In myelinated fibers of the vertebrate nervous system, glial-ensheathing cells interact with axons at specialized adhesive junctions, the paranodal septate-like junctions 1. The axonal proteins ...paranodin/Caspr and contactin form a cis complex in the axolemma at the axoglial adhesion zone, and both are required to stabilize the junction 2, 3. There has been intense speculation that an oligodendroglial isoform of the cell adhesion molecule neurofascin, NF155, expressed at the paranodal loop 4, 5 might be the glial receptor for the paranodin/Caspr-contactin complex, particularly since paranodin/Caspr and NF155 colocalize to ectopic sites in the CNS of the dysmyelinated mouse Shiverer mutant 5. We report that the extracellular domain of NF155 binds specifically to transfected cells expressing the paranodin/Caspr-contactin complex at the cell surface. This region of NF155 also binds the paranodin/Caspr-contactin complex from brain lysates in vitro. In support of the functional significance of this interaction, NF155 antibodies and the extracellular domain of NF155 inhibit myelination in myelinating cocultures, presumably by blocking the adhesive relationship between the axon and glial cell. These results demonstrate that the paranodin/Caspr-contactin complex interacts biochemically with NF155 and that this interaction is likely to be biologically relevant at the axoglial junction.
High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Several reports have suggested that HDB treatment may be associated with an increased risk of relapse. We ...aimed to determine whether HDB increases the risk of clinical relapse in PMS and describe the characteristics of the patients who experience it. We conducted a French, multicenter, retrospective study, comparing a group of PMS patients treated with HDB to a matched control group. Poisson regression was applied to model the specific statistical distribution of the annualized relapse rate (ARR). A propensity score (PS), based on the inverse probability of treatment weighting (IPTW), was used to adjust for indication bias and included the following variables: gender, primary PMS or not, age, EDSS, time since the last relapse, and co-prescription of a DMT. Two thousand six hundred twenty-eight patients treated with HDB and 654 controls were analyzed with a follow-up of 17 ± 8 months. Among them, 148 validated relapses were observed in the group treated with biotin and 38 in the control group (
p
= 0.62). After adjustment based on the PS, the ARR was 0.044 ± 0.23 for the biotin-treated group and 0.028 ± 0.16 for the control group (
p
= 0.18). The more relapses there were before biotin, the higher the risk of relapse during treatment, independently from the use of HDB. While the number of relapses reported for patients with no previous inflammatory activity receiving biotin has gradually increased, the present retrospective study is adequately powered to exclude an elevated risk of relapse for patients with PMS treated with HDB.
Objective
Neuromyelitis optica (NMO) is a very severe autoimmune disorder of the central nervous system. It affects young subjects and has a poor prognosis both on a functional and vital level. ...Therefore, it is imperative to reduce the frequency of relapses. The purpose of this study was to evaluate the clinical and neuroradiological effectiveness of rituximab (RTX) on active forms of NMO.
Methods
We conducted a 2-year open prospective multicenter study that included 32 patients treated with RTX at a dose of 375 mg/m
2
/week for 1 month. When the number of circulating CD19+ B cells reached 1%, a maintenance therapy was started, consisting of two infusions of 1 g of RTX, administered at a 15-day interval. The primary objective was to reduce the annual relapse rate (ARR), in comparison to that observed in the 2 years before treatment onset.
Results
Rituximab administration reduced the ARR from 1.34 to 0.56 (
p
= 0.0005). The average Expanded Disability Status Scale (EDSS) score significantly improved by 1.1 point, from 5.9 (2–9) to 4.8 (0–9) after 2 years (
p
= 0.03). Anti-aquaporin-4 antibodies’ level predicted treatment failure (
p
= 0.03). Frequency of Gad+ lesions in spinal cord decreased from 23.3 to 14.2%. RTX treatment did not prevent the death of three patients (treatment failure in two patients and acute myeloid leukemia in a patient previously treated with mitoxantrone).
Conclusion
Rituximab is clinically effective in active forms of NMO, although few patients are resistant to the treatment.
Abstract The optineurin (OPTN) gene, known to be implicated in primary open-angle glaucoma (POAG), is the more recent genetic factor linked to ALS. We report the case of a 75 year-old man who ...developed ALS and whose medical history was dominated by a familial POAG. The absence of OPTN gene mutation in a patient who suffered from two conditions linked to mutations of this gene does not support involvement of OPTN in ALS.
A 57-year-old man with chronic inflammatory demyelinating polyneuropathy associated with hepatitis C virus infection was treated successfully with the combination of peginterferon-alpha-2b and ...ribavirin. Viral eradication was confirmed during the 4th week of treatment and was followed 3 weeks later by neurologic improvement. The patient resumed normal activity 1 year after the therapy was completed.
Viral, bacterial, or fungal infections are suspected of triggering multiple sclerosis (MS) and promoting relapses of the disease and are likely to be promoted by immune-active treatments. This raises ...questions about the infectious workup and preventive treatment of these infections prior to their initiation.
To establish recommendations on infections and MS. Provide information to patients and healthcare professionals on the minimal infectious workup to be performed in an MS patient at diagnosis and prior to initiation of immuno-active therapy in MS.
The recommendation attempts to answer four main questions about infections and MS. The French Group for Recommendations in Multiple Sclerosis (France4MS) did a systematic review of articles from PubMed and universities databases (from January 1975 to June 2020), using the RAND/UCLA formalized consensus method. The RAND/UCLA method has been developed to synthesize the scientific literature and expert opinions on health care topics and was used for reaching a formal agreement. Twenty-three experts contributed to the detailed review and a group of 63 multidisciplinary health professionals validated the final version of 36 recommendations.
It is recommended that MS patients undergo a minimal infectious workup, check their vaccination status at diagnosis, and repeat it during follow-up and before starting immunotherapy. Screening and preventive treatment of viral (group Herpes virus, HPV, JCV, HCV, HBV), bacterial (mycobacteria) and fungal (Cryptococcus) infections is recommended prior to the initiation of certain immuno-active MS therapies.
At diagnosis of MS and prior to the choice of therapeutic strategy, it is recommended to update the vaccination schedule of MS patients in reference to the HCSP vaccination schedule and the SFSEP recommendations. Before starting immunosuppressive treatment, it is recommended to inform patients of the risks of infections and to look for a constitutive or acquired immune deficiency. Health professionals and patients should be informed of the updated recommendations on infections and MS.
Amyotrophic lateral sclerosis is the most common motor neuron disorder in adults. Although the diagnosis appears obvious in theory, clinical practice shows the contrary as diagnosis is delayed in ...many patients; the average time between symptom onset and diagnosis can reach 12 months. The delay can be explained by the variability of the clinical presentation and by the absence of diagnostic markers. In order to standardize diagnosis for enrollment in clinical research, diagnostic criteria for ALS were created and revisited during the last 20 years. In 2006, the Awaji criteria for the diagnosis of ALS were proposed, adding two major points to the diagnostic criteria: electromyography is considered equivalent to clinical examination for the identification of LMN signs and fasciculation potentials resume their prominent place in the diagnosis. Comparisons of the accuracy of the revisited El Escorial and Awaji criteria support improved diagnostic sensitivity without any effect on specificity with the new classification. The only weakness of the new classification involves patients with UMN signs in one region and LMN in two regions; these patients were previously classified as laboratory-supported probable ALS and currently as possible ALS, a lower level of diagnostic certainty. In all other instances the accuracy appears to be improved by the Awaji criteria. Nevertheless, there is a body of evidence suggesting the need for a revision of these new criteria, giving more weight to clinical and complementary findings of UMN involvement. The need to diagnose and treat ALS quickly could be facilitated by the inclusion of complementary investigations that detect UMN signs.
Establish recommendations for the management of UTIs in MS patients.
Urinary tract infections (UTIs) are common during multiple sclerosis (MS) and are one of the most common comorbidities potentially ...responsible for deaths from urinary sepsis.
The recommendations attempt to answer three main questions about UTIs and MS. The French Group for Recommendations in MS (France4MS) did a systematic review of articles from PubMed and universities databases (01/1980–12/2019). The RAND/UCLA appropriateness method, which has been developed to synthesize the scientific literature and expert opinions on health care topics, was used for reaching a formal agreement. 26 MS experts worked on the full-text review and a group of 70 multidisciplinary health care specialists validated the final evaluation of summarized evidences.
UTIs are not associated with an increased risk of relapse and permanent worsening of disability. Only febrile UTIs worsen transient disability through the Uhthoff phenomenon. Some immunosuppressive treatments increase the risk of UTIs in MS patients and require special attention especially in case of hypogammaglobulinemia. Experts recommend to treat UTIs in patients with MS, according to recommendations of the general population. Prevention of recurrent UTIs requires stabilization of the neurogenic bladder. In some cases, weekly oral cycling antibiotics can be proposed after specialist advice. Asymptomatic bacteriuria should not be screened for or treated systematically except in special cases (pregnancy and invasive urological procedures).
Physicians and patients should be aware of the updated recommendations for UTis and MS.
In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la ...Sclérose en Plaques.
A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.
The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio OR 0.60,
< 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54,
< 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39,
< 0.001).
After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.
This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.
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