Scoping review of clinical decision support systems for multiple sclerosis management: Leveraging information technology and massive health data.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system, with numerous therapeutic options, but a lack of biomarkers to support a mechanistic approach to precision medicine. A computational approach to precision medicine could proceed from clinical decision support systems (CDSSs). They are digital tools aiming to empower physicians through the clinical applications of information technology and massive data. However, the process of their clinical development is still maturing; we aimed to review it in the field of MS. METHODS: For this scoping review, we screened systematically the PubMed database. We identified 24 articles reporting 14 CDSS projects and compared their technical and software development aspects. RESULTS: The projects position themselves in various contexts of usage with various algorithmic approaches: expert systems, CDSSs based on similar patients' data visualization, and model-based CDSSs implementing mathematical predictive models. So far, no project has completed its clinical development up to certification for clinical use with global release. Some CDSSs have been replaced at subsequent project iterations. The most advanced projects did not necessarily report every step of clinical development in a dedicated article (proof of concept, offline validation, refined prototype, live clinical evaluation, comparative prospective evaluation). They seek different software distribution options to integrate into health care: internal usage, "peer-to-peer," and marketing distribution. CONCLUSIONS: This review illustrates the potential of clinical applications of information technology and massive data to support MS management and helps clarify the roadmap for future projects as a multidisciplinary and multistep process.

Treatment regimens for neuromyelitis optica spectrum disorder attacks: a retrospective cohort study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) attacks require an urgent probabilistic anti-inflammatory therapeutic strategy. As inadequately treated attacks result in disability, there is a need to identify the optimal attack-treatment regimen. Our study aimed to identify predictors of outcome after a first attack in patients with an NMOSD presentation and propose the best treatment strategy. METHODS: We performed a retrospective cohort study on the French national NMOSD registry (NOMADMUS), a nested cohort of the French multiple sclerosis observatory (OFSEP) recruiting patients with NMOSD presentations in France. We studied the first attack for any independent locations of clinical core characteristic of NMOSD, in treatment-naïve patients. The primary outcome was the evolution of the Expanded Disability Status Scale (EDSS) score at 6 months, stratified in two ways to account for recovery (return to baseline EDSS score) and treatment response (classified as "good" if the EDSS score decreased by ≥ 1 point after a nadir EDSS score ≤ 3, or by ≥ 2 points after a nadir EDSS score > 3). We used ordinal logistic regression to infer statistical associations with the outcome. RESULTS: We included 211 attacks among 183 patients (104 with anti-AQP4 antibodies, 60 with anti-MOG antibodies, and 19 double seronegative). Attack treatment regimens comprised corticosteroids (n = 196), plasma exchanges (PE; n = 72) and intravenous immunoglobulins (n = 6). Complete recovery was reached in 40 attacks (19%) at 6 months. The treatment response was "good" in 134 attacks (63.5%). There was no improvement in EDSS score in 50 attacks (23.7%). MOG-antibody seropositivity and short delays to PE were significantly and independently associated with better recovery and treatment response. CONCLUSIONS: We identified two prognostic factors: serostatus (with better outcomes among MOG-Ab-positive patients) and the delay to PE. We, therefore, argue for a more aggressive anti-inflammatory management of the first attacks suggesting an NMOSD presentation, with the early combination of PE with corticosteroids.

Ischemic stroke risk factors not included in the CHADS-VASC score in patients with non-valvular atrial fibrillation.

BACKGROUND: In patients with atrial fibrillation, the CHA2DS2-VASC score guides stroke prevention using anticoagulants, but it is an imperfect score. Other potential risk factors such as renal failure, the type of atrial fibrillation, active smoking, cancer, sleep apnea or systemic inflammation have less well been investigated. OBJECTIVE: To assess the impact of these factors on ischemic stroke risk in patients with non-valvular atrial fibrillation. METHODS: On a population of 248 patients (124 patients with acute ischemic stroke and 124 controls), we performed a logistic regression to assess the impact of multiple non-classic risk factors for the prediction of acute ischemic stroke. Their impact on mortality was assessed by performing a survival analysis. RESULTS: A high CHA2DS2-VASc score (OR 1.75; 95% CI 1.13-2.70; p = 0.032), treatment with anticoagulants (OR 0.19; 95% CI 0.07-0.51; p < 0.001) and permanent atrial fibrillation (OR 6.31; 95% CI 2.46-16.19; p < 0.001) were independently associated with acute ischemic stroke. Renal failure and chronic obstructive pulmonary disease predicted a higher mortality. After adjusting for age, sex, the CHA2DS2-VASc score and the use of anticoagulants, the only risk factor predictive for acute ischemic stroke was the permanent type of AF (OR: 8.0 [95% CI 2.5-25.5], p < 0.001). CONCLUSIONS: The CHA2DS2-VASc score, the absence of anticoagulants and the permanent type of atrial fibrillation were the main predictive factors for the occurrence of acute ischemic stroke. Larger studies are necessary for conclusive results about other factors.

ANTECEDENTES: Em pacientes com fibrilação atrial, o escore CHA2DS2-VASC orienta a prevenção de AVC com anticoagulantes, mas é um escore imperfeito. Outros fatores de risco potenciais, como insuficiência renal, o tipo de fibrilação atrial, tabagismo ativo, câncer, apnéia do sono ou inflamação sistêmica foram menos bem investigados. OBJETIVO: Avaliar o impacto desses fatores no risco de AVC isquêmico em pacientes com fibrilação atrial não valvular. MéTODOS: Em uma população de 248 pacientes (124 pacientes com AVC isquêmico agudo e 124 controles), realizamos uma regressão logística para avaliar o impacto de múltiplos fatores de risco não clássicos na predição de AVC isquêmico agudo. O seu impacto na mortalidade foi avaliado através da realização de uma análise de sobrevivência. RESULTADOS: Escore CHA2DS2-VASc alto (OR 1,75; IC 95% 1,13­2,70; p = 0,032), tratamento com anticoagulantes (OR 0,19; IC 95% 0,07­0,51; p < 0,001) e fibrilação atrial permanente (OR 6,31; 95% CI 2,46­16,19; p < 0,001) foram independentemente associados ao AVC isquêmico agudo. Insuficiência renal e doença pulmonar obstrutiva crônica previram maior mortalidade. Após ajuste para idade, sexo, pontuação CHA2DS2-VASc e uso de anticoagulantes, o único fator de risco preditivo para AVC isquêmico agudo foi o tipo permanente de FA (OR: 8,0 [IC 95% 2,5­25,5], p < 0,001). CONCLUSõES: O escore CHA2DS2-VASc, a ausência de anticoagulantes e o tipo permanente de fibrilação atrial foram os principais fatores preditivos para a ocorrência de AVC isquêmico agudo. Estudos maiores são necessários para resultados conclusivos sobre outros fatores.

Strokecopilot: a literature-based clinical decision support system for acute ischemic stroke treatment.

BACKGROUND: Acute ischemic stroke (AIS) is an immediate emergency whose management is becoming more and more personalized while facing a limited number of neurologists with high expertise. Clinical decision support systems (CDSS) are digital tools leveraging information and artificial intelligence technologies. Here, we present the Strokecopilot project, a CDSS for the management of the acute phase of AIS. It has been designed to support the evidence-based medicine reasoning of neurologists regarding the indications of intravenous thrombolysis (IVT) and endovascular treatments (ET). METHODS: Reference populations were manually extracted from the field's main guidelines and randomized clinical trials (RCT). Their characteristics were harmonized in a computerized reference database. We developed a web application whose algorithm identifies the reference populations matching the patient's characteristics. It returns the latter's outcomes in a graphical user interface (GUI), whose design has been driven by real-world practices. RESULTS: Strokecopilot has been released at www.digitalneurology.net . The reference database includes 25 reference populations from 2 guidelines and 15 RCTs. After a request, the reference populations matching the patient characteristics are displayed with a summary and a meta-analysis of their results. The status regarding IVT and ET indications are presented as "in guidelines", "in literature", or "outside literature references". The GUI is updated to provide several levels of explanation. Strokecopilot may be updated as the literature evolves by loading a new version of the reference populations' database. CONCLUSION: Strokecopilot is a literature-based CDSS, developed to support neurologists in the management of the acute phase of AIS.

Effect of Ocrelizumab on B- and T-Cell Receptor Repertoire Diversity in Patients With Relapsing Multiple Sclerosis From the Randomized Phase III OPERA Trial.

BACKGROUND AND OBJECTIVES: The B cell-depleting anti-CD20 antibody ocrelizumab (OCR) effectively reduces MS disease activity and slows disability progression. Given the role of B cells as antigen-presenting cells, the primary goal of this study was to evaluate the effect of OCR on the T-cell receptor repertoire diversity. METHODS: To examine whether OCR substantially alters the molecular diversity of the T-cell receptor repertoire, deep immune repertoire sequencing (RepSeq) of CD4+ and CD8+ T-cell receptor ß-chain variable regions was performed on longitudinal blood samples. The IgM and IgG heavy chain variable region repertoire was also analyzed to characterize the residual B-cell repertoire under OCR treatment. RESULTS: Peripheral blood samples for RepSeq were obtained from 8 patients with relapsing MS enrolled in the OPERA I trial over a period of up to 39 months. Four patients each were treated with OCR or interferon ß1-a during the double-blind period of OPERA I. All patients received OCR during the open-label extension. The diversity of the CD4+/CD8+ T-cell repertoires remained unaffected in OCR-treated patients. The expected OCR-associated B-cell depletion was mirrored by reduced B-cell receptor diversity in peripheral blood and a shift in immunoglobulin gene usage. Despite deep B-cell depletion, longitudinal persistence of clonally related B-cells was observed. DISCUSSION: Our data illustrate that the diversity of CD4+/CD8+ T-cell receptor repertoires remained unaltered in OCR-treated patients with relapsing MS. Persistence of a highly diverse T-cell repertoire suggests that aspects of adaptive immunity remain intact despite extended anti-CD20 therapy. TRIAL REGISTRATION INFORMATION: This is a substudy (BE29353) of the OPERA I (WA21092; NCT01247324) trial. Date of registration, November 23, 2010; first patient enrollment, August 31, 2011.

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Exit strategies such as de-escalations have not been evaluated for rituximab in patients with neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that they are associated with disease reactivations and aimed to estimate this risk. METHODS: We describe a case series of real-world de-escalations from the French NMOSD registry (NOMADMUS). All patients met the 2015 International Panel for NMO Diagnosis (IPND) diagnostic criteria for NMOSD. A computerized screening of the registry extracted patients with rituximab de-escalations and at least 12 months of subsequent follow-up. We searched for 7 de-escalation regimens: scheduled discontinuations or switches to an oral treatment after single infusion cycles, scheduled discontinuations or switches to an oral treatment after periodic infusions, de-escalations before pregnancies, de-escalations after tolerance issues, and increased infusion intervals. Rituximab discontinuations motivated by inefficacy or for unknown purposes were excluded. The primary outcome was the absolute risk of NMOSD reactivation (one or more relapses) at 12 months. AQP4+ and AQP4- serotypes were analyzed separately. RESULTS: We identified 137 rituximab de-escalations between 2006 and 2019 that corresponded to a predefined group: 13 discontinuations after a single infusion cycle, 6 switches to an oral treatment after a single infusion cycle, 9 discontinuations after periodic infusions, 5 switches to an oral treatment after periodic infusions, 4 de-escalations before pregnancies, 9 de-escalations after tolerance issues, and 91 increased infusion intervals. No group remained relapse-free over the whole de-escalation follow-up (mean: 3.2 years; range: 0.79-9.5), except pregnancies in AQP+ patients. In all groups combined and within 12 months, reactivations occurred after 11/119 de-escalations in patients with AQP4+ NMOSD (9.2%, 95% CI [4.7-15.9]), from 0.69 to 10.0 months, and in 5/18 de-escalations in patients with AQP4- NMOSD (27.8%, 95% CI [9.7-53.5]), from 1.1 to 9.9 months. DISCUSSION: There is a risk of NMOSD reactivation whatever the rituximab de-escalation regimen. TRIAL REGISTRATION INFORMATION: Registered on ClinicalTrials.gov: NCT02850705. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that de-escalation of rituximab increases the probability of disease reactivation.

A rise in cases of nitrous oxide abuse: neurological complications and biological findings.

BACKGROUND: The recent lockdown due to the COVID-19 pandemic has been linked to a higher incidence of psychiatric manifestations and substance abuse. The recreative use of nitrous oxide is more and more widespread and neurological complications are frequent. METHODS: We report clinical characteristics and biological findings of five consecutive patients presenting to our tertiary care center between April 2020 and February 2021 with various neurological symptoms occurring after recent nitrous oxide abuse. RESULTS: Our patients presented with subacute combined degeneration of the spinal cord (4/5 patients) or with acute inflammatory demyelinating polyneuropathy (1/5 patients). No patient had reduced vitamin B-12 titer, but all had elevated blood levels of homocysteine and methylmalonic acid. This reflects the functional deficit in vitamin B-12 that can be linked to nitrous oxide consumption. After vitamin B-12 supplementation, clinical signs regressed at least partially in all 5 patients. CONCLUSION: We report an elevated incidence of neurological complications of nitrous oxide abuse occurring during the recent COVID-19 lockdown. Nitrous oxide abuse should be tracked down in patients presenting with compatible neurological symptoms and elevated homocysteinemia. Vitamin B-12 should be supplemented as soon as the diagnosis is made.

Rheumatic presentations of Guillain-Barré syndrome as a diagnostic challenge: A case series.

BACKGROUND: Guillain-Barré syndrome (GBS) is an immune-mediated acute polyradiculoneuritis often in post-infectious context. It is a therapeutic emergency as early treatment may prevent disabilities. Pain in GBS has been described extensively, may precede neurological symptoms and bring the patient to rheumatology departments in the first place. OBJECTIVE: To describe the clinical presentations and diagnosis of GBS cases referred to rheumatology departments. METHOD: For this retrospective case-series, we screened patients of the rheumatology department (university hospitals of Strasbourg), whose hospitalization records were associated with the ICD-10 Code G61.0 (GBS) from 1993 to 2020. We included patients fulfilling the 1990 NINDS criteria and level one of the Brighton collaboration criteria. We measured the time from symptoms onset to admission and from admission to lumbar puncture as a marker of outpatient and inpatient diagnosis delay, respectively. RESULTS: We describe 8 GBS cases. Six had nociceptive-like prodromal pain: back pain (n=3), peripheral arthralgia (n=1) or diffuse myalgia (n=3). The median time from symptoms onset to admission was 7days [range: 3-60] and the median time from admission to lumbar puncture was 2days [range: 0-8]. Two patients became severely tetraparetic, one requiring intubation. At last follow-up (median: 5.5years; range: 0.5-23years), 4 patients had recovered completely and 4 kept disabilities. CONCLUSIONS: Rheumatic presentations of GBS are rare and diverse. Rheumatologists should be aware of this presentation because early diagnosis and treatment may prevent rapid motor worsening. Rapidly progressive symmetric weakness and areflexia appear as the best clinical diagnosis markers.

Ischemic stroke risk factors not included in the CHADS-VASC score in patients with non-valvular atrial fibrillation / Fatores de risco de AVC isquêmico não incluídos no escore CHADS-VASC em pacientes com fibrilação atrial não valvar

Abstract Background In patients with atrial fibrillation, the CHA2DS2-VASC score guides stroke prevention using anticoagulants, but it is an imperfect score. Other potential risk factors such as renal failure, the type of atrial fibrillation, active smoking, cancer, sleep apnea or systemic inflammation have less well been investigated. Objective To assess the impact of these factors on ischemic stroke risk in patients with non-valvular atrial fibrillation. Methods On a population of 248 patients (124 patients with acute ischemic stroke and 124 controls), we performed a logistic regression to assess the impact of multiple non-classic risk factors for the prediction of acute ischemic stroke. Their impact on mortality was assessed by performing a survival analysis. Results A high CHA2DS2-VASc score (OR 1.75; 95% CI 1.13-2.70; p = 0.032), treatment with anticoagulants (OR 0.19; 95% CI 0.07-0.51; p < 0.001) and permanent atrial fibrillation (OR 6.31; 95% CI 2.46-16.19; p < 0.001) were independently associated with acute ischemic stroke. Renal failure and chronic obstructive pulmonary disease predicted a higher mortality. After adjusting for age, sex, the CHA2DS2-VASc score and the use of anticoagulants, the only risk factor predictive for acute ischemic stroke was the permanent type of AF (OR: 8.0 [95% CI 2.5-25.5], p < 0.001). Conclusions The CHA2DS2-VASc score, the absence of anticoagulants and the permanent type of atrial fibrillation were the main predictive factors for the occurrence of acute ischemic stroke. Larger studies are necessary for conclusive results about other factors.

Resumo Antecedentes Em pacientes com fibrilação atrial, o escore CHA2DS2-VASC orienta a prevenção de AVC com anticoagulantes, mas é um escore imperfeito. Outros fatores de risco potenciais, como insuficiência renal, o tipo de fibrilação atrial, tabagismo ativo, câncer, apnéia do sono ou inflamação sistêmica foram menos bem investigados. Objetivo Avaliar o impacto desses fatores no risco de AVC isquêmico em pacientes com fibrilação atrial não valvular. Métodos Em uma população de 248 pacientes (124 pacientes com AVC isquêmico agudo e 124 controles), realizamos uma regressão logística para avaliar o impacto de múltiplos fatores de risco não clássicos na predição de AVC isquêmico agudo. O seu impacto na mortalidade foi avaliado através da realização de uma análise de sobrevivência. Resultados Escore CHA2DS2-VASc alto (OR 1,75; IC 95% 1,13-2,70; p = 0,032), tratamento com anticoagulantes (OR 0,19; IC 95% 0,07-0,51; p < 0,001) e fibrilação atrial permanente (OR 6,31; 95% CI 2,46-16,19; p < 0,001) foram independentemente associados ao AVC isquêmico agudo. Insuficiência renal e doença pulmonar obstrutiva crônica previram maior mortalidade. Após ajuste para idade, sexo, pontuação CHA2DS2-VASc e uso de anticoagulantes, o único fator de risco preditivo para AVC isquêmico agudo foi o tipo permanente de FA (OR: 8,0 [IC 95% 2,5-25,5], p < 0,001). Conclusões O escore CHA2DS2-VASc, a ausência de anticoagulantes e o tipo permanente de fibrilação atrial foram os principais fatores preditivos para a ocorrência de AVC isquêmico agudo. Estudos maiores são necessários para resultados conclusivos sobre outros fatores.

Cerebellar compartmentation of prion pathogenesis.

In prion diseases, the brain lesion profile is influenced by the prion "strain" properties, the invasion route to the brain, and still unknown host cell-specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP22L , PrPME7 ), but not bovine spongiform encephalopathy PrP6PB1 , accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice. Such banding pattern of PrP22L aggregation did not depend on the neuroinvasion route, but coincided with the parasagittal compartmentation of the cerebellum mostly defined by the expression of zebrins, such as aldolase C and the excitatory amino acid transporter 4, in Purkinje cells. We provide evidence that Purkinje cells display a differential, subtype-specific vulnerability to 22L prions with zebrin-expressing Purkinje cells being more resistant to prion toxicity, while in stripes where PrP22L accumulated most zebrin-deficient Purkinje cells are lost and spongiosis accentuated. In addition, in PrP22L stripes, enhanced reactive astrocyte processes associated with microglia activation support interdependent events between the topographic pattern of Purkinje cell death, reactive gliosis and PrP22L accumulation. Finally, we find that in preclinically-ill mice prion infection promotes at the membrane of astrocytes enveloping Purkinje cell excitatory synapses, upregulation of tumor necrosis factor-α receptor type 1 (TNFR1), a key mediator of the neuroinflammation process. These overall data show that Purkinje cell sensitivity to prion insult is locally restricted by the parasagittal compartmentation of the cerebellum, and that perisynaptic astrocytes may contribute to prion pathogenesis through prion-induced TNFR1 upregulation.

Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients.

A role of B cells in multiple sclerosis (MS) is well established, but there is limited understanding of their involvement during active disease. Here, we examined cerebrospinal fluid (CSF) and peripheral blood (PB) B cells in treatment-naive patients with MS or high-risk clinically isolated syndrome. Using flow cytometry, we found increased CSF lymphocytes with a disproportionate increase of B cells compared with T cells in patients with gadolinium-enhancing (Gd+) lesions on brain MRI. Ig gene heavy chain variable region (Ig-VH) repertoire sequencing of CSF and PB B cells revealed clonal relationships between intrathecal and peripheral B cell populations, which could be consistent with migration of B cells to and activation in the CNS in active MS. In addition, we found evidence for bystander immigration of B cells from the periphery, which could be supported by a CXCL13 gradient between CSF and blood. Understanding what triggers B cells to migrate and home to the CNS may ultimately aid in the rational selection of therapeutic strategies to limit progression in MS.