Emerging imaging markers in radiologically isolated syndrome: implications for earlier treatment initiation.

The presence of central nervous system lesions fulfilling the criteria of dissemination in space and time on MRI leads to the diagnosis of a radiologically isolated syndrome (RIS), which may be an early sign of multiple sclerosis (MS). However, some patients who do not fulfill the necessary criteria for RIS still evolve to MS, and some T2 hyperintensities that resemble demyelinating lesions may originate from mimics. In light of the recent recognition of the efficacy of disease-modifying therapy (DMT) in RIS, it is relevant to consider additional imaging features that are more specific of MS. We performed a narrative review on cortical lesions (CL), the central vein sign (CVS), and paramagnetic rim lesions (PRL) in patients with RIS. In previous RIS studies, the reported prevalence of CLs ranges between 20.0 and 40.0%, CVS + white matter lesions (WMLs) between 87.0 and 93.0% and PRLs between 26.7 and 63.0%. Overall, these imaging findings appear to be frequent in RIS cohorts, although not consistently taken into account in previous studies. The search for CLs, CVS + WML and PRLs in RIS patients could lead to earlier identification of patients who will evolve to MS and benefit from DMTs.

Neuropsychological functioning and its correlates at 1 year follow-up of severe COVID-19.

BACKGROUND: Short-term cognitive impairment is associated with SARS-CoV-2 infection but the long-term impact is yet to be examined in detail. We aim to study the evolution of these symptoms in severe COVID-19 patients admitted to the intensive care unit (ICU) between April and December 2020 1 year after hospital discharge and to analyze its clinical correlates. METHOD: A total of 58 patients agreed to participate in the 6 months follow-up and 30 at 1 year after hospital discharge. Demographic, clinical and laboratory data were collected and a comprehensive neuropsychological battery including validated tests for the main cognitive domains was administered. To test the magnitude of neurocognitive sequelae, two standard deviations below normative group were considered. To compare the neuropsychological performance at 6 and 12 months follow-up we used repeated measures tests. Finally, regression analyses were performed to test the main effects of medical and psychological factors on multiple cognition. RESULTS: Almost half of the sample continued to have impaired performance on neuropsychological tests at 12 months follow-up. In comparison with the results obtained at 6 months, significant improvements were found in immediate recall (d = 0.49), delayed recall (d = 0.45), and inhibitory control (d = 0.53). Medical variables predicted cognitive performance at 6 months but not at 12 months follow-up, while anxiety and depression predicted cognitive deficits in the long-term. CONCLUSIONS: A generalised improvement was observed in severe COVID-19 patients at follow-up. This improvement was particularly notable in verbal memory and executive functioning. However, a considerable proportion of the sample continued to present deficits at 1 year follow-up.

Relapse of neurosymptomatic cerebrospinal fluid HIV RNA escape.

OBJECTIVES: Our objectives were to investigate the characteristics of people living with HIV who presented with new or recurrent symptoms in the context of re-emergence of cerebrospinal fluid HIV RNA escape after antiretroviral therapy (ART) modification (termed relapse of CSF HIV RNA escape). METHODS: People living with HIV-1 with known CSF HIV RNA escape were identified, with clinical and laboratory data obtained from records in a tertiary centre. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in the presence of unquantifiable plasma HIV-RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV-RNA was quantifiable. Relapse was defined as a re-emergence of CSF HIV RNA escape with new symptoms after ART therapy intensification post-initial CSF HIV RNA escape. RESULTS: Among 40 people living with HIV who presented with neurosymptomatic CSF HIV RNA, eight (20%) presented with a relapse of CSF HIV RNA escape. Symptoms on relapse included confusion (n = 2), cognitive decline (n = 2), cerebellar dysfunction (n = 2) and worsening of pre-existing seizures (n = 1). Prior to their relapse, three people underwent drug therapy modification, with two people stopping raltegravir intensification, and one person switched from tenofovir alafenamide, emtricitabine and raltegravir for a new regimen. CONCLUSIONS: People with a relapse of CSF HIV RNA escape within this cohort presented with varied symptoms similar to their initial CSF HIV RNA escape. Clinicians should be vigilant of relapse of symptoms, particularly when simplifying ART regimens in people with CSF HIV RNA escape.

The impact of smoking cessation on multiple sclerosis disease progression.

The negative impact of smoking in multiple sclerosis is well established; however, there is much less evidence as to whether smoking cessation is beneficial to progression in multiple sclerosis. Adults with multiple sclerosis registered on the United Kingdom Multiple Sclerosis Register (2011-20) formed this retrospective and prospective cohort study. Primary outcomes were changes in three patient-reported outcomes: normalized Multiple Sclerosis Physical Impact Scale (MSIS-29-Phys), normalized Multiple Sclerosis Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS). Time to event outcomes were clinically significant increases in the patient-reported outcomes. The study included 7983 participants; 4130 (51.7%) of these had ever smoked, of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all patient-reported outcomes, current smokers at the time of completing their first questionnaire had higher patient-reported outcomes scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 points for HADS-Anxiety and HADS-Depression). There was no improvement in patient-reported outcomes scores with increasing time since quitting in former smokers. Nine hundred and twenty-three participants formed the prospective parallel group, which demonstrated that MSIS-29-Phys [median (IQR) 5.03 (3.71, 6.34)], MSWS-12 [median (IQR) 5.28 (3.62, 6.94)] and HADS-Depression [median (IQR) 0.71 (0.47, 0.96)] scores worsened over a period of 4 years, whereas HADS-Anxiety remained stable. Smoking status was significant at Year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores [median (IQR) 3.05 (0.22, 5.88) and 1.14 (0.52, 1.76), respectively] while former smokers had a lower MSIS-29-Phys score of -2.91 (-5.03, -0.79). A total of 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all patient-reported outcomes (MSIS-29-Phys: n = 4436, P = 0.0013; MSWS-12: n = 3902, P = 0.0061; HADS-Anxiety: n = 4511, P = 0.0017; HADS-Depression: n = 4511, P < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-Anxiety and HADS-Depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with multiple sclerosis.

Association between Human Leukocyte Antigen and End-Stage Renal Disease in Patients from Transylvania, Romania.

End-stage renal disease (ESRD) is the final stage of chronic kidney disease. This study explored the association between human leukocyte antigen (HLA) and ESRD. The interaction between genetic and environmental factors may also play a role in the development of ESRD. The study included 2392 ESRD patients who were awaiting renal transplantation. Blood samples were genotyped by SSOP and SSP-PCR methods. Multivariate logistic regression analysis showed that HLA-A*11 (p = 0.027), HLA-A*34 (p = 0.017), HLA-A*69 (p = 0.012), HLA-B*41 (p < 0.001), HLA-B*50 (p = 0.004), HLA-DRB1*10 (p = 0.027), and HLA-DRB1*14 (p = 0.004) were positively associated with ESRD (OR > 1); HLA-DRB1*07 (p < 0.001), HLA-DRB1*08 (p = 0.005), and HLA-DRB1*13 (p < 0.001) were protective against ESRD (OR < 1); and the three-locus haplotype HLA-A*02-B*41-DRB1*03, containing one susceptible allele, was strongly associated with ESRD (p < 0.001, OR = 3.15). In conclusion, this retrospective analysis of HLA typing in patients with ESRD of various etiologies suggests that molecular data on the HLA polymorphism should be collected in order to identify high-risk ESRD patients and to improve graft survival after kidney transplantation.

Non-Coding RNAs: Prevention, Diagnosis, and Treatment in Myocardial Ischemia-Reperfusion Injury.

Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia-reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.

Cognitive and Neurologic Rehabilitation Strategies for Central Nervous System HIV Infection.

PURPOSE OF REVIEW: Cognitive impairment leading to disability is increasingly seen in people living with human immunodeficiency virus (PLWH). Rehabilitation can alleviate the effects of cognitive impairment upon function. The aim of this paper is to discuss the strategies that have been used in cognitive and neurologic rehabilitation in PLWH. RECENT FINDINGS: Studies examining pharmacological and non-pharmacological strategies were analysed. Medical management of HIV and co-morbidities should be optimised. Non-pharmacological strategies, including nerve stimulation techniques, exercise-based interventions, and paper and computer-based cognitive rehabilitation, have some evidence supporting their use in PLWH either as stand-alone interventions or as part of a multidisciplinary approach. Both pharmacological and non-pharmacological rehabilitation strategies have been used with PLWH. More intervention trials are needed to assess cognitive and neurological rehabilitation strategies and further evaluate their potential benefit in PLWH.

Weedy ferns (Polypodiopsida) in Argentina: diversity, distribution and impact on human activities and ecosystems.

Currently, in Argentina 368 species of true ferns (i.e. Polypodiopsida class) are distributed throughout the country, however, only four of them have been mentioned until now as weeds and ruderal species. The goal of this work was to generate an update of weedy ferns from Argentina, including morphology, distribution, and type of weed according to their impact on natural habitats and/or human activities. All Argentinian fern species were analyzed based on references, herbarium specimens, and field trips. As a result of our study 25 species were recorded from Argentina and classified as segetal, ecological, or aquatic weeds, and ruderal and/or toxic species. Current taxonomic identity, diagnostic characters, origins, habitats, geographical distribution, common names, and impact and potential risks were indicated by species. In addition, we provide a dichotomous key to species, presence of these species in southern South American countries, as well as and photographs in natural habitat. This work represents the first review on native and exotic ferns from Argentina that cause an impact on human activities or disturbe native habitats. The results provide information for the development of weed management tools and priority areas to implement them.

Protecting people with multiple sclerosis through vaccination.

Vaccination is one of the most effective and cost-efficient methods for protecting people with multiple sclerosis (MS) from infections. However, use of vaccines has often been problematic because of misguided concerns that they may exacerbate the disease and/or that some disease-modifying therapies may influence the immune response to immunisations and/or their safety. People with MS risk higher morbidity and mortality from vaccine-preventable infections. It is, therefore, important to address any patient's reluctance to accept vaccination and to provide clear guidance for clinicians on which vaccinations to consider proactively. We have reviewed the current literature and provide recommendations regarding vaccines in adults with MS, including specific advice regarding vaccination safety in patients receiving-or going to receive-disease-modifying therapies, vaccination during pregnancy, pretravel counselling and patient education.

Alemtuzumab depletion failure can occur in multiple sclerosis.

Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Although these anti-drug responses have been reported to be of no significance, we hypothesized that they will affect the depleting capacity and treatment response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population level there was lack of influence of 'ever-positive' alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and adverse effects during the 2-year trial. This was not surprising as no one before the first infusion, and only 0·6% of people before the second-infusion, had pre-infusion, neutralizing antibodies (NAbs). However, at the individual level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, which suggests that problems may occur in people requiring additional alemtuzumab cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Hence, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete poorly, probably due to biological-response variation and NAbs, and this may lead to treatment failure. Monitoring depletion following infusion and assessment of the neutralizing response before re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure.

IgG4-related disease: a rare but treatable cause of refractory intracranial hypertension.

Hypertrophic pachymeningitis secondary to IgG4-related disease is a rare but sometimes devastating cause of intracranial hypertension. It has the potential for an excellent response to corticosteroids or rituximab. We discuss the clinical presentation, imaging, histology (with its difficult distinction from lymphoma), management and follow-up of a case, including relapse and re-treatment following an initial response to rituximab.

Switching patients at high risk of PML from natalizumab to another disease-modifying therapy.

There are several options for switching people with multiple sclerosis (MS) who are at high risk of developing progressive multifocal leukoencephalopathy (PML) from natalizumab to alemtuzumab. However, some of these have risks that need to be managed, for example, the risks of carrying over asymptomatic PML from natalizumab on to the new therapy, and the risk of rebound disease activity associated with a prolonged washout after starting natalizumab. We propose a pragmatic bridging strategy, using another disease-modifying therapy (DMT), to reduce the risk of switching from natalizumab to alemtuzumab. We also discuss the caveats and subtleties associated with sequencing DMTs in MS and the complex decision making involved.

Deep Sequencing of HIV-1 in Cerebrospinal Fluid.

Using deep sequencing, human immunodeficiency virus (HIV) resistance-associated mutations were detected as minority species in the cerebrospinal fluid (CSF) of 4 patients with higher HIV type 1 RNA load in CSF than in plasma, but not in 2 patients with higher plasma viral load. Deep sequencing could help our understanding of viral escape in the central nervous system.

Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats.

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) in young adults. Chronic treatments with histone deacetylase inhibitors (HDACis) have been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, by targeting immune responses. We have recently shown that the HDAC inhibition/knockdown in the presence of thyroid hormone (T3) can also promote oligodendrocyte (OL) differentiation and expression of myelin genes in neural stem cells (NSCs) and oligodendrocyte precursors (OPCs). In this study, we found that treatment with an HDACi, valproic acid (VPA), and T3, alone or in combination, directly affects encephalitogenic CD4+ T cells. VPA, but not T3, compromised their proliferation, while both molecules reduced the frequency of IL-17-producing cells. Transfer of T3, VPA and VPA/T3 treated encephalitogenic CD4+ T cells into naïve rats induced less severe EAE, indicating that the effects of these molecules are persistent and do not require their maintenance after the initial stimuli. Thus, we investigated the effect of acute treatment with VPA and l-thyroxine (T4), a precursor of T3, on myelin oligodendrocyte glycoprotein-induced EAE in Dark Agouti rats, a close mimic of MS. We found that a brief treatment after disease onset led to sustained amelioration of EAE and prevention of inflammatory demyelination in the CNS accompanied with a higher expression of myelin-related genes in the brain. Furthermore, the treatment modulated immune responses, reduced the number of CD4+ T cells and affected the Th1 differentiation program in the brain. Our data indicate that an acute treatment with VPA and T4 after the onset of EAE can produce persistent clinically relevant therapeutic effects by limiting the pathogenic immune reactions while promoting myelin gene expression.

Mononeuritis multiplex as the first presentation of refractory sarcoidosis responsive to etanercept.

BACKGROUND: Several disorders may present with mononeuritis multiplex and the etiological diagnosis can be challenging. CASE PRESENTATION: We report a 42 year-old female who presented with severe lower limb neuropathic pain, asymmetric weakness and sensory impairment and was diagnosed with mononeuritis multiplex. Biopsy showed a granulomatous vasculitic process with eosinophils, scarce granulomata and axonal neuropathy and granulomatosis with poliangiitis was assumed. Steroids, cyclophosphamide, alemtuzumab, azathioprine, mycophenolate mofetil and rituximab were used, all with transient and insufficient response. Skin biopsy performed in a further exacerbation allowed sarcoidosis diagnosis. Infliximab and, later, adalimumab induced good clinical and laboratorial response, but neutralizing antibodies developed to both drugs, so etanercept was tried with good clinical response. CONCLUSIONS: To the best of our knowledge, this is the first report of sarcoidosis successfully treated with etanercept. This drug may be considered in refractory sarcoidosis after other TNF-α inhibitors failure, having the advantage of not being associated with neutralizing antibodies development.

New-onset Diabetes Mellitus after EUS-guided Drainage with LAMS: A Pilot Study.

BACKGROUND AND AIMS: Walled-off necrosis (WON) is a serious complication of severe pancreatitis, patients with necrotizing pancreatitis having an increased risk of developing diabetes mellitus (DM). The aim of this study was to assess the frequency of new-onset diabetes (NOD) in patients with symptomatic WON after endoscopic ultrasound (EUS)-guided drainage with lumen-apposing metal stents (LAMS). METHODS: We retrospectively analyzed a prospectively collected database of patients with symptomatic WON treated by EUS-guided drainage with LAMS in a tertiary referral center. The patients were followed-up for at least 12 months after stent removal. These patients were compared with age- and sex-matched asymptomatic WON controls without interventional treatment and healthy controls to assess the one-year occurrence of DM. Diabetes was defined according to the American Diabetes Association criteria. RESULTS: Of the 50 patients with symptomatic WON included in the study (male/female ratio, 33:17; median age, 60 years), 13 patients (26%) had pre-existing DM and were excluded. Ten of the remaining 37 patients (27%) without prior DM developed NOD within one year after stent removal, this frequency being higher than in asymptomatic WON controls (18.9%, p=0.581) and healthy controls (2%, p = 0.002). In the symptomatic WON group, NOD patients compared to non-DM patients were older (63.5 vs. 56 years old, p=0.042), had more frequent necrosis > 50% of the pancreatic parenchyma (p=0.002) and had a body-tail location of WON (p<0.001). On multivariate analysis, the number of direct endoscopic necrosectomy (DEN) sessions was the only significant factor for NOD occurrence (OR=7.05, p=0.010). NOD patients had poor glycemic control and required more DEN sessions to achieve WON resolution than patients with prior DM (p=0.017). CONCLUSIONS: In patients with symptomatic WON treated by EUS-guided drainage, DM occurred in 27% of previously non-diabetic patients within one year of follow-up. Patients with extensive pancreatic necrosis were more likely to develop NOD, a high number of DEN sessions being a significant risk factor for NOD occurrence.

Disease activity 4.5 years after starting cladribine: experience in 264 patients with multiple sclerosis.

Background: Cladribine is an effective immunotherapy for people with multiple sclerosis (pwMS). Whilst most pwMS do not require re-treatment following standard dosing (two treatment courses), disease activity re-emerges in others. The characteristics of pwMS developing re-emerging disease activity remain incompletely understood. Objectives: To explore whether clinical and/or paraclinical baseline characteristics, including the degree of lymphocyte reduction, drug dose and lesions on magnetic resonance imaging (MRI) are associated with re-emerging disease activity. Design: Service evaluation in pwMS undergoing subcutaneous cladribine (SClad) treatment. Methods: Demographics, clinical, laboratory and MRI data of pwMS receiving two courses of SClad were extracted from health records. To assess associations of predictor variables with re-emerging disease activity, a series of Cox proportional hazards models was fitted (one for each predictor variable). Results: Of n = 264 pwMS 236 received two courses of SClad and were included in the analysis. Median follow-up was 4.5 years (3.9, 5.3) from the first, and 3.5 years (2.9, 4.3) from the last SClad administration. Re-emerging disease activity occurred in 57/236 pwMS (24%); 22/236 received further cladribine doses (SClad or cladribine tablets) at 36.7 months [median; interquartile range (IQR): 31.7, 42.1], and 22/236 other immunotherapies 18.9 months (13.0, 30.2) after their second course of SClad, respectively. Eligibility was based on MRI activity in 29, relapse in 5, both in 13, elevated cerebrospinal fluid neurofilament light chain level in 3, deterioration unrelated to relapse in 4 and other in 3. Only 36/57 of those eligible for additional immunotherapy had received a reduced dose of SClad for their second treatment course. Association was detected between re-emerging disease activity and (i) high baseline MRI activity and (ii) low second dose of SClad. Conclusion: Re-emerging disease activity was associated with baseline MRI activity and low dose second course of SClad.

Killer Cell Immunoglobulin-like Receptor Genotypes and Reproductive Outcomes in a Group of Infertile Women: A Romanian Study.

A growing body of evidence suggests that endometrial immune disorders may be responsible for endometrial dysfunctions that can lead to gynecological and obstetrical pathology. The aim of this study was to explore the potential relationship between different killer cell immunoglobulin-like receptor (KIR) genotypes and reproductive outcomes. We conducted a prospective cohort study that included 104 infertile patients undergoing an in vitro fertilization procedure. All participants underwent clinical and ultrasound examination, genetic evaluation (KIR genotyping), endometrial washing fluid sampling for cytokine determination, endometrial tissue sampling for histologic assessment and hysteroscopic evaluation. Our analysis showed statistically significant lower levels of uterine cytokines TNF-α (p = 0.001) and IL-1beta (p = 0.000) in the KIR AA genotype group as compared to KIR AB and BB among study participants with chronic endometritis. The study results suggest that the KIR AA genotype population subgroups may be more susceptible to developing endometrial disorders such as chronic endometritis. The changes in the behavior of NK cells seem to be subtle and expressed as an altered regulatory pattern.

Development of resistance to biologic therapies with reference to IFN-ß.

All biotherapeutics have the potential to generate anti-drug antibodies (ADAs) in patients. The main factors leading to an immune response are thought to be product, treatment and patient related. In this review, reasons for the formation of ADAs, and particularly neutralizing antibodies (NAbs), are considered, with a focus on IFN-ß as a well-studied example. The time course for the production of NAbs, the measurement of NAbs, the defining of IFN-ß responders and non-responders, the implications for disease progression in patients, and future methods for avoiding the production of ADAs and of tolerizing patients are considered.