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.

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

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

Atypical myelitis in patients with multiple sclerosis: Characterization and comparison with typical multiple sclerosis and neuromyelitis optica spectrum disorders.

BACKGROUND: Atypical myelitis in multiple sclerosis (MS) is characterized by extensive myelitis in the longitudinal (longitudinally extensive transverse myelitis) or axial plane (transverse myelitis). OBJECTIVE: To characterize a cohort of MS patients with atypical myelitis. METHODS: Atypical myelitis was extracted from the French and Luxembourg MS databases and compared to two cohorts of MS patients with typical myelitis and neuromyelitis optica spectrum disorders (NMOSDs) patients with myelitis. RESULTS: We enrolled 28 MS patients with atypical myelitis, 68 MS patients with typical myelitis and 119 NMOSD patients with a first episode of myelitis. MS patients with atypical myelitis were characterized by a mean age of 34.0 (±10.7) years and 64.3% were women. In 82.1% of the patients, atypical myelitis was the first episode of MS. Mean Expanded Disability Status Scale (EDSS) scores at nadir and 3-6 months after onset were 4.1 ± 2.1 and 3.3 ± 2, respectively. Differences between groups revealed a predominance of cervicothoracic myelitis and a higher level of disability in NMOSD patients. Disability in MS patients with atypical myelitis was more severe than in the MS patients with typical myelitis; 28% had already converted to progressive MS within our mean follow-up of 39.6 (±30.4) months. CONCLUSION: Atypical myelitis may be the first presentation of MS and is associated with poorer prognosis.

Acute retinal arterial ischaemia: silent brain infarcts prevalence and short-term recurrence.

BACKGROUND AND PURPOSE: The purpose was to evaluate, in a consecutive series of patients with isolated acute retinal ischaemia, the proportion of patients with acute silent brain infarcts (SBIs) on diffusion-weighted imaging (DWI) and to assess risk of recurrence within 3 months. METHODS: In all, 103 consecutive patients with isolated acute retinal ischaemia (central retinal artery occlusion, branch retinal artery occlusion or transient monocular vision loss) were included between January 2015 and December 2016. They all had cerebral magnetic resonance imaging including DWI as well as a standardized aetiological workup and 3 months of follow-up. The presence of DWI-positive cerebral lesions was recorded. Main clinical and radiological characteristics between DWI-positive and DWI-negative patients were compared. RESULTS: Of the 103 patients (including 42 transient monocular vision loss), 20 (19.5%) had SBIs on DWI, which were ipsilateral to the acute retinal ischaemia in 30% and involved different and/or multiple vascular territories in 70% of cases. Ipsilateral carotid stenosis and occlusion were respectively identified in 17 and eight patients whereas cardioaortic embolism was found in 19 patients. Overall, patients with and without acute SBIs were comparable. The topography of SBIs was related to the aetiology of the acute retinal ischaemia. At 3 months of follow-up, one patient suffered from ischaemic stroke and five had recurrent retinal ischaemia. CONCLUSIONS: Irrespective of the baseline characteristics of the patients, SBIs are present in about 20% of patients with isolated acute retinal ischaemia and may be of interest in the aetiological workup. Overall risk of recurrence is low, favoured by rapid aetiological workup and appropriate treatment.

MSCopilot, a new multiple sclerosis self-assessment digital solution: results of a comparative study versus standard tests.

BACKGROUND AND PURPOSE: Assessing patients' disability in multiple sclerosis (MS) requires time-consuming batteries of hospital tests. MSCopilot is a software medical device for the self-assessment of patients with MS (PwMS), combining four tests: walking, dexterity, cognition and low contrast vision. The objective was to validate MSCopilot versus the Multiple Sclerosis Functional Composite (MSFC). METHODS: This multicentre, open-label, randomized, controlled, crossover study enrolled 141 PwMS and 76 healthy controls (HCs). All participants performed MSCopilot and MSFC tests at day 0. To assess reproducibility, 46 PwMS performed the same tests at day 30 ± 3. The primary end-point was the validation of MSCopilot versus MSFC for the identification of PwMS against HCs, quantified using the area under the curve (AUC). The main secondary end-point was the correlation of MSCopilot z-scores with MSFC z-scores. RESULTS: In all, 116 PwMS and 69 HCs were analysed. The primary end-point was achieved: MSCopilot performance was non-inferior to that of MSFC (AUC 0.92 and 0.89 respectively; P = 0.3). MSCopilot and MSFC discriminated PwMS and HCs with 81% and 76% sensitivity and 82% and 88% specificity respectively. Digital and standard test scores were highly correlated (r = 0.81; P < 0.001). The test-retest study demonstrated the good reproducibility of MSCopilot. CONCLUSION: This study confirms the reliability of MSCopilot and its usability in clinical practice for the monitoring of MS-related disability.

Do disease-modifying drugs (DMD) have a positive impact on the occurrence of secondary progressive multiple sclerosis? No.

RR MS evolution has changed since the beginning of the availability of MS disease-modifying drugs (DMD). Before concluding a unique impact of the efficiency of DMD, careful analysis of long-term studies has to be conducted. Analysis of the literature points out a few bias in the long-term follow of MS patients under DMD: indication of DMD has changed since 20 years, diagnosis criteria are not the same (including the Will Rogers phenomen), and so far population are not homogeneous and comparable. Analysis criteria of the efficiency of the treatments are not the same, pending on the date of the publications. References concerning the long-term impact of DMD are in fact very limited. In addition, long-term efficiency of 2nd line treatments is not available. Another explanation of the change of MS evolution could be the lower evolutivity of MS patients since 2 decades. Analysis of placebo group in pivotal studies, argues to a decrease of the relapse annual rate and mean EDSS score in the more recent studies and recent MS diagnosed patients. To conclude, long-term evolution of MS patients is more favorable, influence of DMD is likely, but not unique.

Diagnostic and therapeutic issues of inflammatory diseases of the elderly.

Inflammatory diseases of the central nervous system (CNS) mainly occur during early adulthood and multiple sclerosis (MS) represents the overwhelming majority of these disorders. Nevertheless, MS only rarely begins after 50 years and a diagnosis of late-onset MS should only be done when clinical as well as radiological and biological findings are typical of MS since the probability of misdiagnosis is higher in elderly patients. Indeed, in patients aged over 50 years, along with a relative decrease of MS incidence, other inflammatory diseases of the CNS but also differential diagnoses including neoplastic as well as infectious disorders should be thoroughly searched to avoid diagnostic mistakes and the prescription of inadequate and potentially harmful immunomodulatory/immunosuppressive therapies. Moreover, aging is associated with diverse immune changes also known as immunosenescence resulting in, notably, higher risk of comorbidities (including vascular diseases) and infections which need to be considered when planning medical treatments of elderly patients with inflammatory diseases of the CNS. Herein, therapeutic and diagnostic challenges faced by neurologists are reviewed to ease patient management.

Atypical inflammatory demyelinating lesions and atypical multiple sclerosis.

Atypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló's concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management.

Efficacy of rituximab in refractory neuromyelitis optica.

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

Brain magnetic resonance imaging helps to differentiate atypical multiple sclerosis with cavitary lesions and vanishing white matter disease.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients can present with atypical cavitary lesions mimicking vanishing white matter disease (VWMD). Our objective was to identify brain magnetic resonance imaging (MRI) findings that differentiate these two disorders. METHODS: A cross-sectional study was performed including 14 patients with MS with cavitary lesions and 14 patients with VWMD. Two neuroradiologists retrospectively reviewed the MRI including at least T1-, T2- and fluid-attenuated inversion recovery weighted images. RESULTS: The main differences included ovoid lesions perpendicular to the lateral ventricle, punctate isolated juxtacortical lesions (both 100% in MS versus 0% in VWMD) and symmetrical infratentorial hyperintensities (0% in MS versus 50% in VWMD). Other statistically significant differences included midbrain (79% in MS versus 29% in VWMD) and thalamus lesions (71% vs. 7%) as well as extensive external capsule involvement (29% vs. 86%) and extensive corpus callosum lesions (64% vs. 100%). Cavitary lesions usually had periventricular predominance in MS (36% vs. 0%) whereas they were more frequently anterior in VWMD (0% in MS versus 57% in VWMD). CONCLUSION: Despite many similar MRI findings, our results suggest that a careful analysis of the morphology and the location of the lesions is helpful to differentiate these distinct disorders.

Use of quantitative susceptibility mapping (QSM) in progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic demyelinating encephalopathy related to JC virus. Its characteristics on conventional brain MRI are well known and are important for the diagnosis. OBJECTIVE: To analyze SWI hypointensities recently described in U-fibers and cortex adjacent to the white matter lesions of PML. METHODS: Prospective study including four patients with an history of definite diagnosis of PML. Clinical data were collected retrospectively. Brain MRI exams were done on a 3T magnet, including FLAIR, T2 GRE sequences and SWI. RESULTS: Four males were included (mean age: 47 years, mean PML duration: 24.2 months). Immunosuppression was related to AIDS (n=2), natalizumab for multiple sclerosis (n=1), B-cell lymphoma treated by chemotherapeutic agents and rituximab (n=1). All patients had SWI hypointensities in cortex and/or U-fibers adjacent to the white matter lesions. QSM always suggested a paramagnetic effect. CONCLUSION: SWI and T2 GRE hypointensities in cortex and U-fibers adjacent to the white matter lesions seem highly prevalent in PML, irrespective of the delay between PML onset and the MRI. QSM data suggest a paramagnetic effect.

Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis.

BACKGROUND: Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment. OBJECTIVE: The objective of this paper is to identify cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages. METHODS: We conducted differential analysis of the CSF proteome from control and relapsing-remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients. RESULTS: Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS. CONCLUSIONS: CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS.

Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects.

OBJECTIVES: The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young female subjects. DESIGN: Systematic case-control study of incident ADs associated with quadrivalent HPV vaccination in young women across France. PARTICIPANTS AND SETTING: A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14-26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice. ANALYSIS: Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs. RESULTS: Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 [95% confidence interval (CI) 0.5-1.5]. The individual ORs were 1.0 (95% CI 0.4-2.6) for ITP, 0.3 (95% CI 0.1-0.9) for MS, 0.8 (95% CI 0.3-2.4) for connective disorders and 1.2 (95% CI 0.4-3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain-Barré syndrome or thyroiditis. CONCLUSIONS: No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs.

Uterine artery embolization for severe symptomatic fibroids: effects on fertility and symptoms.

STUDY QUESTION: Does uterine artery embolization (UAE) permit fertility in childbearing women who have extensive symptomatic fibroids and are not eligible for surgery? SUMMARY ANSWER: Although UAE was effective in improving bleeding, bulking and pain symptoms, and in sparing the ovarian reserve, no woman in this study delivered successfully after UAE. WHAT IS KNOWN ALREADY: Although pregnancies have been reported after UAE, the actual fertility rate after this treatment remains uncertain. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 66 women who desired a future pregnancy and were treated with UAE for symptomatic fibroids. PARTICIPANTS/MATERIALS, SETTING, METHODS: This cohort of consecutive patients had extensive symptomatic fibroids but were not eligible for abdominal myomectomy because of fibroid recurrence despite previous surgery, because of current risks of surgery, or because of patient refusal. The patients were enrolled in a tertiary referral center for fibroid treatment. All patients had a pre-operative ovarian function assessment and underwent bilateral superselective embolization of both uterine arteries using 500-1200 µm Tris acryl microspheres. MAIN RESULTS AND THE ROLE OF CHANCE: Fibroid symptoms including menorrhagia (OR 0.08, 95% CI 0.02-0.27), metrorrhagia (OR 0.05, 95% CI 0.01-0.39), pain (OR 0.08, 95% CI 0.03-0.22) and bulk syndrome (OR 0.02, 95% CI 0.01-0.07) were significantly improved after UAE. According to magnetic resonance imaging, the dominant fibroid volume decreased by 31.8% (95% CI 12.2-51.3%). Ovarian reserve demonstrated no change after embolization. Thereafter the women were prospectively followed, and 31 of them (aged 37.3 ± 3.5 years) were actively trying to conceive. In spite of 33.4 ± 14.5 months of attempts, only 1 in 31 women became pregnant and she finally miscarried (monthly fecundability rate 0.1% 95% CI 0-0.3%). LIMITATIONS, REASONS FOR CAUTION: The high rate of associated infertility factors in our population, and the high frequency of previous surgery, could in part explain these poor reproductive outcomes; however, they should not account for the total absence of ongoing pregnancy. Embolization might have had a negative impact on fertility in our population, which may not be related to ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: The low reproductive outcomes reported in the present study suggest that UAE should not be performed routinely in young women of childbearing age with extensive fibroids. Although this finding was established in a population for whom abdominal myomectomy was declined, a possible adverse effect of UAE on fertility potential should be considered for woman of childbearing age scheduled for embolization. STUDY FUNDING/COMPETING INTEREST(S): No particular funding was obtained for this study and the authors have no conflict of interest.

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.

[Natalizumab as induction therapy in multiple sclerosis]. / Traitement d'induction dans la sclérose en plaques: place du natalizumab.

BACKGROUND: Current treatment options for first-line immunotherapy in relapsing-remitting multiple sclerosis (MS) are recombinant interferon-ß and glatiramer acetate. However, these therapies are only partially effective and certain patients may fail to respond. For this reason, it is important to elaborate alternative treatment strategies. Induction therapy represents a more aggressive approach in which powerful drugs are used right from the beginning to tackle the disease process hard and early. Natalizumab is a powerful monoclonal antibody approved for the treatment of relapsing-remitting MS and is known to silence disease activity. METHODS: We describe here the early outcome at 1 month and at 6 months of three patients treated with natalizumab for relapsing-remitting MS. RESULTS: All three patients had a high disease activity before the initiation of natalizumab, with 4, 8 and 5 gadolinium-enhancing lesions on brain MRI respectively. On the MRI scans made at 1 month after the first infusion, and at 6 months, there was no more gadolinium-enhancement and no new T2-lesion. Clinically, they did not experience any relapse. DISCUSSION: In these three cases, natalizumab showed a dramatic efficacy: the patients became "disease activity free" right from the first infusion. To our knowledge, natalizumab is not classically used as an induction therapy, unlike mitoxantrone. However, this treatment has potential hematological and cardiac toxicity and its use can be limited. Thus, in JC virus negative patients, natalizumab could be an interesting alternative treatment. CONCLUSION: Our report suggests that induction strategy with natalizumab may be applicable in patients with aggressive multiple sclerosis. A study of more similar cases may be interesting to confirm these preliminary results.

[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.

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.

Longitudinal follow-up of vision in a neuromyelitis optica cohort.

BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory disease associated with optic neuritis and myelitis. Recently, several studies showed that optical coherence tomography (OCT) could be an interesting method for the evaluation of disease severity; however, to date there are no studies with a longitudinal follow-up of visual function in NMO. The aim of this study was to assess the ability of OCT to evaluate the progression of visual dysfunction in NMO. PATIENTS AND METHODS: A group of 30 NMO patients (thus, 60 eyes), comprised of 20 women and 10 men with a mean age of 43.7 +/- 12.3 years, were prospectively evaluated clinically and by a whole neuro-ophthalmological work-up, including: visual acuity (VA), fundoscopy, visual evoked potential (VEP), visual field (VF) and optical coherence tomography (OCT). All patients were tested at baseline (after a mean disease duration of 6.1 years) and after a mean time of follow-up of 18 months (range: 12-36 months). RESULTS: Mean VA was similar at the two evaluation times (0.77 +/- 0.36 versus 0.77 +/- 0.35). The mean VF defect decreased slightly, but the difference was not significant (-5.9 +/- 1.3 dB versus -5.3 +/- 1.3 dB). In contrast, the mean retinal thickness seen on OCT decreased from 87.4 +/- 23.3 µm to 79.7 +/- 22.4 µm (p = 0.006). These modifications were only observed in eyes with a past or a recent history of optic neuritis (-15.1 µm; p < 0.001) and not in eyes without any history of optic neuritis (-2.4 µm; not significant). Also, they occurred independently of the occurrence of relapses (n = 13) and especially optic neuritis episodes; however, the number of optic neuritis episodes was low (n = 5). CONCLUSION: OCT seems to be a more sensitive test than VA or VF for monitoring ophthalmological function in NMO and it seems to be helpful for the detection of infra-clinical episodes in patients with a past history of optic neuritis. Our results suggest that this easily performed technique should be used in the follow-up of NMO, but complementary studies are warranted to confirm its interest at an individual level.

I123-FP-CIT single-photon emission tomography in patients with long-standing mixed tremor.

BACKGROUND AND PURPOSE: Essential tremor is an abnormal movement characterized by postural and/or kinetic tremor. In some essential tremor patients, rest tremor (RT) is observed but it is not clear if this RT is a feature of essential tremor or a symptom of Parkinson's disease (PD). I123-FP-CIT single-photon emission tomography is used to distinguish essential tremor and PD. OBJECTIVES: To analyse I123-FP-CIT single-photon emission tomography in a larger series of patients with mixed tremor (i.e. action tremor associated with RT) without PD criteria. METHODS: We studied 33 consecutives patients (18 men and 15 women) with mixed tremor, clinically and by neuroimaging in all cases. RESULTS: I123-FP-CIT single-photon emission tomography was abnormal in 25 of our patients (75.7%) with mixed tremor, and we noted a reduced uptake mostly in the putamen. In our patients with abnormal imaging, RT was unilateral in 52%. In 15 of these 25 patients, putaminal reduced uptake was bilateral and symmetrical. In the other 10 patients, putaminal reduced uptake was asymmetrical or unilateral. In these 10 cases, six had a unilateral RT corresponding to (crossed) predominant reduced uptake in three cases. In our patients with normal imaging, RT was unilateral in 87.5%. CONCLUSIONS: This study shows that mixed tremor is a heterogeneous entity. The majority of patients with mixed tremor showed nigrostriatal dysfunction on I123-FP-CIT single-photon emission tomography, suggesting that mixed tremor may be a parkinsonian syndrome rather than a clinical variant of essential tremor.