Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions for the Diagnostic and Prognostic Workup of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes. METHODS: In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes. RESULTS: The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL. DISCUSSION: The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.

A Comparison Study of Lymph Node Tuberculosis and Sarcoidosis Involvement to Facilitate Differential Diagnosis and to Establish a Predictive Score for Tuberculosis.

Background: Tuberculosis (TB) and sarcoidosis are two common granulomatous diseases involving lymph nodes. Differential diagnosis is not always easy because pathogen demonstration in tuberculosis is not always possible and both diseases share clinical, radiological and histological patterns. The aim of our study was to identify factors associated with each diagnosis and set up a predictive score for TB. Methods: All cases of lymph node tuberculosis and sarcoidosis were retrospectively reviewed. Demographics, clinical characteristics, laboratory and imaging data, and microbiological and histological results were collected and compared. Results: Among 441 patients screened, 192 patients were included in the final analysis. The multivariate analysis showed that weight loss, necrotic granuloma, normal serum lysozyme level and hypergammaglobulinemia were significantly associated with TB. A risk score of TB was built based on these variables and was able to discriminate TB versus sarcoidosis with an AUC of 0.85 (95% CI: 0.79-0.91). Using the Youden's J statistic, its most discriminant value (-0.36) was associated with a sensitivity of 80% and a specificity of 75%. Conclusions: We developed a score based on weight loss, necrotic granuloma, normal serum lysozyme level and hypergammaglobulinemia with an excellent capacity to discriminate TB versus sarcoidosis. This score needs still to be validated in a multicentric prospective study.

Intravascular large cell B lymphoma presenting as central nervous system pseudo-vasculitis: A rare diagnostic challenge.

Intravascular large B cell lymphoma (IVLBCL) is a very rare subtype of aggressive non-Hodgkin B cell lymphoma characterized by intravascular proliferation of clonal B lymphocytes, classically associated with pulmonary and cutaneous disease and, less frequently, with central nervous system (CNS) involvement. Brain imaging findings are usually non-specific, with evidence of multiple vascular occlusions and stroke as non-specific multifocal abnormalities. We present an exceptionally rare case of IVLBCL in a patient with unexplained inflammatory syndrome with B symptoms and rapidly progressive neurological impairment, with multifocal hemorrhagic and tumefactive brain lesions seen on MRI. We suggest that in this clinical setting, the presence of tumefactive and hemorrhagic lesions should raise suspicion for IVLBCL and lead to the decision to perform a biopsy, which, nonetheless, remains the diagnostic gold standard.

[18F]FDG-PET/CT in Idiopathic Inflammatory Myopathies: Retrospective Data from a Belgian Cohort.

[18F]FDG-PET/CT is a useful tool for diagnosis and cancer detection in idiopathic inflammatory myopathies (IIMs), especially polymyositis (PM) and dermatomyositis (DM). Data deriving from Europe are lacking. We describe [18F]FDG-PET/CT results in a Belgian cohort with IIMs, focusing on patients with PM and DM. All of the cases of IIMs admitted between December 2010 and January 2023 to the Cliniques Universitaires Saint-Luc (Belgium) were retrospectively reviewed. In total, 44 patients were identified with suspected IIMs; among them, 29 were retained for final analysis. The mean age of the retained patients was 48.7 years; 19 patients were female (65.5%). Twenty-two patients had DM and seven had PM. The mean serum creatinine kinase (CK) and the mean CRP levels were 3125 UI/L and 30.3 mg/L, respectively. [18F]FDG-PET/CT imaging was performed for 27 patients, detecting interstitial lung diseases (ILDs) in 7 patients (25.9%), cancer in 3 patients (11.1%), and abnormal muscle FDG uptake compatible with myositis in 13 patients (48.1%). All of the patients who were detected to have ILDs via PET/CT imaging were confirmed using a low-dose lung CT scan. Among the patients who were detected to have abnormal muscle FDG uptake via PET/CT scans (13/28), the EMG was positive in 12 patients (p = 0.004), while the MRI was positive in 8 patients (p = 0.02). We further observed that there was a significantly higher level of CK in the group with abnormal muscle FDG uptake (p = 0.008). Our study showed that PET/CT is useful for detecting cancer and ILDs. We showed that the detection of abnormal muscle uptake via PET/CT was in accordance with EMG and MRI results, as well as with the mean CK value, and that the presence of dyspnea was significantly associated with the presence of ILDs detected via PET/CT imaging (p = 0.002).

Epidemiology, clinical presentation, treatment, and outcome of neurosarcoidosis: A mono-centric retrospective study and literature review.

Introduction: Neurosarcoidosis is a rare granulomatous disorder, and treatment guidelines are mainly based on retrospective studies. Materials and methods: This retrospective study was performed to provide a detailed description of the clinical characteristics and treatment outcomes of patients with neurosarcoidosis followed at Cliniques Universitaires Saint Luc in Belgium. The second objective of our study was to perform a comparative literature review of neurosarcoidosis, with a focus on treatment outcomes with the use of TNF-α antagonist. Results: Among 180 patients with sarcoidosis followed in our hospital, 22 patients with neurosarcoidosis were included in the final analysis. Our literature research identified 776 articles of which 35 articles met our inclusion criteria, including 1,793 patients diagnosed with neurosarcoidosis. In our cohort, the majority of patients (86%) were diagnosed with systemic sarcoidosis which was similar to that reported in the literature (83%). Serum CRP and calcemia were elevated only in 33 and 18% of patients, respectively. Serum lysozyme and angiotensin-converting enzyme were elevated in 79 and 16% of patients, respectively. Lumbar puncture and CSF fluid analysis were performed in 15/22 patients and were abnormal in all patients. Brain MRI was performed in 21/22 patients and showed abnormalities in 16 patients consisting of parenchymal lesions in 63%, hypothalamic-pituitary axis lesions in 38%, and meningeal enhancement in 31%. In both cohort patients, methotrexate was the most frequently used treatment (>45% of cases) with a favorable outcome in an average of 50% of patients. A TNF-α antagonist was administered in 9% of patients in our cohort and in 27% of patients in the literature review. The proportion of favorable outcomes in literature research was significantly higher in patients treated with TNF-α antagonists compared to methotrexate (p < 0.0001), mycophenolate mofetil (p < 0.0001), or azathioprine (p < 0.0001). Conclusion: The results of our cohort and literature review confirm that neurosarcoidosis occurred most frequently in the context of systemic sarcoidosis. Methotrexate is the most frequent second-line therapy. The effectiveness of therapy with TNF-α antagonists is well-demonstrated and associated with a better outcome. Their earlier use during the disease course among aggressive and/or refractory neurosarcoidosis should be considered.

Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of "Vascular Memory".

Background: Activation of the renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of hypertension. Published evidence on a putative "memory effect" of AngII on the vascular components is however scarce. Aim: To evaluate the long-term effects of transient exposure to AngII on the mouse heart and the arterial tissue. Methods: Blood pressure, cardiovascular tissue damage and remodeling, and systemic oxidative stress were evaluated in C57/B6/J mice at the end of a 2-week AngII infusion (AngII); 2 and 3 weeks after the interruption of a 2-week AngII treatment (AngII+2W and AngII +3W; so-called "memory" conditions) and control littermate (CTRL). RNAseq profiling of aortic tissues was used to identify potential key regulated genes accounting for legacy effects on the vascular phenotype. RNAseq results were validated by RT-qPCR and immunohistochemistry in a reproduction cohort of mice. Key findings were reproduced in a homotypic cell culture model. Results: The 2 weeks AngII infusion induced cardiac hypertrophy and aortic damage that persisted beyond AngII interruption and despite blood pressure normalization, with a sustained vascular expression of ICAM1, infiltration by CD45+ cells, and cell proliferation associated with systemic oxidative stress. RNAseq profiling in aortic tissue identified robust Acta2 downregulation at transcript and protein levels (α-smooth muscle actin) that was maintained beyond interruption of AngII treatment. Among regulators of Acta2 expression, the transcription factor Myocardin (Myocd), exhibited a similar expression pattern. The sustained downregulation of Acta2 and Myocd was associated with an increase in H3K27me3 in nuclei of aortic sections from mice in the "memory" conditions. A sustained downregulation of ACTA2 and MYOCD was reproduced in the cultured human aortic vascular smooth muscle cells upon transient exposure to Ang II. Conclusion: A transient exposure to Ang II produces prolonged vascular remodeling with robust ACTA2 downregulation, associated with epigenetic imprinting supporting a "memory" effect despite stimulus withdrawal.

Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?

In medicine, a legacy effect is defined as the sustained beneficial effect of a given treatment on disease outcomes, even after cessation of the intervention. Initially described in optimized control of diabetes, it was also observed in clinical trials exploring intensification strategies for other cardiovascular risk factors, such as hypertension or hypercholesterolemia. Mechanisms of legacy were particularly deciphered in diabetes, leading to the concept of metabolic memory. In a more discreet manner, other memory phenomena were also described in preclinical studies that demonstrated long-lasting deleterious effects of lipids or angiotensin II on vascular wall components. Interestingly, epigenetic changes and reactive oxygen species (ROS) appear to be common features of "memory" of the vascular wall.

Validation of Neutrophil-to-Lymphocyte Ratio Cut-off Value Associated with High In-Hospital Mortality in COVID-19 Patients.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) could be a predictive factor of severe COVID-19. However, most relevant studies are retrospective, and the optimal NLR cut-off point has not been determined. The objective of our research was identification and validation of the best NLR cut-off value on admission that could predict high in-hospital mortality in COVID-19 patients. METHODS: Medical files of all patients admitted for COVID-19 pneumonia in our dedicated COVID-units between March and April 2020 (derivation cohort) and between October and December 2020 (validation cohort) were reviewed. RESULTS: Two hundred ninety-nine patients were included in the study (198 in the derivation and 101 in the validation cohort, respectively). Youden's J statistic in the derivation cohort determined the optimal cut-off value for the performance of NLR at admission to predict mortality in hospitalized patients with COVID-19. The NLR cut-off value of 5.94 had a sensitivity of 62% and specificity of 64%. In ROC curve analysis, the AUC was 0.665 [95% CI 0.530-0.801, p= 0.025]. In the validation cohort, the best predictive cut-off value of NLR was 6.4, which corresponded to a sensitivity of 63% and a specificity of 64% with AUC 0.766 [95% CI 0.651-0.881, p <0.001]. When the NLR cut-off value of 5.94 was applied in the validation cohort, there was no significant difference in death and survival in comparison with the derivation NLR cut-off. Net reclassification improvement (NRI) analysis showed no significant classification change in outcome between both NLR cut-off values (NRI:0.012, p=0.31). CONCLUSION: In prospective analysis, an NLR value of 5.94 predicted high in-hospital mortality upon admission in patients hospitalized for COVID-19 pneumonia.

Determinants of IgG antibodies kinetics after severe and critical COVID-19.

The kinetics of IgG antibodies after coronavirus disease 2019 (COVID-19) remain poorly understood. We investigated factors influencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibody levels and time to seronegativation during the follow-up of severe and critically ill patients. We retrospectively reviewed serological evaluations drawn during the follow-up of severe or critical laboratory-proven COVID-19 patients hospitalized at a large academic hospital. Specific IgG titers were measured using a chemiluminescent assay targeting anti-spike and anti-nucleocapsid protein IgG. The influence of time, demographic factors, clinical and paraclinical characteristics, and COVID-19 therapeutics on IgG levels were assessed through linear regression using a mixed-effect model, and delay until IgG negativation through a Weibull regression model. The cohort included 116 patients with a total of 154 IgG measurements drawn at a median of 79 days after diagnosis. IgG antibodies were increased with age (p = 0.005) and decreased significantly over time (p = 0.0002). Using elapsed time and age as covariates, we demonstrated higher IgG levels in patients with a higher body mass index (BMI) (p = 0.0026) and lower IgG levels in immunocompromised patients (p = 0.032). A high BMI was further found to delay and immunodeficiency to hasten significantly seronegativation, whereas no significant effect was observed with corticosteroids. These data highlight the waning over time of IgG antibodies after severe or critical COVID-19. Age, BMI, and immunosuppression also appear to influence the IgG kinetics, while short-term corticotherapy does not. Those data improve the understanding of SARS-CoV-2 serology while further research should determine the determinants of long-term seroprotection.

Follow-up of functional exercise capacity in patients with COVID-19: It is improved by telerehabilitation.

BACKGROUND: The impact of the COVID-19 pandemic on functional exercise capacity seemed quickly clinically evident. The objective of this study was to assess the functional exercise capacity of patients with severe COVID-19 and to evaluate the effect of a telerehabilitation program in the specific context of the COVID-19 pandemic. METHOD: Patients hospitalized for severe or critical COVID-19 were recruited. The functional exercise capacity (1-min sit-to-stand test (STST)) was prospectively quantified at discharge. A telerehabilitation program was then proposed. A control group was composed with the patients refusing the program. RESULTS: At discharge, none of the 48 recruited patients had a STST higher than the 50th percentile and 77% of them were below the 2.5th percentile. SpO2 was 92.6 ± 3.0% after STST and 15 patients had oxygen desaturation. After 3-months of follow-up, the number of repetitions during STST significantly increased either in telerehabilitation (n = 14) (p < 0.001) or in control groups (n = 13) (p = 0.002) but only one patient had a result higher than the 50th percentile (in Telerehabilitation group) and 37% of them were still under the 2.5th percentile for this result. The improvement was significantly and clinically greater after the telerehabilitation program (p = 0.005). No adverse events were reported by the patients during the program. CONCLUSIONS: Patients hospitalized for COVID-19 have a low functional exercise capacity at discharge and the recovery after three months is poor. The feasibility and the effect of a simple telerehabilitation program were verified, this program being able to substantially improve the functional recovery after three months.

Integrative respiratory follow-up of severe COVID-19 reveals common functional and lung imaging sequelae.

BACKGROUND: COVID-19 pandemic resulted in an unprecedented number of hospitalizations in general wards and intensive care units (ICU). Severe and critical COVID-19 patients suffer from extensive pneumonia; therefore, long-term respiratory sequelae may be expected. RESEARCH QUESTION: We conducted a cohort study to determine respiratory sequelae in patients with severe and critical COVID-19. We aimed at evaluating the proportion of patients with persisting respiratory symptoms and/or abnormalities in pulmonary function tests (PFT) or in lung imaging. STUDY DESIGN: and methods: This is a single center cohort study including COVID-19 survivors who underwent a three-month follow-up with clinical evaluation, PFT and lung high-resolution computed tomography (HRCT). All clinical, functional, and radiological data were centrally reviewed. Multiple linear regression analysis was performed to identify factors associated with residual lesions on HRCT. RESULTS: Full clinical evaluation, PFT and lung HRCT were available for central review in 126, 122 and 107 patients, respectively. At follow-up, 25% of patients complained from dyspnea and 35% from fatigue, lung diffusion capacity (DLCO) was decreased in 45%, 17% had HRCT abnormalities affecting more than 5% of their lung parenchyma while signs of fibrosis were found in 21%. In multiple linear regression model, number of days in ICU were related to the extent of persisting lesions on HRCT, while intubation was associated with signs of fibrosis at follow-up (P = 0.0005, Fisher's exact test). In contrast, the severity of lung imaging or PFT changes were not predictive of fatigue and dyspnea. INTERPRETATION: Although most hospitalized COVID-19 patients recover, a substantial proportion complains from persisting dyspnea and fatigue. Impairment of DLCO and signs suggestive of fibrosis are common but are not strictly related to long-lasting symptoms.

Hydroxychloroquine in the post-COVID-19 era: will this pandemic upset decades of clinical practice?

In the early stage of the COVID-19 pandemic, Belgian health authorities endorsed the interim guidelines for the treatment of COVID-19 pneumonia: hydroxychloroquine (HCQ) recommended for treatment of hospitalized patients with moderate to severe disease. As a growing number of patients were admitted, inevitably, our internal medicine team questioned the efficacy and safety of HCQ, especially with regard to cardiac side effects. In parallel with our concerns, data regarding the safety and efficacy of HCQ were published, with discordant results and debate in the medical community. Media coverage of the possible risks and benefits of HCQ use in COVID-19 also caused confusion amongst the public. In this Perspectives in Rheumatology article, we review the use and safety of HCQ in autoimmune disease and its putative efficacy and toxicity in COVID-19. Finally, we share our concern about the future of this widely used and inexpensive drug after the COVID-19 pandemic has passed.

Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.

BACKGROUND: Evidence of immune-mediated neurological syndromes associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is limited. We therefore investigated clinical, serological and CSF features of coronavirus disease 2019 (COVID-19) patients with neurological manifestations. METHODS: Consecutive COVID-19 patients with neurological manifestations other than isolated anosmia and/or non-severe headache, and with no previous neurological or psychiatric disorders were prospectively included. Neurological examination was performed in all patients and lumbar puncture with CSF examination was performed when not contraindicated. Serum anti-gangliosides antibodies were tested when clinically indicated. RESULTS: Of the 349 COVID-19 admitted to our center between March 23rd and April 24th 2020, 15 patients (4.3%) had neurological manifestations and fulfilled the study inclusion/exclusion criteria. CSF examination was available in 13 patients and showed lymphocytic pleocytosis in 2 patients: 1 with anti-contactin-associated protein 2 (anti-Caspr2) antibody encephalitis and 1 with meningo-polyradiculitis. Increased serum titer of anti-GD1b antibodies was found in three patients and was associated with variable clinical presentations, including cranial neuropathy with meningo-polyradiculitis, brainstem encephalitis and delirium. CSF PCR for SARS-CoV-2 was negative in all patients. CONCLUSIONS: In SARS-Cov-2 infected patients with neurological manifestations, CSF pleocytosis is associated with para- or post-infectious encephalitis and polyradiculitis. Anti-GD1b and anti-Caspr2 autoantibodies can be identified in certain cases, raising the question of SARS-CoV-2-induced secondary autoimmunity.

SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome.

Nephrotic syndrome without kidney injury revealing intravascular large B cell lymphoma.

We describe the case of a 64-year-old woman admitted for fever of unknown origin, who developed nephrotic syndrome during hospitalisation and pulmonary infiltrates. Renal biopsy disclosed intracapillary glomerular invasion by intravascular large B cell lymphoma. Clinical and biological evolution was favourable after rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone (R-CHOP) treatment and autologous stem cell transplant. Two years after diagnosis the patient was considered in remission.