Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with ...recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation.
•Type I IFN therapies can cause a dose-dependent TMA.•Recombinant type I IFN therapies should be stopped at the earliest opportunity in patients who develop TMA.
The outcome of Guillain‐Barré syndrome (GBS) remains unchanged since plasma exchange and intravenous immunoglobulin (IVIg) were introduced over 20 years ago. Pathogenesis studies on GBS have ...identified the terminal component of complement cascade as a key disease mediator and therapeutic target. We report the first use of terminal complement pathway inhibition with eculizumab in humans with GBS. In a randomised, double‐blind, placebo‐controlled trial, 28 subjects eligible on the basis of GBS disability grade of at least 3 were screened, of whom 8 (29%) were randomised. Five received eculizumab for 4 weeks, alongside standard IVIg treatment. The safety outcomes, monitored via adverse events capture, showed eculizumab to be well‐tolerated and safe when administered in conjunction with IVIg. Primary and secondary efficacy outcomes in the form of GBS disability scores (GBS DS), MRC sum scores, Rasch overall disability scores, and overall neuropathy limitation scores are reported descriptively. For the primary efficacy outcome at 4 weeks after recruitment, two of two placebo‐ and two of five eculizumab‐treated subjects had improved by one or more grades on the GBS DS. Although the small sample size precludes a statistically meaningful analysis, these pilot data indicate further studies on complement inhibition in GBS are warranted.
Fisher syndrome is one of the regional variants of Guillain-Barré syndrome, characterised by impairment of eye movements (ophthalmoplegia), incoordination (ataxia) and loss of tendon reflexes ...(areflexia). It can occur in more limited forms, and may overlap with Guillain-Barré syndrome. A further variant is associated with upper motor neuron signs and disturbance of consciousness (Bickerstaff's brainstem encephalitis). All of these variants are associated with anti-GQ1b IgG antibodies. Intravenous immunoglobulin (IVIg) and plasma exchange are often used as treatments in this patient group. This review was undertaken to systematically assess any available randomised controlled data on acute immunomodulatory therapies in Fisher Syndrome or its variants.
To provide the best available evidence from randomised controlled trials on the role of acute immunomodulatory therapy in the treatment of Fisher Syndrome and related disorders.
We searched the Cochrane Neuromuscular Disease Trials register (March 2004), MEDLINE (from January 1966 to November 2004), EMBASE (from January 1980 to November 2004), CINAHL (from January 1982 to November 2004) and LILACS (from January 1982 to November 2004) for randomised controlled trials, quasi-randomised trials, historically controlled studies and trials with concurrent controls. We adapted this strategy to search MEDLINE from 1966 and EMBASE from 1980 for comparative cohort studies, case-control studies and case series.
All randomised and quasi-randomised controlled clinical trials (in which allocation was not random but was intended to be unbiased, e.g. alternate allocation, and non-randomised controlled studies were to have been selected. Since no such clinical trials were discovered, all retrospective case series containing five or more patients were assessed and summarised in the discussion section.
All studies of Fisher Syndrome and its clinical variants were scrutinised for data on patients treated with any form of acute immunotherapy. Information on the outcome was then collated and summarised.
We found no randomised or non-randomised prospective controlled trials of immunotherapy in Fisher Syndrome or related disorders. We summarised the results of retrospective series containing five or more patients in the discussion section.
There are no randomised controlled trials of immunomodulatory therapy in Fisher Syndrome or related disorders on which to base practice.
Human and animal studies on antibody‐mediated neuropathy implicate complement in pathogenesis. In animal models complement inhibition is therapeutically beneficial. The monoclonal antibody, ...eculizumab (Soliris™, Alexion Pharmaceuticals, Cheshire, CT), prevents cleavage of C5 and thus inhibits terminal complement activation. In an open label study, 13 multifocal motor neuropathy patients received eculizumab for 14 weeks, 10 of whom were concomitantly receiving intravenous immunoglobulin. The primary outcome was safety of eculizumab, and the secondary outcomes included change in intravenous immunoglobulin (IVIg) dosing frequency, performance, and electrophysiological parameters. Adverse events were minor during the study. Nine of 10 patients on IVIg maintenance continued to require IVIg. IVIg dosing interval was not different between the run‐in and the treatment period. There were improvements in patient‐rated subjective scores and selected clinical and electrophysiological measurements. Overall, a small treatment effect occurred in some patients that appeared supplementary to and independent of the IVIg treatment effect, and occurred more frequently in patients with higher baseline motor function.
Background Autoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies ...targeting the N -methyl- d -aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidence-based disease modifying treatment in AIE. Objectives CIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE. Study design CIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments. Endpoints The primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured. Conclusion The innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE.
Human prion diseases have acquired, sporadic, and inherited aetiologies, show wide phenotypic heterogeneity, and are associated with propagation of infectious prions of many distinct strain types.1 ...Since 1994, about 200 cases of vCJD, causally related to exposure to bovine spongiform encephal opathy (BSE) prions, have been identified worldwide. vCJD is generally seen in young adults, has characteristic neuropathological features and tissue distribution of infectivity, and a distinctive type 4 (London classification) molecular strain type.1 A polymorphism at codon 129 (encoding methionine or valine) of the human prion protein gene (PRNP), constitutes a powerful susceptibility factor in all types of prion disease. There is a report of a recipient of a blood transfusion from a donor incubating vCJD who died of unrelated causes but showed signs of prion infection at autopsy and was PRNP codon 129 hetero zygous.3 Animal studies have suggested that different clinicopathological phenotypes could occur in people with various PRNP codon 129 genotypes.4,5 The majority of the UK population have potentially been exposed to BSE prions but the extent of clinically silent infection remains unclear.
Long lists of causes of peripheral neuropathy make peripheral nerve disease a dry and uninspiring subject. A simple scheme based on the answers to just six questions should enable the clinician to ...recognise characteristic patterns, investigate relevant subgroups appropriately, and identify treatable disorders quickly: which systems are involved? What is the distribution of weakness? What is the nature of the sensory involvement? Is there any evidence of upper motor neuron involvement? What is the temporal evolution? Is there any evidence for a hereditary neuropathy? Standard screening investigations suffice for the common length dependent axonal neuropathies while complex presentations need more detailed investigations targeted to their clinical phenotype.
Background
Global increases in opioid prescribing and misuse have prompted calls for closer regulation. Opioid prescription following surgery may lead to long term opioid use. A study was conducted ...evaluating opioid prescriptions on hospital discharge following common general surgery operations in the Bay of Plenty.
Methods
Retrospective observational study over a two‐year period in two regional New Zealand hospitals. Six hundred and eleven patients aged 18–64 years were assessed. Patients with complications, readmission, and a prescription of opioids in the preceding 3 months were excluded.
Results
A total of 460 patients (165 Laparoscopic Cholecystectomy (LC), 200 Laparoscopic Appendicectomy (LA) and 95 Open Inguinal Hernia Repair (OIHR)) were included in analysis. Opioids were prescribed to 53% of LC, 55% of LA, and 60% of OIHR patients, with a mean of 75.8 Morphine Milligram Equivalents (MMEs), 75.3 MMEs, and 82.8 MMEs respectively. Seven percent of patients (18/254) received a second opioid prescription within 3 months, and of those only 1.6% (4/254) received a further prescription between 3 and 6 months from discharge. Opioid prescribing did not correlate with operation, ethnicity, age, length of stay, or gender, except for males receiving a more MMEs than females following LC (mean 102.0 MMEs versus 65.4 MMEs, P = 0.017).
Conclusion
This study shows a rate of opioid prescribing lower than the USA, and greater than seen in an Australian setting. Substantial amounts of opioids were prescribed following uncomplicated surgery, with significant variability. Improvements in training in post‐operative opioid prescribing are needed. Fortunately, rates of ongoing opioid use were low.
A retrospective study evaluating postoperative opioid prescribing patterns in 460 opioid naïve patients, following uncomplicated common general surgery procedures in a New Zealand setting. This study shows a rate of opioid prescribing lower than the USA, and more than seen in an Australian setting, rates of ongoing opioid use were low. Substantial amounts of opioids were prescribed following uncomplicated surgery, with significant variability.
Neurofilament is a biomarker of axonal injury proposed as a useful adjunct in the monitoring of patients with multiple sclerosis (MS). We conducted a systematic review and meta-analysis of ...case-control studies that have measured neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of people with MS (pwMS), in order to determine whether, and to what degree, CSF NfL levels differentiate MS from controls, or the subtypes or stages of MS from each other.
Guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. Electronic databases were searched for published and 'grey' literature, with 151 hits. Of 51 full articles screened, 20 were included in qualitative analysis, and 14 in meta-analysis.
CSF NfL was higher in 746 pwMS than 435 (healthy and disease) controls, with a moderate effect size of 0.61 (p < 0.00001). Mean CSF NfL levels were significantly higher in 176 pwMS with relapsing disease than 92 with progressive disease (2124.8 ng/L, SD 3348.9 vs 1121.4 ng/L, SD 947.7, p = 0.0108). CSF NfL in 138 pwMS in relapse (irrespective of MS subtype) was double that seen in 268 pwMS in remission (3080.6 ng/L, SD 4715.9 vs 1541.7 ng/L, SD 2406.5, p < 0.0001).
CSF NfL correlates with MS activity throughout the course of MS, reflecting the axonal damage in pwMS. Relapse is more strongly associated with elevated CSF NfL levels than the development of progression, and NfL may be most useful as a marker of disease 'activity' rather than as a marker of disability or disease stage.
PDF
