{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:21:22Z","timestamp":1780449682040,"version":"3.54.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T00:00:00Z","timestamp":1680566400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T00:00:00Z","timestamp":1680566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Royal Library, Copenhagen University Library"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neurochir"],"abstract":"<jats:title>Abstract\n<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner\u2019s syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and\/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5\u2013120\u00a0min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We included 15 comatose ICU patients (seven women, mean age 59\u2009\u00b1\u200913.8\u00a0years) and 15 controls (seven women, mean age 55\u2009\u00b1\u200916.3\u00a0years). At 30\u00a0min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil:\u2009\u2212\u20091.31\u00a0mm, 95% CI [\u2212\u20091.51;\u2009\u2212\u20091.11], <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), but in none (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) of the 15 ICU patients (mean difference: 0.09\u00a0mm, 95% CI [\u2212\u20090.12;0.30], <jats:italic>p<\/jats:italic>\u2009&gt;\u20090.99). This effect was unchanged after 120\u00a0min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the \u201cintermediate zone\u201d of disorders of consciousness in the ICU seems warranted.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00701-023-05569-8","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T11:52:19Z","timestamp":1680609139000},"page":"1483-1494","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Brimonidine eye drops reveal diminished sympathetic pupillary tone in comatose patients with brain injury"],"prefix":"10.1007","volume":"165","author":[{"given":"Elisabeth Waldemar","family":"Jakobsen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vardan","family":"Nersesjan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon Sander","family":"Albrechtsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan H.","family":"Othman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshgan","family":"Amiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels Vendelbo","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merlin D.","family":"Larson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hassager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"M\u00f8ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Kjaergaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5562-9808","authenticated-orcid":false,"given":"Daniel","family":"Kondziella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,4]]},"reference":[{"key":"5569_CR1","doi-asserted-by":"publisher","unstructured":"Albrechtsen SS, Riis RGC, Amiri M, Tanum G, Bergdal O, Blaabjerg M, Simonsen CZ, Kondziella D (2022) Impact of MRI on decision-making in ICU patients with disorders of consciousness. Behav Brain Res 421:113729. https:\/\/doi.org\/10.1016\/j.bbr.2021.113729","DOI":"10.1016\/j.bbr.2021.113729"},{"key":"5569_CR2","first-page":"174","volume":"101","author":"M Bonvallet","year":"1963","unstructured":"Bonvallet M, Zbrozyna A (1963) Reticular control of the autonomic system, and particularly, the sympathetic and parasympathetic innervation of the pupil. Arch Ital Biol 101:174\u2013207","journal-title":"Arch Ital Biol"},{"key":"5569_CR3","doi-asserted-by":"publisher","first-page":"2497","DOI":"10.1056\/NEJMoa1812757","volume":"380","author":"J Claassen","year":"2019","unstructured":"Claassen J, Doyle K, Matory A, Couch C, Burger KM, Velazquez A et al (2019) Detection of brain activation in unresponsive patients with acute brain injury. N Engl J Med 380:2497\u20132505","journal-title":"N Engl J Med"},{"key":"5569_CR4","first-page":"1","volume":"3","author":"DASAIM","year":"2022","unstructured":"DASAIM (2022) Sedationsstrategi - M\u00e5lrettet behandling af gener forbundet med kritisk sygdom. Guidel - Dansk Selsk An\u00e6stesiologi og Intensiv Med 3:1\u201339","journal-title":"Guidel - Dansk Selsk An\u00e6stesiologi og Intensiv Med"},{"key":"5569_CR5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1227\/01.NEU.0000163425.79170.CB","volume":"57","author":"R Du","year":"2005","unstructured":"Du R, Meeker M, Bacchetti P, Larson MD, Holland MC, Manley GT (2005) Evaluation of the portable infrared pupillometer. Neurosurgery 57:198\u2013202","journal-title":"Neurosurgery"},{"key":"5569_CR6","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1007\/s12028-013-9870-x","volume":"19","author":"BL Edlow","year":"2013","unstructured":"Edlow BL, Giacino JT, Hirschberg RE, Gerrard J, Wu O, Hochberg LR (2013) Unexpected recovery of function after severe traumatic brain injury: the limits of early neuroimaging-based outcome prediction. Neurocrit Care 19:364\u2013375","journal-title":"Neurocrit Care"},{"key":"5569_CR7","doi-asserted-by":"publisher","first-page":"2399","DOI":"10.1093\/brain\/awx176","volume":"140","author":"BL Edlow","year":"2017","unstructured":"Edlow BL, Chatelle C, Spencer CA, Chu CJ, Bodien YG, O\u2019Connor KL et al (2017) Early detection of consciousness in patients with acute severe traumatic brain injury. Brain 140:2399\u20132414","journal-title":"Brain"},{"key":"5569_CR8","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.bja.2017.10.002","volume":"120","author":"D Harvey","year":"2018","unstructured":"Harvey D, Butler J, Groves J, Manara A, Menon D, Thomas E et al (2018) Management of perceived devastating brain injury after hospital admission: a consensus statement from stakeholder professional organizations. Br J Anaesth 120:138\u201345","journal-title":"Br J Anaesth"},{"key":"5569_CR9","doi-asserted-by":"publisher","unstructured":"Kato COS, Shimizu K, Kamiya K, Ishikawa H, Igarashi A (2018) Effects of brimonidine tartrate 0.1% ophthalmic solution on the pupil, refraction, and light reflex. Sci Rep 88(1):9003. https:\/\/doi.org\/10.1038\/s41598-018-27436-8","DOI":"10.1038\/s41598-018-27436-8"},{"key":"5569_CR10","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1097\/00055735-199912000-00005","volume":"10","author":"A Kawasaki","year":"1999","unstructured":"Kawasaki A (1999) Physiology, assessment, and disorders of the pupil. Curr Opin Ophthalmol 10:394\u2013400","journal-title":"Curr Opin Ophthalmol"},{"key":"5569_CR11","doi-asserted-by":"publisher","first-page":"213","DOI":"10.4037\/ajcc2016554","volume":"25","author":"RG Kerr","year":"2016","unstructured":"Kerr RG, Bacon AM, Baker LL, Gehrke JS, Danielle Hahn K, Lillegraven CL et al (2016) Underestimation of pupil size by critical care and neurosurgical nurses. Am J Crit Care 25:213\u2013219","journal-title":"Am J Crit Care"},{"key":"5569_CR12","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1016\/j.jcrs.2004.02.043","volume":"30","author":"A Kesler","year":"2004","unstructured":"Kesler A, Shemesh G, Rothkoff L, Lazar M (2004) Effect of brimonidine tartrate 0.2% ophthalmic solution on pupil size. J Cataract Refract Surg 30:1707\u201310","journal-title":"J Cataract Refract Surg"},{"key":"5569_CR13","doi-asserted-by":"crossref","unstructured":"Kondziella D, Amiri M, Othman M, Beghi E, Bodien Y, Citerio G et al (2022) Incidence and prevalence of coma in the United Kingdom and the United States. Brain Commun 4:fcac188","DOI":"10.1093\/braincomms\/fcac188"},{"key":"5569_CR14","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1111\/ene.14151","volume":"27","author":"D Kondziella","year":"2020","unstructured":"Kondziella D, Bender A, Diserens K, van Erp W, Estraneo A, Formisano R et al (2020) European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness. Eur J Neurol 27:741\u2013756","journal-title":"Eur J Neurol"},{"key":"5569_CR15","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1136\/jnnp-2015-310958","volume":"87","author":"D Kondziella","year":"2016","unstructured":"Kondziella D, Friberg CK, Frokjaer VG, Fabricius M, M\u00f8ller K (2016) Preserved consciousness in vegetative and minimal conscious states: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 87:485\u2013492","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"5569_CR16","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1097\/00000542-199610000-00009","volume":"85","author":"MD Larson","year":"1996","unstructured":"Larson MD, Tayefeh F, Sessler DI, Daniel M, Noorani M (1996) Sympathetic nervous system does not mediate reflex pupillary dilation during desflurane anesthesia. Anesthesiology 85:748\u2013754","journal-title":"Anesthesiology"},{"key":"5569_CR17","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/BF00913471","volume":"12","author":"IE Loewenfeld","year":"1958","unstructured":"Loewenfeld IE (1958) Mechanisms of reflex dilatation of the pupil; historical review and experimental analysis. Doc Ophthalmol 12:185\u2013448","journal-title":"Doc Ophthalmol"},{"key":"5569_CR18","volume-title":"The pupil: anatomy, physiology and clinical applications","author":"IE Loewenfeld","year":"1999","unstructured":"Loewenfeld IE (1999) The pupil: anatomy, physiology and clinical applications. Wayne State University Press, Detroit"},{"key":"5569_CR19","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1111\/j.1749-6632.1964.tb48169.x","volume":"117","author":"O Lowenstein","year":"1964","unstructured":"Lowenstein O, Loewenfeld IE (1964) The sleep-waking cycle and pupillary activity. Ann N Y Acad Sci 117:142\u2013156","journal-title":"Ann N Y Acad Sci"},{"key":"5569_CR20","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1007\/s12028-016-0275-5","volume":"25","author":"CJ Ong","year":"2016","unstructured":"Ong CJ, Dhand A, Diringer MN (2016) Early withdrawal decision-making in patients with coma after cardiac arrest: a qualitative study of intensive care clinicians. Neurocrit Care 25:258\u201365","journal-title":"Neurocrit Care"},{"key":"5569_CR21","doi-asserted-by":"crossref","unstructured":"Opic P, R\u00fcegg S, Marsch S, Gut SS, Sutter R (2021) Automated quantitative pupillometry in the critically ill: a systematic review of the literature. Neurology [Internet]. Neurology [cited 2022 Jun 2] 97:e629\u201342. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/34045270\/","DOI":"10.1212\/WNL.0000000000012295"},{"key":"5569_CR22","doi-asserted-by":"publisher","unstructured":"Peinkhofer C, Knudsen GM, Moretti R, Kondziella D (2019) Cortical modulation of pupillary function: systematic review. PeerJ 7:e6882. https:\/\/doi.org\/10.7717\/peerj.6882","DOI":"10.7717\/peerj.6882"},{"key":"5569_CR23","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1002\/ana.25045","volume":"82","author":"F Raimondo","year":"2017","unstructured":"Raimondo F, Rohaut B, Demertzi A, Valente M, Engemann DA, Salti M, Slezak DF, Naccache L, Sitt JD (2017) Brain-heart interactions reveal consciousness in noncommunicating patients. Ann Neurol 82:578\u2013591","journal-title":"Ann Neurol"},{"key":"5569_CR24","doi-asserted-by":"publisher","first-page":"254","DOI":"10.2174\/157015908785777193","volume":"6","author":"E Samuels","year":"2008","unstructured":"Samuels E, Szabadi E (2008) Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans. Curr Neuropharmacol 6:254\u2013285","journal-title":"Curr Neuropharmacol"},{"key":"5569_CR25","doi-asserted-by":"publisher","first-page":"235","DOI":"10.2174\/157015908785777229","volume":"6","author":"E Samuels","year":"2008","unstructured":"Samuels E, Szabadi E (2008) Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr Neuropharmacol 6:235\u2013253","journal-title":"Curr Neuropharmacol"},{"key":"5569_CR26","doi-asserted-by":"publisher","first-page":"1779","DOI":"10.1016\/j.resuscitation.2014.08.011","volume":"85","author":"C Sandroni","year":"2014","unstructured":"Sandroni C, Cariou A, Cavallaro F, Cronberg T, Friberg H, Hoedemaekers C et al (2014) Prognostication in comatose survivors of cardiac arrest: an advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine. Resuscitation 85:1779\u20131789","journal-title":"Resuscitation"},{"key":"5569_CR27","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1001\/jamaneurol.2015.2899","volume":"72","author":"ND Schiff","year":"2015","unstructured":"Schiff ND (2015) Cognitive motor dissociation following severe brain injuries. JAMA Neurol 72:1413\u20131415","journal-title":"JAMA Neurol"},{"key":"5569_CR28","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/0002-9394(71)91323-7","volume":"72","author":"HS Thompson","year":"1971","unstructured":"Thompson HS, Mensher JH (1971) Adrenergic mydriasis in Horner\u2019s syndrome. Hydroxyamphetamine test for diagnosis of postganglionic defects. Am J Ophthalmol 72:472\u201380","journal-title":"Am J Ophthalmol"},{"issue":"4","key":"5569_CR29","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1007\/s10792-021-02109-0","volume":"42","author":"D Top Karti","year":"2022","unstructured":"Top Karti D, Karti O, SaruhanDurmaz G, Gokcay F, Celebisoy N (2022) The evaluation of patient demographics, etiologies and apraclonidine test results in adult Horner\u2019s syndrome. Int Ophthalmol 42(4):1233\u20131239","journal-title":"Int Ophthalmol"},{"key":"5569_CR30","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1503\/cmaj.101786","volume":"183","author":"AF Turgeon","year":"2011","unstructured":"Turgeon AF, Lauzier F, Simard JF, Scales DC, Burns KEA, Moore L et al (2011) Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study. CMAJ 183:1581\u20131588","journal-title":"CMAJ"},{"key":"5569_CR31","doi-asserted-by":"publisher","unstructured":"Vassilieva A, Olsen MH, Peinkhofer C, Knudsen GM, Kondziella D (2019) Automated pupillometry to detect command following in neurological patients: a proof-of-concept study. PeerJ\u00a07:e6929. https:\/\/doi.org\/10.7717\/peerj.6929","DOI":"10.7717\/peerj.6929"},{"key":"5569_CR32","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1002\/ana.20611","volume":"58","author":"EFM Wijdicks","year":"2005","unstructured":"Wijdicks EFM, Bamlet WR, Maramattom BV, Manno EM, McClelland RL (2005) Validation of a new coma scale: the FOUR score. Ann Neurol 58:585\u201393","journal-title":"Ann Neurol"},{"key":"5569_CR33","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1097\/00000542-200312000-00008","volume":"99","author":"LL Yang","year":"2003","unstructured":"Yang LL, Niemann CU, Larson MD (2003) Mechanism of pupillary reflex dilation in awake volunteers and in organ donors. Anesthesiology 99:1281\u20131286","journal-title":"Anesthesiology"},{"key":"5569_CR34","doi-asserted-by":"publisher","first-page":"3291","DOI":"10.1093\/brain\/awab290","volume":"144","author":"MJ Young","year":"2021","unstructured":"Young MJ, Bodien YG, Giacino JT, Fins JJ, Truog RD, Hochberg LR et al (2021) The neuroethics of disorders of consciousness: a brief history of evolving ideas. Brain 144:3291\u20133310","journal-title":"Brain"}],"container-title":["Acta Neurochirurgica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00701-023-05569-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00701-023-05569-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00701-023-05569-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,29]],"date-time":"2023-05-29T08:06:10Z","timestamp":1685347570000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00701-023-05569-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,4]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["5569"],"URL":"https:\/\/doi.org\/10.1007\/s00701-023-05569-8","relation":{},"ISSN":["0942-0940"],"issn-type":[{"value":"0942-0940","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,4]]},"assertion":[{"value":"26 September 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 February 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"We confirm that this study adheres to the ethical guidelines and was approved by the Ethics Committee of the Capital Region of Denmark (file number: H-19044446).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all participants or their next-of-kin.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}