Cognitive dysfunction is increasingly recognized in early phase of multiple sclerosis (MS) and clinically isolated syndrome (CIS) patients [
In this study we aimed to evaluate the frequency and pattern of cognitive impairment in patients with CIS and early phase of multiple sclerosis. We assessed relationship of cognitive impairment with the physical disability and fatigue. Furthermore we were interested in detecting a screening instrument that is simple, sensitive, and well tolerated by patients.
Subjects aged between 18 and 50 with CIS or definite diagnosis of RRMS who have onset of their symptoms within the last 2 years were recruited from our multiple sclerosis outpatient department. CIS/MS subjects underwent a neurological examination that included a complete history and determination of current disability using the Expanded Disability Status Scale (EDSS) and neuropsychological evaluation. MRI of the patients was evaluated retrospectively. All RRMS patients fulfilled the MRI criteria which demonstrate dissemination of lesions in time and in space.
The volunteers with major psychiatric illness, other neurological disease, learning disability, drug or alcohol abuse, and severe physical disability interfering tests were excluded from the study. To screen alcohol dependence and substance abuse we questioned the participants according to DSM-IV substance abuse and alcohol dependence criteria. We did not include the participants who had a drug abuse or alcohol dependence problem at some time in their life. All evaluations were performed at least 30 days after the end of a relapse. All patients fulfilled the 2005 Mc Donald’s diagnostic criteria. All participants gave informed consent to participate in this study, which was approved by the Ethics Committee of the Hospital.
To assess cognition we created a battery with neuropsychological tests most of which have reliability and validity studies for Turkish patients lasting about 1.5 hour. We tried to evaluate several cognitive domains and chose the tests among the ones which were frequently used for evaluation of neurological disorders in Turkey. Hamilton Depression Status Scale was used to quantify the severity of depression. Participants with moderate and severe depression (who have scores over 16) were excluded from the study. To assess fatigue severity of the patients Modified Fatigue Impact Scale (MFIS) with physical, cognitive, and psychosocial subscales was used. The neuropsychological tests were considered to have failed when the results were outside the normal range (means ±2 SDs obtained by the healthy control group). Neuropsychological tests included the following.
All statistical analyses were performed using SPSS for Windows version 15.0. The significance level was set at 0.05. The correlations between the demographic parameters and the cognitive subgroups were tested using Fisher’s exact test and Pearson’s
181 patients were screened through the database of the MS outpatient unit between years 2010 and 2011. A total of 61 consecutive patients who met the inclusion criteria were invited to participate in the study. Six patients refused to participate in the study. Nine patients with a Hamilton Depression Status Scale score 16 or above were excluded from the study. A series of 40 volunteers who had no history of neurological or psychiatric disease, alcoholism, or substance abuse were recruited from relatives of patients and community of neurology department.
Demographic and clinical characteristics of the patients and the healthy controls are presented in Table
Clinical and demographic characteristic of the patients and controls.
Early MS | Controls | |
---|---|---|
Number | 46 | 40 |
CIS | 8 | — |
RRMS | 38 | — |
Age |
|
|
Gender (female/male) |
|
|
Education years |
|
|
EDSS |
0.0 (0.0–5.0) | — |
Disease duration at the time of evaluation, years |
|
— |
Time from onset of symptoms to definite diagnosis of RRMS, months |
|
— |
Table
Neuropsychological tests used and raw performances for healthy controls and patients. Results are expressed as percentages of controls and patients whose scores were outside the normal range for each cognitive task.
Control |
Early CIS/RRMS |
|||
---|---|---|---|---|
Mean ± SD |
% | Mean ± SD |
% | |
PASAT 3 (3 sec correct responses) |
|
0 |
|
4.3 |
PASAT 2 (2 sec correct responses) |
|
0 |
|
10.9 |
FST (complete time/number of correct responses) |
|
8.7 |
|
8.7 |
Phonological fluency (number of words in 60 sec) |
|
0 |
|
15.2 |
Semantic fluency (names of animals in 60 sec) |
|
0 |
|
2.2 |
Stroop 1 (name the color print of color words, sec) |
|
0 |
|
19.6 |
Stroop 2 (name the color print of color words, errors) |
|
2.5 |
|
0 |
TMT-A (complete time in sec) |
|
2.5 |
|
17.4 |
TMT-B (complete time in sec) |
|
5 |
|
26.1 |
RAVLT 1 (sum of number of words recalled after each repeat) |
|
5 |
|
19.6 |
RAVLT 2 (total number of words recalled after 40-minute delay) |
|
5 |
|
17.4 |
Clock drawing test | 1.0 | 0 |
|
4.4 |
The highest performance of early CIS/RRMS group whose scores were outside the normal range that occurred in the following tests: TMT part B (26.1%), Stroop test (19.6%), RAVLT 1 (19.6%), RAVLT 2 (17.4%), TMT part A (17.4%), and phonological verbal fluency (15.9%).
Statistically significant differences were observed between patients and controls in the following tests: TMT part A (
Of the 40 healthy controls 77% obtained scores outside the normal range in at least one test, 12.5% failed at least 2 tests, and 5.3% failed at 3 tests. Nobody in the control group failed at more than 4 tests. Therefore failure at 4 and more tests was considered as cognitive impairment. In early MS group 54.4% of subjects were impaired on a single cognitive measure, 4.3% were impaired on 2, and 20% were impaired on 3 cognitive measure. Based on the criteria employed 19.6% of early CIS/MS group (
No significant relationship was found between cognitive impairment and age, sex, fatigue, and EDSS scores.
Cognitive impairment should be considered among the main manifestations of MS even in the earliest stages of the disease. These deficits are a significant source of patient morbidity, impacting heavily on employment status and social functioning. Detecting such dysfunction as early as possible could help in adapting disease modifying therapeutic strategies. In the studies evaluating long term outcome of MS patients it is shown that cognitive impairment is one of the major reasons of neurological disability [
The nature of neuropsychological tests most frequently failed by early MS group suggested impairments focused on cognitive abilities such as attentional systems, cognitive flexibility, verbal fluency, executive functions, and learning, whereas semantic verbal fluency and visuospatial functions seemed to be spared. Although both fluency tasks draw on frontal and temporal lobe processes, the retrieval by letter is thought to be more dependent upon frontal lobe than on temporal lobe functioning, while retrieval by category is thought to be more dependent upon temporal as compared to frontal processes [
Studies reporting on the frequency of disturbance of cognitive functions in MS patients show significant interpatient variability and depend on the methods used and on the type of patients examined [
Fatigue has a high prevalence in MS and potentially makes worse cognitive deficit just as presence of anxiety or depression. But we could not find any association between fatigue scores and cognition. If the patient presents with anxiety or depression, a specific psychiatric interview should be performed before assessing cognition [
It is now recognized that axonal injury due to inflammation and neurodegenerative processes already occur in the earliest stages of MS [
None of the authors has any conflict of interests to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
The authors are grateful to Peter Scherer who supplied the FST original test forms for them. The authors thank to Hatice Uluer for statistical assistance.