Visual Outcome Improvement in Tacrolimus-Related Bilateral Optic Neuropathy

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Visual Outcome Improvement in Tacrolimus-Related Bilateral Optic Neuropathy Marie Demontes, MD, Kim Thia-Soui-Tchong, MD, Solène Ronsin, MD, Virginie Desestret, MD, PhD, Alain Vighetto, MD, Caroline Tilikete, MD, PhD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/04/2022 W e report a 60-year-old woman who underwent renal transplantation in 1998. She was on methylprednisolone 5 mg, mycophenolate mofetil 1000 mg, and tacrolimus 2 mg per day for years, with no recent modification. None of her other medications was associated with neurotoxicity. Her history was also notable for diabetes mellitus, dyslipidemia, and hypertension. In August 2018, the patient noticed a dramatic subacute vision loss in her right eye, without any pain. Ophthalmological examination demonstrated swollen right optic disk, and visual acuity was limited to hand motion detection in the right eye. Motility, intraocular pressure, and slit-lamp examination were normal. Best-corrected left eye visual acuity was 20/20. Optical coherence tomography (OCT) showed retinal nerve fiber layer (RNFL) thickness of 198 mm in the right eye and 108 mm in the left eye. Visual field was not able to be completed in the right eye and was normal on the left. Complete blood count, erythrocyte sedimentation rate, and C-reactive protein were normal. Nonarteritic anterior ischemic optic neuropathy was suspected, and aspirin was initiated. Two months later, she was referred to our clinics for a subacute left-sided central visual loss. Left visual acuity had worsened from 16/20 to 2/20 within 48 hours. Visual field showed a left central scotoma (Fig. 1A) and ophthalmological examination demonstrated left optic disc swelling (Fig. 2A). Right visual acuity was unchanged (hand motion detection), and fundus showed optic atrophy. Brain MRI disclosed mild T1 gadolinium enhancement of the right optic nerve and a normal left optic nerve (Fig. 2B). Tacrolimus blood levels were within the therapeutic range. HIV, B hepatitis, C hepatitis, toxoplasmosis, syphilis, and Lyme serologies were negative. AntiMOG and antiAQP4 antibodies were negative. Cerebrospinal fluid demonstrated normal cell count, protein of 0.41 mg/dL, and 2 oligoclonal bands on isofocalization. Hospices Civils de Lyon (MD, KT-ST, SR, VD, AV, CT), NeuroOphthalmology and Neuro-Cognitive Unit, Hôpital Neurologique Pierre Wertheimer, Bron, France; Lyon I University (VD, AV, CT), Lyon, France; and CRNL INSERM U1028 CNRS UMR5292 (AV, CT), ImpAct Team, Bron, France. FIG. 1. Goldmann perimetry in the left eye at (A) 6 weeks and (B) 3 months (C) after optic neuropathy of the left eye. The authors report no conflicts of interest. Address correspondence to Caroline Tilikete, MD, PhD, ImpAct Team, CRNL INSERM U1028 CNRS UMR5292, University Lyon 1, HCL, 16, Avenue du Doyen Lépine, Bron Cedex 69676, France; E-mail: [e-mail] e22 Tacrolimus-related bilateral optic neuropathy was suspected, and tacrolimus was discontinued. Ciclosporine was started as a switch for immunosuppression. Five days of Demontes et al: J Neuro-Ophthalmol 2021; 41: e22-e24 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A. Fundi demonstrated optic disc edema on the left eye and optic atrophy on the right eye. B. Optic nerve MRI disclosed a T1 gadolinium enhanced signal in the right optic nerve (arrow) and was unremarkable in the left optic nerve. high-dose intravenous (IV) corticosteroids (120 mg/day) were administered on day 3 following onset of left eye symptoms. After IV corticosteroids, the patient experienced improvement of her left eye vision. Ophthalmological examination 6 weeks later demonstrated improvement of the left visual field (Fig. 1B), with a stable right eye. RNFL thickness decreased to 120 mm on the left eye and was stable for the right eye (54 mm). Her left eye visual acuity was 2/20 and right visual acuity was unchanged. Four months later, even if both fundus and OCT showed optic atrophy (RNFL right eye 54 mm; left eye 60 mm) and visual acuity have not changed, the left visual field still showed further improvement (Fig. 1C). Our patient demonstrated bilateral, subacute, and painless optic neuropathy. The lack of obvious other explanation, of other neurotoxic treatment, of infectious or autoimmune disease leads us to a diagnosis of tacrolimus-related bilateral optic neuropathy. Discontinuation of tacrolimus and IV corticosteroids allowed visual field improvement. Although neurovisual disorders due to posterior reversible encephalopathy syndrome have been most frequently reported as visual consequences of tacrolimus, optic neuropathy may also be a toxic consequence of this treatment Demontes et al: J Neuro-Ophthalmol 2021; 41: e22-e24 (1–3). Most of the patients develop optic neuropathy that begins with unilateral symptoms (1); this may become bilateral within days to weeks. Severity of optic nerve damage is variable from slight visual deficit to blindness. MRI shows no abnormalities and especially no association with posterior reversible encephalopathy. However, as we observed in our case, some subtle enhancement of both optic nerves has been described (3). LP can show pleiocytosis and a high protein level (3). Interestingly, in our patient, 2 oligoclonal bands were found on cerebrospinal fluid isofocalization, a test that has never been mentioned in previous publications (3). Mostly, toxicity appears a few months after tacrolimus introduction, but the delay between treatment initiation and symptom onset is variable. Our patient had the longer period of exposure described. This is indicative of delayed toxicity, as described in cases of neurotoxic effects of other calcineurin inhibitors. There appears to be no link between neurotoxicity and toxic blood level of tacrolimus. We report the first case of visual outcome improvement after tacrolimus discontinuation and corticosteroid treatment. This favorable outcome was highlighted by visual field evaluation, a test that has not been performed in published e23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence cases. This emphasizes the need to assess not only visual acuity but also visual field in the follow-up. Our patient improved only in the left eye, with treatment initiation 3 days after symptom onset. Therefore, our patient improvement may be explained by an early introduction of IV corticosteroids. In other cases, no indication of time delay between symptom onset and treatment was available, and oral corticosteroids were introduced or increased without evident improvement (4). In a previous publication (1), the patient was treated with corticosteroids and aspirin without success, but tacrolimus was maintained. The pathophysiological mechanism of this toxicity remains unclear. The first hypothesis is an ischemic mechanism, consistent with the subacute clinical presentation (2). Tacrolimus modifies interactions between prostacyclin and thromboxane A2, inducing an increase in the thromboxane A2 level and resulting in vasoconstriction and tissue ischemia. The second hypothesis is inflammatory. Indeed, optic nerve biopsy was performed in 1 case showing prominent loss of myelin with preserved axonal elements and absence of significant vascular changes (5). This physiopathology has already been described for other calcineurins inhibitors. Interestingly, our patient had 2 oligoclonal bands on LP and slight gadolinium enhancement on optic nerve MRI. These results, and the fact that our patient improved on the most recently e24 affected eye after IV corticosteroids, could give credence to the inflammatory hypothesis. In the case of subacute visual loss for patients receiving tacrolimus, the hypothesis of tacrolimus-induced toxic optic neuropathy must be suspected. High-dose IV corticosteroid therapy, with discontinuation of tacrolimus at an early stage of the disease, seem to be helpful options. Follow-up should include visual field. Additional knowledge about the physiopathology of this entity is needed to improve patient care. REFERENCES 1. Ascaso FJ, Mateo J, Huerva V, Cristóbal JA. Unilateral tacrolimus-associated optic neuropathy after liver transplantation. Cutan Ocul Toxicol. 2012;31:167–170. 2. Brazis PW, Spivey JR, Bolling JP, Steers JL. A case of bilateral optic neuropathy in a patient on tacrolimus (FK506) therapy after liver transplantation. Am J Ophthalmol. 2000;129:536–538. 3. Rasool N, Boudreault K, Lessell S, Prasad S, Cestari DM. Tacrolimus optic neuropathy. J Neuroophthalmol 2018;38:160– 166. 4. Gupta M, Bansal R, Beke N, Gupta A. Tacrolimus-induced unilateral ischaemic optic neuropathy in a non-transplant patient. BMJ Case Rep. 2012;2012:bcr2012006718. 5. Venneti S, Moss HE, Levin MH, Vagefi MR, Brozena SC, Pruitt AA, Mourelatos Z, Trojanowski JQ, Galetta SL, Balcer LJ. Asymmetric bilateral demyelinating optic neuropathy from tacrolimus toxicity. J Neurol Sci. 2011;301:112–115. Demontes et al: J Neuro-Ophthalmol 2021; 41: e22-e24 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.