Inaugural tumor-like multiple sclerosis: clinical presentation and medium-term outcome in 87 patients.

BACKGROUND: Tumefactive demyelinating lesions of the central nervous system can be the initial presentation in various pathological entities [multiple sclerosis (the most common), Balo's concentric sclerosis, Schilder's disease and acute disseminated encephalomyelitis] with overlapping clinical presentation. The aim of our study was to better characterize these patients. METHODS: Eighty-seven patients (62 women and 25 men) from different MS centers in France were studied retrospectively. Inclusion criteria were (1) a first clinical event (2) MRI showing one or more large demyelinating lesions (20 mm or more in diameter) with mass-like features. Patients with a previous demyelinating event (i.e. confirmed multiple sclerosis) were excluded. RESULTS: Mean age at onset was 26 years. The most common initial symptoms (67% of the patients) were hemiparesis or hemiplegia. Aphasia, headache and cognitive disturbances (i.e. atypical symptoms for demyelinating diseases) were observed in 15, 18 and 15% of patients, respectively. The mean largest diameter of the tumefactive lesions was 26.9 mm, with gadolinium enhancement in 66 patients (81%). Twenty-one patients (24%) had a single tumefactive lesion. During follow-up (median time 5.7 years) 4 patients died, 70 patients improved or remained stable and 12 worsened. 86% of patients received initial corticosteroid treatment, and 73% received disease-modifying therapy subsequently. EDSS at the end of the follow-up was 2.4 ± 2.6 (mean ± SD). CONCLUSION: This study provides further evidence that the clinical course of MS presenting with large focal tumor-like lesions does not differ from that of classical relapsing-remitting MS, once the noisy first relapsing occurred.

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.

[Cavitary lesions in multiple sclerosis: multicenter study on twenty patients]. / Formes cavitaires de sclérose en plaques: étude multicentrique sur vingt patients.

INTRODUCTION: Cavitary white matter changes are mainly described in leukodystrophies and especially in vanishing white matter disease. Large cavitary lesions are not typical for multiple sclerosis (MS). METHODS: We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), mini mental state (MMS), vanishing white matter disease genetic analysis, and MRI characteristics of the cavitary lesions were analyzed. RESULTS: Twenty patients were analyzed (6 men and 14 women). Mean age at disease onset was 37.6 (range 17-58). Mean disease duration was 10 years (range 2-20). Five patients had initial relapsing-remitting MS and nine patients had primary-progressive MS. Mean EDSS was 5.5 (range 2-8). Mean MMS was 20/30. Vanishing white matter disease genetic analysis was performed and negative in seven patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance. CONCLUSION: MS patients with large cavitary lesions seem to represent a MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.

Olfactory dysfunction in multiple sclerosis: evidence of a decrease in different aspects of olfactory function.

BACKGROUND/AIMS: Numerous authors have described olfactory dysfunction in multiple sclerosis (MS) in recent years. The aim of this study was to specify the aspects of olfactory perception that are most affected and to identify any correlations with clinical, anatomical and functional data. METHODS: 50 patients with remitting or secondary progressive MS were included. Personal data were collected (medical history, characteristics of their disease, depression and disability scores and number of lesions on cerebral imaging). An olfactory test (Sniffin Sticks®) was used to evaluate subjects' olfactory function. RESULTS: The odor detection threshold is the most sensitive marker, with 40% of patients presenting hyposmia. The ability to identify odors is affected later on, and is inversely correlated with the level of disability. CONCLUSION: Our results confirm that several aspects of olfactory function are altered in MS, particularly those aspects requiring greater cognitive involvement, such as discrimination and identification of odors.

Establishing an evaluation scale for the perception of quality of life related to relapsing-remitting forms of multiple sclerosis and feasibility study.

Relapses are particularly stressful for patients with multiple sclerosis (MS). The impact of relapses on the quality of life (QoL) of patients has been described in the literature. Several QoL scales have already been validated for MS. However, none of them focuses specifically on how patients perceive relapse periods. The objective of this research was to establish a self-questionnaire to evaluate QoL related to MS and relapses: the PERSEPP scale. This scale is based on individual semidirective interviews with patients with a relapsing-remitting form of MS, health workers, and focus groups. The thematic content analysis of these interviews allowed us to obtain 574 items related to various dimensions of QoL. After selecting items in several stages, we drew up the PERSEPP scale with 37 items and five additional modules. A preliminary feasibility study was conducted with 40 patients to assess the PERSEPP scale. The feasibility study showed a good acceptability and a good understanding of the items of the PERSEPP scale. This article deals with the selection of items and the acceptability study. Psychometric validation of this scale, involving 305 patients, is currently in progress in various hospitals in France.

[Diagnostic norms of RAPID neuropsychological battery tests for subjects aged 60 to 89 years with Alzheimer's disease]. / Normes diagnostiques de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 60 à 89ans présentant une maladie d'Alzheimer.

INTRODUCTION: The aim of this study was to propose diagnostic norms for the rapid neuropsychological battery, in the detection of cognitive impairment due to Alzheimer's disease. POPULATION AND METHODS: Three hundred and fifty-two control subjects (mean MMSE : 27.3 ± 2.5) and 676 patients with Alzheimer's disease (mean MMSE : 22.9 ± 2.6) at a mild stage (CDR = 1) were selected according to age (60-69, 70-79 and 80-89 years) and educational level (French primary Education Certificate or lower versus Certificate of Professional Aptitude or the School Leaving Certificate versus the Baccalaureate or higher). Age and education-adjusted cut-off scores were calculated using Receiver Operating Characteristic curves so as to determine the discriminative ability (sensitivity, specificity) of each test from the RAPID neuropsychological battery. Cut-off scores with a specificity set at least at 90% were also proposed. RESULTS: The Free and Cued Recall Test exhibited good sensitivity (from 87% to 100% for free recall and from 85% to 98% for total recall) and specificity (from 85% to 96% for free recall and from 86% to 100% for total recall). For the other tests, sensitivities and specificities were lower. CONCLUSION: The use of these two types of cut-off scores should help the clinician in the diagnosis of Alzheimer's disease by limiting the risk of false positives and false negatives. The choice of the cut-off scores will depend on the patient's individual clinical context.

Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p.

BACKGROUND: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. METHODS: A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. RESULTS: This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at theta = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. CONCLUSIONS: We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.

Evaluation of brain atrophy estimation algorithms using simulated ground-truth data.

A number of analysis tools have been developed for the estimation of brain atrophy using MRI. Since brain atrophy is being increasingly used as a marker of disease progression in many neuro-degenerative diseases such as Multiple Sclerosis and Alzheimer's disease, the validation of these tools is an important task. However, this is complex, in the real scenario, due to the absence of gold standards for comparison. In order to create gold standards, we first propose an approach for the realistic simulation of brain tissue loss that relies on the estimation of a topology preserving B-spline based deformation fields. Using these gold standards, an evaluation of the performance of three standard brain atrophy estimation methods (SIENA, SIENAX and BSI-UCD), on the basis of their robustness to various sources of error (bias-field inhomogeneity, noise, geometrical distortions, interpolation artefacts and presence of lesions), is presented. Our evaluation shows that, in general, bias-field inhomogeneity and noise lead to larger errors in the estimated atrophy than geometrical distortions and interpolation artefacts. Experiments on 18 different anatomical models of the brain after simulating whole brain atrophies in the range of 0.2-1.5% indicate that, in the presence of bias-field inhomogeneity and noise, a mean error of 0.64+/-0.53%,4.00+/-2.41% and 1.79+/-0.97% may be expected in the atrophy estimated by SIENA, SIENAX and BSI-UCD, respectively.

[Comparative norms of RAPID neuropsychological battery tests for subjects aged between 50 and 89 years]. / Normes comparatives de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 50 à 89 ans.

INTRODUCTION: RAPID, a battery of rapid neuropsychological tests, includes neuropsychological tests calibrated for different populations according to diverse methodologies. This makes the comparison and interpretation of the results difficult. The aim of this study was to build comparative norms for the RAPID battery using a single methodology in a unique population. POPULATION AND METHODS: The RAPID Battery includes nine different tests: the Memory Impairment Screen, the Isaacs Set Test, the Mini-Mental State Examination, the Free and Cued Recall Test, the Trail Making Test, a test for copying geometric figures as part of the BEC 96, a test for verbally naming images and a test for matching categories. A cohort of 476 subjects aged 50 to 89 were randomly selected from the medical records of 11 practitioners. RESULTS: The norms were stratified according to age (50-59, 60-69, 70-79 and 80-89 years) and education level of the subjects. The first level includes subjects with the French Primary Education Certificate or lower. The second level includes subjects with the Certificate of Professional Aptitude or the Brevet (equivalent to the GCSE). The third level includes subjects with the Baccalaureate or higher. Given that most of the tests did not satisfy the normal distribution, percentiles (tenth, twenty-fifth, seventy-fifth, ninetieth percentile and median) were used to define age and education norms. The results show a high participation rate (75 %) and are similar to those obtained in the literature: The results decreased with age and improved in grade level. Nevertheless, the results exhibited great variability for the tenth percentile in comparison with results reported in the literature. CONCLUSION: The development of comparative norms for the RAPID battery from a same sample facilitates the interpretation of individual results in terms of cognitive profile.

Familial cortical myoclonic tremor with epilepsy (FCMTE): Clinical characteristics and exclusion of linkages to 8q and 2p in a large French family.

INTRODUCTION: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by an autosomal-dominant inheritance, adult onset of myoclonus of the extremities, infrequent epileptic seizures, a non-progressive course, polyspikes on electroencephalography (EEG), photosensitivity, giant somatosensory-evoked potentials (SEP), enhancement of C-reflex and a premyoclonus spike detected by jerk-locked EEG back-averaging. Two genes yet to be identified are mapped to 8q23.3-q24.1 and 2p11.1-q12.2. METHODS: The present study involved five generations of a French family presenting with FCMTE, including 76 family members. Clinical analyses were performed in 39 living subjects and electrophysiological studies in five patients. Altogether, 27 relatives (21 living and six deceased) had the clinical characteristics of FCMTE, 17 of whom were analyzed. Linkage analyses were performed with microsatellites encompassing the two known loci (8q 23.3-q24.1 and 2p11.1-q12.2). RESULTS: Mean age at onset in the 17 living patients was 28.8 years (range 24-41). All had myoclonus/cortical tremor, and 11/17 had generalized tonic-clonic seizures. Other clinical symptoms were photosensitivity (16 cases), partial seizures (five cases), sensitivity to starvation/exercise (six cases) and vibration (four cases), ophthalmic migraine (six cases) and gait disorders (10 cases). Electrophysiological studies confirmed the FCMTE diagnosis in the five studied patients. Of the remaining relatives, 14 were considered healthy (asymptomatic subjects aged more than 40years) and eight were of unknown status (asymptomatic aged lesser than 40years). The pattern of inheritance was consistent with autosomal-dominant inheritance, although the two loci responsible for FCMTE were excluded. CONCLUSION: This large family highlights some unusual clinical characteristics and suggests the presence of a third gene. Genetic research is ongoing to identify the mutated gene.

An a contrario approach for change detection in 3D multimodal images: application to multiple sclerosis in MRI.

Estimating significant changes between two images remains a challenging problem in medical image processing. This paper proposes a non-parametric region based method to detect significant changes in 3D multimodal Magnetic Resonance (MR) sequences. The proposed approach relies on an a contrario model which defines significant changes as events with very low probability. We adapt the a contrario framework to deal with multimodal images from which are extracted measures related to intensity and volume changes. Two fusion rules are carefully designed to handle a set of decision thresholds and a set of image measures. The final decision is taken using multiple testing procedures. The efficiency of the algorithm is demonstrated in the context of multiple sclerosis (MS) lesion analysis over time in multimodal MR sequences. We evaluate the proposed method on synthetic images using the Brainweb simulator. Finally, promising results on multimodal sequences on clinical data are presented.

[The organisation of health care and epidemiology of multiple sclerosis in France]. / Données épidémiologiques et analyse de l'offre de soins de la sclérose en plaques en France.

STATE OF THE ART: According to the available previous studies, France is considered a zone of medium to high risk of multiple sclerosis (MS) with an estimated overall prevalence of at least 50/100,000 inhabitants, incidence rates were stable in some areas but increased over time in others and a strong ethnic effect on the incidence, clinical presentation, and course of MS is reported. RESULTS: Based on two health insurance survey the prevalence has been deduced. At January 1, 2003 from the data of agricultural health insurance the prevalence is evaluated at 65.5/100,000 inhabitants (95p.cent CI=62.5-67.5) with a gradient of North East towards South-West. The data from the national health insurance were very near. During the period 2000-2004, recent studies in Auvergne and Brittany demonstrated an annual incidence comprising between 4.2 and 5.1 per 100,000 inhabitants. In Lorraine, in a large population-based study, in December 31, 2004 the prevalence rate was 120/100,000 (95p.cent CI: 119 to 121). During the period 1990-2002, the average age- and sex-adjusted annual incidence rate was 5.5/100,000 (95p.cent CI: 4.4-6.6). In Lorraine, we found that the age-adjusted incidence rate increased during the period 1990-2002. The incidence of MS in women increased, whereas that in men did not change significantly during this period. Similarly, in Norway, North Ireland and Denmark, the incidence among women increased the most. The clinical features of MS were compared in 211 North Africans patients and 2 945 Europeans patients in two French MS centres (Lorraine and Nice) with definite MS according to McDonald's criteria. The course of MS appears more aggressive in North Africans than in Europeans patients. For example, we demonstrated a shorter time to reach the Expanded Disability Status Scale score of 4.0 (p=0.001) or 6.0 (p<0.0001) in North Africans patients. PERSPECTIVES AND CONCLUSIONS: The incidence rates found in these studies were comparable to those reported in several European populations. This undoubtedly places France in the category of regions with a high risk zone of MS. The incidence of MS in women increased; thus, exogenous (or epigenetic) factors vary over time and may affect men and women differently. The course of MS appears more aggressive in North Africans than in Europeans patients.

[CARIMS (Cancer Risk In Multiple Sclerosis) project: impact of long-term treatment]. / Cancer et sclérose en plaques. Impact des traitements de fonds et présentation du projet CARIMS (Cancer Risk In Multiple Sclerosis).

Controversial results have been published on potential link between cancer and multiple sclerosis. Multiple sclerosis has been linked to reduced rates of cancer prior to the era of immunomodulating or immunosuppressive treatments and until today, only 9 studies can be found in the literature. New strategies and early use of IM or IS drugs in MS justify to study and follow patients to detect a potential increase of cancer's incidence in treated patients. It is important to follow and collect prospectively in MS centers, patients with history of cancer, to document histologies, and potential relations with repeated IM or IS treatments. A prospective study is in progress in French MS centers on behalf the Club Francophone de la SEP (CARIMS Project).

[Acute leukaemia in two multiple sclerosis patients treated with mitoxantrone]. / Leucémies aiguës chez deux patients atteints de sclérose en plaques et traités par 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.

[Role of immunity in the development of progressive multifocal leukoencephalopathy: a report of three patients with type B lymphoma and humoral immunodeficiency and six others with acquired immunodeficiency syndrome]. / Rôle de l'immunité dans le développement de la leucoencéphalopathie multifocale progressive.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) mostly occurs in different conditions of impaired cellular immunity like acquired immunodeficiency syndrome (AIDS) and rarely when humoral immunity is involved. PML remains unusual although there is a high prevalence of JCV among the population and immunosuppression is not rare because of chemotherapies. METHODS: We present two groups of patients: first, we studied reports of three patients suffering from lymphoma type B who developed a PML, proved by cerebral biopsy. The second group included six HIV-infected patients who developed a PML. No biopsy was made but MRI and the physical examination suggested strong arguments for the diagnosis. RESULTS: In the first group, PML was furthered by humoral immunosuppression (rate of immunoglobulin G under 4 g/l). Average survival was five months. In the second group, HIV-infected patients had a survival range from 2 to 58 months after the first PML symptoms and one of them is still alive. CONCLUSION: Humoral immunosuppression in lymphoma can contribute to the development of PML. PML prognosis is often severe but prolonged survivals were described. So it is necessary to restore a sufficient immunity level. But immunity failure may be insufficient to lead to PML. In the case of lymphomas, the role of malignant lymphocytes in multiplication and mutation of JCV might be an interesting pathophysiological hypothesis.

Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study.

OBJECTIVE: To assess whether modafinil, a wakefulness-promoting agent, is useful for fatigue in patients with multiple sclerosis (MS). METHODS: Patients with MS with stable disability, and a baseline score of 45 or more on the Modified Fatigue Impact Scale (MFIS), were eligible for the 5-week randomized, double-blind, placebo-controlled, parallel group study. The initial daily dose of modafinil was 200 mg for 1 week. Depending on tolerance, the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35. The primary outcome variable was the change of MFIS score at day 35. RESULTS: A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis. The mean MFIS score at baseline was 63 +/- 9 in the placebo group and 63 +/- 10 in the modafinil group. MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups, but no significant difference was detected between the two groups. There was no major safety concern. CONCLUSIONS: There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale.

Impaired cardiovascular autonomic control in newly and long-term-treated patients with Parkinson's disease: involvement of L-dopa therapy.

In idiopathic Parkinson's disease (PD), autonomic dysfunction is frequent, causing orthostatic hypotension. The respective roles of disease progression and dopaminergic treatment remain unclear. In this study, we investigated the autonomic control of cardiovascular functions and its relation to L-dopa therapy in both newly diagnosed (ND) and long-term-treated (LT) patients. Study subjects were: (1) nine ND patients never having undergone treatment with L-dopa; (2) 18 LT patients who had been receiving L-dopa treatment for a long period. ND patients were investigated before L-dopa treatment and after stabilization of their L-dopa dosage. LT patients were investigated once with their regular treatment and once after a 12-h interruption of L-dopa treatment; (3) nine healthy subjects served as controls. At each test session, blood pressure (BP), heart rate (HR), plasma catecholamines, heart rate variability (HRV), and spontaneous baroreflex sensitivity were assessed in the supine and upright positions. Before receiving L-dopa medication, ND patients had reduced E/I ratios (HR response/deep breathing) and lowered HRV when compared to controls; this was evidence of early effects of the disease on autonomic HR control. Introduction of L-dopa treatment reduced BP, HR, and plasma levels of adrenaline and noradrenaline. Similar changes were found in LT patients when contrasting the short-term treatment interruption and the usual L-dopa dosage. The treatment-linked increase in plasma dopamine also correlated with the decrease in noradrenaline. These results showed that mild impairment of autonomic cardiovascular control occurred early in the course of PD. They also provided evidence that the side effects of L-dopa aggravated the impairment of the autonomic control of BP and HR.