Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension.

BACKGROUND: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study).

OBJECTIVE: Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. METHODS: We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. RESULTS: One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. INTERPRETATION: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

The lipid-poor hemangioma: an investigation into the behavior of the "atypical" hemangioma.

OBJECTIVE: Most vertebral hemangiomas contain high signal intensity on T1-weighted MRI images. Atypical vertebral hemangiomas, which are defined as showing low-signal intensity on T1-weighted images, have been described as lesions which are prone to aggressive behavior. This study was performed to assess behavior of atypical hemangiomas. MATERIALS AND METHODS: Thoracic and lumbar spine MRI reports for the year 2012 were reviewed for diagnosis of atypical hemangioma. Images were reviewed by two independent observers, and cases which showed atypical vertebral hemangioma, and had imaging or clinical follow-up, were included in our study. RESULTS: Thirty atypical hemangiomas which had follow-up data were identified out of 2784 thoracic and lumbar MR examinations performed during 2012 at a single institution. Imaging follow-up was available for 23 lesions (mean follow-up 32 months), while there was clinical follow-up for the remaining seven lesions (mean 43.6 months). Twenty-two lesions were stable on imaging, while one demonstrated significant growth over approximately 6 years, developing MRI signal characteristics of a typical hemangioma. Eleven lesions had CT scans showing typical features of hemangioma. Two of the index lesions could not be identified on follow-up CT examinations, which showed normal-appearing spines. The remaining seven lesions were followed clinically; none of the patients reported symptoms in the region of the index lesions. CONCLUSIONS: Atypical hemangiomas are uncommon lesions. The cases in our population did not show aggressive behavior. A more appropriate designation for these lesions may be lipid-poor hemangioma, to distinguish them from aggressive hemangiomas.

Charcot-Marie-Tooth: From Molecules to Therapy.

Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are X-linked and autosomal recessive subtypes. In addition to a variety of inheritance patterns, there are a myriad of genes associated with CMT, reflecting the heterogeneity of this disorder. Next generation sequencing (NGS) has expanded and simplified the diagnostic yield of genes/molecules underlying and/or associated with CMT, which is of paramount importance in providing a substrate for current and future targeted disease-modifying treatment options. Considerable research attention for disease-modifying therapy has been geared towards the most commonly encountered genetic mutations (PMP22, GJB1, MPZ, and MFN2). In this review, we highlight the clinical background, molecular understanding, and therapeutic investigations of these CMT subtypes, while also discussing therapeutic research pertinent to the remaining less common CMT subtypes.

Sciatic neuropathy due to popliteal fossa nerve block.

INTRODUCTION: Sciatic neuropathy after popliteal nerve block (PNB) for regional anesthesia is considered uncommon but has been increasingly recognized in the literature. We identified a case of sciatic neuropathy that occurred after bunionectomy during which a PNB had been performed. METHODS: To understand the frequency of PNB-related sciatic neuropathy, we performed a retrospective review of sciatic neuropathies at our center over a 5-year period. RESULTS: Forty-five cases of sciatic neuropathy were reviewed. Similar to earlier reports, common etiologies of sciatic neuropathy, including compression, trauma, fractures, and hip arthroplasty, were noted in the majority of our cases (60%, n = 27). Unexpectedly, PNB was the third most common etiology (16%, n = 7). CONCLUSIONS: Our results suggest PNB is a relatively common etiology of sciatic neuropathy and is an important consideration in the differential diagnosis. These findings should urge electromyographers to assess history of PNB in sciatic neuropathies, particularly with onset after surgery. Muscle Nerve 56: 822-824, 2017.

A national survey of neurological monitoring practice after obstetric regional anaesthesia in the UK.

Neuraxial anaesthesia is widely used in obstetrics and neurological complications are rare. However, when they occur, subsequent investigation and management are time-critical and correlate with the extent of neurological recovery. The Third National Audit Project recommended the implementation of guidelines in obstetric epidural management, including advice on monitoring for early signs of problems and acting upon concerns. However, no national guideline exists for postoperative management in the obstetric population. We conducted a national survey of monitoring after obstetric neuraxial blockade and the management of an abnormally prolonged block. We received responses from 112/189 (59.3%) obstetric anaesthetic leads invited to participate. We determined that post-neuraxial blockade monitoring in the UK is highly variable: only 63/112 (56.3%) respondents' units had a monitoring policy in place, although most of these did not undertake formal neurological monitoring, and a range of different monitoring methods and schedules were employed. In 12/63 (19%) local policies, the first review of neurology was performed at the standard postoperative visit the following day, and 66/112 (58.9%) units had no protocol in place to address emergency management of abnormally prolonged neuraxial blockade. Where a policy was in place, the initial recommended action and the type of imaging used were variable.

Additionality and permanence standards in California's Forest Offset Protocol: A review of project and program level implications.

A key component of California's cap-and-trade program is the use of carbon offsets as compliance instruments for reducing statewide GHG emissions. Under this program, offsets are tradable credits representing real, verifiable, quantifiable, enforceable, permanent, and additional reductions or removals of GHG emissions. This paper focuses on the permanence and additionality standards for offset credits as defined and operationalized in California's Compliance Offset Protocol for U.S. Forest Projects. Drawing on a review of the protocol, interviews, current offset projects, and existing literature, we discuss how additionality and permanence standards relate to project participation and overall program effectiveness. Specifically, we provide an overview of offset credits as compliance instruments in California's cap-and-trade program, the timeline for a forest offset project, and the factors shaping participation in offset projects. We then discuss the implications of permanence and additionality at both the project and program levels. Largely consistent with previous work, we find that stringent standards for permanent and additional project activities can present barriers to participation, but also, that there may be a trade-off between project quality and quantity (i.e. levels of participation) when considering overall program effectiveness. We summarize what this implies for California's forest offset program and provide suggestions for improvements in light of potential program diffusion and policy learning.

Assessing the height of block for caesarean section over the past three decades: trends from the literature.

There are multiple methods of assessing the height of block before caesarean section under regional anaesthesia, and surveys of practice suggest considerable variation in practice. So far, little emphasis has been placed on the guidance to be gained from published research literature or textbooks. We therefore set out to investigate the methods of block assessment documented in published articles and textbooks over the past 30 years. We performed two searches of PubMed for randomised clinical trials with caesarean section and either spinal anaesthesia or epidural anaesthesia as major Medical Subject Headings. A total of 284 papers, from 1984 to 2013, were analysed for methods of assessment of sensory and motor block, and the height of block deemed adequate for surgery. We also examined 45 editions of seven anaesthetic textbooks spanning 1950-2014 for recommended methods of assessment and height of block required for caesarean section. Analysis of published papers demonstrated a wide variation in techniques, though there has been a trend towards the increased use of touch, and an increased use of a block height of T5 over the study period. Only 115/284 (40.5%) papers described the method of assessing motor block, with most of those that did (102/115; 88.7%) describing it as the 'Bromage scale', although only five of these (4.9%) matched the original description by Bromage. The required height of block recommended by textbooks has risen over the last 30 years to T4, although only four textbooks made any recommendation about the preferred sensory modality. The variation in methods suggested by surveys of practice is reflected in variation in published trials, and there is little consensus or guidance in anaesthetic textbooks.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data.

OBJECTIVE: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. METHODS: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. RESULTS: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). INTERPRETATION: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.