Secondary progressive multiple sclerosis: A national consensus paper on diagnostic criteria.

BACKGROUND: In clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care. METHODS: Eight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document. RESULTS: Based on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS. CONCLUSIONS: The experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease.

Isolated CNS Sarcoidosis Versus Systemic Sarcoidosis With CNS Involvement: A Same Disease?

Neurological involvement occurs in 5 to 15% of patients with sarcoidosis. It rarely represents the sole manifestation of the disease, a condition called isolated neurosarcoidosis. Objectives: To describe patients with definite isolated central neurosarcoidosis. To compare their characteristics to a group of systemic sarcoidosis with central neurologic involvement. Methods: Monocentric retrospective study of all patients presenting with central neurosarcoidosis (NS) over a 10 year period, subsequently divided into 2 groups: isolated neurosarcoidosis (INS) and systemic neurosarcoidosis (SNS). Results: We report 10 cases of INS and subsequently, we compared their characteristics to a group of 30 patients with SNS. INS patients exhibited brain parenchymal involvement (8/10), meningeal disease (8/10), myelitis (3/10), cranial neuropathy (3/10), neuroendocrine impairment (1/10). Cerebro-spinal fluid (CSF) analysis was conducted in 8/10 patients and showed pleocytosis in 6/8 (75%), elevated protein level in (4/8) 50%, oligoclonal intrathecal synthesis in 1/5 (20%). All patients received steroids, 7/10 (70%) required associated immunosuppressive therapy, 5 of which TNFα inhibitors. When compared to patients with SNS, INS patients were more likely to experience seizures (60% vs 23.3%); display encephalic parenchymal enhancing lesions (80% vs 39.3%) or encephalic leptomeningeal involvement (80% vs 35.7%). Serum angiotensin converting enzyme (ACE) was elevated in a third of patients with SNS but none of those with INS. Conclusion: The phenotypes of patients with INS are similar to the ones described in SNS. Serum ACE should not be regarded as a diagnostic test in patients with isolated neurosarcoidosis but could be useful in detecting subclinical extra neurologic involvement during follow up.

SMILE: a predictive model for Scoring the severity of relapses in MultIple scLErosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients. OBJECTIVE: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS. METHODS: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients. RESULTS: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations. CONCLUSION: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

Do disease-modifying drugs (DMD) have a positive impact on the occurrence of secondary progressive multiple sclerosis? Comment.

Very recent data from cohorts, such as that of the French Observatory of Multiple Sclerosis (OFSEP) and the MSBase cohort, are the subject of new statistical analyses using propensity scores that enable the matching of relapses frequency, EDSS, age, and sex ratio in patient populations for comparisons with each other, which reduces selection biases. The first data from these cohorts revealed a decline in transition to secondary progressive MS with the most effective disease-modifying drugs currently available, especially when these drugs were used early in the disease. However, these studies remain limited regarding the number of patients, the duration of follow-up, the use of imperfect methodologies, and the level of evidence remains low. The Gothenburg cohort in Sweden, which has been followed since the 1950s, found that 14% of benign non-progressive multiple sclerosis (MS) never evolved to secondary progression after more than 45 years of evolution. EDSS 7 was reached after 48 years of disease (median), and 50% evolved to secondary progressive MS after 15 years (consistent with data from the historic London, Ontario cohort). These data demonstrate that most people living with MS evolve without treatment to a significant long-term disability and that this evolution is closely linked to secondary progression (more than the relapse frequency). Benign forms appear as MS that never passes into secondary progressive MS. Recent data demonstrate that the delay until transition to secondary progression (more than 30 years in the MSBase cohort) and the delay in reaching EDSS 6 decreased since the introduction of disease-modifying drugs 20 years ago. However, randomized placebo-controlled trials do not last more than 2 or 3 years, and many biases may be involved in long-term follow-up studies: worsening patients who are lost to follow-up ("informative censoring" bias: only good responders to treatment remain primarily under the same long-term treatment and are followed); changes in the populations in the most recent studies with a lower rate of relapse and lower progression of disability at the beginning of the disease prior to initiating treatments; and environmental changes that remain largely misunderstood and may contribute to a natural evolution towards less severe disease.

Is the Choosing Wisely® campaign model applicable to the management of multiple sclerosis in France? A GRESEP pilot study.

BACKGROUND: Launched in the US in 2012, Choosing Wisely® is a campaign promoted by the American Board of Internal Medicine (ABIM) Foundation with the goal of improving healthcare effectiveness by avoiding wasteful or unnecessary medical tests, treatments and procedures. It uses concise recommendations produced by national medical societies to start discussions between physicians and patients on the relevance of these services as part of a shared decision-making process. The Multiple Sclerosis Focus Group (Groupe de Reflexion Autour de la Sclérose en Plaques; GRESEP) undertook a pilot study to assess the relevance and feasibility of this approach in the management of multiple sclerosis (MS) in France. METHODS: Recommendations were developed using the formal consensus method from the guidelines of the French National Health Authority (HAS). A steering committee selected the themes and drafted concise evidence reviews. An independent rating group then assessed these recommendations for clarity, relevance and feasibility. RESULTS: Seven recommendations were accepted: (1) avoid systematic ordering of multimodal evoked potential studies for diagnosing MS; (2) do not treat MS relapses with low-dose oral corticosteroids; (3) when treating MS relapse with high-dose corticosteroids, the systematic use of the intravenous route is unnecessary if the oral route can be used; (4) systematic hospitalization is not necessary for treating MS relapse with high-dose corticosteroid therapy, particularly if the oral route is used, except for the first treated relapse and the presence of exclusion or non-eligibility criteria; (5) in the absence of clinical signs or symptoms of urinary infection, avoid systematic screening with urine microscopy and culture before the administration of corticosteroid therapy for MS relapse in patients using intermittent self-catheterization; (6) avoid antibiotic treatment of clinically asymptomatic MS patients using intermittent self-catheterization, even if urine microscopy and culture reveal the presence of microorganisms; and (7) avoid introducing symptomatic drug treatment for MS-related fatigue. CONCLUSION: This pilot study, the first of its kind in France, has demonstrated the relevance and feasibility of adapting the Choosing Wisely® model to MS by practitioners specializing in the disorder. However, the acceptability of these recommendations by other practitioners in other specialist fields as well as their impact on everyday clinical practices now need to be studied.

Efficacy of rituximab in refractory neuromyelitis optica.

BACKGROUND: Despite a growing use of rituximab (RTX) in neuromyelitis optica (NMO), data are lacking in patients with refractory NMO (RNMO), defined as cases with at least one relapse during immunosuppressive therapy. OBJECTIVE: The purpose of this study was to assess RTX as a maintenance therapy in RNMO. METHODS: Out of a total of 305 NMO cases from a population-based cohort, 21 RNMO patients received RTX during a mean follow-up period of 31 months. RESULTS: After RTX, 11 patients (52.3%) were relapse free, meaning that 47.7% were refractory to RTX. The mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and median EDSS from 5 to 3 (p=0.02). Body mass index (BMI) was predictive of EDSS worsening. CONCLUSIONS: RTX is an effective and well-tolerated treatment in RNMO. BMI could be a predictive factor for efficacy.

Isolated tumefactive demyelinating lesions: diagnosis and long-term evolution of 16 patients in a multicentric study.

Isolated tumefactive demyelinating lesion (TDL) is a rare disease and a challenging entity especially for the differential diagnosis, biopsy indications, and therapeutic decisions. Long-term evolution is not well known. The objective of the study is to describe clinical and MRI characteristics and long-term follow-up of patients with isolated TDL. We performed a retrospective study including patients (1) with one TDL radiologically defined by a ≥20 mm FLAIR hyperintensity involving the white matter associated with T1 hypointensity that enhanced after gadolinium injection and (2) without any other MS lesion on the first MRI. Tumor, abscess, or other inflammatory diseases (ADEM, Baló's concentric sclerosis, systemic disease) were excluded. Sixteen patients (11 females/5 males) were included. The mean age of onset was 35.7 years (range 20-65). MRI disclosed supratentorial lesions with a mean size of 39.4 mm and usually mild edema/mass effect. Peripheral (mainly open-ring pattern) and central (mainly heterogeneous) enhancement were respectively seen in 9/16 and 11/16 patients. CSF study (n = 15) found oligoclonal bands (OCB) in seven. A cerebral biopsy was performed in 11 cases showing acute inflammatory demyelination. Thirteen patients were treated by pulse steroids with marked improvement in ten. At last clinical follow-up (mean 65.8 months, range 6-181), diagnosis was MS in 5 (31 %), isolated TDL in 10 (63 %) and one patient had a second TDL (6 %). Isolated tumefactive demyelinating lesions are a rare diagnostic entity. After a mean follow-up of 5 years, almost one-third became MS whereas most of the patients had no further event.

Targeted clinical audits immediately following the establishment of clinical practice guidelines for multiple sclerosis in 17 neurology departments: A pragmatic and collaborative study.

UNLABELLED: Following the publication practice guidelines for multiple sclerosis by a group of neurologists (multiple sclerosis study group [GRESEP]), the primary objective of this study was to compare the reality of practice to the guidelines according to the targeted clinical audit (TCA) method. The study was conducted at 17 neurology sites and was administered during two periods of MS care (diagnostic - TCA-DIAG, and disease course - TCA-EVOL). Two complementary surveys were done on the record keeping and the root causes of the deviations. The percentages of compliance ranged from 8 to 98% for the TCA-DIAG, and from 15 to 99% for the TCA-EVOL, with wide disparity between sites. The audits were able to identify causes of the flaws in traceability or accessibility. At the end of the study, despite its limitations, we think that the sharing of the results from different sites provided interesting approaches for the use of the assessment criteria defined by GRESEP in a complete audit cycle. This study is to our knowledge the first report of an experiment in which guidelines were created, and subsequently followed by the development of assessment criteria and then the performance of targeted clinical audits using them, all by the same participants. CONTEXT: Clinical practice guidelines (CPGs) are intended to help practitioners and patients make informed treatment choices, but their integration into actual practice remains problematic. This study was done immediately following the publication of CPGs for multiple sclerosis (MS) by the multiple sclerosis study group [GRESEP]. The primary objective was to generate quality criteria, to test them within the same group, and to analyze the observed deviations. MATERIALS AND METHODS: The study was conducted in the 17 voluntary departments that had participated in the development of the CPGs. The targeted clinical audit method was administered during two periods of MS care (diagnostic - TCA-DIAG, and disease course - TCA-EVOL). All the files were evaluated by a clinical research technician using digital format, which ensured thoroughness of the collection. Two complementary surveys were done on the record keeping and the potential causes of the deviations. RESULTS: The percentages of compliance to the criteria ranged from 8 to 98% (out of 240 files) for the TCA-DIAG, and from 15 to 99% (221 files) for the TCA-EVOL, with wide disparity between sites (interquartile distance ranges: TCA-DIAG between 0% and 55%; TCA-EVOL between 0% and 70%). The mean percentage of compliance with all the criteria as measured by the TCA-DIAG was 83.9% for the sites with digital files vs. 76.4% for those with only paper files (P<0.01). For the TCA-EVOL, the difference was not significant. Explanations for the observed deviations were suggested (1 to 9 according to the participants). DISCUSSION AND CONCLUSION: The quantified results could not be compared to other studies given the unique nature of the experiment. The importance of the traceability of practices in the patient files was discussed and assessed with regard to continuity and safety of care, as well as the medical-legal perspectives. Causes of lack of compliance were suggested (particularly the absence of reminders, the lack of means and/or time). Despite the limitations of the study, we think it is advisable that when a group becomes involved in the development of CPGs that they follow with the development of assessment criteria in order to evaluate the validity as well as their character as intermediate indicators of the quality of practices.

MS lesions are better detected with 3D T1 gradient-echo than with 2D T1 spin-echo gadolinium-enhanced imaging at 3T.

BACKGROUND AND PURPOSE: In multiple sclerosis, gadolinium enhancement is used to classify lesions as active. Regarding the need for a standardized and accurate method for detection of multiple sclerosis activity, we compared 2D-spin-echo with 3D-gradient-echo T1WI for the detection of gadolinium-enhancing MS lesions. MATERIALS AND METHODS: Fifty-eight patients with MS were prospectively imaged at 3T by using both 2D-spin-echo and 3D-gradient recalled-echo T1WI in random order after the injection of gadolinium. Blinded and independent evaluation was performed by a junior and a senior reader to count gadolinium-enhancing lesions and to characterize their location, size, pattern of enhancement, and the relative contrast between enhancing lesions and the adjacent white matter. Finally, the SNR and relative contrast of gadolinium-enhancing lesions were computed for both sequences by using simulations. RESULTS: Significantly more gadolinium-enhancing lesions were reported on 3D-gradient recalled-echo than on 2D-spin-echo (n = 59 versus n = 30 for the junior reader, P = .021; n = 77 versus n = 61 for the senior reader, P = .017). The difference between the 2 readers was significant on 2D-spin-echo (P = .044), for which images were less reproducible (κ = 0.51) than for 3D-gradient recalled-echo (κ = 0.65). Further comparisons showed that there were statistically more small lesions (<5 mm) on 3D-gradient recalled-echo than on 2D-spin-echo (P = .04), while other features were similar. Theoretic results from simulations predicted SNR and lesion contrast for 3D-gradient recalled-echo to be better than for 2D-spin-echo for visualization of small enhancing lesions and were, therefore, consistent with clinical observations. CONCLUSIONS: At 3T, 3D-gradient recalled-echo provides a higher detection rate of gadolinium-enhancing lesions, especially those with smaller size, with a better reproducibility; this finding suggests using 3D-gradient recalled-echo to detect MS activity, with potential impact in initiation, monitoring, and optimization of therapy.

Multiple sclerosis and pregnancy.

The question of pregnancy in patients with multiple sclerosis is regularly raised due to the prevalence of the disease in middle age women. The multiple sclerosis think tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]) decided to develop recommendations on this issue, with consideration to both the impact of multiple sclerosis on pregnancy, and that of pregnancy on the disease. As with topics of previous works, the formal expert consensus method was used. The working group was composed of hospital-based and private practice neurologists. The reading group was composed of neurologists, anaesthetists and obstetricians. Each recommendation is presented with the relevant level of consensus.

A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort.

BACKGROUND AND PURPOSE: BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment. METHODS: Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y ). RESULTS: NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found. CONCLUSIONS: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.

Recommendations for useful serum testing with suspected multiple sclerosis.

Several practical questions useful for management of patients with multiple sclerosis remain unanswered in the current scientific literature. Decisions are often made individually, without the support of solid scientific evidence. In order to facilitate concurring practices, we present guidelines concerning useful serum exams for the diagnosis of multiple sclerosis. The methodology used was that of a formal expert consensus. A working group performed a systematic analysis of the literature, taking into account both previously existing recommendations and original articles, and then drafted guideline proposals. These proposals were subjected to the critical review of a rating group. Three written drafts, followed by rating of the guideline proposals culminated in a consensual document, which was submitted for review to a second independent reading group. The final resulting document provided the material for the present article, in which each recommendation is presented with its grade according to the level of proof or its degree of consensus in the absence of scientific proof.

Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis.

The aim of the Multiple Sclerosis Think Tank (Groupe de réflexion sur la sclérose en plaques [GRESEP]) is to prescribe recommendations following a systematic literature search and using a Rand Corporation and California University (RAND/UCLA) appropriateness derived method, in response to practical questions that are raised in the management of patients with multiple sclerosis (MS). The topics of this working program were chosen because they were not addressed in the French recommendations and because of the few data in the literature that enabled practices to be based on validated data. Following the theme on useful serum testing with suspected multiple sclerosis, the subjects of the present work concern the detection and management of cognitive impairment in the beginning stages of the disease course. Two clinical questions were asked: which complementary exams (besides physical examination and neuropsychological tests) would help in the screening of cognitive impairment at the beginning of the disease? What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)? The recommendations are the result of a consensus amongst a working group, a rating group and a reading group comprised of hospital neurologists involved in the management of patients with multiple sclerosis. Each recommendation is presented with the degree of consensus that it was accorded.

Recommendations for the management of multiple sclerosis relapses.

The aim of the Multiple Sclerosis Think Tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]), composed of hospital neurologists involved in the management of patients with multiple sclerosis, is to provide recommendations in response to clinical questions that are raised when managing these patients. After work done on the themes of useful serum testing with suspected multiple sclerosis, detection and management of cognitive disorders early in the course of the disease, and definition and early management of the disease, GRESEP wanted to develop recommendations on the management of multiple sclerosis (MS) relapse. Following a systematic analysis of the literature, the procedure of formal expert consensus enabled consensual recommendations among a working group, a rating group and a reading group to be written. Each recommendation is presented with its grade or the degree of consensus that it was accorded.

Recommendations for a definition of multiple sclerosis in support of early treatment.

The aim of the Multiple Sclerosis Think Tank (Groupe de Réflexion sur la Sclérose en Plaques: GRESEP), composed of hospital neurologists involved in the management of patients with multiple sclerosis, is to provide recommendations in response to clinical questions that are raised when managing these patients. After work done on the themes on useful serum testing with suspected multiple sclerosis, as well as the detection and management of cognitive disorders early in the course of the disease, the subject of the present work is the early definition and early treatment of the disease. Following a systematic literature review, a RAND/UCLA appropriateness-derived method enabled consensual recommendations among a working group, a rating group and a reading group to be developed and formulated. Each recommendation is presented with the degree of consensus that it was accorded.

[Immunomodulatory treatments for multiple sclerosis: lessons from direct comparative studies]. / Traitements de fond de la sclérose en plaques: enseignements des études randomisées comparatives directes.

INTRODUCTION: Several first-line immunomodulatory treatments are available to physicians for treating patients with relapsing-remitting multiple sclerosis, namely three interferon-beta preparations and glatiramer acetate. In order to enlighten their choice of treatment, physicians need data from good quality comparative clinical trials. METHODS: This review outlines and compares the findings of the various randomized clinical trials that have assessed the efficacy and safety of immunomodulatory treatments for multiple sclerosis. Six such studies have been reported to date, a Danish study (interferon-beta 1a sc versus interferon-beta 1b sc), the EVIDENCE study (interferon-beta 1a sc versus interferon-beta 1a im), the INCOMIN study (interferon-beta 1b sc versus interferon-beta 1a im), the BECOME and BEYOND studies (interferon-beta 1b sc versus glatiramer acetate) and the REGARD study (interferon-beta 1a sc versus glatiramer acetate). RESULTS: These studies have demonstrated somewhat superior efficacy for interferon-beta preparations administered subcutaneously several times a week compared to preparations administered intramuscularly once a week. In contrast, no difference in efficacy has been demonstrated between the two subcutaneously administered interferon-beta preparations, or between either of these preparations and glatiramer acetate. Differences in the safety profile of the four immunomodulatory treatments were observed, in particular a more favorable skin tolerance with intramuscularly administered interferon-beta and a better systemic adverse event profile for glatiramer acetate. CONCLUSIONS: These various randomized comparative trials have provided objective criteria that can be used by physicians for choosing between immunomodulatory treatments.

Should SDMT substitute for PASAT in MSFC? A 5-year longitudinal study.

BACKGROUND: The multiple sclerosis functional composite (MSFC) includes the Paced Auditory Serial Addition test (PASAT) as a measure of cognition. OBJECTIVES AND METHODS: We compared the MSFC incorporating the Symbol Digit Modalities test (SDMT) (MSFC [sdmt]) to the usually applied MSFC (MSFC [pasat]) in a sample of 46 ptients with relapsing-remitting MS who were followed over a five-year period. Magnetic resonance imaging was performed at baseline. RESULTS: The Expanded Disability Status scale (EDSS) deteriorated significantly over 5 years (P < 0.01), but MSFC scores remained stable. MSFC [sdmt] correlated with EDSS at all time points of evaluation, but MSFC [pasat] correlated with EDSS only at baseline, 1, and 5 years. The 5-year EDSS correlated significantly with baseline MSFC [sdmt] and MSFC [pasat] but did not correlate after adjustment for baseline EDSS. No significant correlation was found at baseline between MSFC and imaging parameters (lesion load, brain parenchymal fraction [BPF], ventricular fraction, mean magnetization transfer ratio of lesions and normal-appearing brain tissue), but baseline BPF correlated significantly with changes of SDMT z score (P = 0.0003), MSFC [pasat] (P = 0.006), and MSFC [sdmt] (P = 0.0002) over 5 years. CONCLUSION: We propose not to substitute PASAT by SDMT in the MSFC but to consider SDMT as a complementary useful approach to evaluate overall MS disease.

[Validation of EHD self questionnaire in multiple sclerosis]. / Validation de l'Echelle d'Humeur Dépressive (EHD), version autoquestionnaire, dans la sclérose en plaques.

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.

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.