The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: ...human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.
HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome.
These were recently shown to comprise copies that retain potential to express retroviral proteins or particles, and can be abnormally expressed in autoimmune, neurodegenerative, chronic inflammatory diseases, and cancer.
Environmental factors such as specific viral infections were shown to potently activate HERVs under tissue-specific and temporal conditions.
Of several diseases in which abnormal activation and expression of HERV proteins have been reported, studies over recent decades have led to a proof of concept that HERVs play a key role in the pathogenesis of MS and ALS.
HERV-W and HERV-K Env proteins induce pathogenic effects in vitro and in vivo that are relevant to the pathognomonic features of these diseases.
These endogenous retroviruses are potential novel therapeutic targets that are now being addressed with innovative therapeutic strategies in clinical trials.
To determine whether rituximab 375 mg/m(2) was efficacious in patients with immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating ...neuropathy).
Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) ≥4 and visual analog pain scale >4 or ataxia score ≥2. The primary outcome was mean change in ISS at 12 months.
Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m(2) rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form-36 questionnaire.
Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis.
This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy.
Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of ...developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.
To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity.
The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.
COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms.
The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 not hospitalized with no limitations on activities to 7 death) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes.
A total of 347 patients (mean SD age, 44.6 12.8 years, 249 women; mean SD disease duration, 13.5 10.0 years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 95% CI, 1.4-2.5), EDSS (OR for EDSS ≥6, 6.3 95% CI. 2.8-14.4), and obesity (OR, 3.0 95% CI, 1.0-8.7) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01).
In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.
Plantar skin sensitivity contributes to the regulation of postural control and, therefore, changing the characteristics of the plantar support surface can modify this control. This study aimed at ...assessing the impact of five different floor coverings on the orthostatic balance in 48 healthy subjects. Static posturography was performed with eyes open or closed on a platform in a control condition (no covering) and with five different covering surfaces: foam, silicone, ethyl vinyl acetate, and two textured mats with small (height 2 mm) or large pimples (7 mm). The average velocity of center of pressure (CoP) displacement was the primary endpoint measure and ten other posturographic variables were assessed. Comfort and pain produced by the covering were also scored. In eyes open condition, the average velocity of CoP displacement was increased when subjects stood on the foam mat, the silicone mat, and especially the textured mat with large pimples. Several other posturographic variables showed significant changes with different types of floor coverings with eyes open. These changes were not correlated to the comfort or pain scores associated with the different surfaces. In contrast, no difference was observed compared to the control condition (no covering) with eyes closed. This study shows that adding smooth or textured floor covering can alter balance in eyes open condition. In eyes closed condition, although more disturbing for balance, healthy subjects achieved better postural adaptation, probably by mobilizing more of their proprioceptive resources. This posturographic examination procedure could, therefore, be used to assess “proprioceptive reserve” capacities in clinical practice.
Abstract
Background
We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept.
Methods
Phase IIb ...open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks.
The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables.
Results
The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product.
Conclusions
Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory.
Trial registration
ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.
Les premières observations de polyradiculonévrites furent rapportées sous le nom de Paralysie Ascendante Aiguë en 1859 par Jean-Baptiste Octave Landry de Thézillat. La description princeps du ...syndrome de Guillain-Barré (SGB) fut la publication en 1916 de l’article signé Guillain, Barré et Strohl dans les Bulletins et Mémoires de la Société Médicale des hôpitaux de Paris : « Sur un syndrome de radiculo-névrite avec hyperalbuminose du liquide céphalorachidien sans réaction cellulaire. Remarques sur les caractères cliniques et graphiques des réflexes tendineux ». Les auteurs insistèrent alors sur l’augmentation de la concentration en albumine du liquide céphalorachidien, sans réaction cellulaire, sous la forme « d’une radiculonévrite » et sur le bon pronostic de la maladie. Les critères diagnostiques ont par la suite évolués pour rendre compte de la diversité des présentations cliniques. Dès 1938, puis en 1953, Guillain proposa quatre présentations touchant les membres inférieurs, une forme spinale et du tronc cérébral, une forme diencéphalique et la polyradiculoneuropathie avec trouble de la conscience. Vingt ans plus tard, Miller Fisher décrivit le syndrome qui porte désormais son nom et Bickerstaff présentait le syndrome qui ressemblait à la polyradiculoneuropathie avec troubles de la vigilance. En 2015, un groupe d’auteurs proposé une démarche clinique permettant de différencier les sous-types de SGB et de syndrome de Miller Fisher. Des critères diagnostiques furent développés en 1978. En 1990, des critères spécifiques aux formes purement motrices, purement sensitives, au Miller Fisher et aux formes localisées furent proposés. En 2001, il fut tenu compte pour la première fois des données neurophysiologiques axonales ou démyélinisantes. Enfin, sur le plan biologique, la dissociation albumino-cytologique a été remplacée par l’hyperprotéinorachie et enrichie des anticorps anti-gangliosides et des anticorps anti-protéines des nœuds de Ranvier. Le SGB englobe désormais un spectre large de neuropathies aiguës, dont le mécanisme est lié à des troubles de l’excitabilité nerveuse.
To perform posturographic measurements with eyes open or closed using floor coverings with different textured surfaces to study postural control in patients with multiple sclerosis (MS).
Static ...posturographic recordings were performed with eyes open and eyes closed on a forceplate with no covering (control condition) or covered by a textured mat with small pimples (height 2 mm) or large pimples (height 7 mm). Several posturographic variables were measured, focusing on displacements of the center of pressure (CoP) including the average velocity (Vav), the total length (L) of all displacements, and the surface (S) of the confidence ellipse. The recordings made with the textured mats were compared to the control condition with eyes open or closed. Then, the differences between the recordings made with large vs. small pimples on the one hand, and with eyes closed vs. open were calculated to assess the impact of pimple height or eye closure on posturographic measurements. Clinical assessment was based on the Expanded Disability Status Scale (EDSS) and its functional system (FS) subscores, the Modified Fatigue Impact Scale (MFIS), the Unipodal Stance test (UST), and the Timed Up-and-Go test (TUG).
Forty-six MS patients (mean EDSS score: 3.6) completed the study. Several posturographic variables, including Vav and L, deteriorated when measured on a textured mat, especially with large pimples and in eyes open condition. In contrast, no difference was found with small pimples and eyes closed, as compared to the control condition (no covering). The deleterious impact of pimple height on posturography correlated positively with the alteration of balance and gait clinically assessed by the UST and the TUG, and also with the MFIS physical and cerebral EDSS-FS subscores, and negatively with the cerebellar and brainstem subscores. On the other hand, the impact of eye closure on posturography was negatively correlated with the visual EDSS-FS subscore.
Static posturographic measurements made with different textured surfaces and visual conditions can be considered as a sensitive tool to measure "proprioceptive reserves". Actually, when cerebellar, brainstem, or visual functions are impaired, the resources of the sensory (proprioceptive) system, if preserved, can be recruited at a higher level and compensate for dysfunctions of other postural controls to maintain a satisfactory balance. In addition, this procedure of static posturographic examination can provide objective measurements correlated with clinical testing of balance and gait and could usefully complement EDSS scoring to assess disability affecting postural control and the risk of falling in MS patients.
We evaluated the effect of DMTs on Covid‐19 severity in patients with MS, with a pooled‐analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with ...Covid‐19 severity was assessed by multivariate ordinal‐logistic models and pooled by a fixed‐effect meta‐analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti‐CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid‐19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled‐analysis confirms an increased risk of severe Covid‐19 in patients on anti‐CD20 therapies and supports the protective role of interferon.
In addition to multiple peripheral neurofibromas, Neurofibromatosis 1 (NF1) predisposes to CNS tumours. Most of them are pilocytic astrocytomas, arise in children and are located in the optic ...pathways or in the brainstem. The majority are indolent, but factors predictive of poor prognosis have yet to be identified. Furthermore, the incidence and natural history of gliomas of a higher grade, arising in adults or involving other locations are largely unknown in NF1. In order to address these issues, we performed a retrospective study of 104 patients followed in seven French centres between 1982 and 2000. Inclusion criteria were a diagnosis of NF1, according to the National Institutes of Health criteria, and the presence of a CNS tumour, regardless of type, location or age of onset. The series included 88 children (age range 3 months to 17 years) and 16 adults (age range 19-52 years). The median follow-up was 5.6 years. One hundred and twenty-seven CNS tumours were observed in the 104 patients. Eighty-four (66%) were optic pathway tumours (OPT) and 43 (34%) extra-optic pathway tumours (extra-OPT) (brainstem: n = 21; other locations: n = 22). Twenty-one patients (20%) had multiple CNS tumours. OPT were symptomatic in 50 patients and extra-OPT in 19. Main clinical findings at presentation included visual loss (n = 29; 58%) and precocious puberty (n = 5; 10%) for OPT, increased intracranial pressure (n = 9; 48%) for extra-OPT. Fourteen out of the 27 symptomatic tumours with histology were pilocytic astrocytomas. The overall survival rate was 90% at 5 years (95% confidence interval 82-95%). Extra-optic location, tumour diagnosis in adulthood and symptomatic tumours were independent factors associated with shorter survival time (P < 0.05, Cox model). Radiotherapy for OPT was associated with vascular complications (ischaemic strokes) and growth hormone deficiency in 32 and 46% of patients, respectively. In conclusion, mortality is high in extra-OPT, particularly in adults, whereas OPT are only exceptionally life-threatening. Radiotherapy of OPT is associated with an important morbidity in NF1.
The precise location of multiple sclerosis (MS) cortical lesions can be very challenging at 3 T, yet distinguishing them from subcortical lesions is essential for the diagnosis and prognosis of the ...disease. Compressed sensing-accelerated fluid and white matter suppression imaging (CS-FLAWS) is a new magnetic resonance imaging sequence derived from magnetization-prepared 2 rapid acquisition gradient echo with promising features for the detection and classification of MS lesions. The objective of this study was to compare the diagnostic performances of CS-FLAWS (evaluated imaging) and phase sensitive inversion recovery (PSIR; reference imaging) for classification of cortical lesions (primary objective) and infratentorial lesions (secondary objective) in MS, in combination with 3-dimensional (3D) double inversion recovery (DIR).
Prospective 3 T scans (MS first diagnosis or follow-up) acquired between March and August 2021 were retrospectively analyzed. All underwent 3D CS-FLAWS, axial 2D PSIR, and 3D DIR. Double-blinded reading sessions exclusively in axial plane and final consensual reading were performed to assess the number of cortical and infratentorial lesions. Wilcoxon test was used to compare the 2 imaging datasets (FLAWS + DIR and PSIR + DIR), and intraobserver and interobserver agreement was assessed using the intraclass correlation coefficient.
Forty-two patients were analyzed (38 with relapsing-remitting MS, 29 women, 42.7 ± 12.6 years old). Compressed sensing-accelerated FLAWS allowed the identification of 263 cortical lesions versus 251 with PSIR ( P = 0.74) and 123 infratentorial lesions versus 109 with PSIR ( P = 0.63), corresponding to a nonsignificant difference between the 2 sequences. Compressed sensing-accelerated FLAWS exhibited fewer false-negative findings than PSIR either for cortical lesions (1 vs 13; P < 0.01) or infratentorial lesions (1 vs 15; P < 0.01). No false-positive findings were found with any of the 2 sequences. Diagnostic confidence was high for each contrast.
Three-dimensional CS-FLAWS is as accurate as 2D PSIR imaging for classification of cortical and infratentorial MS lesions, with fewer false-negative findings, opening the way to a reliable full brain MS exploration in a clinically acceptable duration (5 minutes 15 seconds).
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