BACKGROUND:Real-world data suggest that the early use of highly active therapies (HAT) may reduce the risk of transition to secondary progressive MS (SPMS). However, current knowledge about predictive factors of outcomes needs to be improved. The primary objective of this study was to determine factors associated with the occurrence of SPMS in patients treated early after MS onset with an HAT. METHODS:Retrospective, multicentric study based on the French MS database. Patients who initiated a HAT within 5 years after MS onset, EDSS ⩽4, and had a follow-up >5 years were included. The association of each covariate at baseline with time to the occurrence of SPMS was quantified by hazard ratios (HRs) in unadjusted and adjusted Cox proportional hazards models. RESULTS:Two thousand two hundred and thirty-seven patients were included in the analysis: mean age 31.6 years, female/male sex ratio 2.3, and median EDSS 2.0. The estimated probability of reaching SPMS, progression independent of relapse activity (PIRA) and progression independent of activity (PIA) at 10 years was 8%, 22%, and 11%, respectively. After adjustment, we found that female patients (HR 0.64, p = 0.036) had a lower risk of developing SPMS. Older age, EDSS >0 (HR 7.44, p < 0.001), and oral versus intravenous HAT (HR 1.97, p = 0.003) were significantly associated with an increased SPMS risk. Early PIRA and PIA predicted conversion to SPMS. CONCLUSIONS:Early HAT use resulted in a low risk of developing SPMS over 10 years. Introducing the HAT before any residual disability was associated with a lower risk of progression.

Reactivation of Multiple Sclerosis (MS) activity has been described after fingolimod cessation. Because of its contra indication during pregnancy, switch towards lower efficacy treatments are frequent in MS patients with childbearing desire but expose them to a risk of disease reactivation. In this retrospective study including 44 women with MS, a significant increase of the median annualized relapse rate was found in the year following fingolimod discontinuation compared to the period before (p < 0.0001), and 57% of women experienced at least one relapse. When considering to start fingolimod, particular attention should be paid to women with a short-term pregnancy desire.

It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing–remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS. Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator’s discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator’s discretion. Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI − 0.51 to − 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9). The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis.

On behalf of all authors, we would like to thank Mr. Tugemann for his interest in our article.1 It is correct that acute progressive multifocal leukoencephalopathy (PML) can, in some circumstances, lead to high(er) CD62L values. However, as the study was conducted prospectively and, more importantly, alongside treatment, we reported all results of samples shipped to us back to the treating physicians. At the time of measurement and reporting, we were not aware of the patients' disease state. Because this is the situation to be expected in postmarketing settings, we chose to report all measured values, even if the samples turned out to be less than 6 months before PML diagnosis. Although the exclusion of these samples would indeed have led to a perfect sensitivity with the threshold of 36.05, we believed that it would not accurately reflect the real-world situation. Similarly, we chose not to focus on other PML risk stratification factors such as previous immune suppression or anti-JC virus antibody serostatus because we could not rely on having this information for all samples shipped to us. We, therefore, decided to report on the feasibility of measuring one biomarker rather than presenting a holistic approach for risk stratification using all available markers, which was addressed before.2 As supported by this study, CD62L was proven to be a useful biomarker for PML risk stratification also in the real-world setting but could also help with monitoring immunologic changes because of natalizumab-extended interval dosing. Owing to its initial detection in a retrospective cohort, the validated methodology3 still requires a mandatory freeze/thaw cycle, thereby limiting its widespread use. However, we would be more than happy if methodological improvements could be achieved here.

Objective To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis. Methods Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included. Results Median age at onset was 36.46 (range 18.0–76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26–0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22–0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07–0.72). Finally, MOG-Ab titers were higher at relapse than in remission (p = 0.009). Conclusion In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.

ACCEPT est un auto-questionnaire validé mesurant l’acceptance des patients pour leur traitement. L’acceptance est définie comme la balance entre avantages et inconvénients d’un traitement, évaluée par le patient lui-même. L’objectif était de déterminer l’acceptance de patients atteints de sclérose en plaques (SEP) pour leur traitement par interféron β-1a intramusculaire (IM IFNβ-1a) et d’en étudier les facteurs associés. Étude observationnelle prospective longitudinale menée en France par 105 neurologues et sur 397 adultes atteints de SEP et initiant un traitement par IM IFNβ-1a. Les caractéristiques cliniques et thérapeutiques étaient collectées à l’inclusion. Les questionnaires ACCEPT (patient/aidant), MMAS (Medication-taking Adherence Scale), MSKQ (Multiple Sclerosis Knowledge Questionnaire) et Alliance Thérapeutique (AT) étaient complétés lors du suivi. Les déterminants de l’acceptance ont été recherchés par analyses de covariance. L’âge moyen des patients était de 38,4 ans et la proportion de femmes de 77,9 %. L’ancienneté moyenne du diagnostic de SEP était de 3,4 ans. Le score moyen d’acceptance générale (AG) était respectivement de 44,9 et 50,0 à 3 et 24 mois (0–100 : faible - forte AG). L’AG à 12 mois était significativement associée à la persistance au traitement à 24 mois (p < 0,001). L’AG du patient était corrélée à l’acceptance de l’aidant et à l’AT. Les scores moyens d’AG pour l’IM INFβ-1a restaient stables entre 3 et 24 mois, avec une concordance forte avec l’AG évaluée par l’aidant. Aucun impact de l’AG sur l’adhésion au traitement n’a été observé, en revanche, une association significative entre acceptance précoce et persistance au traitement a été mise en évidence. Le niveau d’alliance thérapeutique entre le médecin et son patient restait élevé tout le long du suivi. Les résultats de l’étude ADOPTE mettent en évidence une forte association entre acceptance et persistance au traitement par IM IFNβ-1a ainsi que le rôle déterminant des aidants et des médecins. L’étude ADOPTE à été financée par Biogen.

The incidence of hematologic malignancies is on the rise worldwide. Kidney disease is ubiquitous in patients with hematologic malignancies, encompassing a wide spectrum of disorders involving each kidney compartment, including the vasculature, tubules, interstitium, and glomerulus, and there is significant overlap of kidney involvement with each hematologic malignancy. Vascular disorders include both microvascular and macrovascular damage, via thrombotic microangiopathy, hyperleukocytosis, hyperviscosity, and cryoglobulinemia. The tubulointerstitial compartment may be affected by prerenal azotemia and acute tubular injury, but malignant infiltration, tumor lysis syndrome, extramedullary hematopoiesis, cast nephropathy, granulomatous interstitial nephritis, and lysozymuria should be considered in certain populations. Obstructive uropathy may occur due to nephrolithiasis or retroperitoneal fibrosis. Glomerular disorders, including membranoproliferative, membranous, minimal change, and focal segmental glomerulosclerosis, can rarely occur. By understanding how each compartment may be affected, care can best be optimized for these patients. In this review, we summarize the widely varied etiologies of kidney diseases stratified by kidney compartment and hematologic malignancy, focusing on demographics, pathology, pathophysiology, mechanism, and outcomes. We conclude with common electrolyte abnormalities associated with hematologic malignancies.

Les nouveaux critères (Polman, 2010) permettent un diagnostic de SEP des le SCI. La prescription des traitements de fond reste soumise à la dissémination temporelle définie par le suivi clinico-radiologique. Décrire la prise en charge clinique, paraclinique et thérapeutique des SCI en pratique libérale ou hospitalière et estimer le taux de conversion en SEP a 2 ans chez ces patients. Deux cent cinquante-deux patients furent inclus prospectivement par 59 neurologues sur une période de 9 mois après un SCI avec une IRM disponible. Le recueil prospectif des données observationnelles pendant 24 mois après l'inclusion avec au moins une visite par an a permis d'analyser la conversion en SEP selon les critères diagnostiques de 2005 et de 2010, la survenue de poussées, l'évolution du score EDSS, les résultats des examens radiologiques et biologiques, l'instauration de traitements. Des données complètes à 2 ans furent obtenues pour 231 patients (âge moyen : 37 ans, sex-ratio F/H : 2,8) ; 26,0 % des patients présentèrent une SEP définie sur la première IRM (2010). Les taux de conversion selon les critères de 2010, 2005 ou SEP cliniquement définie furent respectivement de 48,6 %, 48,8 % et 38,4 % à 24 mois. Seize (14 % des 114 convertis) patients furent traites par un immunomodulateur avant la conversion selon les critères de 2005. Les critères diagnostiques de SEP de 2010 sont plus simples et plus sensibles que ceux de 2005 qui régissent la prescription des immunomodulateurs. Ces nouveaux critères diagnostiques semblent accélérer la prescription des traitements de fond de la SEP pour un petit nombre de patients, qui voient leur taux de conversion clinique diminuer. L'accélération du diagnostic de SEP semble associée a une prescription précoce des traitements de fond après un SCI et a une réduction du risque de conversion en SEP cliniquement définie.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP) Emmanuelle Le Page, David Veillard, David A Laplaud, Stéphanie Hamonic, Rasha Wardi, Christine Lebrun, Fabien Zagnoli, Sandrine Wiertlewski, Véronique Deburghgraeve, Marc Coustans, et al.

April 29, 2014April 8, 2014Free AccessOral versus Intravenous High Doses of Methylprednisolone in Multiple Sclerosis Relapses, a Double Blinded Randomised Controlled Trial (COPOUSEP) : Results at 1 Month (Primary End Point) (P3.168)Emmanuelle Le Page, David Veillard, David Laplaud, Rasha Wardi, Christine Lebrun Frenay, Fabien Zagnoli, Sandrine Wiertlewski, Veronique Deburghgraeve, Marc Coustans, and Gilles EdanAuthors Info & AffiliationsApril 8, 2014 issue82 (10_supplement)https://doi.org/10.1212/WNL.82.10_supplement.P3.168 Letters to the Editor

OBJECTIVE: To collect prospectively safety and efficacy outcomes in relapsing remitting multiple sclerosis (RRMS) patients switching from natalizumab (NTZ) to fingolimod (FTY) therapy.

Metallo-β-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to β-lactam antibiotics. MBLs are highly worrying because of their carbapenemase activity, their rapid spread in major human opportunistic pathogens while no clinically useful inhibitor is available yet. In this context, we are exploring the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs, and diversely substituted at its positions 4 and 5. Here, we present a new series of compounds substituted at the 4-position by a thioether-containing alkyl chain with a carboxylic and/or an aryl group at its extremity. Several compounds showed broad-spectrum inhibition with Ki values in the μM to sub-μM range against VIM-type enzymes, NDM-1 and IMP-1. The presence of the sulfur and of the aryl group was important for the inhibitory activity and the binding mode of a few compounds in VIM-2 was revealed by X-ray crystallography. Importantly, in vitro antibacterial susceptibility assays showed that several inhibitors were able to potentiate the activity of meropenem on Klebsiella pneumoniae clinical isolates producing VIM-1 or VIM-4, with a potentiation effect of up to 16-fold. Finally, a selected compound was found to only moderately inhibit the di-zinc human glyoxalase II, and several showed no or only moderate toxicity toward several human cells, thus favourably completing a promising behaviour.

The gene COL4A1 encodes the α1 chain of type IV collagen, a basement-membrane protein implying vascular parietal strength. Mutations in the gene COL4A1 have been described in families with diffuse small-vessel disease of the brain, resulting in perinatal stroke, congenital porencephaly, extensive leukoencephalopathy, intracerebral hemorrhage, and retinal arteriolar tortuosity.1–4 Our observation extends the clinical and magnetic resonance (MR) phenotype of COL4A1 mutation. ### Case reports. A 21-year-old man without neurologic medical history presented with acute urinary retention. He had a right amblyopia due to a congenital strabismus surgically treated in childhood. Clinical examination showed brisk lower limb reflexes and a left Babinski sign. Blood pressure was normal. The Mini-Mental State Examination score was strictly normal. The patient declined further neuropsychological testing. Brain CT showed diffuse leukoencephalopathy and multiple supratentorial microcalcifications (figure, A). Brain MRI revealed widespread white matter hyperintensities on T2 and fluid-attenuated inversion recovery sequences, dilated perivascular spaces, and lacunar infarctions. Leukoencephalopathy involved the cerebral periventricular and cerebellar deep white matter (figure, B). Multiple microbleeds were seen on gradient echo sequences, involving brainstem and supratentorial white matter (figure, C). MR angiography of cervical and intracranial arteries was normal, as was spinal …

It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, ‘Phase 1’, from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, ‘Phase 2’, from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan–Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26 273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, ≥15 years) in the whole population, and in both phenotypes. In relapsing onset multiple sclerosis, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of multiple sclerosis were found to be independent predictive factors of disability progression, but only during Phase 1. Our findings demonstrate that multiple sclerosis disability progression follows a two-stage process, with a first stage probably dependant on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in multiple sclerosis.

BACKGROUND:Mitoxantrone was approved by the French health authority (AFSAPPS) in October 2003 to treat patients with aggressive multiple sclerosis (MS). OBJECTIVE:To report the long term effectiveness and safety of mitoxantrone as induction therapy in patients with aggressive relapsing-remitting MS, and to assess treatment response factors. MATERIAL AND METHODS:100 consecutive patients with aggressive relapsing-remitting MS received mitoxantrone 20 mg monthly combined with methylprednisolone 1 g for 6 months. Relapses, Expanded Disability Status Scale (EDSS) and drug safety were assessed every 6 months for up to at least 5 years. Within 6 months after induction, 73 patients received maintenance therapy (mitoxantrone every 3 months (n = 21); interferon beta (n = 25); azathioprine (n = 15); methotrexate (n = 7); glatiramer acetate (n = 5)). RESULTS:During the 12 months following initiation of mitoxantrone, the annual relapse rate (ARR) was reduced by 91%, 78% of patients remained relapse free, MRI activity was reduced by 89%, the mean EDSS decreased by 1.2 points (p<10(-6)) and 64% of patients improved by 1 point or more on the EDSS. In the longer term, the ARR reduction was sustained (0.29-0.42 for up to 5 years), the median time to the first relapse was 2.8 years and disability remained improved after 5 years. Younger age and lower EDSS score at the start of mitoxantrone treatment were predictive of better treatment response. Three patients presented with an asymptomatic decrease in left ventricular ejection fraction to less than 50% (one reversible). One patient was diagnosed with acute myeloid leukaemia (remission 5 years after diagnosis). CONCLUSION:Mitoxantrone monthly for 6 months as induction therapy followed by maintenance treatment showed sustained clinical benefit for up to 5 years with an acceptable adverse events profile in patients with aggressive relapsing-remitting MS.