Lucien Rumbach

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.

Automatic change detection in multimodal serial MRI: application to multiple sclerosis lesion evolution

The automatic analysis of subtle changes between MRI scans is an important tool for assessing disease evolution over time. Manual labeling of evolutions in 3D data sets is tedious and error prone. Automatic change detection, however, remains a challenging image processing problem. A variety of MRI artifacts introduce a wide range of unrepresentative changes between images, making standard change detection methods unreliable. In this study we describe an automatic image processing system that addresses these issues. Registration errors and undesired anatomical deformations are compensated using a versatile multiresolution deformable image matching method that preserves significant changes at a given scale. A nonlinear intensity normalization method is associated with statistical hypothesis test methods to provide reliable change detection. Multimodal data is optionally exploited to reduce the false detection rate. The performance of the system was evaluated on a large database of 3D multimodal, MR images of patients suffering from relapsing remitting multiple sclerosis (MS). The method was assessed using receiver operating characteristics (ROC) analysis, and validated in a protocol involving two neurologists. The automatic system outperforms the human expert, detecting many lesion evolutions that are missed by the expert, including small, subtle changes.

IN VIVO DETERMINATION OF MULTIEXPONENTIAL T2 RELAXATION IN THE BRAIN OF PATIENTS WITH MULTIPLE SCLEROSIS

In vivo measurement of T2 relaxation times in multiple sclerosis (MS) lesions by magnetic resonance imaging (MRI) is potentially useful for the evaluation of the disease activity. Seven patients with definite MS were investigated over a period of three years (19 examinations), using a whole-body MRI scanner operating at 0.15 T with a specially designed high-power radio-frequency head coil. A modified CPMG sequence with a 180 degree pulse interval of TE = 6 msec and 128 echoes was used for the T2 relaxation measurement of the areas of increased signal (AIS) and white matter (WM). A biexponential T2 analysis of each pixel of the spin-echo images was computed. The T2 relaxation processes were found to be a monoexponential function in WM. The T2 relaxation times of apparently normal white matter in MS patients was significantly longer than in control subjects. The T2 relaxation curves of the AIS were found in most cases to fit a biexponential function characterized by a short and a long T2. T2 long relaxation times of AIS were spread out over a wide range (150-560 msec). The study of T2 long histograms shows that some AIS can be divided into two or three parts depending on the T2 long values. Each of these parts may correspond to a pathological process such as edema, demyelination and gliosis. Evolution of T2 relaxation times over a period of time cannot as yet be correlated with modifications in the clinical state.

Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis:

Background Prior to the era of immunomodulating or immunosuppressive (IS) treatments Multiple Sclerosis (MS) was linked to reduced rates of cancer. Method A descriptive study of MS patients with a documented oncological event was performed. From 1 January 1995 to 30 June 2006, we collected and studied the profile of 7418 MS patients gathered from nine French MS centers. We evaluated the incidence of cancer in a Cancer Risk In MS Cohort. Results Thirty one patients (1.75%) with confirmed MS had a history of cancer: mean age at MS diagnosis of 37.9 years and a mean age at cancer diagnosis of 46.4 years. The most frequent cancers were breast (34.5%), gynecological (12.5%), skin (10.2%), acute leukemia and lymphoma (5.9%), digestive (8.8%), kidney and bladder (5.1%), lung (3.4%) and central nervous system (3%). Calculated standardized incidence rates were 0.29 (0.17—0.45) for men and 0.53 (0.42—0.66) for women. The incidence of cancer in this MS population was lower than that expected for the general population. Matched to age, gender and histology, cancers in MS were associated with a young age and exposure to IS treatments. When considering all patients, treated patients had a 3-fold higher risk of developing cancer, if they had a history of IS (P = 0.0035). For treated patients, the cancer sites were more likely the breast, the urinary tract, the digestive system and the skin. Conclusion Our data suggest that MS patients do not have an increased risk of cancer. Rather for several types of cancer a significantly reduced risk was observed, except for breast cancer in women treated with IS. The relative increased risk of breast cancer in MS women under IS treatment warrants further attention. Multiple Sclerosis 2008; 14: 399—405. http://msj.sagepub.com

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 θ = 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.

INTRAFAMILIAL DIVERSITY OF PHENOTYPE ASSOCIATED WITH APP DUPLICATION

Different APP locus duplications have been recently identified in rare families with autosomal dominant early onset Alzheimer disease (AD) and Aβ-related cerebral amyloid angiopathy (CAA).1–3 We report a novel family revealing a very large diversity of phenotype including dementia with Lewy bodies (DLB). ### Methods. Family members gave informed consent according to a protocol approved by the ethics committees of the CCPPRB Pitie-Salpetriere and Paris-Necker. Characterization of five patients, with two detailed neuropsychological evaluations, brain MRI of three patients, and one neuropathologic evaluation, were assessed. APP locus was analyzed by quantitative multiplex PCR of short fluorescent fragments (QMPSF) in three patients. Patients were considered affected if they had dementia, intracerebral hemorrhage (ICH), or epilepsy (e-Methods on the Neurology ® Web site at www.neurology.org). ### Results. The proband (II-1, figure e-1) developed bradykinesia, memory problems, and apraxia when she was 44 years old. She developed paranoid delusion with visual hallucinations at 50 years of age. The association with bilateral tremor, rigidity, and bradykinesia was suggestive of DLB. Several T2 lesions were noted on MRI. She died at 55 years of age. Patients I-2 and I-3 had progressive memory disturbances with behavioral changes suggestive of AD since they were 55 and 60 years of age. Patient II-3 had partial visual seizures at the age …

Social cognition impairments in relapsing-remitting multiple sclerosis.

Theory of Mind (ToM) is the ability to attribute independent mental states to self and others to explain and predict behavior. Impairment of ToM is well established in developmental pathologies. In neurological populations, investigation of ToM is still rare but data suggest that ToM impairment could contribute to behavioral and social disturbances. In addition to neurological signs, multiple sclerosis (MS) presents with disorders of cognition and behavior directly related to brain damage. The aim of this study was to assess ToM abilities and recognition of facial emotional expression in adults with MS. We compared 64 patients with relapsing MS and 30 matched healthy controls on three levels of ToM tasks, a facial emotion recognition task, and a neuropsychological assessment. MS patients performed significantly worse than controls in emotion recognition and all ToM tasks (p < .02). These deficits were not correlated with demographic variables or neuropsychological test performance. These findings underscore the importance of assessing ToM and facial recognition in MS, as dysfunction in these areas may impact upon social interaction and, thus, impair quality of life for both patients with MS and their families.

A case report of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for Alzheimer disease

Department of Clinical Psychiatry, University Hospital of Besancon, France EA 481 Neuroscience, IFR 133, University of Franche-Comt e, Besancon, France Clinical Investigation Center CIC-IT 808 INSERM, University Hospital of Besancon, France Department of Neurology, University Hospital of Besancon, France Memory Center of Research and Resources (MCRR), University Hospital of Besancon, France Rapid-Fr Network (Regional Network for Diagnostic Aid and Management of patients with Cognitive Impairment in the Franche-Comt e geographical area), Besancon, France

Acute aphasia in multiple sclerosis: A multicenter study of 22 patients.

Aphasia is usually considered to be rare in multiple sclerosis (MS). To determine the clinical and radiologic characteristics of MS patients with acute aphasia, the authors investigated data from 2,700 patients from three MS centers and found 22 patients with acute aphasia (0.81%). Aphasia was the first clinical manifestation of MS in eight patients (36%). Brain MRI showed giant plaques in eight cases (40%). A full recovery was observed in 14 patients (64%). Furthermore, acute aphasia did not appear to be a criterion for poor prognosis.

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.