To determine whether there is an association between an acute preceding hepatitis E virus (HEV) infection and neuralgic amyotrophy (NA), and if so, whether patients with HEV-related NA differ from ...patients without an associated HEV infection.
HEV testing was conducted in a retrospective cohort of 28 Cornish patients with NA (2011-2013) and a prospective cohort of 38 consecutive Dutch patients with NA (2004-2007). Acute-phase serum samples were analyzed for the presence of anti-HEV immunoglobulin (Ig) M and IgG and HEV RNA (quantitative real-time PCR).
Five cases (10.6%) of acute hepatitis E infection were identified in a total group of 47 patients with NA of whom serum samples were available. In 4 patients, HEV RNA was detected in serum samples taken at presentation. All patients with HEV-associated NA had clinical and electrophysiologic evidence of bilateral brachial plexus involvement. Anti-HEV IgM positivity was not related to age, sex, disease severity, disease course, or outcome.
Acute hepatitis E is found in 10% of patients with NA from the United Kingdom and the Netherlands. Further research is required to investigate the role of HEV in NA in other geographical locations and to determine pathophysiologic mechanisms.
Summary Background Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the ...development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. Methods Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov , number NCT00704301. Findings Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7–14·2) than in the placebo group (3·0 days, IQR 1·0–9·3; p=0·06). Interpretation Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. Funding ZonMw, the Netherlands Brain Foundation, and Novartis.
Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic ...interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.
Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of ...antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as “responders”, experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.
Display omitted
•Antiretroviral therapy for 24 weeks decreased HERV-K (HML-2) levels in most patients with ALS.•A rebound in HML-2 levels occurred after discontinuation of the antiretroviral drugs.•Patients that had an antiviral effect against HML-2 showed a trend for slower progression in several clinical parameters.
Background and purpose
RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron ...degeneration in amyotrophic lateral sclerosis (ALS).
Methods
We conducted a randomized, multicenter, placebo‐controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double‐blind period, all patients received RT001 during an open‐label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS‐R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.
Results
In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least‐squares mean difference in ALSFRS‐R total score at week 24 of treatment was 1.90 (95% confidence interval = −1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.
Conclusions
Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.
The Gold Coast criteria (GCC) have been proposed as a means of selecting patients for amyotrophic lateral sclerosis (ALS) clinical trials. We aimed to characterise disease progression according to ...the GCC.
Data from population-based ALS registries from the Netherlands and Belgium were analysed. The GCC additionally define ALS as lower motor neuron (LMN) dysfunction in ≥2 body regions without upper motor neuron dysfunction. Therefore, the revised El Escorial criteria (rEEC) were supplemented with a 'Gold Coast ALS' category for patients with only LMN dysfunction in ≥2 body regions. We assessed survival time, ALS Functional Rating Scale (ALSFRS-R) progression rates and between-patient variability per diagnostic category.
We included 5957 ALS patients, of whom 600 (10.1%) fulfilled the GCC but not the rEEC, and 95 (1.6%) fulfilled only the rEEC. ALSFRS-R progression rates were similar for the rEEC (0.84 points/month) and GCC (0.81 points/month) with similar variability (standard deviation of 0.59 vs. 0.60) and median survival time (17.8 vs.18.7 months). Survival time and average progression rates varied (p<0.001) between categories. Per category, however, there was considerable between-patient variability with progression rates ranging from: -2.10 to -0.14 (definite), -1.94 to -0.06 (probable), -2.10 to -0.02 (probable laboratory supported), -1.79 to -0.02 (possible) and -1.31 to 0.08 (Gold Coast).
The GCC broaden the definition of ALS, allowing more patients to participate in trials, while minimally impacting population heterogeneity. Given the large variability per diagnostic category, selecting only specific categories for trials may not result in a more homogeneous study population.
Background
Actigraphy has been proposed as a measure for tracking functional decline and disease progression in patients with Motor Neuron Disease (MND). There is, however, little evidence to show ...that wrist-based actigraphy measures correlate with functional decline, and no consensus on how best to implement actigraphy. We report on the use of wrist actigraphy to show decreased activity in patients compared to controls, and compared the utility of wrist- and hip-based actigraphy for assessing functional decline in patients with MND.
Methods
In this multi-cohort, multi-centre, natural history study, wrist- and hip-based actigraphy were assessed in 139 patients with MND (wrist,
n =
97; hip,
n =
42) and 56 non-neurological control participants (wrist,
n =
56). For patients with MND, longitudinal measures were contrasted with clinical outcomes commonly used to define functional decline.
Results
Patients with MND have reduced wrist-based actigraphy scores when compared to controls (median differences: prop. active = − 0.053 − 0.075, − 0.026, variation axis 1 = − 0.073 − 0.112, − 0.021). When comparing wrist- and hip-based measures, hip-based accelerometery had stronger correlations with disease progression (prop. active:
τ
= 0.20 vs 0.12; variation axis 1:
τ
= 0.33 vs 0.23), whereas baseline wrist-based accelerometery was better related with future decline in fine-motor function (τ = 0.14–0.23 vs 0.06–0.16).
Conclusions
Actigraphy outcomes measured from the wrist are more variable than from the hip and present differing sensitivity to specific functional outcomes. Outcomes and analysis should be carefully constructed to maximise benefit, should wrist-worn devices be used for at-home monitoring of disease progression in patients with MND.
Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss ...efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials.
Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size.
Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15% reduction in ALSFRS-R decline and 34% decline in hazard with 80% power after 18 months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end point 1,274 patients, the CAFS 576 patients and the joint model 464 patients.
Joint models have superior statistical power to analyze simultaneous effects on survival and function and may circumvent pitfalls encountered by other end points. Optimizing trial end points is essential, as selecting suboptimal outcomes may disguise important treatment clues.
Abstract Hepatitis E virus (HEV) infections are not limited to the liver but may also affect other organs. Several diseases, including Guillain-Barré syndrome, neuralgic amyotrophy, ...glomerulonephritis, cryoglobulinemia, pancreatitis, lymphoma, thrombopenia, meningitis, thyreoiditis and myocarditis have been observed in the context of hepatitis E. To date the definite pathophysiological links between HEV and extrahepatic manifestations are not yet established. However, it is suggested that HEV-infection might be causative based on serological studies, case series, in vitro data and animal models. In particular neuronal and renal diseases as well as pancreatitis seem to be caused by HEV, while a causative relationship between HEV and other diseases is more doubtful. Either direct cytopathic tissue damage by extrahepatic replication or immunological processes induced by an overwhelming host immune response are possible origins of HEV-associated extrahepatic manifestations. Hepatologists should be aware of the possibility of acute or chronically HEV-infected patients to develop extrahepatic manifestations while neurologists, nephrologists, rheumatologists and other groups of physicians should consider HEV-infection as a potential differential diagnosis when observing one of the hereby described diseases. Ribavirin and steroids have been used in small groups of patients with extrahepatic manifestations, but the efficacy of these drugs still needs to be verified by large, multicenter studies. This article comprehensively reviews the published literature regarding HEV and extrahepatic manifestations and discusses the probability of specific extrahepatic diseases to be caused by previous or ongoing HEV-infection and summarizes the published knowledge about antiviral treatment in extrahepatic disorders.
PDF
