Management of Fulminant Multiple Sclerosis With Rituximab: A Case Report.

INTRODUCTION: Malignant variant is a rare subtype of multiple sclerosis (MS) that is rapidly progressive and may lead to significant disability or even death. No consensus exists on best management of this disorder, although corticosteroids and plasmapheresis are commonly used in the acute phase, followed either by MS-specific disease-modifying therapy or an immunosuppressant. CASE REPORT: The patient is a 30-year-old man with relapsing-remitting MS previously well controlled with natalizumab, who has developed fulminant disease activity upon natalizumab cessation. In the acute phase, patient had a suboptimal response to multiple corticosteroid treatments but responded very well to plasmapheresis. Patient continued to have worsening disease activity despite fingolimod treatment. Disease control has been eventually achieved by switching to rituximab. CONCLUSION: Rituximab treatment should be considered for a patient with fulminant MS who responded well to plasmapheresis.

Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance.

BackgroundBipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.AimsWe sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.MethodTo detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.ResultsIntegrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85×10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54×10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.ConclusionsOur findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.

Binge eating in binge eating disorder: a break-down of emotion regulatory process?

Current explanatory models for binge eating in binge eating disorder (BED) mostly rely onmodels for bulimianervosa (BN), although research indicates different antecedents for binge eating in BED. This studyinvestigates antecedents and maintaining factors in terms of positive mood, negative mood and tension in asample of 22 women with BED using ecological momentary assessment over a 1-week. Values for negativemood were higher and those for positive mood lower during binge days compared with non-binge days.During binge days, negative mood and tension both strongly and significantly increased and positive moodstrongly and significantly decreased at the first binge episode, followed by a slight though significant, andlonger lasting decrease (negative mood, tension) or increase (positive mood) during a 4-h observation periodfollowing binge eating. Binge eating in BED seems to be triggered by an immediate breakdown of emotionregulation. There are no indications of an accumulation of negative mood triggering binge eating followed byimmediate reinforcing mechanisms in terms of substantial and stable improvement of mood as observed inBN. These differences implicate a further specification of etiological models and could serve as a basis fordeveloping new treatment approaches for BED.

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response.

RATIONALE: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. OBJECTIVE: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). METHODS: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. RESULTS: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. CONCLUSION: The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.

Validation de la version française du questionnaire I7 d'impulsivité. Influence de la personnalité, du sexe et de la religion = Validation of the french version of the eysenck's impulsiveness questionnaire (I7). Influence of personality, gender, and religion

L'objectif de cette étude est de vérifier la validité interne de la version française du questionnaire d'impulsivité d'Eysenck (I7), traduite par Dupont et al., sur un échantillon d'étudiants suisses (n = 220). Dans leur questionnaire, Eysenck et Eysenck proposent trois échelles : les deux premières évaluant deux composantes distinctes de l'impulsivité (l'Impulsivité caractérisant les individus qui agissent sans penser, sans être conscients des risques associés à leurs actions, et la Recherche d'aventure caractérisant les individus qui agissent en étant conscients, et en tenant compte des risques associés à leurs actions), et la troisième servant de « distracteur » (l'Empathie caractérisant les individus qui ont la faculté de s'identifier à l'autre). La structure à trois facteurs de l'instrument a été confirmée par notre analyse factorielle en composantes principales. La solution factorielle retenue n'explique toutefois qu'une faible proportion de la variance (21.9 %). L'homogénéité interne des échelles, mesurée à l'aide d'alphas de Cronbach, est acceptable pour l'échelle d'Impulsivité (.78) et de Recherche d'aventure (.71), mais elle est, en revanche, faible pour l'échelle d'Empathie (.62). Les échelles de l'I7 d'Eysenck entretiennent des corrélations cohérentes avec les cinq grandes dimensions de la personnalité mesurées par le NEO PI-R. L'Impulsivité est associée négativement à la dimension Conscience (r = - .32), alors que la Recherche d'aventures est associée positivement à la dimension Extraversion (r = .33). Le sexe a un impact sur les échelles Recherche d'aventure et Empathie. Les qualités métrologiques de la version française du questionnaire d'impulsivité d'Eysenck (I7) sont satisfaisantes, mais l'estimation d'autres indices de validité, comme la fidélité test-retest et la validité convergente, devrait être réalisée.

Epidemiology of multiple congenital anomalies in Europe: a EUROCAT population-based registry study.

BACKGROUND: This study describes the prevalence, associated anomalies, and demographic characteristics of cases of multiple congenital anomalies (MCA) in 19 population-based European registries (EUROCAT) covering 959,446 births in 2004 and 2010. METHODS: EUROCAT implemented a computer algorithm for classification of congenital anomaly cases followed by manual review of potential MCA cases by geneticists. MCA cases are defined as cases with two or more major anomalies of different organ systems, excluding sequences, chromosomal and monogenic syndromes. RESULTS: The combination of an epidemiological and clinical approach for classification of cases has improved the quality and accuracy of the MCA data. Total prevalence of MCA cases was 15.8 per 10,000 births. Fetal deaths and termination of pregnancy were significantly more frequent in MCA cases compared with isolated cases (p < 0.001) and MCA cases were more frequently prenatally diagnosed (p < 0.001). Live born infants with MCA were more often born preterm (p < 0.01) and with birth weight < 2500 grams (p < 0.01). Respiratory and ear, face, and neck anomalies were the most likely to occur with other anomalies (34% and 32%) and congenital heart defects and limb anomalies were the least likely to occur with other anomalies (13%) (p < 0.01). However, due to their high prevalence, congenital heart defects were present in half of all MCA cases. Among males with MCA, the frequency of genital anomalies was significantly greater than the frequency of genital anomalies among females with MCA (p < 0.001). CONCLUSION: Although rare, MCA cases are an important public health issue, because of their severity. The EUROCAT database of MCA cases will allow future investigation on the epidemiology of these conditions and related clinical and diagnostic problems.

Volumetric MRI changes, cognition and personality traits in old age depression.

BACKGROUND: The presence of cognitive and structural deficits in euthymic elderly depressed patients remains a matter of debate. Integrative aetiological models assessing concomitantly these parameters as well as markers of psychological vulnerability such as persistent personality traits, are still lacking for this age group. METHODS: Cross-sectional comparisons of 38 elderly remitted patients with early-onset depression (EOD) and 62 healthy controls included detailed neuropsychological assessment, estimates of brain volumes in limbic areas and white matter hyperintensities, as well as evaluation of the Five-Factor personality dimensions. RESULTS: Both cognitive performances and brain volumes were preserved in euthymic EOD patients. No significant group differences were observed in white matter hyperintensity scores between the two groups. In contrast, EOD was associated with significant increase of Neuroticism and decrease of Extraversion facet scores. LIMITATIONS: Results concern the restricted portion of EOD patients without psychiatric and physical comorbidities. Future longitudinal studies are necessary to determine the temporal relationship between the occurrence of depression and personality dimensions. CONCLUSIONS: After remission from acute depressive symptoms, cognitive performances remain intact in elderly patients with EOD. In contrast to previous observations, these patients display neither significant brain volume loss in limbic areas nor increased vascular burden compared to healthy controls. Further clinical investigations on EOD patterns of vulnerability in old age will gain from focusing on psychological features such as personality traits rather than neurocognitive clues.

Effect of vitamin D on Epstein-Barr (EBV)-specific CD8+T cells in patients with early multiple sclerosis (MS)

Background: Infection with EBV and a lack in vitamin D may be important environmental triggers of MS. 1,25-(OH)2D3 mediates a shift of antigen presenting cells (APC) and CD4+ T cells to a less inflammatory profile. Although CD8+ T cells do express the vitamin D receptor, a direct effect of 1,25(OH)2D3 on these cells has not been demonstrated until now. Since CD8+ T cells are important immune mediators of the inflammatory response in MS, we examined whether vitamin D directly affects the CD8+ T cell response, and more specifically if it modulates the EBV-specific CD8+ T cell response. Material and Methods: To explore whether the vitamin D status may influence the pattern of the EBV-specific CD8+ T cell response, PBMC of 10 patients with early MS and 10 healthy controls (HC) were stimulated with a pool of immunodominant 8-10 mer peptide epitopes known to elicit CD8+ T cell responses. PBMC were stimulated with this EBV CD8 peptide pool, medium (negative control) or anti- CD3/anti-CD28 beads (positive control). The following assays were performed: ELISPOT to assess the secretion of IFN-gamma by T cells in general; cytometric beads array (CBA) and ELISA to determine whichcytokines were released by EBV-specific CD8+ T cells after six days of culture; and intracellular cytokine staining assay to determine by which subtype of T cells secreted given cytokines. To examine whether vitamin D could directly modulate CD8+ T cell immune responses, we depleted CD4+ T cells using negative selection. Results: We found that pre-treatment of vitamin D had an antiinflammatory action on both EBV-specific CD8+ T cells and on CD3/ CD28-stimulated T cells: secretion of pro-inflammatory cytokines (IFNgamma and TNF-alpha) was decreased, whereas secretion of antiinflammatory cytokines (IL-5 and TGF-beta) was increased. At baseline, CD8+ T cells of early MS patients showed a higher secretion of TNFalpha and lower secretion of IL-5. Addition of vitamin D did not restore the same levels of both cytokines as compared to HC. Vitamin D-pretreated CD8+T cells exhibited a decreased secretion of IFN-gamma and TNF-alpha, even after depletion of CD4+ T cells from culture. Conclusion: Vitamin D has a direct anti-inflammatory effect on CD8+ T cells independently from CD4+ T cells. CD8+ T cells of patients with earlyMS are less responsive to the inflammatory effect of vitamin D than HC, pointing toward an intrinsic dysregulation of CD8+ T cells. The modulation of EBV-specific CD8+T cells by vitaminDsuggests that there may be interplay between these twomajor environmental factors of MS. This study was supported by a grant from the Swiss National Foundation (PP00P3-124893), and by an unrestricted research grant from Bayer to RDP.

Statin use and peripheral blood progenitor cells mobilization in patients with multiple myeloma.

PURPOSE: Statins have beneficial effects in patients after myocardial infarction and at least part of the benefit results from mobilization of marrow endothelial progenitors to repopulate damaged myocardial tissues. This study examines if statins may have the same effect in mobilizing marrow progenitors to be harvested and subsequently used in high-dose chemotherapy with progenitor cell rescue in multiple myeloma. METHODS: From 2006 to 2012, 86 patients with multiple myeloma were mobilized with the use of G-CSF and were retrospectively analyzed. Patients with other malignancies or mobilized with the use of chemotherapy or with plerixafor were excluded. RESULTS: The median age of the patients was 60 years. 72 patients had received one line of chemotherapy and 14 patients two or more lines of chemotherapy. Twenty patients were taking statins at the time of the harvest while 66 patients were not. In the group of patients taking statins the success rate of first leukapheresis (obtaining the target number of 4 × 10(6) CD34+ cells/kg) was 85 % while in the group not taking statins this rate was 63.6 %. Despite the comparatively small number of patients this difference approached statistical significance (χ (2) = 0.07). CONCLUSION: This retrospective analysis of 86 patients shows for the first time a possible benefit of statins for peripheral blood progenitor cells mobilization in patients with multiple myeloma. Larger studies would be required to clarify the issue. If their effectiveness is confirmed, statins could be a safe and cheaper addition to chemotherapy and plerixafor for peripheral hematopoietic stem cell mobilization.

Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis Mimicking a Primary Psychiatric Disorder in an Adolescent.

Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis likely has a wider clinical spectrum than previously recognized. This article reports a previously healthy 16-year-old girl who was diagnosed with anti-NMDA receptor encephalitis 3 months after onset of severe depression with psychotic features. She had no neurological manifestations, and cerebral magnetic resonance imaging (MRI) was normal. Slow background on electroencephalogram and an oligoclonal band in the cerebrospinal fluid prompted the search for anti-NMDA receptor antibodies. She markedly improved over time but remained with mild neuropsychological sequelae after a trial of late immunotherapy. Only a high index of suspicion enables recognition of the milder forms of the disease masquerading as primary psychiatric disorders.

Controversies about a common etiology for eating and mood disorders.

Obesity and depression represent a growing health concern worldwide. For many years, basic science and medicine have considered obesity as a metabolic illness, while depression was classified a psychiatric disorder. Despite accumulating evidence suggesting that obesity and depression may share commonalities, the causal link between eating and mood disorders remains to be fully understood. This etiology is highly complex, consisting of multiple environmental and genetic risk factors that interact with each other. In this review, we sought to summarize the preclinical and clinical evidence supporting a common etiology for eating and mood disorders, with a particular emphasis on signaling pathways involved in the maintenance of energy balance and mood stability, among which orexigenic and anorexigenic neuropeptides, metabolic factors, stress responsive hormones, cytokines, and neurotrophic factors.

First use of multiple substances: Identification of meaningful patterns

Context: Understanding the process through which adolescents and young adults are trying legal and illegal substances is a crucial point for the development of tailored prevention and treatment programs. However, patterns of substance first use can be very complex when multiple substances are considered, requiring reduction into a few meaningful number of categories. Data: We used data from a survey on adolescent and young adult health conducted in 2002 in Switzerland. Answers from 2212 subjects aged 19 and 20 were included. The first consumption ever of 10 substances (tobacco, cannabis, medicine to get high, sniff (volatile substances, and inhalants), ecstasy, GHB, LSD, cocaine, methadone, and heroin) was considered for a grand total of 516 different patterns. Methods: In a first step, automatic clustering was used to decrease the number of patterns to 50. Then, two groups of substance use experts, three social field workers, and three toxicologists and health professionals, were asked to reduce them into a maximum of 10 meaningful categories. Results: Classifications obtained through our methodology are of practical interest by revealing associations invisible to purely automatic algorithms. The article includes a detailed analysis of both final classifications, and a discussion on the advantages and limitations of our approach.