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Metabolic myopathies are inborn errors of metabolism that result in impaired energy production due to defects in glycogen, lipid, mitochondrial, and possibly adenine nucleotide metabolism. Fatty acid oxidation defects (FAOD), glycogen storage disease, and mitochondrial myopathies represent the 3 main groups of disorders, and some consider myoadenylate deaminase (AMPD1 deficiency) to be a metabolic myopathy. Clinically, a variety of neuromuscular presentations are seen at different ages of life. Newborns and infants commonly present with hypotonia and multisystem involvement (liver and brain), whereas onset later in life usually presents with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, the glycogen storage diseases result in high-intensity exercise intolerance, whereas the FAODs and the mitochondrial myopathies manifest predominately during endurance-type activity or under fasted or other metabolically stressful conditions. The clinical examination is often normal, and testing requires various combinations of exercise stress testing, serum creatine kinase activity and lactate concentration determination, urine organic acids, muscle biopsy, neuroimaging, and specific genetic testing for the diagnosis of a specific metabolic myopathy. Prenatal screening is available in many countries for several of the FAODs through liquid chromatography-tandem mass spectrometry. Early identification of these conditions with lifestyle measures, nutritional intervention, and cofactor treatment is important to prevent or delay the onset of muscle weakness and to avoid potential life-threatening complications such as rhabdomyolysis with resultant renal failure or hepatic failure. This article will review the key clinical features, diagnostic tests, and treatment recommendations for the more common metabolic myopathies, with an emphasis on mitochondrial myopathies.

The ascending projections to the lateral lemniscal nuclei and the inferior colliculus were investigated in the albino rat by using Fluoro-Gold, either alone or in combination with other retrograde tract tracers. Injections were made into the central nucleus of the inferior colliculus (ICC), the dorsal nucleus of the lateral lemniscus (DNLL), the intermediate nucleus of the lateral lemniscus (INLL), or the ventral nucleus of the lateral lemniscus (VNLL). The ICC receives both ipsilateral and contralateral projections from the DNLL and the lateral superior olive, major ipsilateral projections from the INLL, VNLL, medial superior olive, and superior paraolivary nucleus, and major contralateral projections from both dorsal and ventral cochlear nucleus. The DNLL receives a similar pattern of projections from the auditory lower brainstem nuclei. The INLL, in contrast, receives its major projections from the ipsilateral VNLL, lateral superior olive, medial superior olive, superior paraolivary nucleus, and medial nucleus of the trapezoid body, but does not receive a heavy projection from the contralateral lateral superior olive. It receives a major contralateral projection from the ventral cochlear nucleus, but a much lighter projection from the contralateral dorsal cochlear nucleus. The VNLL receives projections from the ipsilateral medial nucleus of the trapezoid body and the contralateral ventral cochlear nucleus, but does not receive projections from the medial or lateral superior olives, the superior paraolivary nucleus, or the dorsal cochlear nucleus. Thus, the three primary subdivisions of the rat's lateral lemniscus can be distinguished from each other on the basis of their distinctive projection patterns.

Adenoviral-mediated transfer of ciliary neurotrophic factor (CNTF) to the retina rescued retinal ganglion cells (RGCs) from axotomy-induced apoptosis, presumably via activation of the high affinity CNTF receptor alpha (CNTFRalpha) expressed on RGCs. CNTF can also activate astrocytes, via its low affinity leukemia inhibitory receptor beta expressed on mature astrocytes, suggesting that CNTF may also protect injured neurons indirectly by modulating glia. Adenoviral-mediated overexpression of CNTF in normal and axotomized rat retinas was examined to determine if it could increase the expression of several glial markers previously demonstrated to have a neuroprotective function in the injured brain and retina. Using Western blotting, the expression of glial fibrillary acid protein (GFAP), glutamate/aspartate transporter-1 (GLAST-1), glutamine synthetase (GS), and connexin 43 (Cx43) was examined 7 days after intravitreal injections of Ad.CNTF or control Ad.LacZ. Compared to controls, intravitreal injection of Ad.CNTF led to significant changes in the expression of CNTFRalpha, pSTAT(3), GFAP, GLAST, GS, and Cx43 in normal and axotomized retinas. Taken together, these results suggest that the neuroprotective effects of CNTF may result from a shift of retinal glia cells to a more neuroprotective phenotype. Moreover, the modulation of astrocytes may buffer high concentrations of glutamate that have been shown to contribute to the death of RGCs after optic nerve transection.

Ciliary neurotrophic factor (CNTF) has recently been demonstrated to be one of the most promising neurotrophic factors to improve both the survival and regeneration of injured retinal ganglion cells (RGCs). In the present study, we used optic nerve transection as an in vivo model to evaluate the effectiveness of a self-inactivating, replication-deficient lentiviral-mediated transfer of human ciliary neurotrophic factor (SIN-PGK-CNTF) on the survival of axotomized adult rat RGCs. Counts of dextran-fluorescein isothiocyanate conjugated (D-FITC)-retrogradely labeled RGCs revealed that the percentage of RGCs was drastically reduced (<90% cell death) 21 days after optic nerve transection. Retinal sections stained with X-gal revealed that intravitreal injection of the control LacZ-expressing lentiviral vector (LV-LacZ) resulted in the transduction of RGCs and retinal pigment epithelium (RPE) cells. A single intravitreal injection of LV-CNTF at the time of axotomy significantly enhanced RGC survival at 14 and 21 days postaxotomy compared to controls. These results demonstrate for the first time that rapid and prolonged delivery of CNTF using lentiviral-mediated gene transfer to the retina is an effective treatment for rescuing axotomized RGCs for an extended period of time. These results suggest that early and continuous administration of CNTF could serve as a potential treatment for retinal disorders involving optic neuropathy and RGC injury such as in glaucoma.

BackgroundThe DAWN and DEFUSE-3 trials showed the benefit of endovascular treatment (EVT) in acute ischemic stroke patients presenting beyond 6 hours from last known well (LKW) and selected by perfusion imaging criteria. The ESCAPE NA1-trial selected patients based on non-contrast CT (NCCT) Alberta Stroke Program Early CT Score (ASPECTS) and multiphase CT angiography (CTA) collateral status. This study compares baseline characteristics, workflow, and outcomes in the EVT arms of DAWN and DEFUSE-3 with late-window patients from the EVT-only arm of ESCAPE-NA1.MethodsAggregate data on baseline characteristics, workflow, reperfusion quality, final infarct volume, and clinical outcomes (modified Rankin Score [mRS] at 90 days) in subjects enrolled in the DAWN and DEFUSE-3 EVT arms were compared with similar data from the ESCAPE-NA1 control arm (EVT-only arm) presenting beyond 6 hours from LKW using descriptive statistics.ResultsBaseline characteristics among late-window patients in the ESCAPE NA1 trial were similar to those in the DAWN and DEFUSE-3 EVT arms. Median time from LKW-to-puncture in subjects enrolled in the ESCAPE NA1 trial was 9 hrs (IQR: 7.5–11 hours) when compared with DAWN (n=107; 12.8 hours, IQR: 10.6–16.7 hours) and DEFUSE-3 (n=92; 11.5 hours, IQR: 9.2–12.8 hours). Median post-treatment infarct-volume was largest in the ESCAPE NA1-patients (47 mL [IQR: 19–146] vs median 8 mL [IQR: 0–48] in the DAWN group and 35 mL [IQR: 18–82] in DEFUSE-3), while % mRS 0–2 at 90 days were similar across the three trials (ESCAPE NA1: 50/111 [45%], DAWN: 52/107 [49%], DEFUSE-3: 41/92 [45%]).ConclusionPatients enrolled beyond 6 hours from LKW in the ESCAPE-NA1 trial based on NCCT-ASPECTS and mCTA had similar clinical outcomes when compared with patients selected by perfusion imaging in the DAWN and DEFUSE-3 trials.

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IMPORTANCE Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes. OBJECTIVETo validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome. DESIGN, SETTING, AND PARTICIPANTS This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included. EXPOSURES Small FIV (volume Յ25th percentile) and large FIV (volume Ն75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score Ն3 despite small FIV or those with mRS scores Յ2 despite large FIV) and nondiscrepant cases. MAIN OUTCOMES AND MEASURES Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score. RESULTS Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women;median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, Յ25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, Ն75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (continued) Key Points Question Why do some patients have poor outcomes despite small infarcts after endovascular therapy, while others with large infarcts fare better? Findings In this cohort study of 1091 patients who received endovascular therapy as part of a randomized clinical trial, discrepancies between infarct volume and function...