Acute flaccid myelitis:cause, diagnosis, and management

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of MM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for MM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population

Current and Emerging Therapies for the Treatment of Multiple Sclerosis: Focus on Cladribine

Multiple Sclerosis (MS) is a chronic inflammatory, immune-mediated, demyelinating disorder of the central nervous system with a heterogeneous clinical presentation and pathology in which activated lymphocytes play an important role in mediating tissue damage. Until recently, all first line therapies for MS were injectable. Several oral medications have been studied for preventative treatment of MS. Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog that has been used for the treatment of several hematologic neoplasms, with a unique lymphcytotoxic mechanism of action. Cladribine has been investigated as treatment of MS for more than 15 years. A recent placebo-controlled, double-blind study of cladribine, CLARITY, showed decreased relapse rates, risk of disability progression and MRI measures of disease activity at 96 weeks. Cladribine's strengths included high efficacy and convenient, biannual oral dosing. However, concerns about safety prevented the FDA from approving cladribine in 2011. Thus, use of cladribine for treatment of relapsing and remitting multiple sclerosis will remain off-label

Table e1 - Exploratory Patient Reported Outcomes Differences Between Study Groups

Table showing the differences in Patient Reported Outcome instruments from baseline to end of study with comparisons between the study groups

Data from: Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis

Objective: To examine whether rituximab induction followed by glatiramer acetate (GA) monotherapy is more effective than GA alone for the treatment of relapsing MS with active disease. Methods: This was a single center, double-blind, placebo-controlled study(NCT01569451). Fifty-five participants were randomly assigned (1:1ratio) to either rituximab (R-GA) or placebo induction (P-GA), followed by all participants initiating GA therapy. Participants were followed up to 3-years. The primary endpoint was the number of participants with no evidence of disease activity (NEDA) (those without relapse, new MRI lesions and sustained change in disability. Results: Twenty-eight and 27 participants received rituximab and placebo induction, respectively, with one participant in each arm withdrawing prior to 6-month MRI. There were no significant differences in baseline characteristics. At end of study, 44.44% of R-GA participants demonstrated NEDA, vs 19.23% of P-GA participants (p = 0.049). A smaller proportion of R-GA participants failed treatment (37.04%R-GA vs 69.23%P-GA, p=0.019), and time to treatment failure was longer (23.32 monthsR-GA vs 11.29 monthsP-GA, p=0.027). Fewer participants in the R-GA arm had new lesions (25.93%R-GA vs 61.54%P-GA, p=0.009), and there were fewer new T2 lesions (0.48R-GA vs 1.96P-GA vs, p=0.027). Probability of demonstrating NEDA in the R-GA arm returned to baseline within the study period. There were no differences in adverse events. Conclusions: Induction therapy with rituximab followed by GA may provide superior efficacy in the short term to GA alone in relapsing MS, but this benefit appears to wane within the study period. Larger studies are needed to assess sustainability of results

Table e2 - Infusion Reactions

Table detailing the various infusion reactions experienced in the two study groups (Rituximab vs Placebo infusion)

Ethnic differences in the relationship of carotid atherosclerosis to coronary calcification: the Multi-Ethnic Study of Atherosclerosis

Ethnic differences in non-invasive measures of atherosclerosis are increasingly being reported, but the relationship of these measures to each other has not been widely explored. Carotid ultrasonographic and computed cardiac tomographic findings were compared in 6814 participants of White, Black, Hispanic, and Chinese ethnicities free of overt cardiovascular disease. Coronary calcium and carotid atherosclerosis were strongly related to each other in all ethnic groups. Associations of coronary calcium prevalence and common carotid intimal-medial thickness (IMT) differed by ethnicity in women, being weakest among Black women (0.07 mm IMT difference between those with and without coronary calcium) compared to the other three groups (0.10-0.12 mm difference, p=0.007). Estimated percent increments in internal carotid IMT per 10% increment in coronary calcium score were highest in Hispanics (18.5%) and lowest in Blacks (6.1%, p<0.01). Coronary calcium may be less strongly associated with carotid atherosclerosis in Blacks, particularly Black women, than in other ethnic groups. These differences should be pursued for relationships to coronary events to determine whether coronary calcium carries the same risk information in other ethnic groups as it does in Whites

Safety and patient experience with at‐home infusion of ocrelizumab for multiple sclerosis

Abstract Objective This study aimed to evaluate safety (infusion‐related reactions [IRRs]) and patient satisfaction (patient‐reported outcomes [PROs]) for at‐home ocrelizumab administration for patients with multiple sclerosis (MS). Methods This open‐label study included adult patients with an MS diagnosis who had completed a ≥ 600‐mg ocrelizumab dose, had a patient‐determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600‐mg ocrelizumab home‐based infusion over 2 h, followed by 24‐h and 2‐week post‐infusion follow‐up calls. IRRs and adverse events (AEs) were documented during infusions and follow‐up calls. PROs were completed before and 2 weeks post infusion. Results Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)—similar to other shorter ocrelizumab infusion studies—and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at‐home infusion process and confidence in the care provided. Patients also reported a significant preference for at‐home infusion compared with prior infusion center experiences. Interpretation IRRs and AEs occurred at acceptable rates during in‐home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home‐based ocrelizumab infusion over a shorter infusion period

Everolimus, an mTORC1/2 inhibitor, in ART‐suppressed individuals who received solid organ transplantation: A prospective study

Pharmacologic inhibition of the mammalian target of rapamycin (mTOR) in the setting of renal transplantation has previously been associated with lower human immunodeficiency virus 1 (HIV-1) DNA burden, and in vitro studies suggest that mTOR inhibition may lead to HIV transcriptional silencing. Because prospective clinical trials are lacking, we conducted an open-label, single-arm study to determine the impact of the broad mTOR inhibitor, everolimus, on residual HIV burden, transcriptional gene expression profiles, and immune responses in HIV-infected adult solid organ transplant (SOT) recipients on antiretroviral therapy. Whereas everolimus therapy did not have an overall effect on cell-associated HIV-1 DNA and RNA levels in the entire cohort, participants who maintained everolimus time-averaged trough levels &gt;5&nbsp;ng/mL during the first 2&nbsp;months of therapy had significantly lower RNA levels up to 6&nbsp;months after the cessation of study drug. Time-averaged everolimus trough levels significantly correlated with greater inhibition of mTOR gene pathway transcriptional activity. Everolimus treatment also led to decreased PD-1 expression on certain T cell subsets. These data support the rationale for further study of the effects of mTOR inhibition on HIV transcriptional silencing in non-SOT populations, either alone or in combination with other strategies. Trial Registration: ClinicalTrials.gov NCT02429869

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

BackgroundRare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown.ObjectiveTo test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS.MethodsWe analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk.ResultsAfter correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501.ConclusionFindings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases

Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis

ObjectiveThe role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have a higher relapse rate compared with MS in adults. Thus, studying the effect of diet on relapse rate in this age group is likely to provide more robust answers.MethodsThis is a multicentre study done at 11 paediatric MS centres in the USA. Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) with disease onset before 18 years of age and duration of less than 4 years were included in this study. Dietary intake during the week before enrolment was assessed with the validated Block Kids Food Screener. The outcome of the study was time from enrolment to the next relapse. 219 patients with paediatric RRMS or CIS were enrolled. Each 10% increase in energy intake from fat increased the hazard of relapse by 56% (adjusted HR 1.56, 95% CI 1.05 to 2.31, p=0.027), and in particular each 10% increase in saturated fat tripled this hazard (adjusted HR: 3.37, 95% CI 1.34 to 8.43, p=0.009). In contrast, each additional one cup equivalent of vegetable decreased the hazard of relapse by 50% (adjusted HR: 0.50, 95% CI 0.27 to 0.91, p=0.024). These associations remained with mutual adjustment and persisted when adjusting for baseline 25(OH) vitamin D serum level. Other studied nutrients were not associated with relapse.ConclusionsThis study suggests that in children with MS, high energy intake from fat, especially saturated fat, may increase the hazard to relapse, while vegetable intake may be independently protective