard neurological examination or by measurement of disability on
the EDSS, a scale heavily weighted for ambulation and motor abilities. Further
research carried out with magnetization transfer imaging40, 41
reveals that in addition to cerebral alterations observable with conventional
magnetic resonance methods, it is possible to identify changes in the normal-appearing
cerebral white matter that are correlated with cognitive dysfunction.
As the disease progresses, the profile of cognitive deficits tends to
expand as processes that initially appear intact become involved. Among our
patients' memory functions, learning (and in particular, recall) and abstract
reasoning were the first to be compromised; impairment in linguistic abilities
(on the Set and Token tests) and attention/short-term spatial memory disturbances
(Corsi Block Tapping) set in later. Language functions have received less
attention than other aspects of cognitive decline in MS and have been considered
to remain relatively intact. However, carefully conducted studies focusing
on linguistic functions of patients with MS42, 43
have shown their difficulties with tests of naming, reading, verbal fluency,
and verbal comprehension. It is hypothesized that such problems are not tied
primarily to a breakdown of linguistic processes but rather derive from damage
to other cognitive faculties. In general, it is highly debatable whether the
heterogeneity of cognitive performance of subjects with MS can be adequately
described by a single pattern. Beatty44 found
that only 12% of patients with MS in his study exhibited the pattern of impairment
expected in subcortical dementia. Most of the neuropsychological investigations
of patients with MS, including our own, are based on group studies, the conclusions
from which may mask individual differences.1
Analyses of correlations between clinical variables and cognitive deficits
have up to now yielded conflicting findings.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
When such an association has been found, its most frequent correlates are
progressive disease course and degree of neurological disability.5, 8, 9, 10 Among
our patients, in contrast to our first study, after a mean disease duration
of about 10 years, higher EDSS scores and progressive course of the disorder
were correlated with the total number of tests failed. This suggests that,
as the illness advances, neurological and cognitive deficits tend to converge.
Similarly, in the article by Comi et al,45
the onset of secondary progression after a relapsing-remitting phase is identified
as a crucial event in the appearance and development of cognitive dysfunction.
Age-related memory decline is well documented in the literature as a demographic
predictor.46
Finally, few authors have specifically assessed the effect of cognitive
impairment on everyday life of patients with MS.7, 13, 47
In our study, while neurological impairment on the EDSS proved to be the only
significant predictor of disability on the ISS, which mainly reflects motor
abilities in daily living activities, the extent of cognitive decline, independently
of the degree of physical disability, again turned out to play a critical
role in limiting a patient's social and workplace activities as measured by
the ESS.
In conclusion, these results point to cognitive impairment as a common
element in the natural history of MS that cannot be ignored. While present
at times from the disease's earliest phases, only in the course of a sufficiently
long follow-up is such dysfunction likely to emerge and progress in a sizable
proportion of patients, although at different rates and with varying degrees
of severity. Moreover, cognitive problems, together with neurological disability,
constitute the principal determinants of a patient's handicap.
In the past few years, new therapies have been approved for patients
with the relapsing-remitting form of MS. These therapies have proven to be
effective in reducing the frequency of relapses and in limiting activity parameters
as well as the cerebral lesion load on magnetic resonance scans.48
On the assumption that the treatment might also positively influence cognitive
outcome by containing lesions within the central nervous system, psychological
assessment should accompany the neurological examination and become a factor
in therapeutic decision-making.
AUTHOR INFORMATION
Accepted for publication June 7, 2001.
We thank Eda Berger Vidale, PhD, for her assistance in translating and
editing the manuscript, Laura Bracco, MD for her assistance in interpreting
neuropsychological findings, and Vieri Boddi, MS, for his assistance in the
statistical analysis.
This article was corrected 10/24/2001.
From the Department of Neurology, University of Florence, Florence,
Italy.
Reprints: Maria Pia Amato, MD, Ia Clinica Neurologica, Department
of Neurology, University of Florence, Viale Morgagni, 85, Florence, Italy
50134 (e-mail: mariapia.amato{at}unifi.it).
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Cognitive functioning in children with multiple sclerosis
Montiel-Nava et al.
Mult Scler 2009;15:266-268.
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Cognitive impairment in multiple sclerosis
Patti
Mult Scler 2009;15:2-8.
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Should SDMT substitute for PASAT in MSFC? A 5-year longitudinal study
Brochet et al.
Mult Scler 2008;14:1242-1249.
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Cognitive assessment and quantitative magnetic resonance metrics can help to identify benign multiple sclerosis
Amato et al.
Neurology 2008;71:632-638.
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Cognitive impairment in multiple sclerosis can be predicted by imaging early in the disease
Summers et al.
J. Neurol. Neurosurg. Psychiatry 2008;79:955-958.
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Cognitive dysfunction 24-31 years after isolated optic neuritis
Nilsson et al.
Mult Scler 2008;14:913-918.
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Memory decline evolves independently of disease activity in MS
Duque et al.
Mult Scler 2008;14:947-953.
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Cognitive and psychosocial features of childhood and juvenile MS
Amato et al.
Neurology 2008;70:1891-1897.
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Cognitive impairment in relapsing--remitting multiple sclerosis can be predicted by imaging performed several years earlier
Summers et al.
Mult Scler 2008;14:197-204.
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APOE {varepsilon}4 allele is associated with cognitive impairment in patients with multiple sclerosis
Shi et al.
Neurology 2008;70:185-190.
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Quantitative Assessment of Iron Accumulation in the Deep Gray Matter of Multiple Sclerosis by Magnetic Field Correlation Imaging
Ge et al.
Am. J. Neuroradiol. 2007;28:1639-1644.
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Association of Neocortical Volume Changes With Cognitive Deterioration in Relapsing-Remitting Multiple Sclerosis
Amato et al.
Arch Neurol 2007;64:1157-1161.
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The relationship between neuropsychological measures and the Timed Instrumental Activities of Daily Living task in multiple sclerosis
Goverover et al.
Mult Scler 2007;13:636-644.
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fMRI study of episodic memory in relapsing-remitting MS: correlation with T2 lesion volume.
Bobholz et al.
Neurology 2006;67:1640-1645.
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The Rao's Brief Repeatable Battery and Stroop test: normative values with age, education and gender corrections in an Italian population
Amato et al.
Mult Scler 2006;12:787-793.
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The Face-Symbol Test and the Symbol-Digit Test are not reliable surrogates for the Paced Auditory Serial Addition Test in multiple sclerosis
Williams et al.
Mult Scler 2006;12:599-604.
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Longitudinal course of depression symptoms in multiple sclerosis
Arnett and Randolph
J. Neurol. Neurosurg. Psychiatry 2006;77:606-610.
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Correlation of global N-acetyl aspartate with cognitive impairment in multiple sclerosis.
Mathiesen et al.
Arch Neurol 2006;63:533-536.
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Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis
Nocentini et al.
Mult Scler 2006;12:77-87.
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A longitudinal study of cognition in primary progressive multiple sclerosis
Camp et al.
Brain 2005;128:2891-2898.
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The association between cognitive impairment and physical disability in multiple sclerosis
Lynch et al.
Mult Scler 2005;11:469-476.
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Cognitive patterns and progression in multiple sclerosis: construction and validation of percentile curves
Achiron et al.
J. Neurol. Neurosurg. Psychiatry 2005;76:744-749.
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The cognitive burden of multiple sclerosis in children
Banwell and Anderson
Neurology 2005;64:891-894.
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A multimodal approach to managing the symptoms of multiple sclerosis
Crayton et al.
Neurology 2004;63:S12-S18.
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The unique impact of changes in normal appearing brain tissue on cognitive dysfunction in secondary progressive multiple sclerosis patients
Cox et al.
Mult Scler 2004;10:626-629.
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Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment
Amato et al.
Neurology 2004;63:89-93.
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Working memory deficits in multiple sclerosis: a controlled study with auditory P600 correlates
Sfagos et al.
J. Neurol. Neurosurg. Psychiatry 2003;74:1231-1235.
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Longitudinal study of cognitive dysfunction in multiple sclerosis: neuropsychological, neuroradiological, and neurophysiological findings
Piras et al.
J. Neurol. Neurosurg. Psychiatry 2003;74:878-885.
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Three screening batteries to detect cognitive impairment in multiple sclerosis
Aupperle et al.
Mult Scler 2002;8:382-389.
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Cognitive Impairments in Essential Tremor and Multiple Sclerosis
JWatch Psychiatry 2001;2001:5-5.
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