Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis

Cognitive impairment in patients with multiple sclerosis (MS) is a common occurrence and is generally fairly circumscribed. The prevalence of the cognitive deficits usually encountered could vary with the clinical course of the disease. To investigate whether the presence of cognitive impairment may occur in the very early stage of MS, we assessed the cognitive status of a group of 40 patients presenting with a recently diagnosed clinically isolated syndrome suggestive of MS (CISSMS), in comparison with 30 age-, sex-, and educational level-matched healthy control subjects. An extensive battery of neuropsychological tests was used to explore verbal and non-verbal memory, attention, concentration, speed of information processing, language and abstract reasoning. Patients with CISSMS had a significant, frequent (57%), and circumscribed cognitive impairment, focused on memory, speed of information processing, attention and executive functions.     

Autobiographical memory, depression and quality of life in multiple sclerosis

The relationship between autobiographical memory, depression and quality of life (QoL) was investigated in a study of 30 persons with severe neurodisability resulting from multiple sclerosis. Sixty percent (n = 18) of patients were found to have deficits in autobiographical memory (AMI) for incidents in their earlier life; these deficits were associated with significant impairments in personal semantic memory of facts from their past life. Patients with impaired autobiographical memory who had been diagnosed for longer than 21 years reported significantly better QoL (SF-36: Role Physical) than those diagnosed more recently, or those with normal autobiographical memory; patients who had been diagnosed for longer were also significantly less depressed than patients diagnosed more recently. Patients with normal autobiographical memory reported the highest levels of depression (HADS) and the lowest levels of QoL (Role Physical). It is concluded that impairment of autobiographical memory affects perception of QoL; patients with deficits in autobiographical memory had impaired knowledge about their past QoL and may therefore be unable to make valid comparative judgements about the quality of their present life.     

Autobiographical Memory,Depression and Quality of Life in Multiple Sclerosis

The relationship between autobiographical memory, depression and quality of life (QoL) was investigated in a study of 30 persons with severe neurodisability resulting from multiple sclerosis. Sixty percent (n = 18) of patients were found to have deficits in autobiographical memory (AMI) for incidents in their earlier life; these deficits were associated with significant impairments in personal semantic memory of facts from their past life. Patients with impaired autobiographical memory who had been diagnosed for longer than 21 years reported significantly better QoL (SF-36: Role Physical) than those diagnosed more recently, or those with normal autobiographical memory; patients who had been diagnosed for longer were also significantly less depressed than patients diagnosed more recently. Patients with normal autobiographical memory reported the highest levels of depression (HADS) and the lowest levels of QoL (Role Physical). It is concluded that impairment of autobiographical memory affects perception of QoL; patients with deficits in autobiographical memory had impaired knowledge about their past QoL and may therefore be unable to make valid comparative judgements about the quality of their present life.     

The initial course of daily functioning in multiple sclerosis: a three-year follow-up study

We studied the initial course of daily functioning in multiple sclerosis (MS). A cohort of 156 recently diagnosed patients was prospectively followed for three years (five measurements). Domains of interest were neurological deficits, physical functioning, mental health, social functioning and general health. An a priori distinction was made between a relapse onset group (n = 128) and a non-relapse onset group (n =28). At baseline, neurological deficits are relatively minor for most patients, 26.3% have aberrant physical functioning scores, 38.5% have aberrant social functioning scores, 9% have aberrant mental health scores and 25% have aberrant general health scores. The neurological deficits and physical functioning deteriorated significantly over time. This deterioration was more pronounced and clinically relevant in the non-relapse onset group only. Mental health showed a significant, but not clinically relevant deterioration over time. Social functioning and general health showed non-significant effects for time. It is concluded that in the initial stage of MS, when neurological deficits are relatively minor and mental health is relatively unaffected, patients in both groups experience limitations in daily functioning. Patients in the non-relapse onset group have progressive neurological symptoms that are accompanied by progressive limitations in physical functioning, but not by progressive limitations in the other domains.     

Patient information and coping styles in multiple sclerosis

BACKGROUND: Patients with multiple sclerose (MS) live with their disease for many years. The cause of the disease is unknown and there are no curative therapies. Patients' adaption to chronic disease is dependent on the effectiveness of coping behaviour. OBJECTIVES: To explore the correlation between the quality of perceived disease information and to estimate the correspondance between the quality of perceived disease information and later coping styles applied by MS-patients in stress situations related to their disease. METHODS: Of a total of 108 patients recently diagnosed with MS, 93 agreed to participate in the study and 86 of these completed two different questionnaires, one assessing quality of the perceived information and the other asessing coping styles (the COPE scale). RESULTS: 43.2% of the patients were dissatisfied or very dissatisfied with the information by the time of diagnosis. MS-related coping styles were influenced by general coping styles and the most frequently employed strategies were ;positive reinterpretation and growth', ;planning' and ;restraint coping' while ;denial' was the most infrequently employed strategy. Patients who were satisfied with the information employed avoidance coping to a lesser extent and more actively both plan and seek information about the situation. CONCLUSION: Optimizing the information process in the early phase of the disease may induce coping styles that produce a better adaption to living with MS.     

The influence of immunomodulation on psycho-neuroimmunological functions in benign multiple sclerosis

OBJECTIVES: In multiple sclerosis (MS), several neuroimmunomodulatory effectors are known, including melatonin. They are able to influence disease-related neurophysiogical changes (disability or impaired vision) as well as neuropsychological performance (e.g. cognition and depression). In this study we assessed the relationship between immunomodulation on psycho-neuroimmunological functions in benign multiple sclerosis. METHODS: We evaluated 26 young female patients with benign MS treated with/without immunomodulating therapies with regard to their physical disabilities (Expanded Disability Status Scale, EDSS), their visually evoked potentials (VEP), their plasma melatonin concentrations as well as their performance regarding emotional and cognitive tests and compared them with healthy matched controls. RESULTS: Patients with MS showed deficits in cognitive and emotional functions compared to healthy controls, which were in accordance with their increase in EDSS over time. However, in contrast to untreated patients, patients receiving immunotherapy showed significantly increased dysfunction with respect to actual mood (p = 0.02) and a tendency to increased depression scores (p = 0.072). However, neither treatment subgroup had cognitive deficits. In untreated patients, melatonin levels correlated with reduced scores in the cognitive tests (p = 0.045) but not with depression or VEP latencies. Patients with long-standing MS (>10 years) showed a significant correlation (p = 0.01) to their increased depression scores and their melatonin levels, but no correlation with VEP or cognitive dysfunction, compared to patients with shorter disease duration (< or =10 years). CONCLUSION: These results indicate that in MS all aspects of the psycho-neuroimmunological network can be affected. Despite the potential influence of immunomodulation on depression, no connection with melatonin representing the retinohypothalamic tract/pineal gland circuits could be detected. However, visual perception as well as visuoconstructive abilities were affected in MS patients. Neuropsychological tests in MS should concentrate on cognitive variables, which reflect the clinical status more accurately and may be used to monitor disease-modifying therapies.     

MRI correlates of cognitive dysfunction in multiple sclerosis patients

Studies with conventional magnetic resonance imaging (MRI) support the hypothesis that cognitive impairment in multiple sclerosis (MS) patients is related with the lesion burden. Patterns of frontal lobe cognitive decline were also found to be related with the corresponding regional lesion load, although the total lesion load on T2-weighted MRI scans of the brain seems to be more relevant in determining frontal lobe deficits. Other non-conventional MRI techniques with a higher specificity to the heterogeneous substrates of MS pathology, such as the assessment of hypointense lesion load on T1-weighted scans and the histogram analysis of magnetisation transfer ratio (MTR) maps, have recently been applied to MS cognitive studies. Results from these studies suggest that three factors play a role in the pathogenesis of MS dementia: the burden of MS lesions, the severity of the pathological damage within individual lesions and that of the normal-appearing white matter.     

Mismatch negativity (MMN) in multiple sclerosis: an event-related potentials study in 46 patients.

OBJECTIVE: To assess pre-attentive detection mechanisms indexed by MMN component of auditory Event-Related Potentials (ERPs) in Multiple Sclerosis (MS) patients. METHODS: 46 MS patients (mean age 43.7 years, mean disease duration 10.1 years, mean EDSS 4.6) and 46 matched controls were assessed with ERPs elicited by a passive oddball paradigm using duration deviants. Auditory P50, N1, P2 components were recorded. MMN and P3a components were calculated as the difference potential between deviants and standard stimuli. Eighteen of these 46 patients underwent also global psychometrical assessment and were sorted in cognitively normal and impaired patients. ERPs of these two groups of patients were compared. RESULTS: MS patients showed reduced MMN and P3a areas as compared to controls, besides exogenous N1-P2 complex amplitude reduction. Among the 18 patients investigated with neuropsychological testings, six were cognitively impaired and 12 cognitively unimpaired. Patients with a global cognitive impairment had reduced MMN as compared to cognitively unimpaired patients. CONCLUSIONS: Auditory MMN and P3a components of auditory ERPs are altered in MS patients. MMN alterations are more pronounced in cognitively impaired patients. SIGNIFICANCE: MMN and P3a areas reduction suggests that MS patients are prone to pre-attentive auditory information processing deficits, besides previously described controlled information processing difficulties. Moreover, MMN alterations may represent an objective index of cognitive disturbances in MS patients.     

Comprehension of affective prosody in multiple sclerosis

Deficits in cognition have been repeatedly documented in patients with multiple sclerosis (MS), but their ability to comprehend emotional information has received little study. Forty-seven patients with MS and 19 demographic controls received the comprehension portion of the Aprosodia Battery, which is known to be sensitive to the impairments of patients with strokes and other neurological conditions. Patients also received tests of hearing, verbal comprehension and naming, a short cognitive battery, and the Beck Depression Inventory. Patients with MS were impaired in identifying emotional states from prosodic cues. The magnitude of the deficits was greatest for patients with severe physical disability and under test conditions of limited prosodic information. Correlational analyses suggested that the patients' difficulties in comprehending affective prosodic information were not secondary to hearing loss, aphasic deficits, cognitive impairment, or depression. For some patients with MS, deficits in comprehending emotional information may contribute to their difficulties in maintaining effective social interactions.     

The association between psychiatric and cognitive symptoms after stroke: a prospective study

BACKGROUND: Stroke patients often have neuropsychiatric symptoms and cognitive deficits. The aim of this study was to investigate whether stroke patients with psychiatric symptoms are at increased risk of developing cognitive deficits. METHODS: Cognitive function (assessed with a neuropsychological test battery) and presence of psychiatric symptoms (assessed with the 90-item Symptom Checklist) were evaluated at 1, 6, 12 and 24 months after stroke. RESULTS: At baseline, 156 patients entered the study, 15 had a diagnosis of vascular dementia, 113 one of post-stroke mild cognitive impairment. Patients with psychiatric symptoms were found to be at increased risk of being diagnosed as having vascular dementia at baseline (OR = 6.9, CI = 1.3-36.8) and showed more decline on cognitive function 6 months after stroke. CONCLUSIONS: Patients with psychiatric symptoms after stroke are at increased risk of cognitive deficits and decline in cognitive functioning.     

Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities

BACKGROUND: Magnetization transfer ratio (MTR) histogram analysis provides a global measure of disease burden in multiple sclerosis (MS). MTR abnormalities in normal appearing brain tissue (NABT) provide quantitative information on the extent of tissue damage undetected by conventional T2-weighted (T2W) magnetic resonance imaging (MRI). AIMS: 1) To compare the MTR histograms from NABT across a broad spectrum of relapse onset MS patients, including relapsing-remitting (RR) MS (including newly diagnosed and benign subgroups) and secondary progressive (SP) MS. 2) To determine the relationship between clinical disability and NABT MTR histograms. METHODS: 2D spin echo magnetization transfer imaging was performed on 70 RRMS and 25 SPMS patients and compared with 63 controls. MTR histograms were acquired for NABT after extracting lesions and cerebrospinal fluid (CSF). T2W images were used to measure the brain parenchymal fraction (BPF) and T2 lesion load. RESULTS: MS patients had a disease duration ranging from 0.5 to 37 years and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 8.5. There was a significant decrease in NABT mean MTR (+/- standard deviation) compared with controls (33.07 pu +/- 1.06 versus 34.26 pu +/- 0.47; P < 0.001) with an effect size of 2.56. The reduction in NABT mean MTR varied among patient groups from 4.9% for SPMS, 3% for all RRMS, 2.7% for early RRMS and 2.5% for benign MS, compared with controls. NABT mean MTR correlated significantly with T2 lesion load (r = -0.82) and BPF (r = 0.58). EDSS score correlated with NABT mean MTR (r = -0.43), BPF (r = -0.33) and with T2 lesion load (r = 0.59). Multivariate analysis using NABT MTR peak height, T2 lesion load and BPF combined only accounted for 38% of the variance in the EDSS (r = 0.62; P < 0.001). Disease duration accounted for an additional 14% of variance in the EDSS (r = 0.72; P < 0.001). CONCLUSIONS: There is evidence of diffuse abnormalities in NABT in addition to global brain atrophy in relapse onset MS patients, including those with recently diagnosed RRMS and benign MS. The abnormalities are greatest in patients with the more disabling SPMS. Atrophy, NABT and lesion abnormalities are all partly correlated; the processes marked by these MR measures all contribute to disability in MS, providing complementary information relevant to the complex pathological processes that occur in MS.     

Neuropsychological deficits but not coping strategies are related to physical disability in multiple sclerosis

Detailed neuropsychological assessment was performed in 86 women (48 patients with stable relapsing-remitting multiple sclerosis (MS) and 38 matched healthy controls (HC)). Patients were categorized into patients without (EDSS < or =1, n = 26) and with physical disability (EDSS > or =2, n = 22). Patients with EDSS > or =2 scored significantly (P < 0.05) higher in Beck's depression inventory (BDI) and depression scores (DS) compared to HC and patients with EDSS < or =1. No significant differences were found with respect to the use of specific coping strategies between the patient groups, who preferred active (EDSS < or =1) or distracting (EDSS > or =2) strategies. Cognitive deficits were significantly increased in MS with EDSS > or =2 with regard to visuo-construction and visual memory, in particular with respect to geometric figures, compared to MS with EDSS < or =1. Significant positive correlations of depression variables (BDI, DS and BL) and depressive as well as denying coping strategies were found. Our results showed increased depression scores and increased cognitive deficits in advanced physically disabled patients, without selection of specific coping strategies. This supports an individual MS-specific neuropsychological therapeutic approach in order to improve disease related deficits together with social functioning.     

Development of neuropsychological deficits in Huntington's disease

Patients with more recently diagnosed Huntington's disease (RHD) were compared on a neuropsychological test battery with patients who had had the disease one to eight years (moderate HD) and with asymptomatic offspring. Though the patients with HD showed deficits in motor and motor-independent abilities, the patients with RHD were less impaired on factors assessing visuospatial ability, cognitive flexibility, and motor steadiness. Of particular interest was the finding that some asymptomatic offspring showed deficits in visuospatial ability and auditory memory that resembled the deficits of patients with RHD. The findings suggest that deficits in HD do not develop at a uniform rate; deficits in cognitive flexibility occur in later stages of the disease; and visuospatial and auditory memory deficits are very early signs and are present in some asymptomatic offspring.     

The role of disability and depression in cognitive functioning within 2 years after multiple sclerosis diagnosis

OBJECTIVES: To investigate cognitive functioning shortly after multiple sclerosis (MS) diagnosis and to examine the relationship with disability, depression and anxiety. METHODS: Data were available for 101 recently diagnosed MS patients and 117 healthy controls. Neuropsychological and clinical assessment included Rao's Brief Repeatable Battery, Expanded Disability Status Scale (EDSS), and Hospital Anxiety and Depression scale (HADS). RESULTS: Patients had lower scores than controls on timed tasks (Paced Auditory Serial Addition Test (PASAT3, p-value adjusted for age, sex and education = 0.04; PASAT2, p = 0.001), Word List Generation Test (WLG, p = 0.04)). Scores on Symbol Digit Modalities Test (SDMT; p = 0.001), PASAT3 (p = 0.01) and PASAT2 (p < 0.001) showed significant association with EDSS. Patients with EDSS >or= 3.0 had significantly lower scores on Selective Reminding Test (SRTC, p = 0.04), SDMT (p = 0.002), PASAT3 (p = 0.002), PASAT2 (p < 0.001) and WLG (p = 0.01) than controls from the general population. Patients with clinically borderline scores of depression scored lower on SDMT (49.5 versus 57.1, p = 0.06) and PASAT3 (39.8 versus 47.1, p = 0.03). However, after adjustment for EDSS and time since disease onset, these differences were not statistically significant. CONCLUSION: Within two years after diagnosis, patients with MS had lower scores compared to healthy controls on timed tasks, suggesting cognitive slowing in patients with early MS. Cognitive impairment was associated with symptoms of depression, but this association could be explained by differences in disability.     

Dementia and cognitive impairment three months after stroke

To investigate the cognitive capacities of a cohort of ischaemic or haemorrhagic stroke survivors and to identify the clinical determinants of post-stroke cognitive impairment, we evaluated 237 patients admitted to a Stroke Unit (mean age 59; SD=12.7). Three months after stroke, patients were submitted to a neuropsychological evaluation that included the Mini-Mental State Examination (MMSE), a complementary battery to assess specific cognitive domains, the Hamilton Depression Rating Scale (HDRS) and the Blessed Dementia Scale (BDS). Disturbed performance on at least one domain was detected on 131 (55%) patients: 27% had cognitive deficits other than memory, 7% had focal memory deficit, 9% had memory and other cognitive deficits and 6% had dementia. Dementia was associated with female gender (P=0.01), older age (P=0.01) and lower education level (P=0.04). Patients with memory deficits were older (P=0.01) with lower educational level (P=0.08) and more left sided lesions (P=0.02) than patients without memory deficits. In this middle aged stroke survivors cognitive impairment was common 3 months after stroke, while dementia was infrequent.     

Treatment options of cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) is a progressive disease of the CNS, characterized by the production of widespread lesions in the brain and spinal cord. Inflammatory demyelination has traditionally been seen as the main disease process in MS; however, axonal damage or loss is increasingly being documented to occur early in the disease. Cognitive deficits can occur independently of physical disability, which complicates their identification and recognition. More recently, cortical demyelination has been identified among possible causes of cognitive impairment in MS. Neuropsychological studies have consistently demonstrated that 40–65% of patients with MS experience cognitive dysfunction, particularly in recent memory, information processing speed, and sustained attention. Early detection of cognitive impairment is essential to enable therapeutic intervention to alleviate symptoms or prevent further cognitive decline, although how best to manage MS-related cognitive impairment is currently unclear. Treatment strategies for cognitive impairment in MS are still in their infancy. This article will summarize several pharmacological attempts to enhance cognitive performances in people with MS.     

Cognition in the early stage of multiple sclerosis

Objective Cognitive dysfunctions may contribute to limitation of everyday activities of patients with multiple sclerosis (MS). Recent studies have demonstrated that 45 to 65% of MS-patients are cognitively impaired. The profile of MS-related cognitive dysfunctions varies greatly. It includes memory and learning deficits, attention deficits, executive dysfunctions and visuo-spatial deficits. Most studies of cognition in MS examined patients in later stages, often including MS-patients with marked physical disabilities. Studies of cognitive dysfunctions in the early stage of the disease are rare. This study specifically aimed at evaluating and characterizing cognitive impairments in the early stage of MS, and determining specific patterns of cognitive dysfunction. Methods 21 MS patients, experiencing their first neurological symptoms not more than two years previously, and 22 healthy controls were compared. A comprehensive neuropsychological test-battery was used to evaluate MS-related cognition. The battery consisted of memory and learning tests, executive functioning tests and a visuo spatial functioning test. A computerized attention test-battery was also included, which assess accuracy and speed of test responses. In addition depression and intellectual capabilities were assessed. Results Compared with healthy controls, MS-patients in the early stage of the disease performed significantly lower on each neuropsychological assessment, except for verbal short-term memory. In particular, MS-patients showed a lengthened reaction time for simple and focused attention (19–38%), impaired non-verbal memory function (RVDLT recognition: 33%) and a planning deficit (24%). Associations between information processing speed and disease course and the employment situation were additionally found. However, patients did not have clinically relevant depression rates on the ADS-L and visuo spatial abilities remain preserved. Conclusion Our findings revealed discrete cognitive dysfunction in MS-patients within the early stage of the disease. Received in revised form: 18 January 2006     

Screening of vascular cognitive impairment on a Hungarian cohort

Cerebrovascular disease is a major public health problem in Eastern European countries. A Hungarian post-stroke population was examined to estimate the rate of dementia, the risk factors for cognitive impairment, and the applicability of a recently established Canadian diagnostic checklist in this cohort. Chronic cerebrovascular outpatients were screened for cognitive impairment with a combined checklist: the Diagnostic Checklist for Vascular Dementia established by the Consortium of Canadian Centres for Clinical Cognitive Research using the Mini Mental State Examination instead of the detailed neuropsychological part of the Checklist. Of the 247 consecutive patients at a cerebrovascular outpatient unit, 176 had cerebrovascular disorder diagnosed either by computed tomography (CT; n=126) or by the clinical signs. Of these, 15% were cognitively impaired and 5% fulfilled the criteria of dementia. The mean age of the patients with cognitive impairment was significantly higher than that of patients with normal cognition (68.2+/-10.2 and 60.5+/-10.5 years, P<0.001). The Barthel index was significantly lower in the cognitively affected group than in non-affected patients (92.4+/-16.0 and 97.1+/-8.7, P=0.027). Diabetes and more than two subcortical infarcts on CT or magnetic resonance imaging were more frequent in patients with cognitive loss (P=0.043 and P=0.013, respectively). Cognitive performance was also influenced by the level of education. Higher age, diabetes, motor deficits, and multiple subcortical infarcts are risk factors for cognitive impairment after stroke. The combined checklist appears to be a practical screening test for cognitive impairment in patients with chronic cerebrovascular diseases.     

Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis

OBJECTIVES: To establish the frequency of cognitive impairment in a population based sample of patients with recently diagnosed relapsing-remitting multiple sclerosis (RRMS), and to determine the relation between cognitive abnormalities and the extent of macroscopic and microscopic tissue damage revealed by magnetic resonance imaging (MRI) and magnetisation transfer (MT) imaging. METHODS: 58 patients with RRMS consecutively diagnosed in the previous six months in Aquitaine and 70 healthy controls underwent a battery of neuropsychological tests. Lesion load and atrophy indices (brain parenchymal fraction and ventricular fraction) were measured on brain MRI. MT ratio (MTR) histograms were obtained from lesions, normal appearing white matter (NAWM), and normal appearing grey matter (NAGM). Gadolinium enhanced lesions were counted. RESULTS: 44 RRMS patients could be individually matched with healthy controls for age, sex, and education. Patients performed worse in tests of verbal and spatial memory, attention, information processing speed, inhibition, and conceptualisation. Measures of attention and information processing speed were correlated with lesion load, mean NAWM MTR, and the peak location of the NAGM MTR histogram in the patients. Multivariate regression analysis showed that lesion load and mean NAWM MTR were among the MR indices that were most significantly associated with impairment of attention and information processing speed in these early RRMS cases. CONCLUSIONS: Cognitive impairment appears to be common in the early stages of RRMS, mainly affecting attention, information processing speed, memory, inhibition, and conceptualisation. The severity of these deficits reflects the extent of the lesions and the severity of tissue disorganisation outside lesions.     

Awareness of deficit in multiple sclerosis

The present study examined awareness of deficits among individuals with multiple sclerosis (MS). A total of 74 pairs of persons with MS and their significant others participated. Awareness of cognitive deficit was measured by discrepancy scores between patient reports of their cognitive abilities and objective test results. Awareness of functional deficit was measured by the discrepancy between the patient and significant other reports of the functional abilities of the patient. Results suggest that about one third of MS patients have diminished awareness of their cognitive and/or functional deficits. Unawareness of deficit was more common among patients with secondary-progressive MS than among those with relapse-remitting MS. Executive dysfunction was strongly associated with unawareness of cognitive deficits but not unawareness of functional deficits. Unawareness of cognitive deficits and unawareness of functional deficits appear to be tapping different aspects of unawareness of deficit.