Excessive sleepiness (ES), one of the main presenting symptoms of OSA, is estimated to persist in 12% to 65% of individuals receiving CPAP therapy. 1-4 The effect of ES on individuals with OSA includes functional impairment, reduced quality of life, and increased risk for occupational and motor vehicle accidents. 5-9 Solriamfetol (formerly known as JZP-110 and ADX-N05) is a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects. Its mechanism of action differs from those of amphetamines, modafinil, and armodafinil. 10 Solriamfetol demonstrated significant efficacy relative to placebo for reducing ES and increasing wakefulness in clinical trials of narcolepsy. 11-13 Efficacy for ES in OSA also was demonstrated by solriamfetol in a 12-week randomized, controlled phase III study. 14 This phase III trial evaluated the maintenance of efficacy and safety of solriamfetol administered once daily compared with placebo for the treatment of ES in adults with OSA. Methods Study Design This was a clinical trial from the Treatment of OSA and Narcolepsy Excessive Sleepiness (TONES) phase III program, the TONES 4 study. This phase III, double-blind, placebo-controlled trial was performed from May 2015 to November 2016 in Finland, France, Germany, Sweden, and the United States. An enriched, randomized withdrawal design was used. The study was approved by the appropriate institutional review boards or independent ethics committees (e-Appendix 1) and was conducted in accordance with the amended Declaration of Helsinki; all participants provided written informed consent (ClinicalTrials. gov identifier NCT02348619; EudraCT number 2014-005515-16). FUNDING/SUPPORT: This study was supported by Jazz Pharmaceuticals. In 2014, Jazz Pharmaceuticals acquired a license to develop and commercialize solriamfetol from Aerial Biopharma. Jazz Pharmaceuticals has worldwide development, manufacturing, and commercialization rights to solriamfetol, excluding certain jurisdictions in Asia. SK Biopharmaceuticals, the discoverer of the compound (also known as SKL-N05), maintains rights in 12 Asian markets, including Korea, China and Japan. Editorial assistance in formatting, proofreading, copyediting, and fact-checking was provided by The Curry Rockefeller Group LLC. Jazz Pharmaceuticals provided funding to The Curry Rockefeller Group LLC for writing and editorial support. *Collaborators from the Tones 4 Study Investigators group are listed in the Acknowledgments.

Seizures occurred in 15% of patients with parenchymal brain hemorrhage (early in 12% and delayed in 3%). Seizures were most frequent with lobar hemorrhages and uncommon with deep subcortical hemorrhages. Lobar hemorrhages in the frontal, parietal, or temporal region were more commonly associated with seizures, whereas occipital hemorrhages were not. Seizures were most common if the hemorrhage was due to an aneurysm, angioma, or neoplasm and less common if hypertensive or spontaneous. If the patient had recurrent seizures or developed delayed seizures, CT showed that the hemorrhage evolved to a hypodense appearance; if the seizure did not recur, CT showed that the hemorrhage evolved to an isodense appearance.

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A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short stature, ataxia, cardiac conduction defects, and pigmentary retinopathy. Muscle biopsy revealed ragged-red fibers. Electron microscopy showed increased numbers of mitochondria with disordered structure and paracrystalline inclusions. Enzymatic analysis revealed a deficiency of complex II of the mitochondrial respiratory chain, and, more specifically, a deficiency of succinic dehydrogenase, although both subunits of this enzyme proved to be present by immunologic analysis. Therapy with vitamin cofactors did not result in short-term improvement. This appears to be the first report of complex II deficiency in a patient with KSS.

Polysomnographic sleep patterns in Huntington's disease (HD) have been studied sporadically in small groups of patients, providing variable results. In this study, by comparing the polysomnographic sleep patterns of HD patients and their unaffected relatives, identifying sleep traits more specifically related to the HD gene was attempted. The results corroborated previously reported findings of prolonged sleep latency and the virtual absence of nocturnal respiratory disturbances in early HD. Sleep latency in the HD patients positively correlated with the results of a screening test for frontal lobe dysfunction. Larger, more standardized studies will be needed to correlate genetic markers and sleep patterns in HD.

Ninety-two percent of 100 patients with putaminal hemorrhage were hypertensive. Of the eight normotensive patients, seven were substance abusers or had bilateral putaminal hemorrhages. The one other normotensive patient was less than 40 years old. The 100 hemorrhages had the following locations: 1. medial putaminal (17 cases; six were normotensive and less than 40 years old and five were substance abusers); 2. lateral putaminal extending through the external capsule (eleven cases); 3. putaminal-capsular and subcortical white matter (32 cases); 4. putaminal cerebral hemispheric (19 cases); 5. putaminal-thalamic (19 cases); 6. bilateral (two cases). A disproportionate number of black patients suffered hematoma extension to the cerebral hemispheres or thalamus (46%) compared to Caucasians (23%). Overall mortality was 20% (17 blacks and three Caucasians) and occurred in patients with hematoma extension to the thalamus or cerebral hemispheres. Contrast-enhanced CT was performed in all 100 patients and provided no additional diagnostic yield. This indicates limited use for enhanced CT in hypertensive patients with putaminal hemorrhage who have a characteristic appearance of the acute hemorrhage on the nonenhanced CT.

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