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Volume 14 No. 08
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Accepted Papers

Letters to the Editor

Adopting the Unentrained Orphan

Roneil G. Malkani, MD, MS; Sabra M. Abbott, MD, PhD; Phyllis C. Zee, MD, PhD
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

We greatly appreciate Dr. Garbazza's important points that highlight the need to improve recognition and increase research on the pathophysiology of non-24-hour sleep-wake disorder (N24SWD), particularly in sighted people.1 First, although assumed to be rare disorder, our clinical experience is that sighted N24SWD is more common than previously thought. While our clinical sample may be biased because it is from a circadian medicine clinic, we see a significant overlap between the extreme delayed sleep-wake phase disorder (DSWPD) and sighted patients with N24SWD. This overlap, and the high frequency of comorbid psychiatric illnesses,2 likely contribute to N24SWD being often overlooked. Second, entrainment in some people with DSWPD may not be stable as was previously assumed. As we showed in our case series,3 DSWPD often precedes N24SWD; hence, those with less stable entrainment may be at risk for developing N24SWD. Given this clinical overlap, patients with N24SWD may be on a spectrum with DSWPD, so people with N24SWD may be misdiagnosed as DSWPD. Improving recognition and consideration of this disorder in the differential diagnosis of circadian rhythm sleep-wake disorders is the first step to estimating the actual prevalence of N24SWD.

Regarding tasimelteon therapy for N24SWD, while the United States prescribing information for tasimelteon does not specify that individuals with N24SWD must be blind, the clinical trials were all performed in blind individuals. Given that the mechanisms that underlie non-entrainment may potentially differ between sighted and non-sighted patients with N24SWD, there is a need to conduct clinical trials in sighted patients to determine the appropriate dose range and timing of this melatonin receptor agonist. It is also unknown whether tasimelteon may be more efficacious than melatonin in this population. We strongly encourage clinical trials of both pharmacotherapy and behavioral treatment approaches in this population.

We fully support the suggestion by Dr. Garbazza that a shared database of these patients will further our understanding of the genetic and pathophysiologic mechanisms underlying N24SWD and help to advance the development of treatments. At the Northwestern University Center for Circadian and Sleep Medicine, we are also developing a database of patients with circadian rhythm sleep-wake disorders, including sighted N24SWD. International collaboration and heightened awareness of N24SWD will be critical to achieve these goals.


Work for this study was performed at Northwestern University. All authors have seen and approved the manuscript. The authors have no conflicts of interest related to the work in this manuscript. Roneil Malkani has received grant support from the National Institutes of Health, Illinois Department of Public Health, Alzheimer's Association, and Northwestern University. Sabra Abbott has received grant support from the American Sleep Medicine Foundation the National Institutes of Health, and the Defense Advanced Research Projects Agency. Phyllis Zee serves as a consultant for Philips, Merck, Eisai and Aptynix received grant support from Eisai, Jazz, and Technogel, Harmony and has stock ownership in Teva. There was no investigational or off label use.


Malkani RG, Abbott SM, Zee PC. Adopting the unentrained orphan. J Clin Sleep Med. 2018;14(8):1447.



Garbazza C. Non-24-hour sleep-wake disorder in sighted patients: dealing with an orphan disease. J Clin Sleep Med. 2018;14(8):1445–1446.


Hayakawa T, Uchiyama M, Kamei Y, et al. Clinical analyses of sighted patients with non-24-hour sleep-wake syndrome: a study of 57 consecutively diagnosed cases. Sleep. 2005;28(8):945–952. [PubMed]


Malkani RG, Abbott SM, Reid KJ, Zee PC. Diagnostic and treatment challenges of sighted non-24-hour sleep-wake disorder. J Clin Sleep Med. 2018;14(4):603–613. [PubMed]