Isolated Bilateral Internal Ophthalmoplegia as an Atypical Initial Presentation of anti-GQ1b Antibody Syndrome

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Isolated Bilateral Internal Ophthalmoplegia as an Atypical Initial Presentation of anti-GQ1b Antibody Syndrome Abigail P. Jebaraj, MD, Cole J. Swiston, MD, Sravanthi Vegunta, MD, Judith E. A. Warner, MD A nti-GQ1b antibody syndrome, formerly known as Miller Fisher variant Guillain–Barré syndrome, is a rare acquired polyneuropathy. It is characterized by the classic triad of ataxia, ophthalmoplegia, and areflexia (1). Serum testing reveals positive anti-GQ1b antibodies in at least 85% of cases (2). We present an atypical case of antiGQ1b antibody syndrome with initial isolated bilateral mydriasis and cholinergic supersensitivity suggesting tonic pupils. This isolated clinical finding was followed by ataxia, ophthalmoplegia, pupillary light-near dissociation, and normal deep tendon reflex testing. A 26-year-old previously healthy woman presented to the emergency room with a 1-day history of acute onset, constant bilateral photophobia, mydriasis, and headache. She had no recent history of trauma or mydriatic agent exposure. She endorsed recent cough and congestion 2 weeks prior for which she tested negative for COVID-19. On initial examination, her best-corrected visual acuity was 20/20 in each eye with normal color vision. Pupil diameters were 8 mm bilaterally in dark and 7.5 mm in light with minimal reactivity to both light and near and no light-near dissociation. Extraocular motility was normal without complaints of diplopia. Slit-lamp and fundus exams were unremarkable without evidence of iris transillumination defects, corectopia, or vermiform iris movements. Coordination testing, gait evaluation, and deep tendon reflexes were normal. MRI brain with and without contrast was unremarkable. Dilute topical pilocarpine testing (0.1%) revealed constriction of both pupils from 8 to 3 mm (Fig. 1). The patient was discharged with topical 0.125% pilocarpine to be used for light sensitivity and clinic follow-up. Given her prodromal upper respiratory illness, GQ1b antibody testing was obtained in addition to a GM1 antibody panel and rapid plasma reagin (RPR). In clinic the following week, she had developed horizontal binocular diplopia and balance difficulty. Her photophobia and headaches improved with topical 0.125% pilocarpine. Visual acuity and color vision testing were stable. Pupillary exam revealed new bilateral light-near dissociation, anisocoria (right eye 7 mm in light, 6 mm in dark; left eye 8 mm in light, 7.5 mm in dark), and vermiform movements of the irides. On extraocular movements, there was new limitation of abduction (20.5) of both eyes. Alternate cover testing was significant for an esotropia of 12 diopters in right gaze and esotropia of 18 diopters in left gaze. Slit-lamp and fundus examination were normal. Coordination testing revealed no dysmetria or ataxia on finger-to-nose or heel-to-shin bilaterally. However, she demonstrated balance difficulty on gait testing and significant instability of tandem gait. Her deep tendon reflexes were normal to slightly hyperreflexic. Review of lab testing revealed strongly positive Gq1b IgG of 308 IV, positive GQ1b IgM of 51 IV, and negative RPR. In clinic, the following month, she reported improvement in her unsteadiness and intermittent diplopia. She reported intermittent mydriasis. Her afferent exam was normal except for pupils that were 8 mm in dark and 7.5 mm in light bilaterally. Her efferent exam was normal except for esophoria of Department of Neuro-Ophthalmology, John A Moran Eye Center, Salt Lake City, Utah. Supported in part by an Unrestricted Grant from Research to Prevent Blindness, New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah. The authors report no conflicts of interest. Address correspondence to Abigail Jebaraj, MD, Moran Eye Center, 65 S Mario Capecchi Dr., Salt Lake City, UT 84132; E-mail: Abigail. [e-mail] Jebaraj et al: J Neuro-Ophthalmol 2022; 42: e389-e390 FIG. 1. External photographs showing (A) round, regular pupils of 8 mm before and (B) 3 mm after instillation of one drop of 0.1% topical pilocarpine to each eye. e389 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence 2–4 diopters, which was significantly improved. Her coordination, gait, and reflexes were normal. Additional treatment options including intravenous immunoglobulin (IVIG) were discussed at each clinic visit, but ultimately not pursued given the lack of data to support use in patients without the full triad of symptoms (partial anti-Gq1b antibody syndrome) and our patient’s relatively mild symptoms and improving examination findings (2). Interval follow-up 2.5 months from initial presentation revealed resolution of diplopia, improvement of coordination and balance, and improved photophobia. Her pupils were 8 mm in dark, 6 mm in light, and 5 mm with accommodation. She had a small comitant exophoria on Maddox rod testing. Fingerto-nose and heel-to-shin testing was normal with normal deep tendon reflex testing. Subsequently, she did not present for the follow-up at 6 months. The pathogenesis of anti-GQ1b antibody syndrome is believed to involve the GQ1b ganglioside, a glycoprotein found in abundance within cell membranes of paranodal myelin in cranial nerves III, IV, and VI. Antibodies targeted to these regions develop in response to similar antigens of invading pathogens (typically Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, or Mycoplasma pneumoniae) (2). The classic ocular presentation of anti-GQ1b antibody syndrome involves external ophthalmoplegia due to involvement of cranial nerves III, IV, and VI. However, pupillary involvement (internal ophthalmoplegia) has also been reported in approximately 50% of cases. The hypothesized molecular target includes GQ1b gangliosides associated with parasympathetic nerve fibers traveling to the pupillary constrictor muscle via the oculomotor nerve, ciliary ganglion, and short ciliary nerve (3). A variety of pupillary presentations have been described in the literature with anti-GQ1b antibody syndrome, ranging from fixed mydriatic pupils, tonic pupils, lightnear dissociation, and anisocoria. However, these findings are nearly universally described in association with external ophthalmoplegia, ataxia, or areflexia, increasing clinical suspicion of the diagnosis. Our unique case demonstrates isolated, bilateral tonic pupils and internal ophthalmoplegia as the initial presentation of anti-GQ1b antibody syn- e390 drome. These isolated findings were present 12 days before onset of any other classic syndromic findings. To our knowledge, only one other such case presentation exists in the literature by Bae et al. (4) This case report was similar to our patient’s case in that both patients had a preceding viral illness with bilateral mydriasis. Bae et al.’s case had lightnear dissociation, which our patient only developed at her 2.5-month follow-up. Our patient also did not have impaired deep tendon reflexes, which made her diagnosis difficult to make. We did not pursue IVIG therapy for our patient, because her symptoms continued to improve quickly. Although additional clinical and biochemical research is needed to fully elicit mechanisms which account for the variance in presentation and timing between ocular motility and pupillary involvement in this disease, our case emphasizes the need to maintain a high clinical suspicion for anti-GQ1b antibody syndrome with isolated pupillary mydriasis. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Jebaraj, C. Swiston, S. Vegunta, and J. Warner; b. Acquisition of data: A. Jebaraj, C. Swiston, S. Vegunta, and J. Warner; c. Analysis and interpretation of data: A. Jebaraj, C. Swiston, and S. Vegunta. Category 2: a. Drafting the manuscript: A. Jebaraj, C. Swiston, and S. Vegunta; b. Revising it for intellectual content: A. Jebaraj, C. Swiston, S. Vegunta, and J. Warner. Category 3: a. Final approval of the completed manuscript: A. Jebaraj, C. Swiston, S. Vegunta, and J. Warner. REFERENCES 1. Jung JH, Oh EH, Shin JH, Kim DS, Choi SY, Choi KD, Choi JH. Atypical clinical manifestations of Miller Fisher syndrome. Neurol Sci. 2019;40:67–73. 2. Teener JW. Miller Fisher’s syndrome. Semin Neurol. 2012;32:512–516. 3. Kaymakamzade B, Selcuk F, Koysuren A, Colpak AI, Mut SE, Kansu T. Pupillary involvement in Miller Fisher syndrome. NeuroOphthalmol. 2013;37:111–115. 4. Bae JS, Kim JK, Kim SH, Kim OK. Bilateral internal ophthalmoplegia as an initial sole manifestation of Miller Fisher syndrome. J Clin Neurosci. 2009;16:963–964. Jebaraj et al: J Neuro-Ophthalmol 2022; 42: e389-e390 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.