Iatrogenic Bilateral Sequential Ocular Sympathetic (Horner Syndrome) Turned Bilateral Parasympathetic Pupil Involvement Associated with Long Coronavirus-Related Dysautonomia: A Case Report

Our case presented with a pharmacologically confirmed bilateral Horner syndrome, which was presumed to be the sequelae of bilateral sequential stellate ganglion blocks (a known side effect of the procedure) [ 2 ]. Later, however, the patient developed larger (rather than smaller pupils), and topical dilute pilocarpine confirmed a bilateral ocular parasympathetic disorder with light-near dissociation and denervation supersensitivity OU. There have been several case reports of Adie’s tonic pupil or Horner syndrome following COVID-19 infection (shown in Table 1 ). However, the development of a bilateral Adie’s tonic pupil following a pharmacologically confirmed bilateral Horner syndrome is the first case to our knowledge to be reported in the literature. This development underscores the evolving presentation of dysautonomia in emerging long COVID cases. Reported cases of anisocoria in COVID-19 COVID-19, coronavirus disease-2019. In the ophthalmic literature, long COVID has been associated with scleritis, uveitis, endophthalmitis, corneal graft rejection, herpes zoster ophthalmicus, and retinal artery and vein occlusion [ 19 ]. Neuro-ophthalmic manifestations of long COVID, however, are limited and rare [ 19 ]. Increasingly, patients diagnosed with long COVID are also presenting with dysautonomia. Systemic dysautonomia can present with many signs and symptoms, including fatigue, dizziness, gastrointestinal, genitourinary, cardiovascular (orthostatic hypotension), neurologic (syncope), and ocular (anisocoria) findings [ 20 ]. While long COVID is often complicated by dysautonomia, the precise pathophysiology remains ill-defined and is likely multifactorial. Several potential mechanisms, however, have been proposed, including direct viral invasion of autonomic centers in the brain, autoimmunity with the production of antibodies against autonomic receptors, persistent inflammation, and renin-angiotensin system imbalance [ 21 ]. In our case, the initial bilateral Horner syndrome was most likely iatrogenic; however, the subsequent development of bilateral Adie’s tonic pupil in the context of worsening long COVID symptoms and dysautonomia suggests it may be influenced by long COVID immune system dysregulation. Adie’s pupil is a tonic, mydriatic pupil, due to aberrant regeneration of parasympathetic nerve fibers after ciliary ganglion damage. While Adie’s tonic pupil has been mainly idiopathic, more cases have been recognized as a post-viral phenomenon [ 12 ]. The proposed pathophysiology could be due to the strong systemic inflammatory response caused by COVID-19, causing systemic damage or denervation of the postganglionic supply to the pupil sphincter and ciliary muscle [ 16 ]. The pharmacological confirmation of bilateral ocular sympathetic-to-parasympathetic phases in the setting of long COVID dysautonomia and presumed neurotropism of COVID suggests a relationship between the onset of Adie’s tonic pupil and long COVID. The patient had comorbidities that we understand could have been differentials regarding her dysautonomia. Seropositive RA has been associated with measurable autonomic nervous system dysfunction [ 22 ]. This may be due to chronic systemic inflammation in RA [ 22 ]. Studies have also discovered that autonomic dysfunction may precede a diagnosis of RA, suggesting autonomic nervous system dysfunction may also be a contributing factor for RA rather than a consequence [ 23 ]. However, RA-associated autonomic dysfunctions usually do not report fixed tonic pupils or parasympathetic failures as part of their autonomic neuropathy but rather increased sympathetic activity. Another differential was the patient’s PTSD, since PTSD and related anxiety disorders have been linked to dysautonomia with a heightened sympathetic nervous system [ 24 ]. In this patient, PTSD and anxiety were both related to her initial episode of COVID and, similar to her RA diagnosis, have been well controlled for over 4 years. Therefore, we are less likely to attribute the underlying cause of her dysautonomia to her psychiatric conditions. While seropositive RA and PTSD may have contributed to dysautonomia, the pharmacological evidence favors true peripheral parasympathetic pupillary denervation as the main mechanism for the tonic pupils observed in this patient. In our patient, these conditions were diagnosed after her first COVID infection, leading us to believe that the underlying dysautonomia can be explained by the unifying diagnosis of long-COVID and psychiatric comorbidities. While there have been individually documented post-COVID manifestations of anisocoria, this case is the first report of both a pharmacologically confirmed iatrogenic bilateral Horner syndrome and bilateral Adie’s tonic pupil occurring sequentially in a patient with long COVID dysautonomia, highlighting the potential for widespread autonomic nervous system involvement of both sympathetic and parasympathetic ocular pathways. Clinicians should be aware of the presentations of dysautonomia in the pupil including Horner syndrome and the tonic pupil. Bilateral cases of either Horner syndrome or Adie’s syndrome are rare and should prompt evaluation including neuroimaging of the ocular sympathetic or parasympathetic pathways, respectively. Testing for syphilis and other treatable etiologies is also recommended for bilateral cases of pupillary autonomic dysfunction. Future work is needed on the ocular manifestations of dysautonomia in COVID-19.

A 41-year-old female presented to our neuro-ophthalmology clinic with acute onset, painless, upper eyelid ptosis in the right eye (OD) with anisocoria. Medical history included seropositive rheumatoid arthritis (RA), post-traumatic stress disorder (PTSD), anxiety, depression, attention deficit disorder, obsessive-compulsive disorder, gastroparesis, gastroesophageal reflux disease, multiple pyelonephritis, endometriosis, polycystic ovary syndrome, fibromyalgia, type 2 diabetes, obstructive sleep apnea, and tachycardia. Her surgical history included a bilateral stellate ganglion block. Her medications were alprazolam, amitriptyline, amphetamine-dextroamphetamine, aripiprazole, hydroxychloroquine, ibuprofen, immune globulin 3%, metformin, metoprolol, montelukast, norethindrone, ondansetron, sennosides-docusate, spironolactone, esketamine, vitamin A, vitamin C, vitamin D2, zinc acetate, and zolpidem. The remainder of the medical, social, and family history was noncontributory. The patient first tested positive for COVID-19 at the beginning of the global pandemic and experienced a second reinfection with COVID-19, 2 years later. After the second episode, she reported dysphonia, but there was no vocal cord paralysis. The patient had persistent and recurrent headaches and facial pain, which failed medical therapy, and she subsequently had bilateral, sequential stellate ganglion blocks. Following the stellate block, she had anisocoria and a mild ptosis OD in her follow-up appointment with the optometrist. After 3 months, she came to our clinic and presented with ptosis that was more pronounced in her left eye (OS). The visual acuity was 20/25 in both eyes (OU). The patient had anisocoria with the pupils measuring 2 mm OD and 3 mm OS in the light and 6 mm OD and 7 mm OS in the dark (shown in Fig. 1 a, b). There was a mild bilateral ptosis OU (shown in Fig. 1 b). Both pupils reacted normally to light and near stimuli. No light-near dissociation or sector iris paresis was noted. The anisocoria was slightly more pronounced in the dim light conditions with a dilation lag OD consistent with Horner syndrome. Bilateral Horner syndrome. Patient’s pupils under light ( a ) and dim light ( b ) conditions. Anisocoria and mild ptosis before ( a ) and after ( c ) the administration of topical apraclonidine, showing dilation of both pupils and reversal of ptosis. Topical apraclonidine was administered to both pupils, and both pupils dilated (shown in Fig. 1 c) compared with pre-apraclonidine baseline (shown in Fig. 1 a). There was partial resolution of the ptosis OU after topical apraclonidine (shown in Fig. 1 c). The dilation of both pupils and reversal of ptosis after the administration of topical apraclonidine OU were consistent with a bilateral Horner syndrome presumed to be secondary to the bilateral sequential stellate ganglion blocks. Magnetic resonance (MR) imaging and MR angiography of the head, neck, and upper chest from the hypothalamus-to-thoracic level T2 in the chest showed no structural lesion. Computed tomography of the chest showed a few scattered calcified benign granulomas but no hilar lymphadenopathy or mass. Serum angiotensin-converting enzyme, lysozyme, magnesium, calcium, complete blood count, liver function studies, and interferon-gamma release assay (QuantiFERON) were negative. Three months later, the patient then developed intermittent postural orthostatic tachycardia syndrome, with orthostatic hypotension and mast cell activation syndrome. The primary care physician noted worsening long COVID symptoms including fatigue, lightheadedness, and generalized muscle pain. She developed multiple recurrent urinary tract infections and a spastic bladder, which was treated with botulinum toxin injections. A diagnosis of long COVID-related dysautonomia was made. The mydriasis from the patient’s bilateral Horner syndrome continued until the patient noticed new symptoms of blurry vision and dry eyes. Five months after her previous appointment with her primary care physician, the patient returned to the neuro-ophthalmology service with new complaints of larger pupils in both eyes. The pupils now measured 6 mm OD and 9 mm OS and were poorly reactive to light with light-near dissociation OU (shown in Fig. 2 a). Topical dilute (0.1%) pilocarpine constricted both pupils (shown in Fig. 2 b). The constriction of pupils after administration of dilute pilocarpine OU is consistent with a bilateral Adie’s tonic pupil. Bilateral Adie’s tonic pupil. The patient demonstrates anisocoria with larger pupils bilaterally in ambient light conditions compared with prior baseline ( a ). After the administration of dilute topical pilocarpine ( b ), both pupils constricted, consistent with ocular parasympathetic denervation and pharmacological supersensitivity. Nerve conduction studies, electromyography, and a skin punch biopsy were negative. The biopsy showed a superficial lymphocytic perivascular inflammation in the right lower thigh biopsy.

In 2019, a novel coronavirus disease 2019 (COVID-19) global pandemic affected more than 777 million individuals. The severe acute respiratory syndrome coronavirus (SARS-CoV-2) responsible for COVID-19 typically results in pneumonia and pulmonary disorders but has well-known extrapulmonary manifestations in the acute and chronic phases. However, long duration and delayed sequelae of COVID-19 can develop months to years after the initial infection. Long COVID, or the post-acute sequelae of SARS-CoV-2, is defined as a chronic condition that is persistent for more than 3 months and cannot be better explained by an alternative diagnosis [ 1 ]. Long COVID typically presents with cognitive impairment, fatigue, and shortness of breath, but up to 67% of patients develop dysautonomia [ 1 ]. After conducting a literature review utilizing PubMed and Google Scholar, using the key words bilateral Horner syndrome and bilateral Adie’s tonic pupil, we did not find any prior reports of a pharmacologically confirmed bilateral Horner syndrome followed by a pharmacologically confirmed bilateral tonic pupil in the same patient. In our case, this presentation is in the setting of sequential oculoparasympathetic dysautonomia from long COVID.

Andrew G. Lee, MD, serves as a consultant for the National Aeronautics and Space Administration (NASA) and the National Football League (NFL) and is a consultant for Amgen (speakers bureau, Advisory Board), AstraZeneca, Bristol-Myers Squibb, Alexion (speakers bureau), Stoke, Viridian, Ethyreal, Catalyst, and the US Department of Justice (DOJ). The views expressed here are the authors’ own and do not necessarily represent those of NASA or the US government. The following authors have no financial disclosures: C.Y.W., J.K.D., E.O.A., S.J., and K.C.L.

This study was not supported by any sponsor or funder.

This case report adheres to the ethical standards outlined in the Declaration of Helsinki. This report was a retrospective review of patient data and therefore did not require ethical approval according to local and national guidelines. Written informed consent for publication was obtained from the patient for this medical case along with any accompanying images. All identifying information has been anonymized to protect the patient’s privacy. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550937 ).

C.Y.W.: conceptualization, investigation, writing – original draft, review, and editing, and visualization. J.K.D.: conceptualization, writing – original draft, review, and editing, and visualization. E.O.A. and S.J.: conceptualization, investigation, and writing – review and editing. K.C.L.: conceptualization, investigation, supervision, and writing – review and editing. A.G.L.: project administration, conceptualization, investigation, supervision, writing – original draft, review, and editing, and visualization.