Isolated Nonreactive Mydriasis in Herpes Zoster Ophthalmicus: An Uncommon Complication

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Isolated Nonreactive Mydriasis in Herpes Zoster Ophthalmicus: An Uncommon Complication Víctor Antonio Blanco-Palmero, MD, Ana Ortueta-Olartecoechea, MD, David UriartePérez de Urabayen, MD, Mario Sánchez-Tornero, MD, Antonio Méndez-Guerrero, MD, Michele Matarazzo, MD H erpes zoster ophthalmicus (HZO) is defined as the reactivation of latent varicella-zoster virus (VZV) infection involving the ophthalmic division of the trigeminal nerve. This condition is associated with a large number of complications that may not only affect the skin and anterior segment of the eye but also the optic and oculomotor nerves, retina, and central nervous system (1). Isolated internal ophthalmoplegia with features of a tonic pupil as the sole cranial nerve complication is a very rare finding in HZO. Here, we present 2 patients who developed this uncommon sign and review all the cases reported associated with VZV infection or reactivation. A 31-year-old woman reported left supraorbital pain 3 days before the onset of a vesicular rash over the V1 and V2 left trigeminal branches. Her medical history was remarkable for untreated chronic HIV infection. Ophthalmological examination on the day the rash appeared revealed conjunctival redness, small corneal epithelial defects, and a pseudodendrite. No inflammatory cells were identified in the anterior chamber. Both pupils were round and regular with normal reaction to light and accommodation and normal visual acuity. She was diagnosed with HZO and started on oral valacyclovir (1g/8 h). At follow-up, 12 days after rash onset, she complained of eyelid edema and blurred vision on near. New vesicular lesions appeared on V1 and V2 skin regions. Slit-lamp examination showed left eye conjunctival ciliary injection, corneal edema, Hospital Universitario 12 de Octubre (VAB-P, DU-PU, MS-T, AM-G), Neurology Department, Madrid, Spain; Hospital Universitario 12 de Octubre (AO-O), Ophthalmology Department, Madrid, Spain; HMCINAC (MM), Hospital Universitario HM Puerta del Sur, Neurology Department, Móstoles, Spain; and Pacific Parkinson’s Research Centre (MM), University of British Columbia, Vancouver, BC, Canada. V. A. Blanco-Palmero is supported by Instituto de Salud Carlos III (ISCIII; Spanish Biomedical Research Institute) through a “Río Hortega” contract (CM 18/00095). V. A. Blanco-Palmero has received speaking fees from Admiral. The remaining authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Víctor Antonio Blanco-Palmero, MD, Hospital Universitario 12 de Octubre, Neurology Department, Avenida de Córdoba s/n, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain; E-mail: [e-mail] e508 marked flare, +++ Tyndall on anterior chamber, and neither posterior nor anterior synechiae. Intraocular pressure was normal, and gonioscopy was not performed. Left pupil was 7 mm, round shaped, and nonreactive to convergence, direct or consensual light stimulation. Right pupil was 4 mm and reacted normally. Funduscopic examination, extraocular motility, and the remaining of the neurological examinations were normal. A contrast-enhanced brain MRI was normal. She received intravenous aciclovir for 21 days and started topical dexamethasone and antiretroviral therapy for HIV. Twelve months later, anisocoria persisted. Left pupil was still unresponsive to light, but mild reaction to convergence was noted. Nasal pupillary edge reacted slightly better. Iris was not atrophic. There were no complaints on near vision. Pilocarpine 0.1% reduced pupillary size from 7 mm to 4 mm in 30 minutes (Fig. 1). A diagnosis of tonic pupil with postganglionic parasympathetic denervation was made. The second patient was an 81-year-old woman with hypertension, who presented with left ocular foreign body sensation and periocular pain, followed by a vesicular rash over the ophthalmic division of the left trigeminal nerve 4 days later. She finally developed a left nonreactive mydriasis 10 days after the onset. Slit-lamp examination showed moderate left conjunctival injection and palpebral edema. No corneal defects, synechia, or uveitis was noted. Left pupil was round shaped and 6 mm in diameter. Direct and consensual light reflexes were lost. The pupil was also unresponsive to convergence. Right pupil was 3 mm and reacted normally (Fig. 2). No visual field defects or extraocular pareses were noted. Funduscopy and intraocular pressure were normal, and gonioscopy was not performed. The patient also reported difficulty on near vision. A contrast-enhanced brain MRI was normal. She was treated with topical dexamethasone and 10 days of oral valacyclovir. Five years later, the pupil was still mydriatic and unresponsive to light. VZV has been associated with the development of multiple neurological complications. Optic neuritis and multiple cranial nerve palsies, especially oculomotor nerves, have been described in the setting of both varicella and HZO (1), and pupillary abnormalities may be accompanying features. However, complete paralytic mydriasis as the only cranial nerve complication is unusual. Blanco-Palmero et al: J Neuro-Ophthalmol 2022; 42: e508-e510 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Patient 1.Anisocoria of 3 mm is noted. Top image: Left pupil is mydriatic and unresponsive to light stimulation. Note the skin scars over left V1 territory. Bottom image: Left pupil constricts after 0.1% pilocarpine. Right pupil shows no change. Pupillary abnormalities after HZO have been known since the 19th century. Several cases of Argyll Robertson pupils and Horner syndrome have been reported from the beginning of 20th century. However, since 1950, only 3 reports addressed an isolated nonreactive mydriasis. In 1979, Sen described a 16-year-old boy with no pupillary response to light in the right eye 4 days after an ipsilateral HZO (2). Of note, accommodation was spared. The author concluded that the condition could be due to a partial third nerve lesion given the absence of miosis after the instillation of 1% physostigmine. Czyz et al reached the same anatomical conclusion when they reported a 76-year-old woman with a left nonreactive mydriasis and accommodation paresis (3). No pharmacological tests were performed. On the contrary, Assal et al localized the lesion at the ciliary ganglion. They described a right internal ophthalmoplegia as the heralding sign of HZO (4). Although they did not find any pupillary reaction after the instillation of 0.1% pilocarpine, they stated that the VZV could have traveled antidromically from the Gasser ganglion to ciliary ganglion before reaching the skin. Thus, pupillary abnormalities were present before the characteristic rash developed. Isolated pupillary abnormalities in children in the setting of varicella are also a rarity. Only 28 cases have been reported to date (5). This complication usually develops on the first day after acute infection, although some cases presented up to 3 months after the skin rash. There is a slight male predilection (3:2). In most patients where follow-up is reported, the anisocoria and light reflex impairment persisted, but mild accommodation improvement could be noted after several months. The pathophysiology of this manifestation is uncertain. Microinfarction from occlusive vasculitis, direct viral cytopathic and neuropathic effect, demyelination, and compression due to orbital inflammation have been proposed to play a role (3). Although VZV is the causal agent of both HZO and varicella, it is unclear whether pupillary abnormalities related to these conditions share the same mechanism. Nonetheless, they have some common clinical features, such as the anterior uveal involvement in about 50% of the cases and the almost exclusive unilateral involvement (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A469). The age difference (average of 54, 6 years for HZO and 7 years for varicella) is probably related to the fact that these 2 diseases occur in different age groups. It is difficult to pinpoint the exact anatomical topography of the lesion, and different cases might not share a common location. Nevertheless, the tonic pupil features, FIG. 2. Patient 2. Left conjunctival injection and palpebral edema. Left pupil is fixed and unresponsive to light and convergence. Note the skin scars over left V1 territory. Blanco-Palmero et al: J Neuro-Ophthalmol 2022; 42: e508-e510 e509 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence together with the response to 0.1% pilocarpine in our first patient, suggest a postganglionic parasympathetic defect (ciliary ganglion or short ciliary nerves), at least on that case. Indeed, we suggest that this damage plays a role in most cases of this neuro-opthalmological rarity. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: V. A. Blanco-Palmero; b. Acquisition of data: V. A. Blanco-Palmero, A. Ortueta-Olartecoechea, D. Uriarte-Pérez de Urabayen, M. Sánchez-Tornero, A. MéndezGuerrero, and M. Matarazzo; c. Analysis and interpretation of data: V. A. Blanco-Palmero, A. Ortueta-Olartecoechea, D. Uriarte-Pérez de Urabayen, M. Sánchez-Tornero, A. Méndez-Guerrero, and M. Matarazzo. Category 2: a. Drafting the manuscript: V. Antonio BlancoPalmero, A. Ortueta-Olartecoechea, and M Matarazzo; b. Revising it for intellectual content: V. A. Blanco-Palmero, A. OrtuetaOlartecoechea, D. Uriarte-Pérez de Urabayen, M. Sánchez-Tornero, A. Méndez-Guerrero, and M. Matarazzo. Category 3: a. Final approval of the completed manuscript: V. A. Blanco-Palmero, A. Ortueta-Olartecoechea, D. Uriarte-Pérez de Urabayen, M. SánchezTornero, A. Méndez-Guerrero, and M. Matarazzo. e510 ACKNOWLEDGMENTS The authors thank Antonio Lalueza-Blanco, MD, PhD, Fernando Ostos-Moliz, MD, Lourdes Domínguez-Domínguez, MD, María Encarnacion Oliveira-Ramírez, MD, and Juan Manuel Ruiz-Morales, MD, for their support while evaluating both patients. REFERENCES 1. Liesegang TJ. Herpes zoster ophthalmicus. Natural history, risk factors, clinical presentation, and morbidity. Ophthalmology. 2008;115(2 suppl):S3–S12. 2. Sen DK. Isolated pupillary paralysis in a case of herpes zoster. J Pediatr Ophthalmol Strabismus. 1979;16:33–34. 3. Czyz CN, Bacon TS, Petrie TP, Justice JD, Cahill KV. Isolated, complete paralytic mydriasis secondary to herpes zoster ophthalmicus. Pract Neurol. 2013;13:183–184. 4. Assal F, Frank HG, von Gunten S, Chofflon M, Safran AB. Internal ophthalmoplegia as a presenting sign of herpes zoster ophthalmicus. Eur Neurol. 2001;45:189–190. 5. Shaw M, Handley SE, Porooshani H. A case of internal ophthalmoplegia associated with varicella zoster. J Pediatr Ophthalmol Strabismus. 2012;49:e44–e47. Blanco-Palmero et al: J Neuro-Ophthalmol 2022; 42: e508-e510 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.