On the nature of memory disturbance in multiple sclerosis

Thirty-seven patients with multiple sclerosis (MS) were compared to 26 normal controls of equivalent age, education, and verbal intelligence on measures of verbal learning and memory (Digit Span and Supraspan, Brown-Peterson Distractor Task, Selective Reminding Test, Story Recall, and Free Verbal Recall) and verbal fluency (Letter and Animal Fluency). The MS patients exhibited deficits on measures of secondary (long-term) memory and verbal fluency, but performed normally on measures of primary (short-term) memory, recognition memory, and rate of forgetting from secondary memory. These results suggest that the memory disturbance in MS results primarily from an imparied ability to access information from secondary memory, while encoding and storage capacity is intact. Degree of memory impairment was unrelated to length of illness, severity of disability, or self-reported depression.     

The nature of multiple sclerosis

Multiple sclerosis (MS) has recently been classified according to its clinical course. Despite relapses and remissions, its course is invariably progressive, and the observed progression from the remitting-relapsing to the secondary progressive form represents the accumulation of permanent damage to the nervous system. Discussions of the nomenclatural position of Schilder's, Marburg's, and Baló's diseases, ignore the fact that the unique, pathognomonic, sharp-edged plaque of MS, is also the pathologic end-result in the three variants. Devic's disease or neuromyelitis optica (NMO) is quite different and with some exceptions, is a particular form of disseminated encephalomyelitis (DEM). There is no evidence that the 'oriental form of MS' is anything but NMO. The suggestion that MS and DEM are variants of the same condition is contradicted by the fact that the pathological characteristics of the two are quite different. While it is probable that the two share aspects of pathogenesis, the patients differ because of their genetic endowment. This was dramatically demonstrated in a group of Japanese patients who died after anti-rabies vaccination and were found to have the typical sharp-edged lesions of MS. The genetic determinant was also crucial in the marmoset in which EAE uniquely resulted in a chronic relapsing-remitting (RR) disease characterized by the classic sharp-edged lesions of MS. The question 'ADEM: distinct disease or part of the MS spectrum?' can be answered with a resounding no. A new classification is proposed separating the different forms of MS from the various types of DEM.     

Fatigue and sleep disturbance in multiple sclerosis

Considering the association of sleep disturbance and fatigue in multiple sclerosis (MS), we investigated the presence of sleep disturbances that may be related to fatigue by using objective and subjective measures. We included 27 MS patients with fatigue, 10 MS patients without fatigue and 13 controls. The Pittsburgh sleep quality index score showed significant differences between patient groups and controls. Beck depression inventory scores were significantly higher in fatigued than non-fatigued patients. Comparison of patient groups and controls revealed significant differences for time in bed, sleep efficiency index, sleep continuity index, wake time after sleep onset, total arousal index and periodic limb movement arousal index. Our study confirms that MS causes sleep fragmentation in terms of both macro and microstructure. Fatigue in MS could be partially explained by disruption of sleep microstructure, poor subjective sleep quality and depression.     

Memory disturbance in chronic progressive multiple sclerosis

Forty-four patients with chronic progressive multiple sclerosis (MS) were compared with age- and education-matched control groups on a battery of clinical and experimental memory measures. Patients with MS performed substantially below the control groups on both immediate learning and delayed recall tasks, particularly in the retrieval of spatial information. The MS sample was subdivided into three groups using a cluster analytic procedure. One group (N = 9) performed well below expectations on memory tasks, exhibited signs of global cognitive disturbance, and had an atypical personality adjustment, characterized by irritability, social withdrawal, and apathy. A second group (N = 19) showed mild memory disturbance, associated with a greater use of psychotropic medications and a higher incidence of reactive depression. A third group (N = 16) performed normally on memory measures. The three groups of patients with MS did not differ in length or overall severity of illness.     

Prospective memory in multiple sclerosis.

There is considerable evidence that multiple sclerosis (MS) is associated with impaired retrospective memory. However, although preliminary evidence suggests that prospective memory is also affected by the disorder, the degree and nature of the impairment remains to be clarified. Twenty participants with MS were compared with 20 matched controls on Virtual Week, a measure of prospective memory that closely represents the types of prospective memory tasks that actually occur in everyday life, and provides an opportunity to investigate the different sorts of prospective memory failures that occur. The results indicated that irrespective of the specific prospective memory task demands, MS participants' performance was significantly impaired relative to controls. MS deficits could not be attributed to problems with retrospective memory because MS participants in the present study did not differ significantly from controls on measures of long- and short-term memory, and significant impairment was observed on a prospective memory task, which imposed only minimal demands on retrospective memory. These results therefore suggest that individuals with MS may experience general difficulties with prospective memory. The practical and theoretical implications of these findings are discussed.     

The nature of caregiving in multiple sclerosis: development of the caregiving tasks in multiple sclerosis scale

Caregivers of persons with multiple sclerosis (MS) engage in many caregiving tasks and spend considerable time on these activities with such caregiving being of immense social and economic value. However, the lack of empirically derived psychometrically sound instruments for measuring caregiving tasks has hampered progress in this field. This study aimed 1) to examine the dimensional and psychometric structure of the Caregiving Tasks in MS Scale (CTiMSS), and 2) to examine caregiver and care recipient correlates of caregiving tasks. Participants were 232 caregivers of persons with MS and their care recipients. Questionnaires were completed at Time 1 and 12 months later (Time 2). Factor analyses showed that the CTiMSS could be represented by a single dimension or four caregiving domains: Instrumental Care, Activities of Daily Living Care, Psycho-emotional Care, Social-practical Care. The CTiMSS factors were psychometrically sound and evidenced differential relations with most caregiver and care recipient characteristics and predicted changes in adjustment over 12 months. Findings delineate the key dimensions of MS caregiving and show the differential links between caregiving task domains and caregiver and care recipient characteristics. Results provide preliminary reliability and validity data on the first published measure of caregiving tasks in MS. Such an instrument is important for theory building, across study comparisons and the development of services.     

The incomplete nature of multiple sclerosis relapse resolution

Relapsing-remitting multiple sclerosis (RRMS) is often associated with accrual of disability, even though it precedes the progressive phase of the disease, in which clinical disability is most apparent. Changes in T1 and T2 magnetic resonance imaging (MRI) findings, as well as clinical trials of drugs that target RRMS, have established correlations between relapse episodes and disability progression. Briefly reviewed herein are relevant data that link relapses with disability accrual, including a recent direct analysis of well-defined clinical trial databases that shows MS relapses to have a measurable and sustained effect on disability. These studies pinpoint the measurable residual deficits of relapses that had, up to this point, only been implied by prior research, confirming the existence of relapse-associated step-wise worsening in patients with RRMS and lending credence to the continued development of long-term treatment targeted at the early phases of the disorder.     

Attention and memory dysfunctions in mild multiple sclerosis

This study investigated the relationship between clinical symptoms and cognitive dysfunction in multiple sclerosis. Cognitive dysfunction and visual evoked potentials (VEPs) were studied in patients free of physical disability and mildly to moderately disabled patients with multiple sclerosis (MS). Disability–free patients (EDSS ≤ 1.5; n = 13),mildly to moderately disabled patients (EDSS ranging from 2 to 6; n = 13) and a healthy matched control group (n = 16) were examined with respect to attention, verbal and nonverbal memory and early visual processing (VEPs). Disability–free patients showed mild impairments on phasic alertness and divided attention. Deficits were more pronounced in mildly to moderately disabled patients who were additionally impaired with respect to non–verbal memory. Despite adequate visual acuity, one half of all patients showed abnormal VEP latencies for both eyes at the same time. The findings suggest that cognitive deficits are already present in multiple sclerosis even in the absence of physical disability. Even with normal visual acuity, perceptual impairments should be considered as part of the CNS affection. Drs. Tinnefeld and Treitz contributed equally to this work.     

Working memory in multiple sclerosis: a review

IntroductionImpairment of working memory (WM) is frequently reported in multiple sclerosis (MS) patients. However, the various methodologies used, as well as the populations selected for study, hinder the interpretation of results. The aim of this study is to propose a review about WM in MS.MethodTwenty studies have presented results on WM with neuropsychological assessment.ResultsAll studies conclude that WM is impaired in MS. Reduced processing speed would be central, with major impact on WM performance. According to Baddeley's model, difficulties may be located at the level of the central executive. MS patients would be sensitive to tasks with a high cognitive load. However, performances seem to become better when the processing speed is adapted. Explanatory models relating to this kind of impairment have been proposed from imaging studies. Compensation could mask deficits in WM at the early stage of the disease, but would become blurred with advancing illness and increasing load required for the task.Conclusions/prospectsIn order to assess WM, adapted tools should be proposed to MS patients. Focus should be placed on processing speed. Further studies are needed, for instance to examine the dissociation of the processes operating within the central executive as described in Miyake's model. Imaging investigations have provided essential data helpful for understanding compensation mechanisms. These data should be useful for developing adapted remediation plans to compensate for the crippling impairment observed in everyday life.     

Automatic memory processes in patients with multiple sclerosis

To better understand the nature of the memory deficit in patients with multiple sclerosis, we designed a study to compare automatic vs effortful memory processes. Forty-one patients with definite multiple sclerosis and 45 demographically matched normal control subjects were administered two tasks designed to assess both automatic (monitoring frequency and modality) and effortful (free and cued-recall) processing. Results indicated that patients with multiple sclerosis, as expected, were significantly impaired on memory measures requiring effort, but performed normally on automatic measures. Performance on the memory indexes did not correlate with self-reported depression. The implications of these findings for delineating the locus of the memory impairment in multiple sclerosis is discussed.     

The nature of inflammatory components during demyelination in multiple sclerosis

Immune reactivity in the central nervous system (CNS) in multiple sclerosis (MS) can be fuelled by activated T lymphocytes sequestered in the brain and those entering systemically. The perivascular cuff of the inflammatory lesion consists predominantly of T cells and macrophages, while the hypercellular interface between normal and degenerating myelin is comprised mainly of macrophages and activated microglia. MHC class II⁺ cells are abundant in the hypercellular zone and expression of both the polymorphic and invariant chains of the molecule are expressed beyond the plaque edge in the white matter where the staining is restricted largely to microglia.

Under carefully controlled staining conditions expression of MHC class II can be demonstrated on microglia in control white matter. Thus the immunological privilege of the CNS does not appear to preclude constitutive expression of MHC antigens or prevent the traffic of activated lymphocytes into the brain parenchyma. However, the antigens priming the immune reaction in the CNS in MS and the role of antibodies in the demyelinating process remain a matter for speculation and the exact mechanisms of demyelination are as yet unresolved.     

Conscious and unconscious uses of memory in multiple sclerosis

Conscious and unconscious uses of memory and priming were studied in 30 patients with multiple sclerosis (MS) and 15 normal control (NC) subjects. MS patients were classified into two subgroups according to their cognitive status; 15 of them were cognitively deteriorated (the MS-D group) and 15 cognitively preserved (the MS-P group). A process dissociation procedure [J. Mem. Lang. 30 (1991) 513] was used to separate conscious and unconscious memory performance in a word stem completion task. The results showed that the MS-D group had deficient conscious memory performance, but had intact unconscious memory as well as priming. The MS-P group showed normal conscious and unconscious uses of memory and priming. Thus, in MS-related cognitive decline, conscious memory seems to be vulnerable, whereas unconscious memory remains intact. The results provide neuropsychological support for the distinction between conscious and unconscious memory processes. Moreover, the results show the importance of studying cognitively homogenous MS groups as opposed to heterogenous ones, in order to find the underlying mechanisms of memory deficits in MS. Interestingly, the neural systems needed for the unconscious use of memory do not seem to deteriorate even in MS patients with deficient overall cognitive capacity. This finding encourages the development of future rehabilitation programs, suggesting that unconscious remembering might help MS patients with deficient conscious memory to cope with their daily activities.     

Computer-assisted memory retraining of patients with multiple sclerosis

This study aimed to assess the efficacy and specificity of direct computer-assisted memory retraining (CR) in MS patients, in comparison to non-specific retraining, while controlling for severity of impairment, psychiatric symptoms and retest effects. Sixty patients with definite MS and a stable clinical condition were selected. All were assessed neuropsychologically and divided into three matched groups. One group received an 8-week specific CR programme (SCRP) and another received a non-specific 8-week CR programme (NCRP) to retrain attention; a third (control) group received no treatment. After the programmes were completed, all patients were reexamined with the same test battery. Patients were impaired on all 11 memory and attention tests at baseline. Those who received SCRP improved on 7 memory outcome measures, compared to only 1 in the NCRP group and none in the control group. Attention training had no significant effect on relevant outcome measures. Some non-retrained patients showed deterioration of cognitive performance at retest. These results indicate that direct memory training in MS patients is effective in the short-term and is specific. In selected cases, benefits extended to everyday life activities.     

Increased functional connectivity within memory networks following memory rehabilitation in multiple sclerosis

Identifying effective behavioral treatments to improve memory in persons with learning and memory impairment is a primary goal for neurorehabilitation researchers. Memory deficits are the most common cognitive symptom in multiple sclerosis (MS), and hold negative professional and personal consequences for people who are often in the prime of their lives when diagnosed. A 10-session behavioral treatment, the modified Story Memory Technique (mSMT), was studied in a randomized, placebo-controlled clinical trial. Behavioral improvements and increased fMRI activation were shown after treatment. Here, connectivity within the neural networks underlying memory function was examined with resting-state functional connectivity (RSFC) in a subset of participants from the clinical trial. We hypothesized that the treatment would result in increased integrity of connections within two primary memory networks of the brain, the hippocampal memory network, and the default network (DN). Seeds were placed in left and right hippocampus, and the posterior cingulate cortex. Increased connectivity was found between left hippocampus and cortical regions specifically involved in memory for visual imagery, as well as among critical hubs of the DN. These results represent the first evidence for efficacy of a behavioral intervention to impact the integrity of neural networks subserving memory functions in persons with MS.     

Multiple memory deficits in patients with multiple sclerosis. Exploring the working memory system

Some patients with multiple sclerosis (MS) demonstrate impaired memory. A group of 16 patients with MS who were mildly to moderately affected (Kurtzke Expanded Disability Status Scale Score = 3.8) were studied, and they were compared with a matched control group on tests of "working memory." The working memory system was explored by evaluating the amount of information that can temporarily be held in a buffer system during encoding. Results indicated that patients with MS have difficulty in processing information at the level of a hypothesized articulatory loop in working memory. This deficit was correlated with their retrieval of verbal information from long-term memory, as well as how accurately they processed verbal information presented at a rapid rate. There was no significant relationship between ratings of MS severity or number of plaques visualized on magnetic resonance imaging scans and the degree of working memory deficit.     

Structural brain correlates of anterograde memory deficits in multiple sclerosis

Summary Progressive decline of anterograde memory functions has been increasingly recognized as a frequent symptom in chronic multiple sclerosis. In order to investigate the brain structures involved, magnetic resonance imaging was performed in 20 patients. Neuropsychological assessment included the WAIS and WMS subtests information, picture completion, similarities, digit span, logical memory, and paired associate learning. All patients with severely impaired memory functions (n=5) showed bilateral lesions in the medial temporal lobe, whereas in those patients with moderate (n=10) or no measurable impairment of memory testing (n=5) either no lesions were seen in the medial temporal lobes or these lesions were restricted to one side. A post hoc cluster analysis strikingly confirmed these results. The differences could not be related to the age of the patients, the disease duration, or the level of education. Extensive lesions in the white matter of the frontal lobes, thinning and lining of the corpus callosum, and bilateral involvement of the anterior cingulate gyrus had no bearing on the neuropsychological results. These findings indicate that bilateral demyelination in the hippocampal regions is the most likely explanation for the impairment of anterograde memory in such patients.Presented in part at the 25th Annual Meeting of the American Society of Neuroradiology, New York, 10–15 May 1987     

Effects of donepezil on memory and cognition in multiple sclerosis

Acetylcholinesterase inhibitors are used to treat dementia associated with Alzheimer's disease, but their cognitive benefits may extend to additional disorders such as multiple sclerosis (MS). A single-center double-blind placebo-controlled randomized clinical trial evaluated the effectiveness of donepezil in a sample of 69 MS persons selected for initial memory difficulties. Subjects received neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in total recall on the Selective Reminding Test, a measure of verbal learning and memory. Secondary outcomes included other neuropsychological tests from the Brief Repeatable Battery, patient-reported change in memory, and physician-reported impression of cognitive change. Donepezil improved memory performance on the SRT compared to placebo. This benefit remained significant after controlling for various covariates including Expanded Disability Status Scale (EDSS), MS subtype, interferon beta use, treatment group beliefs, gender, baseline selected reminding test (SRT) score, and reading ability. Subjects on donepezil were more likely to report memory improvement (65.7%) than those on placebo (32.4%). The clinician also reported cognitive improvement in more donepezil (54.3%) than placebo (29.4%) subjects. No serious adverse events related to study medication occurred. However, more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams. Donepezil improved learning and memory in MS patients with initial cognitive difficulties in a single-center clinical trial. Replication of results in a larger multi-center investigation is warranted in order to more definitively assess the efficacy of this intervention.