Anti-CD20 monoclonal antibodies in multiple sclerosis: Rethinking the current treatment strategy.

Anti-CD20 monoclonal antibodies are highly-effective B-cell-depleting therapies in multiple sclerosis (MS). These treatments have expanded the arsenal of highly effective disease-modifying therapies, and have changed the landscape in understanding the pathophysiology of MS and the natural course of the disease. Nevertheless, these treatments come at the cost of immunosuppression and risk of serious infections, diminished vaccination response and treatment-related secondary hypogammaglobulinemia. However, the COVID pandemic has given way to a possibility of readapting these therapies, with most notably extended dosing intervals. While these new strategies show efficacy in maintaining inflammatory MS disease control, and although it is tempting to speculate that tailoring CD20 therapies will reduce the negative outcomes of long-term immunosuppression, it is unknown whether they provide meaningful benefit in reducing the risk of treatment-related secondary hypogammaglobulinemia and serious infections. This review highlights the available anti-CD20 therapies that are available for treating MS patients, and sheds light on encouraging data, which propose that tailoring anti-CD20 monoclonal antibodies is the next step in rethinking the current treatment strategy.

French protocol for the diagnosis and management of hematopoietic stem cell transplantation in autoimmune diseases.

Hematopoietic stem cell transplantation (HSCT) for severe ADs was developed over the past 25years and is now validated by national and international medical societies for severe early systemic sclerosis (SSc) and relapsing-remitting multiple sclerosis (MS) and available as part of routine care in accredited center. HSCT is also recommended, with varying levels of evidence, as an alternative treatment for several ADs, when refractory to conventional therapy, including specific cases of connective tissue diseases or vasculitis, inflammatory neurological diseases, and more rarely severe refractory Crohn's disease. The aim of this document was to provide guidelines for the current indications, procedures and follow-up of HSCT in ADs. Patient safety considerations are central to guidance on patient selection and conditioning, always validated at the national MATHEC multidisciplinary team meeting (MDTM) based on recent (less than 3months) thorough patient evaluation. HSCT procedural aspects and follow-up are then carried out within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and SFGM-TC accredited centres in close collaboration with the ADs specialist. These French recommendations were performed according to HAS/FAI2R standard operating procedures and coordinated by the Île-de-France MATHEC Reference Centre for Rare Systemic Autoimmune Diseases (CRMR MATHEC) within the Filière FAI2R and in association with the Filière MaRIH. The task force consisted of 3 patients and 64 clinical experts from various specialties and French centres. These data-derived and consensus-derived recommendations will help clinicians to propose HSCT for their severe ADs patients in an evidence-based way. These recommendations also give directions for future clinical research in this area. These recommendations will be updated according to newly emerging data. Of note, other cell therapies that have not yet been approved for clinical practice or are the subject of ongoing clinical research will not be addressed in this document.

Training first-year medical residents to break bad news using healthcare role-play and trainees as simulated patients: Experience of the "ADIAMED" program from Lille University School of Medicine.

INTRODUCTION: Several studies suggest the relevance of healthcare simulation to prepare future doctors to deliver bad news. A such, we designed a role-play workshop to train first-year residents enrolled in Lille University School of Medicine to break bad news. The objective of this work is to report on our experience of this training and to assess its educational value through its capacity to satisfy residents' expectations, to induce a feeling of ease towards bad news disclosure, and to change trainees' preconceptions regarding these situations. METHODS: The training consisted of a 45-minute heuristic reflective activity, aimed at identifying residents' preconceptions regarding bad news disclosure, followed by 4 30-min role-plays in which they played the parts of the physician, the patient and/or their relatives. Trainees were asked to answer 2 questionnaires (pre- and post-training), exploring previous experiences, preconceived ideas regarding bad news disclosure and workshop satisfaction. RESULTS: Almost all residents felt very satisfied with the workshop, which they regarded as formative (91%) and not too stressful (89%). The majority felt "more capable" (53% vs. 83%) and "more comfortable" (27% vs. 62%) to deliver bad news, especially regarding "finding the right words" (12% vs. 22%). Trainees tended to overestimate their skills before the workshop and lowered their assessment of their performance after attending the training, especially when they played the role of a patient in the simulation. CONCLUSION: Healthcare role-play seems an interesting technique for training to breaking bad news. Placing residents in the role of patients or relatives is an active approach that encourages reflexivity.

Evaluation of a self-questionnaire to screen for neurological complications associated with immunological checkpoint inhibitors: Are we missing something?

INTRODUCTION: Immunological checkpoint inhibitors (ICI) have led to a therapeutic revolution in the management of many cancers and indications are increasing. Neurological complications seem to have a profile quite distinct from that of toxicities related to chemotherapy, although it is possible that some manifestations remain under-reported or misdiagnosed. OBJECTIVES: (i) To evaluate the value of a self-questionnaire in screening for neurological ICI-related complications. (ii) To investigate whether, apart from the subacute complications described in the literature, neurological complications of more insidious onset might occur. METHOD: Patients followed in dermatology department for skin cancers treated with ICI, completed every infusion a neurological screening auto-questionnaire. Patients were selected for a neurological expertise based on the questionnaire's data. RESULTS: In total, 149 patients completed≥1 questionnaire, with a median delay of 174 days from the start of treatment. A total of 229 questionnaires were completed between July 2019 and December 2019. 38 patients were identified for a neurological consultation. None of these patients had a neurological event attributable to ICI. During the follow-up, only one patient had a neurological event related to ICI, which was not revealed by the questionnaire. DISCUSSION: Neurological signs in ICI-treated-skin-cancer context are more often due to tumoral progression. Neurological complications of ICI remain rare and unpredictable. The systematic neurological questionnaire has not been shown to be useful in this context. These results highlight the need to educate patients about possible subacute signs that should lead to contact the treating physicians and the need for a close cooperation between dermatologists/oncologists and neurologists.

Evaluation of risk management in a natalizumab home infusion procedure.

Natalizumab is a well-established disease-modifying therapy used in active multiple sclerosis (MS). The most serious adverse event is progressive multifocal leukoencephalopathy. For safety reasons, hospital implementation is mandatory. The SARS-CoV-2 pandemic has deeply affected hospital practices leading French authorities to temporarily authorize to administer the treatment at home. The safety of natalizumab home administration should be assessed to allow ongoing home infusion. The aim of the study is to describe the procedure and assess the safety in a home infusion natalizumab model. Patients presenting relapsing-remitting MS treated by natalizumab for over two years, non-exposed to John Cunningham Virus (JCV) and living in the Lille area (France) were included from July 2020 to February 2021 to receive natalizumab infusion at home every four weeks for 12 months. Teleconsultation occurrence, infusion occurrence, infusion cancelling, JCV risk management, annual MRI completion were analyzed. The number of teleconsultations allowing infusion was 365 (37 patients included in the analysis), all home infusions were preceded by a teleconsultation. Nine patients did not complete the one-year home infusion follow-up. Two teleconsultations canceled infusions. Two teleconsultations led to a hospital visit to assess a potential relapse. No severe adverse event was reported. All 28 patients who have completed the follow-up benefited from biannual hospital examination and JCV serologies and annual MRI. Our results suggested that the established home natalizumab procedure was safe using the university hospital home-care department. However, the procedure should be evaluated using home-based services outside the university hospital.

Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis.

BACKGROUND: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. METHODS: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. RESULTS: Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. CONCLUSIONS: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Characterization of alexithymia in clinically isolated syndrome.

BACKGROUND: In multiple sclerosis (MS), the prevalence of alexithymia, defined as an inability to identify and describe emotions, is close to 50% but the prevalence of this symptom in clinically isolated syndrome (CIS) is unknown. Characterizing alexithymia at an early stage of the disease can help to clarify psychobehavioural disturbances in CIS patients. METHODS: Forty CIS patients, who fulfilled the MRI criteria for dissemination in space, were matched with 40 healthy subjects. They completed self-assessment scales for alexithymia, depression, anxiety, apathy and empathy. Cognitive functions were assessed using a battery of neuropsychological tests. RESULTS: The mean delay (± standard deviation) between the occurrence of CIS and inclusion in the study was 3.9 (2.8) months. The frequency of alexithymia was higher in CIS patients than in controls, with a prevalence of 42% (P<0.0001). Alexithymia correlated with anxiety and depression but not with cognition. Alexithymia was dependent only on depression (P=0.003). CONCLUSION: Alexithymia, characterized by difficulty identifying feelings, is present in patients in the early stage of MS, and seems to be strongly associated with depression. Difficulty in social interaction could be a risk of future affective disorders.

MRI characteristics of MOG-Ab associated disease in adults: An update.

Our knowledge of the radiological spectrum of myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is growing rapidly. An update on the radiological features of the disease, and its evolution is thus necessary. Magnetic resonance imaging (MRI) has an increasingly important role in the differential diagnosis of MOGAD particularly from aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and multiple sclerosis (MS). Differentiating these conditions is of prime importance because the management is different between the three inflammatory diseases, and thus could prevent further attack-related disability. Therefore, identifying the MRI features suggestive of MOGAD has diagnostic and prognostic implications. We herein review optic nerve, spinal cord and the brain MRI findings from MOGAD adult patients, and compare them to AQP4-NMOSD and MS.

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.

Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders

There is growing evidence of a preventive effect of Rituximab (RTX) in neuromyelitis optica spectrum disorders (NMO-SD). This monoclonal antibody against CD20 is becoming the most widely used preventive therapy in NMO-SD, as a first-line therapy or as a rescue therapy. Nevertheless, considerable heterogeneity still exists concerning the pre-treatment work-up, the vaccinations required before and under treatment, the number and dosage of infusions, prevention of the risk of infusion-related reactions, prevention of infections under treatment, and frequency of therapeutic cycles. Thanks to a collaborative work among NMO-SD experts belonging to the NOMADMUS project, we provide here recommendations for all these topics concerning RTX use in NMO-SD.

Progress in understanding the pathophysiology of multiple sclerosis.

Multiple sclerosis (MS) arises in people who have a genetic susceptibility to environmental factors and events, which ultimately trigger the disease. It is thought that peripheral immune cells are mobilized and enter the CNS through the impaired blood-brain barrier in the subarachnoid space, as acute lesions show large numbers of macrophages and CD8+ T cells and, to a lesser extent, CD4+ T cells, B cells and plasma cells. Demyelination is mostly localized to focal lesions in early relapsing-remitting (RR) MS, whereas other areas of white matter appear normal. Over time, T-cell and B-cell infiltration becomes more diffuse and axonal injury more widespread, leading to self-perpetuating atrophy in both white and gray matter. With disease progression, inflammatory processes are predominantly driven by the action of CNS resident microglia cells. In addition, there is evidence that meningeal lymphoid-like structures can form and contribute to late-stage inflammation. In general, however, despite dynamic changes over time in MS pathology, lesions do not appear to differ significantly in the different classic forms of MS already identified. While all treatments approved for MS management target inflammatory components of RRMS, the B-cell-depleting antibody ocrelizumab is the first such treatment approved recently for primary progressive (PP) MS. However, recent pathological and imaging findings have prompted reconsideration of the clinical phenotypes of MS patients proposed by Lublin's 2013 classification, including clinical and MRI signs of activity, and new imaging biomarkers of remyelination are now being investigated for new strategies of MS management.

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.

[Myelitis as a differential diagnosis of spinal cord tumors]. / Diagnostic différentiel des tumeurs intramédullaires : les myélites.

BACKGROUND AND PURPOSE: Myelitis is common, related to multiple aetiologies and constitute in some cases a differential diagnosis for spinal cord tumors. Our objective was to review the clinical and paraclinical aspects of the main aetiologies of myelitis. METHODS: These aetiologies will be reviewed based on data not only from the scientific literature but also from our personal experience reported in different cohorts of patients. RESULTS: Multiple sclerosis is the main cause of partial myelitis in young adults. Neuromyelitis optica is now a well-known specific entity frequently revealed by a transverse myelitis. The diagnosis is based on specific criteria, including the presence of anti-NMO antibodies. In our cohorts, approximately 12 % of the patients admitted for an acute or subacute myelitis were related to infections, mainly of a viral origin. Patients with myelitis must be screened for systemic diseases. As for neuromyelitis optica, patients with myelitis related to a systemic disease should be treated in emergency. Acute myelitis is sometimes the first symptom of a systemic lupus or of a sarcoidosis. Sjögren syndrome can mimic myelitis related to primary progressive multiple sclerosis. Spinal cord imaging contributes greatly to defining the myelitis. CONCLUSION: In most cases, a routine clinical and paraclinical examination and the follow-up of the patients can contribute to establishing the aetiology of a myelitis.

Should a psychotic or manic episode be considered an early manifestation of Multiple Sclerosis? A multiple case study.

BACKGROUND: Early manifestations of Multiple Sclerosis (MS) can be atypical and misleading, and several case report studies have highlighted that MS onset sometimes takes the form of a psychotic or manic episode. METHODS: All neurologists belonging to the French Multiple Sclerosis Observatory network were contacted by email and were asked to find patients with MS who presented with a history of psychiatric episode(s) near MS onset. RESULTS: Seventeen patients were selected that met the criteria of presenting with psychotic or manic symptoms either before the diagnosis of MS (N=8), or at the time of the first neurological episode or shortly after (N=9). Patients with a history of a psychiatric episode occurring before the first neurological episode were diagnosed on average 7 years later than patients with either a first neurological or a mixed (both neurological and psychiatric) episode. However, psychiatric symptoms in the first group and the first neurological symptoms of MS in the second group occurred at a similar age. CONCLUSION: Based on this multiple case study, we question whether past psychotic or manic episode should be considered equivalent to a first manifestation of MS.

Length of optic nerve double inversion recovery hypersignal is associated with retinal axonal loss.

OBJECTIVES: To assess the association between optic nerve double inversion recovery (DIR) hypersignal length and retinal axonal loss in neuroinflammatory diseases affecting optic nerves. METHODS: We recruited patients previously affected (> 6 months) by a clinical episode of optic neuritis (ON). We had 25 multiple sclerosis (MS) patients, eight neuromyelitis optica spectrum disorder (NMOSD) patients and two patients suffering from idiopathic caused ON undergo brain magnetic resonance imaging (MRI); including a 3-dimensional (3D) DIR sequence, optical coherence tomography (OCT) examination and visual disability evaluation. Evaluation criteria were retinal thickness/volume, optic nerve DIR hypersignal length and high/low contrast vision acuity. RESULTS: In the whole cohort, we found good associations (< 0.0001) between optic nerve DIR hypersignal length, peripapillary retinal nerve fiber layer thickness, inner macular layers volumes, and visual disability. We found subclinical radiological optic nerve involvement in 38.5% of non-ON MS eyes. CONCLUSIONS: Optic nerve DIR hypersignal length may be a biomarker for retinal axonal loss, easily applicable in routine and research on new anti-inflammatory or neuroprotective drug evaluation. Detection of subclinical ON with 3D-DIR in a non-negligible proportion of MS patients argues in favor of optic nerve imaging in future OCT MS studies, in order to achieve a better understanding of retinal axonal loss in non-ON eyes.

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.

High-affinity σ1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis.

BACKGROUND AND PURPOSE: Selective agonists of the sigma-1 receptor (σ1 protein) are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high-affinity binding sites for compounds binding to the σ1 protein and potential immunomodulatory properties have been described for σ1 protein ligands. Experimental autoimmune encephalomyelitis (EAE) is recognized as a valuable model of the inflammatory aspects of multiple sclerosis (MS). Here, we have assessed the role of a σ1 protein agonist, containing the tetrahydroisoquinoline-hydantoin structure, in EAE. EXPERIMENTAL APPROACH: EAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP)139-151 peptide. The σ1 protein agonist was injected i.p. at the time of immunization (day 0). Disease severity was assessed clinically and by histopathological evaluation of the CNS. Phenotyping of B-cell subsets and regulatory T-cells were performed by flow cytometry in spleen and cervical lymph nodes. KEY RESULTS: Prophylactic treatment of EAE mice with the σ1 protein agonist prevented mononuclear cell accumulation and demyelination in brain and spinal cord and increased T2 B-cells and regulatory T-cells, resulting in an overall reduction in the clinical progression of EAE. CONCLUSIONS AND IMPLICATIONS: This σ1 protein agonist, containing the tetrahydroisoquinoline-hydantoin structure, decreased the magnitude of inflammation in EAE. This effect was associated with increased proportions of B-cell subsets and regulatory T-cells with potential immunoregulatory functions. Targeting of the σ1 protein might thus provide new therapeutic opportunities in MS.

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.

[Cerebrotendinous xanthomatosis: a multicentric retrospective study of 15 adults, clinical and paraclinical typical and atypical aspects]. / Étude rétrospective multicentrique de 15 cas adultes de xanthomatose cérébrotendineuse : aspects cliniques et paracliniques typiques et atypiques.

INTRODUCTION: Cerebrotendinous xanthomatosis, a metabolic leukodystrophy with an autosomal recessive inheritance, is secondary to deficiency of sterol 27-hydroxylase, an enzyme involved in cholesterol catabolism. Classical symptoms include clinical or infraclinical xanthomas affecting the skin and tendons, early cataracts, neurological signs and diarrhea. Brain imaging reveals involvement of the dentate nuclei and periventricular white matter hyperintensities. The diagnosis is based on an increased cholestanol level in serum, confirmed by the presence of a mutation in the CYP27A1 gene. Treatment is based on chenodeoxycholic acid. METHOD: We report a retrospective multicentric study of 15 cases of cerebrotendinous xanthomatosis diagnosed in French adults. Clinical, molecular and MRI findings were recorded in all patients. RESULTS: The average age at diagnosis was 39years (range 27-65). Disease onset occurred in childhood in 73% of patients and in adulthood in 27%. All patients with a pediatric onset were diagnosed during adulthood (age range 28-65years). Clinical symptoms variably associated cerebellar syndrome, pyramidal syndrome, cognitive decline, epilepsy, neuropathy (sought in 10 of our patients, present in forms in 8), psychiatric disorders, cataract and xanthomas. One patient had an atypical presentation: monoparesis associated with xanthomas. Brain MRI was abnormal in all: findings consisted in T2-weighted hyperintensity of the dentate nuclei (47%), periventricular leuoencephalopathy (73%) which preferentially involved the posterior cerebral part (60%), leucoencephalopathy with a vascular pattern (7%), hyperintensity of the cortico-spinal tracts (53%), globi pallidi, corpus callosum and cerebral atrophy (33%). Serum cholestanol was elevated in 93% of patients. The most frequent mutation was 1183C>T (n=5/15). Under treatment with chenodeoxycholic acid, eight patients improved initially, followed by stabilization in five of them, and worsening in the others. Four patients died. CONCLUSION: Patients with the xanthoma-neurological disorder association should be tested for cerebrotendinous xanthomatosis. The disease often begins in childhood with a diagnostic delay but also in adulthood. Involvement of the dentate nuclei is specific but not sensitive and the supratentorial leucoencephalopathy is not specific but with an antero-posterior gradient. A vascular distribution and involvement of the corpus callosum are possible. Serum cholestanol assay is very reliable: an elevated level provides the diagnosis, which must nevertheless be confirmed by molecular biology.

Accuracy of postcontrast 3D turbo spin-echo MR sequence for the detection of enhanced inflammatory lesions in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Therapeutic strategies for patients with MS partly rely on contrast-enhanced MR imaging. Our aim was to assess the diagnostic performance of 3D turbo spin-echo MR imaging with variable refocusing flip angles at 3T for the detection of enhanced inflammatory lesions in patients with multiple sclerosis. MATERIALS AND METHODS: Fifty-six patients with MS were prospectively investigated by using postcontrast T1-weighted axial 2D spin-echo and 3D TSE MR images. The order in which both sequences were performed was randomized. Axial reformats from 3D T1 TSE were generated to match the 2D spin-echo images. The reference standard was defined by using clinical data and all MR images available. Three separate sets of MR images (2D spin-echo images, axial reformats, and multiplanar images from 3D TSE sequences) were examined in a blinded fashion by 2 neuroradiologists separately for the detection of enhanced MS lesions. Image artifacts and contrast were evaluated. RESULTS: No artifacts related to vascular pulsation were observed on 3D TSE images, whereas image artifacts were demonstrated on 2D spin-echo images in 41 patients. One hundred twelve enhanced MS lesions were identified in 19 patients. Sixty-four lesions were correctly diagnosed by using 2D spin-echo images; 90, by using 3D TSE axial reformatted views; and 106, by using multiplanar analysis of the 3D TSE sequence. Multiplanar analysis was 94.7% sensitive and 100% specific for the diagnosis of patients with at least 1 enhanced lesion. Contrast of enhanced MS lesions was significantly improved by using the 3D TSE sequence (P < .011). CONCLUSIONS: The 3D TSE sequence with multiplanar analysis is a useful tool for the detection of enhanced MS lesions.