Première évaluation d’un programme de remédiation cognitive chez des patients atteints de sclérose en plaques : PROCOG-SEP

Background

Although cognitive disorders are well-known in multiple sclerosis (MS), even in earlier stages of the disease, their management may be overlooked. Our objective was to elaborate and evaluate the efficiency of a remedial program (PROCOG-SEP) designed for MS patients. The evidence-based program proposes exercises to both stimulate preserved functions and develop new abilities compensating for cognitive disabilities.

Design/Methods

Twenty-four patients with MS participated in 10/2-hour PROCOG-SEP sessions over a 6-month period. A neuropsychologist recorded BCcog-SEP performances before and after the PROCOG-SEP program. In addition, the same neuropsychologist conducted psychoclinical interviews to complete the before and after cognitive evaluations. The statistical analysis used the t-test performed with Excel.

Results

Compared with the initial levels, subtests of BCcog-SEP showing improvement after PROCOG-SEP were: verbal memory (SRT), visuospatial memory (10/36), verbal fluency (animal categories) and response to conflicting orders. Also, individual psychological interviews tended to be in favor of a general improvement in quality of life (more social interactions for instance).

Conclusions/Relevance

To our knowledge, the management program we have elaborated is the first designed to improve cognitive deficits in MS. These encouraging results suggest possibilities for improving cognition and thus quality-of-life in MS patients.     

Vitamin D and multiple sclerosis. A prospective survey of patients of Poitou-Charentes area

Introduction

Recent reports demonstrate the implication of vitamin D in multiple sclerosis (MS).

Methods

In a multicentric regional study (Poitou-Charentes area) during the first trimester 2010, we measured the 25-OH vitamin D serum level in 170 consecutive MS patients, and in 170 controls matched for age (± 4 years), sex and date of blood sample analysis. We searched for correlations between 25-OH vitamin D serum levels and the MS form, the disability (EDSS), the relapse rate during the previous year and the presence and number of enhancing lesions on T1-weighted MRI dating less than 12 months in relapsing MS.

Results

Hypovitaminosis D was very frequent in MS patients and 25-OH vitamin D serum level was significantly lower (14,5 ± 9,2 mcg/mL) in MS patients than in the control group (16,7 ± 9,6 mcg/mL). This serum level was inversely correlated with the degree of disability measured with EDSS score and was lower in secondary progressive (RR-SP) and primary progressive (PP) MS than in relapsing MS (RR). No correlation was found between 25-OH vit D serum level and relapse rate during the previous year in RR MS and the presence and number of enhancing lesions on T1-weighted MRI dating from less than 12 months.

Conclusion

25-OH vit D serum level is very low in MS, mainly in RR-SP and PP MS and is correlated with disability. This suggests MS patients should be screened for vitamin D deficiency and given supplementation systematically when hypovitaminosis D is discovered.     

High prevalence of restless legs syndrome in multiple sclerosis

Prevalence of restless legs syndrome (RLS), a clinically defined disorder, varies from 2.5 to 15% among populations. In the French adult population, prevalence is estimated to be 8.5%. RLS is often secondary to a variety of disorders. Neurological conditions usually associated with RLS are neuropathies and Parkinson's disease. There are few studies of its association with multiple sclerosis (MS). The aim of this study was to estimate RLS prevalence in a population of French MS patients. During one month, 17 neurologists from the G-SEP group prospectively recruited 242 patients who fulfilled the Mc Donald criteria for MS. Each patient underwent a standardised questionnaire to verify the international criteria of RLS. We collected date of birth, gender, MS course (relapsing remitting, primary progressive and secondary progressive) and MS duration. Forty-one subjects (18%) met the criteria for RLS. Comparing the RLS group with the group without RLS, no significant differences were found in age, gender and MS duration. RLS was more prevalent in the relapsing remitting MS group. Prevalence of RLS seems to be doubled in MS patients compared to the general population. This finding warrants further study. Identification of this syndrome in MS patients might lead to specific treatments.     

Contribution of cognitive evoked potentials for detecting early cognitive disorders in multiple sclerosis

In Multiple Sclerosis (MS), one of the most frequent neurological diseases in young adults, cognitive dysfunctions have been under considered whereas their evolution may produce a fronto-sous-cortical deterioration and more than half of the MS patients present such dysfunctions. Nevertheless sensory evoked-potentials are classically used in this disease, event-related potentials (ERP) are not included in the clinical exploration of MS. Two studies are presented aimed at further tracking the usefulness of ERP for detecting early cognitive dysfunctions in MS. All of the patients presented a relapsing remitting MS for less than 5 years with a moderate physical handicap and complained from their memory. They performed a neuropsychological set and ERP were elicited using the oddball paradigm in both modalities, visual and auditory. In the first study, 10 patients without cognitive dysfunction at the neuropsychological evaluation and 10 patients with an attention deficit participated with 10 age-matched controls. In the second study, 10 patients with memory impairment at the neuropsychological evaluation and 10 age-matched controls were included. Our data argue for an earlier modification of ERP parameters in the visual modality than in the auditory one, even before the modification of cognitive scores. In both studies, P300 parameters were correlated to neuropsychological performances (and especially to the attention examination in the first study and to memory tests in the second study) in both modalities. Taking into account the clinical usefulness of ERPs, it is nowadays important to include this electrophysiological method in evaluation and follow-up of MS, and not only using the auditory modality but also the visual presentation in order to detect earlier cognitive dysfunctions even before modification of neuropsychological performances.     

Cognitive impairment and quality of life in multiple sclerosis patients

INTRODUCTION: Cognitive disorders may bias perception of quality-of-life in patients with multiple sclerosis (MS). METHODS: Neuropsychological tests (WAIS-vocabulary, Gr?ber and Buschke, Stroop, WCST, WAIS-similitude, fluency, Hamilton's depression scale) along with a French health-related quality of life self questionnaire for MS patients (the SEP59) were performed by 117 MS patients with a minor cognitive impairment (Mini Mental State over 24) in order to explore the links between quality of life perception and cognitive functioning. RESULTS: Main Component Analysis and correlation analysis showed that cognitive impairment produced an overrating of the self perception of quality of life. Threshold analysis, splitting patients between the most and the less cognitively impaired, confirmed this relationship. CONCLUSION: The level of cognitive functioning must be considered with caution when analyzing health-related quality of MS patients.     

L’IRM est-elle utile dans le suivi des patients atteints de sclérose en plaques ? Non

Is regular MRI monitoring useful in clinical practice in multiple sclerosis patients treated with disease modifying therapy (DMT) drugs? My answer is no. Tacking a DMT drug is not by itself a pertinent criterion for requiring a systematic MRI monitoring in MS patients. Five clinical criteria should be taken into consideration before prescribing regular MRI examinations. The clinical form of the disease: MRI monitoring in DMT treated patients, has been demonstrated as useful only in pure relapsing-remitting MS patients. Up to now, there is no convincing demonstration of therapeutic efficacy with any DMT drug, neither first-line nor second-line drugs in patients with primary or secondary progressive MS disease. The duration of the disease, epidemiological data leading to the concept of a two-stage disability progression in MS, emphasizes the importance of treating as early as possible RRMS patients in order to stop accumulation of new focal MRI CNS lesions. In this regard, an annual monitoring for the 5 first years of the disease looks reasonable in order to better personalize the treatment choice among the few approved DMT drugs. The duration of the treatment: a first MRI assessment at month 6 after initiating a new DMT drug is adequate in order to better distinguish responder versus no responder. The persistence of Gado + lesions at 6 months is a strong indication for considering alternative treatment. The disease activity: both criteria, clinical and MRI, are needed to recognized very active or aggressive relapsing MS patients, leading to decide a rapid use of second-line treatment therapy. The treatment choice: in JC positive MS patients treated with natalizumab, the risk of PML is as high as more than 1 % in those JC + MS patients that are treated continuously more than 24 months. A regular MRI monitoring (3 or 6 months) is recommended in order to detect as early as possible MRI abnormalities suggesting PML.     

Prevalence of depression in multiple sclerosis: a review and meta-analysis

INTRODUCTION: The aim of this paper was to review and summarize the data about the frequency of depression during multiple sclerosis (MS). MATERIAL AND METHODS: We performed a metaanalysis to combine the results of the studies which compared the frequency of depression in MS patients with the prevalence in patients with other chronic diseases. Eight controlled studies were identified via manual and computerized search of the Medline and PsychInfo databases. Given the various ways these studies reported their results, we used statistical procedures based on the combination of significance levels (the method of adding Zs and the method of adding ts). An additional statistical procedure, Cohen's d, was performed to estimate the effect of size. RESULTS: The two statistical methods yielded highly significant summary statistics: z=4.15 and z=3.98, respectively (p<0.0001). The effect of size (Cohen's d), which ranged from 0.02 to 0.70 with an average of 0.29 (95 percent confidence interval: 0.09-0.49), can be considered as medium and hence clinically meaningful. CONCLUSION: These results suggest that the association between MS and depression is specific, that is not just casual nor due to the nonspecific factors inherent in every chronic disease.     

Mood and emotional disorders in Multiple Sclerosis: a literature review

INTRODUCTION: Even though mood and emotion are closely related concepts, they differ in some ways. This article aims to review the main mood and emotional disorders most often found in Multiple Sclerosis (MS). STATE OF ART: Studies related to four fields are presented and discussed: assessment tools and methodological problems; prevalence, etiology and symptoms of mood as well as emotional disorders in MS; relationship between cognition and emotion. Beside these main subjects, we tackle some interesting questions which concern patients as well as clinicians, such as the risk of depression and protective factors, the relationship between depression and fatigue and the impact of beta-interferon on depression. PROSPECTIVES: We focus on a new promising trend aiming to link neuroimaging data to psychological variables. CONCLUSIONS: These four fields cover a large portion of the questions about mood and emotional disorders in MS. Due to their frequency as well as to their impact on quality of life, specific attention should be given to these disorders.     

Rétinopathie liée à l’interféron-ß 1a sous-cutané

Introduction

Interferon-α associated retinopathy is an ocular complication of hepatitis C treatment well established in the literature. But, there are far fewer reports on multiple sclerosis related interferon-ß retinopathy.

Case report

A 58-year-old male while receiving subcutaneous interferon-ß 1a 44 μg thrice a week since 2001 for multiple sclerosis developed blurred vision. Visual acuity remained stable throughout the course of surveillance. Cotton wool spots were found on fundus exam. The retinopathy disappeared without specific therapy 2 months after discontinuing interferon injections. The diagnosis of interferon-ß 1a retinopathy was retained due to the lack of any other etiology.

Conclusion

An ophthalmological examination including a fundus examination to search for a retinopathy should be undertaken when new ocular symptoms develop in a multiple sclerosis patient receiving interferon. An adverse event linked to interferon can be discussed and favored if the retinopathy resolves after interferon withdrawal.     

Traitement d’induction dans la sclérose en plaques : place du natalizumab

Background

Current treatment options for first-line immunotherapy in relapsing-remitting multiple sclerosis (MS) are recombinant interferon-β and glatiramer acetate. However, these therapies are only partially effective and certain patients may fail to respond. For this reason, it is important to elaborate alternative treatment strategies. Induction therapy represents a more aggressive approach in which powerful drugs are used right from the beginning to tackle the disease process hard and early. Natalizumab is a powerful monoclonal antibody approved for the treatment of relapsing-remitting MS and is known to silence disease activity.

Methods

We describe here the early outcome at 1 month and at 6 months of three patients treated with natalizumab for relapsing-remitting MS.

Results

All three patients had a high disease activity before the initiation of natalizumab, with 4, 8 and 5 gadolinium-enhancing lesions on brain MRI respectively. On the MRI scans made at 1 month after the first infusion, and at 6 months, there was no more gadolinium-enhancement and no new T2-lesion. Clinically, they did not experience any relapse.

Discussion

In these three cases, natalizumab showed a dramatic efficacy: the patients became “disease activity free” right from the first infusion. To our knowledge, natalizumab is not classically used as an induction therapy, unlike mitoxantrone. However, this treatment has potential hematological and cardiac toxicity and its use can be limited. Thus, in JC virus negative patients, natalizumab could be an interesting alternative treatment.

Conclusion

Our report suggests that induction strategy with natalizumab may be applicable in patients with aggressive multiple sclerosis. A study of more similar cases may be interesting to confirm these preliminary results.     

Acute leukaemia in two multiple sclerosis patients treated with mitoxantrone

INTRODUCTION: Mitoxantrone (Mx) is used as a second-line treatment in multiple sclerosis. Since 1998, eight cases of acute leukemia (AL) have been described. We report two new cases of myeloid AL that occurred during treatment with Mx. OBSERVATIONS: The first case concerned a women who was treated with Mx for 3 months. In spite of a very low total dose (58.32 mg), she developed promyelocytic AL. The second patient died of myeloid AL, 27 months after the last injection of Mx. DISCUSSION: All the reported cases of AL occurring after Mx respond to the criteria of leukemia induced by anti-topoisomerases II. Epidemiological data and those from animal experiments suggest that Mx has direct role in the occurrence of leukemia. CONCLUSION: It must be remembered that even if the risk of Mx-induced leukemia is low, blood cell counts must be closely monitored for at least five years after the last injection of this treatment.     

Le réseau cérébral par défaut : rôle cognitif et perturbations dans la pathologie

Introduction

A “resting state” or “default mode network” has been highlighted in functional neuroimaging studies as a set of brain regions showing synchronized activity at rest or in task-independent cognitive state.

State of the art

A considerable and increasing number of studies have been conducted over the last few years so as to unravel the cognitive function(s) of this brain network.

Perspectives

This review gives an overview of anatomical, physiological and phenomenological data regarding the default mode network. Different hypotheses have been proposed regarding the role of this network. Several studies have highlighted its involvement in autobiographical memory, prospection, self, attention, and theory of mind. The influence of the attention level and consciousness onto resting state brain network activity has also been discussed. Specific changes have been described in normal aging, Alzheimer's disease (AD) and multiple sclerosis (MS).

Conclusions

These studies altogether contribute to a better definition of the default mode network, in terms of implicated brain structures, subtending mechanisms, and potential cognitive roles. For instance, similarities and relationships were found between self-related brain activity and resting-state activity in regions belonging to this network, namely posterior cingulate and prefrontal areas that may reflect introspective activity experienced, more or less consciously, when the brain is not specifically engaged in a cognitive task. As a whole, the default mode network appears as a non human-specific intrinsic functional network, active all over the life from birth until aging where it is progressively modified, and sensitive to different pathologies including AD and MS. On the other hand, many points remain to be clarified concerning this network, such as the exact part of its activity dedicated to self-related cognitive processes (introspection, imaginary mental scenario based on past autobiographical experiences) and that involved in a sentinel-like attentional process designated to react to possible environmental events. Indeed, it seems that this network is functional even in case of low level of consciousness, i.e., during light sleep. Conversely, a loss of self and environment perception as in coma, deep sleep or anesthesia might modulate its connectivity along the anteroposterior axis, i.e., frontal activity disappearance associated with a parietal reinforcement of connectivity. Since studies aiming at highlighting these points are still uncommon to date, exhaustive and objective explorations are needed to better understand all these resting state processes.     

Validation of EHD self questionnaire in multiple sclerosis

Depressive Mood Scale (EHD) aims at assessing the various depressive mood dimensions as "blunted affect" and "lack of emotional control". It is an 18 items hetero-evaluation scale. The aim of this study was the validation of an EHD self questionnaire version. Self questionnaire items were generated from genuine scale items. As in the former version, response format was a Lickert 5 point scale. This validation study was carried out on 77 Multiple Sclerosis (MS) patients. Mood disorders are frequent during the course of MS and might be triggered or worsened by immuno-modulation therapies. Principal Component Analysis (ACP) with Varimax rotation revealed a two factors structure. The first one, corresponding to a "blunted affect" dimension, explained 33.5% of the scale variance and was composed of 7 items. The second one, corresponding to a "lack of emotional control" dimension, explained 20% of total scale variance and was composed of 4 items. The questionnaire internal coherence coefficient (Cronbach alpha) was excellent (=0.87) and the two sub-scales ones were satisfactory [0.89 for "blunted affect" dimension and 0.71 for "lack of emotional control" dimension. The questionnaire's external validity was confirmed by a positive correlation between "lack of control" sub-score and state sub-score of the Stait-Trait Anger eXpression Inventory (STAXI)] (r=0.55, p<0.01). Moreover we found a positive correlation between the total EHD autoquestionnaire score and both sub-scores on the one hand, and the Beck Depression Inventory score on the second hand (EHD/BDI: r=0.76, p<0.01; "lack of emotional control"/BDI: r=0.68, p<0.01; "blunted affect"/BDI: r=0.63, p<0.01). Test-retest reliability was good with a positive correlation between all the initial scores and their retests, a week later. Secondarily, a structural equation modeling analysis confirmed the two-factors structure model suggested by ACP. Various indicators showed a good fit between theoretical variance-covariance matrix and the observed one (chi(2)=41.55, p=0.49, ddl=42, Goodness Fit Index GFI=0.91, Root Mean Square Residual RMSEA=0.00). Thus, we proposed a well validated self questionnaire that allows the assessment of "blunted affect" and "lack of emotional control". It should be challenging to correlate those dimensions with neuro-psycho-logical testing and neuro-imagery, in patients affected by CNS diseases. Moreover, the assessment of those dimensions during interferon treatment in MS could allow a more precise evaluation of the emotional changes potentially induced by immuno-modulatory treatments.     

Aspects cliniques, radiologiques, pronostiques et thérapeutiques des lésions démyélinisantes extensives

Background

Demyelinating diseases presenting with a tumefactive demyelinating lesion (TDL) raise questions about classification, diagnosis, prognosis, and treatment. Their long-term course is not well described in literature.

Patients/methods

In a retrospective study, we describe the main characteristics of 29 patients with TDLs. In a case control study, we compared two cohorts of multiple sclerosis (MS) patients: 24 MS patients with TDL versus a reference cohort of patients with relapsing remitting MS. We compared the extended disability status score (EDSS) concerning the first demyelinating event (DE) with TDL, EDSS score at the end of follow-up and treatment intake. The objective was to discuss the prognosis and the management of TDL.

Results

In our study, the prognosis was better for patients with non-prevalent TDL (first DE without TDL) compared with patients with prevalent TDL (first DE with TDL) and was not different compared with the MS reference cohort. At the end of follow-up, there was no significant difference between patients treated with immunosuppressors after a first DE with TDL and patients with classical MS. The EDSS at the end of follow-up was statistically more severe for untreated patients after a first DE with TDL than for classical MS patients (P = 0.0047).

Discussion

The prognosis of patients with TDL is difficult to assess because of its multifactorial nature (underlying disease and treatment impact). In our cohort, outcome of MS patients whose first severe DE involved a TDL was better when they received an early immunosuppressive treatment.     

From psychometry to neuropsychological disability in multiple sclerosis: a new brief French cognitive screening battery and cognitive risk factors

INTRODUCTION: Cognitive deficit in multiple sclerosis (MS) is a frequent early feature in the disease course, which conditions patients' overall disability. The goals of this study were to validate a reproducible brief screening battery written in French and to examine cognitive risk profiles in patients with a mild physical disability. METHODS: Cognitive performances of 40 patients with EDSS <4.5 were compared with those of a control group. The study was completed with an analysis of socio-demographic, clinical and psychological variables (questionnaires). RESULTS: Three tests were discriminative with satisfactory predictive values (positive: 88 percent; negative: 96 percent) and a time duration <30 minutes: PASAT (hard condition), backward digit span, learning stage of California Verbal Learning Test. Four variables were associated with cognitive deficit: educational level <11 years, age >40 years, pathological laughing-crying, unemployment. CONCLUSIONS: Our brief battery is an easy and reproducible tool. Completed with warning signs indicating the need for neuropsychological screening, this tool provides the practitioner with a global means of assessing disease activity and potentially therapeutic efficacy.     

Dystonie paroxystique et sclérose en plaques

Introduction

Movement disorders are uncommon in multiple sclerosis, except for tremor. Patients rarely have paroxysmal dystonia (or tonic spasm), which can be the presenting manifestation of the disease.

Observations

Two videotaped observations are presented. The first patient was a 27-year-old woman, treated for relapsing-remitting multiple sclerosis, who presented daily several short (<1 minute) paroxysms of right hemibody dystonia. Brain MRI revealed several areas of cerebral demyelination, including the posterior limb of the left internal capsule with gadolinium enhancement. These events disappeared 7 days after corticosteroid infusion. The second patient was a 62-year-old man who presented brief episodes (<1 minute) of daily painful left hemibody dystonia. Three months later, similar paroxysms affecting the right hemibody including the face occurred. At times, the two hemibodies were affected simultaneously. The brain MRI showed multiple areas of white matter hyperintensity, including two symmetrical areas in the posterior limb of the internal capsules. Multiple sclerosis was diagnosed on clinical, MRI and biological data. Four days after starting corticosteroids, these paroxysmal phenomena disappeared totally.

Conclusion

Dystonia is an under-recognized aspect of paroxysmal events during multiple sclerosis. It might involve ephaptic transmission among abnormal demyelinated neurons; this ectopic excitation can arise at variable levels of the corticospinal tract, but the analysis of reported cases and those described in this study shows that impairment of the posterior limb of the internal capsule seems to be a prevalent topography. Inflammation is likely to play a role because steroids often improve these phenomena. In this article, we review the clinical aspects, pathophysiology and outcome of paroxysmal dystonia in multiple sclerosis.