Sleep-Induced Apraxia of Eyelid Opening

Original Contribution Sleep-Induced Apraxia of Eyelid Opening Sara N. Reggie, MD, John J. Chen, MD, PhD, Michael S. Lee, MD, Sophia M. Chung, MD Background: Apraxia of eyelid opening (AEO) primarily has been described as bilateral loss of volitional ability to open the eyes at certain times and often associated with neurodegenerative disease. Rarely, it can occur in isolation and as an idiopathic phenomenon. There are a few reports of unilateral AEO only on awakening from sleep. We report an additional 11 patients with this unusual variation of AEO. Methods: Retrospective, observational case series of patients collected from 3 separate neuro-ophthalmology practices. Results: All 11 patients were Caucasian women with a mean age of 59 years (range 35-80 years). All experienced AEO on awakening from sleep. Eight patients had unilateral AEO, and 3 had bilateral symptoms. The duration of episodes ranged from 3 weeks to several years. Ten of the patients reported manually elevating the eyelid to open it, while 1 patient waited for the eyelid to open spontaneously. After initial manual elevation, all patients reported normal function and position of the eyelids for the remainder of the day. Seven patients had a history of autoimmune disease. Slitlamp and fundus examinations were negative for ocular pathology to explain the patients' symptoms, and 9 patients had unremarkable brain imaging. Conclusions: AEO occurring only on awakening from sleep is a rare entity. Neuroimaging and extensive laboratory testing are not indicated without associated neurologic or ocular findings. There may be a Caucasian female preponderance and autoimmune link in patients with AEO, but further studies are required. Journal of Neuro-Ophthalmology 2017;37:390-392 doi: 10.1097/WNO.0000000000000512 © 2017 by North American Neuro-Ophthalmology Society I n 1965, Goldstein and Cogan (1) initially described apraxia of eyelid opening (AEO) as "a non-paralytic motor abnormality characterized by the patient's difficulty initiating the act Department of Ophthalmology (SNR, SMC), Saint Louis University, Saint Louis, Missouri; Department of Ophthalmology (JJC), Mayo Clinic, Rochester, Minnesota; and Department of Ophthalmology (MSL), University of Minnesota, Minneapolis, Minnesota. The authors report no conflicts of interest. Address correspondence to Sophia M. Chung, MD, 1755 South Grand Boulevard, Saint Louis, MO 63104; E-mail: [e-mail] 390 of lid elevation." Eyelid opening requires activation of the levator palpebrae superioris (LPS) with concurrent inhibition of the orbicularis oculi muscle. AEO may involve prolonged inhibition of the LPS with or without simultaneous contraction of the pretarsal portion of the orbicularis oculi muscle. Therefore, this entity may represent a form of eyelid dystonia (2,3). AEO previously has been described as a bilateral occurrence associated with benign essential blepharospasm, extrapyramidal disease, and hemispheric lesions (i.e., stroke) (1-5). Rare cases have been reported without an associated neurologic disorder and resolving with manual elevation of the eyelid (6). Cherian and Foroozan (7) published a case series of 5 patients who had benign unilateral AEO on awakening from sleep. We present an additional 11 patients with this unique form of AEO. METHODS A Health Insurance Portability and Accountability Act (HIPAA)-compliant, retrospective, and institutional review board-approved analysis was performed of patients treated at 3 separate neuro-ophthalmology academic centers (Saint Louis University in Saint Louis, Missouri, Mayo Clinic in Rochester, MN, and University of Minnesota in Minneapolis, MN) from March 2015 to February 2016. Patients selected for review had symptoms consistent with unilateral or bilateral AEO distinctly on awakening from sleep. Additional data extracted from the charts included patients' age, sex, and race; frequency and duration of symptoms; past medical and ocular history; current medications; examination findings; laboratory tests and neuroimaging results; and if/when symptom resolution occurred. RESULTS Of the 11 patients included in our study, all were Caucasian women with a median age of 59 years (range 35-80 years). Each experienced inability to open an upper eyelid only after awakening from sleep. Three patients reported AEO after naps and nocturnal sleep, one of whom specified that symptoms occurred every time she napped for 30 minutes or longer. The Reggie et al: J Neuro-Ophthalmol 2017; 37: 390-392 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution other patients did not specify a certain period during which they had to be asleep for symptoms to occur. Eight patients had unilateral involvement. One patient had bilateral involvement at onset of her symptoms, whereas 2 patients initially experienced unilateral AEO which, over several months, evolved into bilateral AEO. Most patients experienced symptoms every morning, but 1 patient experienced apraxia only once a week. Patients reported manually elevating the eyelid on awakening led to complete resolution of AEO for the rest of the day. Also, they denied crusting or sticky sensation to the eyelids and often reported the eyelids as "weak." If the eyelid was not manually lifted on awakening, the duration of ptosis ranged from 1.5 to 4 minutes before the eyelid spontaneously opened; thereafter, the eyelid remained open in a normal position for the remainder of the day. All patients denied variability in lid position, diplopia, and associated vision changes. On examination, 2 patients had mild superficial punctate epithelial erosions consistent with dry eye. One patient, who had experienced bilateral AEO, exhibited mild left eyelid ptosis with miosis; however, apraclonidine testing was negative for Horner Syndrome. Beyond these findings, none of the patients had ocular pathology on examination to explain their AEO on awakening. Nine patients underwent brain MRI, which did not show any explanatory abnormalities. Seven of the 11 patients had a medical history of one or more autoimmune diseases including hypothyroidism (n = 3), systemic lupus erythematosus (n = 1), psoriasis (n = 2), polymyalgia rheumatic (n = 1), giant cell arteritis (n = 1), and multiple sclerosis (n = 1). The duration of AEO episodes in our patients ranged from 3 weeks to several years, some of which were still ongoing at the time of our study. Five patients had spontaneous and complete resolution over the ensuing 3- 16 months. One patient with bilateral AEO experienced resolution of the left eyelid ptosis after 1.6 years but had persistent apraxia of right upper eyelid opening on awakening at the time of last follow-up. Five patients with unresolved symptoms were instructed to use ophthalmic lubricating ointment in the affected eye(s) at bedtime to better evaluate the link, if any, of this phenomenon to dry eye disease. All 5 patients reported no change in the AEO after 1 month of ointment use. The remaining 6 patients either had complete resolution before the ointment trial was performed, or they were lost to follow-up. DISCUSSION AEO is a nonparalytic motor abnormality defined by difficulty initiating eyelid elevation. The term reflects the inability to open the eyes at will with preservation of the ability to open them and to keep them open at other times (4). Ipsilateral levator palpebrae inhibition has been proposed as the underlying mechanism with another being the pretarsal contraction of the orbicularis muscle. AEO has been associated with benign essential blepharospasm, Reggie et al: J Neuro-Ophthalmol 2017; 37: 390-392 extrapyramidal syndromes, and hemispheric lesions, and it has been speculated that AEO occurs as a result of loss of supranuclear control of the LPS nuclear complex (1-5). Cherian and Foroozan (7) reported a series of 5 patients with unilateral AEO only on awakening. In each case, AEO occurred only after sleep, resolved with manual elevation of the eyelid, and was not associated with any neurological disease. Four of these 5 patients experienced resolution of symptoms in 6-12 months. Similar to our report, their patients exhibited a female preponderance (3 of 5) with an age range of 49-71 years. Sleep and wakefulness have been shown to be an intricate balance of multiple neurotransmitters released from the hypothalamus. Arousal is promoted by release of acetylcholine, norepinephrine, and histamine (8). During sleep, there is an inhibition of ascending cholinergic tracts by gamma-aminobutyric acid and galanin and therefore a disconnection between the brainstem and higher brain centers (7,9). When awakening occurs, an impulse is generated through electrical coupling which reverses this inhibitory process (7,9). Thus, balance of these excitatory and inhibitory neurotransmitters influences control over the muscles of the eyelid as part of the sleep/wake process. It is believed that the periaqueductal gray (PAG) receives afferent signals for arousal and awakening from the limbic and reticular systems and sequentially stimulates the nearby central caudate nucleus (CCN) of the oculomotor nerve complex and, in turn, the LPS (10). Although the nuclear control of the LPS is considered unpaired, the premotor control of the muscles is partially lateralized (7,9). Schmidtke and Buttner-Ennever (10) hypothesized that perhaps the phylogenetically old concept of the LPS being innervated by contralateral neurons may be retained at the premotor level. Stimulation of the PAG, which lies directly dorsal to the oculomotor nucleus, has been shown in animal studies to elicit both unilateral and bilateral eyelid retraction (7,10). Moreover, supranuclear and cerebral lesions can cause either unilateral or bilateral reduction of LPS tonus (10). It has been suggested that perhaps the manual elevation of the eyelid by the patient represents a geste antagoniste similar to that in eyelid opening apraxia after blepharospasm (7). In patients who had spontaneous resolution of symptoms after 3-4 minutes, the stimulation of the CCN is likely delayed. This may lead to prolonged rapid eye movement sleep muscle atonia or localized sleep paralysis of the eyelid. It is likely that spontaneous resolution would occur in all the patients if allowed sufficient time, but most patients are disturbed by the ptosis and will voluntarily elevate the eyelid. Some ophthalmologists may attribute our patients' symptoms to the overnight effects of dry eye. As the eyes dry out, mucus seals the lid margins, and air and fluid are expressed between the eyelids, creating a suction effect and causing mechanical difficulty of opening the eyes on awakening. We believe this unlikely as only 2 of our patients had examination findings consistent with dry eye syndrome. 391 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution The common unilaterality of the AEO and the relatively young age of many of our patients make dry eye an unlikely explanation. Typically, these patients complain of foreign body sensation, grittiness, and tired red eyes worse at the end of the day and worse in areas of low humidity. Nine of the 11 patients did not voice such complaints and failed to show anterior segment pathology. In addition, lubricating ointment did not improve the symptoms in patients who had persistent AEO. Finally, since dry eye syndrome is a very common ophthalmologic problem, one would expect that ophthalmologists would encounter many more patients with AEO than is currently reported. Interestingly, 7 of our 11 patients had a medical history of one or more autoimmune diseases. By contrast, only 1 of the 5 patients reported by Cherian and Foroozan (7) had a history of an autoimmune disease, perhaps because of a smaller sample size. The fact that autoimmune diseases are more common in Caucasian women may explain why our patients share the same demographic. Interestingly, based on our literature review, no systemic autoimmune disease has been associated with AEO only on awakening from sleep. Our case series was limited by the retrospective nature of the study. The fact that our patients were gathered from 3 separate centers creates a lack of standardization in gathering examination findings, as well as systematic ancillary laboratory testing and neuroimaging. Nevertheless, our study and previous reports indicate that AEO on awakening is a benign disorder requiring patient reassurance rather than undertaking extensive laboratory testing and neuroimaging. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. N. Reggie, J. J. Chen, M. S. Lee, and S. M. Chung; b. Acquisition of data: S. N. Reggie, J. J. Chen, 392 M. S. Lee, and S. M. Chung; c. Analysis and interpretation of data: S. N. Reggie, J. J. Chen, M. S. Lee, and S. M. Chung. Category 2: a. Drafting the manuscript: S. N. Reggie, J. J. Chen, M. S. Lee, and S. M. Chung; b: Revising it for intellectual content: S. N. Reggie, J. J. Chen M. S. Lee, and S. M. Chung. Category 3: a. Final approval of the completed manuscript: S. N. Reggie, J. J. Chen, M. S. Lee, and S. M. Chung. ACKNOWLEDGMENTS S. N. Reggie had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. REFERENCES 1. Goldstein JE, Cogan DG. 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