Bilateral Internuclear Ophthalmoplegia as a Manifestation of Varicella Zoster Encephalitis

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Bilateral Internuclear Ophthalmoplegia as a Manifestation of Varicella Zoster Encephalitis Young-Bin Park, MD, Seol-Hee Baek, MD, Sun-Uk Lee, MD, Sungwook Yu, MD, PhD, Ji-Soo Kim, MD, PhD I nternuclear ophthalmoplegia (INO) is ascribed to a discrete lesion involving the medial longitudinal fasciculus (MLF), of which the etiology is mostly an infarction or multiple sclerosis (1). Herein, we describe a patient with varicella zoster encephalitis presenting with bilateral INO. A 72-year-old immunocompetent man presented with headache, diplopia, vomiting, and fever for 3 days. The patient had been taking oral acyclovir for 2 weeks for varicella zoster in his cheek. The diplopia was binocular and diagonal without any changes in his visual acuity. At admission, the body temperature was 38.2°C. The patient showed meningeal irritation sign. Neurologic examination revealed 16 Prism diopter (PD) of exotropia and 10 PD of hypertropia in the left eye on primary gaze. The hypertropia did not change during upward or downward gaze but decreased to 7 PD while supine. Convergence was Department of Neurology (Y-BP, S-HB, S-UL, SY), Korea University Medical Center, Seoul, Republic of Korea; Department of Neurology (SUL, J-SK), Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Neurology (SY), Korea University College of Medicine, Seoul, Republic of Korea; and Dizziness Center (J-SK), Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare (HI14C3477), and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (no. NRF-2016R1D1A1B04935568). J.-S. Kim serves as an associate editor of Frontiers in Neuro-otology and on the editorial boards of the Journal of Clinical Neurology, Frontiers in Neuro-ophthalmology, Journal of Neuro-ophthalmology, Journal of Vestibular Research, Journal of Neurology, and Medicine. 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). Y.-B. Park analyzed and interpreted the data and wrote the manuscript. S.-H. Baek, S. Yu and J.-S. Kim analyzed and interpreted the data, and revised the manuscript. S.-U. Lee designed and conceptualized the study, interpreted the data, and revised the manuscript. This study followed the tenets of the Declaration of Helsinki and was performed according to the guidelines of Institutional Review Board of Korea University Anam Hospital (2021AN0048). Address correspondence to Sun-Uk Lee, MD, Department of Neurology, Korea University Medical Center, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02843, Republic of Korea; E-mail: sulee716@ gmail.com Park et al: J Neuro-Ophthalmol 2023; 43: e79-e81 impaired. He showed adduction limitation in the left eye in association with dissociated abducting nystagmus in the right eye during attempted rightward gaze (Fig. 1A, See Supplemental Digital Content, Video E1, http://links.lww. com/WNO/A506). During leftward gaze, he also showed an adduction lag in the right eye and dissociated abducting nystagmus in the left eye (See Supplemental Digital Content, Video E1, http://links.lww.com/WNO/A506). Smooth pursuit was impaired to the right during right eye viewing. The patient showed gaze-evoked vertical nystagmus during vertical gazes. Vertical saccades were normal, and vertical smooth pursuit was impaired in both directions. He also showed right, upbeat nystagmus with counterclockwise torsional component without visual fixation (Fig. 1B, See Supplemental Digital Content, Video E1, http://links.lww. com/WNO/A506). Video head-impulse tests revealed decreased gain of the vestibulo-ocular reflex (VOR) for the right posterior canal (PC, Fig. 1C). Fundus photography showed abnormal extorsion of the right eye (Fig. 1D). The patient also showed a rightward tilt of the subjective visual vertical (SVV) (right eye 30.2°, left eye 23.4°, both eyes 24.3°). Results of cervical vestibular-evoked myogenic potentials (VEMPs) were normal, whereas the ocular VEMPs exhibited delayed responses in the left eye. Otherwise, neurologic examination was unrevealing without facial palsy, motor weakness, sensory changes, or limb dysmetria. Brain MRI disclosed a lesion primarily involving the dorsal portion of the pons on both sides (Fig. 1E). Magnetic resonance angiography was unrevealing. Cerebrospinal fluid (CSF) analysis showed white blood cells of 800 per cubic millimeter (lymphocyte 98%), protein of 264 mg/dL, and glucose of 44 mg/dL (serum glucose at 92 mg/dL). The CSF was positive for varicella zoster virus (VZV) DNA. The patient was subjected to 1.8 gm per day of intravenous acyclovir, 1 gm per day of intravenous methylprednisolone, and 100 mg per day of aspirin. Headache and fever resolved within a week as along with an improvement of spontaneous nystagmus and INO. Our patient presented with bilateral INO from varicella zoster encephalitis. In addition to the bilateral INO, the patient showed other ocular motor signs from the involvement of the MLF: upbeat-torsional nystagmus, ocular tilt reaction, SVV tilt, and decreased gain of the VOR for the PC. e79 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Nine gaze photographs of the patient show exotropia and hypertropia of the left eye during attempted straight ahead gaze. The patient also shows adduction limitation of the left eye during rightward gaze. B. Video-oculography (SLVNG, SLMED, Seoul, South Korea) shows nystagmus beating rightward, counterclockwise (upper poles of the eyes beating to the left ear), and upward with a larger counterclockwise component in the left eye and larger right-beating and upbeating components in the right eye without a visual fixation. C. Video-head impulse tests show a decreased gain for the right posterior canal and small corrective saccades for the right horizontal canal. D. Fundus photography shows an abnormal extorsion of the right eye. E. Three-dimensional, fluid-attenuated, inversion recovery images shows a lesion involving the tectal and tegmental portion of the pontomesencephalic junction on both sides. VZV can cause various neurologic complications that include stroke, meningitis, and cranial neuropathies (2). The virus can involve small- to large-sized vessels to result in inflammation, fibrinoid vascular necrosis, and thrombosis. Otherwise, due to its proclivity for ventricular spread, it can also cause ventriculitis. Because the neural structures responsible for eye movements mostly reside in the dorsal portion of the brainstem, certain diseases that can spread by CSF, such as neuromyelitis optica spectrum diseases or lymphoma, can often manifest with ocular motor abnormalities (3). Previously, only a few anecdotes reported INO as a predominant or associated clinical presentation of VZV encephalitis (4,5). As in our patient, those patients usually presented INO during their disease course of varicella zoster infection. The mechanism of INO is explained by direct invasion of the virus or immunologically mediated demyelination (5). Along with INO, combined multiple cranial neuropathies corroborated the CNS involvement in those patients. By contrast, our patient presented MLF syndrome and meningismus as a sole manifestation of VZV encephalitis. Fortunately, MRIs also documented a e80 responsible lesion for the MLF syndrome. Because 17%48% of MRIs can be negative in INO patients (6,7), analyses of the ocular motor findings can be paramount for diagnosis. Together with prior anecdotes, our patient implicates that VZV should be also considered in those presenting with MLF syndrome in association with meningismus, especially when patients have history or currently on zoster infection. Apart from the MLF syndrome, convergence was impaired in our patient. Because the vergence pathway is known to bypass the ascending VOR pathway in the brainstem, impaired convergence implies a lesion extending into the neighboring mesencephalic reticular formation or medial rectus nuclear subdivision in our patient. However, convergence may be impaired in unilateral or bilateral INO (8). Indeed, convergence was impaired even when the MLF is severed pharmacologically at the level between the trochlear and abducens nuclei, thereby suggesting that the MLF itself also carries a vergence signal (8). The vertical misalignment of the eyes could eventually be ascribed to a fascicular oculomotor nerve palsy in our patient. However, the preserved saccadic Park et al: J Neuro-Ophthalmol 2023; 43: e79-e81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence velocity and comitant strabismus in the vertical plane favor skew deviation rather than paralytic vertical strabismus. STATEMENT OF AUTHORSHIP Conception and design: S.-U. Lee; Acquisition of data: S.-H. Baek, S. Yu, Y.-B. Park; Analysis and interpretation of data: J.-S. Kim. Drafting the manuscript: Y.-B. Park; Revising it for intellectual content: S.-H. Baek, S. Yu, Y.-B. Park, J.-S. Kim. Final approval of the completed manuscript: S.-U. Lee. REFERENCES 1. Keane JR. Internuclear ophthalmoplegia: unusual causes in 114 of 410 patients. Arch Neurol. 2005;62:714–717. 2. Nagel MA, Cohrs RJ, Mahalingam R, Wellish MC, Forghani B, Schiller A, Safdieh JE, Kamenkovich E, Ostrow LW, Levy M, Greenberg B, Russman AN, Katzan I, Gardner CJ, Häusler M, Nau R, Saraya T, Wada H, Goto H, de Martino M, Ueno M, Brown Park et al: J Neuro-Ophthalmol 2023; 43: e79-e81 WD, Terborg C, Gilden DH. The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology. 2008;70:853–860. 3. Lee SU, Kim HJ, Choi JH, Choi JY, Kim JS. 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