[Show abstract][Hide abstract] ABSTRACT: Animal model Thiopalmitoylated P0 peptide Chronic EAN CIDP Electrophysiology Sciatic nerve immunohistochemistry Immunology Our objective was to develop a chronic model of EAN which could be used as a tool to test treatment strategies for CIDP. Lewis rats injected with S-palmitoylated P0(180–199) peptide developed a chronic, sometimes relapsing– remitting type of disease. Our model fulfills electrophysiological criteria of demyelination with axonal degener-ation, confirmed by immunohistopathology. The late phase of the chronic disease was characterized by accumu-lation of IL-17 + cells and macrophages in sciatic nerves and by high serum IL-17 levels. In conclusion, we have developed a reliable and reproducible animal model resembling CIDP that can now be used for translational drug studies.
Journal of Neuroimmunology 01/2015; 278:1-10. · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The clinical impact of neutralizing antibodies against interferon-beta (NAb) is controversial. Their presence can lead to a decrease in interferon-beta (IFNß) efficacy. Fatigue reported in patients with multiple sclerosis (MS) may be associated with an unfavorable clinical course. We conducted a prospective multicentre study to assess the association between response to IFNß, NAb and fatigue.Methods
Patients with relapsing-remitting MS on IFNß treatment were included. During the second year of treatment, the patients were analyzed for NAb status and non-response criteria to IFNß (number of relapses ¿1 during the follow-up period, increase in the Expanded Disability Status Scale ¿0.5). The score on the Modified Fatigue Impact Scale (MFIS pathological if score ¿35) was noted for each patient.ResultsOf the 176 patients included: 22.3% were NAb positive, 54.5% presented non-response criteria to IFNß, and 57.4% had a pathological MFIS score. Fatigue was increased in NAb¿+¿patients (p¿=¿0.0014) and they were more likely to present non-response criteria to IFNß (p¿=¿0.041) than NAb- patients. Multivariate logistic regression analysis showed that the presence of NAb was related to fatigue (p¿=¿0.0032) and denoted disease activity in these patients (p¿=¿0.026).Conclusions
This study demonstrates the impact of NAb on the non-clinical response to IFNß. Fatigue assessment is an indicator of IFNß responsiveness and a predictive biomarker of deterioration on patient¿s neurological status.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening (n = 175) were randomized 1:1:2 to continue natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during natalizumab interruption did not exceed pre-natalizumab levels or levels seen in historical control patients.
[Show abstract][Hide abstract] ABSTRACT: Our aim was to investigate the functional underpinnings of autobiographical memory (AM) impairment in multiple sclerosis (MS) patients. To that end, 18 patients and 18 controls underwent the autobiographical interview (AI). Subsequently, the 36 participants underwent a functional magnetic resonance imaging (fMRI) session designed to assess the construction and elaboration of AMs. A categorical control task was also presented. Patients were trained in the fMRI procedure to optimise the procedural aspects accompanying the task itself. Although the patients obtained significantly poorer AI scores (p < .001), their performance on the easier AM fMRI task was efficiently carried out, allowing relevant comparisons with healthy controls. Relatively to healthy controls, the patients showed increased and bilateral cerebral activations (p < .005) during the construction and elaboration phases. The prefrontal, temporal and posterior cerebral region activations were located within the core network sustaining AM, with the bilateral prefrontal region being centrally involved. The parametric neural responses to the difficulty of access and amount of details of memories were also significantly different for the two groups, with the right hippocampal region showing a particularly increased recruitment (p < .005). The findings suggested the presence of functional cerebral changes during AM performance and supported the presence of AM retrieval deficit in MS patients.
[Show abstract][Hide abstract] ABSTRACT: Neuromyelitis optica (NMO) is a rare disease including both optic neuritis and myelitis together or successively. Recently, a specific antibody named anti-NMO has been discovered allowing a more precise diagnosis. This antibody is directed againbst abti-AQP4 protein, a watter chanel protein. This discovery enlarged the spectrum of NMO to patients with recurrent optic neuritis and positive antibodies, now include in the NMO spectrum disorder (NMOSD). MRI frequently shows intense hypersignal of optic nerve and spinal cord with normal or atypical brain MRI for MS. NMO is frequently associated with other auto-immune diseases such as Sjogren syndrome ou lupus. The outcome of the disease may be severe with blindness and para/tetraplegia implying that an intensive treatment should be propose as soon as the diagnosis has been made.
[Show abstract][Hide abstract] ABSTRACT: Recent studies has shown that neuromyelitis optica (NMO) is clearly a different disease compared with multiple sclerosis (MS). Several MS drugs may increase inflammation process in NMO, especially interferon beta, natalizumab and fingolimod. This fact has 2 important consequences : First the diagnosis of NMO has to been done as soon as possible in order to differentiate NMO and MS patients. Second, as NMO is an antibody mediated disease immunosuppressive grugs should be proposed if the diagnosis is done. First step therapy is based on azathioprine, mycophenolate mofetil and methotrexate. Second step therapy are Rituximab, cyclophosphamide and mitoxantrone. Several drugs (with atarget on complement subunites or several cytokine, especially IL6 or IL17) are currently tested in phase II or III trials. Symptomatic treatments directed against fatigue, urinary or bowel dysfunctions, pain remains also of importance. Commercial interest
[Show abstract][Hide abstract] ABSTRACT: The aims of the present study were (i) to explore autobiographical memory and episodic future thought in multiple sclerosis (MS), using Levine’s Autobiographical Interview. (ii) To investigate the influence of the Interview’s high retrieval support condition (the specific probe phase) on MS patients’ past and future simulation. (iii) To obtain the patients’ estimations of their own difficulties, during the test, and in everyday life.
To that end, we examined 39 non-depressed relapsing-remitting MS patients and 34 healthy subjects matched for gender, age and education level. The 73 participants underwent an adapted version of the Autobiographical Interview in two conditions: remembering and imagining personal events. The group of patients also underwent an extended neuropsychological baseline, including particularly, anterograde memory and executive functions.
The results showed that the MS patients’ scores on the baseline were mildly or not impaired. On the contrary, the Autobiographical Interview measure, i.e., the mean number of internal details, for each of the two phases of the test -free recall and specific probe- was significantly lower in simulated past and future events in comparison with the healthy controls. Within each group, autobiographical memory performance was superior to episodic future thought performance. A strong positive correlation was observed between past and future mental simulation scores in both groups.
In conclusion, our results showed, for the first time, the co-occurrence of deficit of remembering the past and imagining the future in MS patients. They also showed more difficulty in imagining future events than remembering past events for both patients and normal controls. MS being a neurological condition very frequent in the young adult population, the clinical considerations of our study might be of interest. Indeed, they give rise to new insights on MS patients’ daily life difficulties related to impaired mental simulation of personal events despite general abilities, including anterograde memory, only mildly or not impaired.
AI, Autobiographical Interview; AM, Autobiographical memory; EDSS, Expanded Disability Status Scale; EFT, Episodic future thought; MS, Multiple Sclerosis
Multiple sclerosis; Cognition; Autobiographical memory; Episodic future thought; Neuropsychology; retrieval conditions
Journal of the Neurological Sciences 07/2014; · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abnormal brain MRI has been described in up to 60% of patients with NMO patients. However, white matter T2 hyperintensities have been rarely observed. We report the case of a 49-year-old woman with long-lasting neuromyelitis optica (NMO) spectrum disorder and diffuse cerebral white matter T2-weighted hyperintensities. Our case suggests that some NMO patients can progressively develop l extensive cerebral involvement.
[Show abstract][Hide abstract] ABSTRACT: Bickerstaff's encephalitis (BE) is an acute post-infectious demyelinating disease with albuminocytological dissociation. A chronic form has rarely been described previously.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Descriptions of Lyme disease and dementia are rare. Objective: To describe patients with dementia and a positive "intrathecal anti-Borrelia antibody index" (AI), specific for neuroborreliosis. Methods: Among 1,594 patients seen for dementia, we prospectively identified and studied 20 patients (1.25%) with dementia and a positive AI. Patients underwent a battery of neuropsychological tests brain, MRI, FDG-PET, and cerebrospinal fluid (CSF) analysis. An etiological diagnosis of the dementia was made at the end of the follow-up of 5.0 ± 2.9 years. Results: We found two groups of patients with dementia, the first (n = 7, 0.44%) with certain neuroborreliosis and stability or mild improvement of dementia after treatment by antibiotics and the second (n = 13, 0.81%) with progressive worsening of dementia, despite the antibiotics. In the second group, the final diagnoses were Alzheimer's disease (AD) (n = 4), AD and Lewy body disease (LBD) (n = 3), LBD (n = 1), FTLD (n = 3), hippocampal sclerosis (n = 1), and vascular dementia (n = 1). We did not observe any differences in cognitive test between the two patient groups at baseline. Brain MRI showed more focal atrophy and FDG-PET showed more frontal hypometabolism in the second group. Tau, p-tau, and Aβ42 concentrations in the CSF were normal in the neuroborreliosis group, and coherent with diagnosis in the second. Conclusion: Pure Lyme dementia exists and has a good outcome after antibiotics. It is advisable to do Lyme serology in demented patients, and if serology is positive, to do CSF analysis with AI. Neurodegenerative dementia associated with positive AI also exists, which may have been revealed by the involvement of Borrelia in the CNS.
Journal of Alzheimer's disease: JAD 04/2014; · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Background and purposeAnti-β2-glycoprotein I (anti-β2-GPI) antibodies are part of the heterogeneous family of antiphospholipid antibodies and seem to be present in various neurological manifestations in addition to antiphospholipid syndrome (APS). Our objective was to analyse the clinical, radiological and therapeutic characteristics of neurological patients with positive anti-β2-GPI antibodies and without the Sapporo criteria for APS.Methods
The medical records were retrospectively reviewed of 28 consecutive patients hospitalized in the Neurology Department of Strasbourg University Hospital, France, in whom anti-β2-GPI antibodies (immunoglobulin G and/or immunoglobulin M) were positive and other antiphospholipid antibodies negative, from November 2005 to July 2011. Clinical, radiological, biological and therapeutic data and clinical course were studied.ResultsPositive anti-β2-GPI antibodies were present in 28 patients. The predominant physiopathological process was mainly inflammatory (25% with myelitis, 14.3% with optic neuritis) or vascular (14.3% with cerebral ischaemia, 7.1% with cerebral vasculitis). Brain magnetic resonance imaging was performed in 89.3% of patients: atypical lesions were observed in 44% and typical inflammatory and vascular lesions in 16% and 12%, respectively.Conclusion
The anti-β2-GPI antibody seems to be involved in two types of neurological disease: vascular or inflammatory ‘multiple sclerosis-like’ disease. These two types of patients frequently develop an autoimmune disease (multiple sclerosis, systemic lupus erythematosus, APS). However, a large proportion of the patients had an undefined profile with aspecific cerebral lesions and required monitoring. This study raises questions about a separate entity at the border between APS and multiple sclerosis which remains to be better defined in a larger cohort.
European Journal of Neurology 04/2014; · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.
Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks.
Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%-29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.
MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.
This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge. OBJECTIVE To collect data from patients with MS switching from natalizumab to fingolimod. DESIGN, SETTING, AND PARTICIPANTS The Enquête Nationale sur l'Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod. MAIN OUTCOMES AND MEASURES Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod. RESULTS Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). CONCLUSIONS AND RELEVANCE In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.