Tacrolimus Optic Neuropathy
Tacrolimus is an immunosuppressive agent that inhibits calcineurin phosphatase thereby irreversibly inhibiting development and function of T cells and synthesis of cytokines and interleukins. It is most commonly used in the setting of solid organ transplants in the prevention of rejection or autoimmune diseases (myasthenia gravis, inflammatory myopathy, ulcerative colitis, and lupus nephritis).  In addition to sequelae related to immunosuppression, tacrolimus can have serious ophthalmic adverse effects. It has been reported in association with tear deficiency, eyelash trichomegaly, conjunctival intraepithelial neoplasia, CMV (cytomegalovirus) retinitis, cortical blindness, and maculopathy. Rarely, tacrolimus use may result in optic neuropathy, leading to potentially irreversible bilateral blindness. Optic neuropathy secondary to tacrolimus use has reportedly occurred between months to years of use. It causes variable degrees of vision loss and is typically bilateral. The optic nerve appearance is also variable and may be normal, edematous, or pale. Cessation of tacrolimus may be considered if tacrolimus optic neuropathy is suspected.
Although onset of tacrolimus-associated optic neuropathy varies between months to years, longer duration of treatment may be associated development of optic neuropathy. Because tacrolimus is not known to be stored in adipose tissue or hepatic tissue, the cumulative damage may be a result of storage of the drug or its active metabolites elsewhere in the body or of progressive subclinical damage. Additionally, individual sensitivity to neurotoxic and ischemic effects of the drug on the optic nerve may serve as a risk factor and help explain the variable presentation of optic neuropathy.
The mechanism of tacrolimus-associated optic neuropathy has not been fully elucidated. Several hypotheses exist to date. One study reported absence of blood flow to the optic disc on fluorescein angiography (FA).3 Similarly, delayed and reduced blood filling of optic discs on FA has also been reported. These findings suggests tacrolimus may increase thromboxane A2 levels thereby causing vasoconstriction with resultant ischemia of optic nerves. Similar to other inhibitors of calcineurin, direct toxicity to the myelin surrounding the optic nerve has also been reported. Studies suggest tacrolimus may have a predilection for myelin due to its lipophilic nature, resulting in damage to the oligodendrocytes.  Neurotoxicity resulting in axonal edema may be another mechanism by which tacrolimus causes optic neuropathy.
Because metabolized products of tacrolimus may still be biologically active, plasma concentrations of the drug are not predictive of the development of optic neuropathy. Kessler et al. described a patient who developed optic neuropathy secondary to tacrolimus despite target plasma levels of the drug, suggesting monitoring plasma levels of tacrolimus may not be useful in preventing optic neuropathy.7 Additionally, tacrolimus is excreted via the biliary excretion. In patients with conditions affecting the biliary system, immunosuppressants with different mechanisms of excretion may be considered as an alternative to tacrolimus. It is important to recognize tacrolimus optic neuropathy early in its course and consider cessation of the offending agent before irreversible damage occurs. There are no available drugs to date to prevent optic neuropathy in the setting of tacrolimus use.
Tacrolimus optic neuropathy is typically characterized by acute or subacute bilateral painless loss of vision that ranges from mild visual acuity loss to complete blindness.1,3-7      Symptoms are typically bilateral; however, if patients initially present with unilateral symptoms, it is common to progress bilaterally in days to weeks. Ascaso et al. reported a case of unilateral optic neuropathy secondary to six months of tacrolimus use that did not progress to bilateral involvement despite continuation of tacrolimus therapy. Although rare, it is important to consider tacrolimus optic neuropathy in patients with unilateral or asymmetric symptoms.
Visual acuity is affected, ranging from mildly decreased from baseline to no light perception (NLP). Visual fields are also variably affected and cases have described superior or inferior nasal visual field loss or global depression.1, 3-7      Optic nerve appearance is variable and may be normal, edematous, or pale. Optic disc edema may present with or without peripapillary hemorrhages. It is possible that the appearance of the optic disc correlates with the duration of visual symptoms although further studies are necessary to evaluate this relationship.
Signs and Symptoms
Patients with tacrolimus optic neuropathy typically present with painless bilateral vision loss. Although vision loss most commonly occurs in days to months, progressive vision loss over one year has been reported. Although unilateral vision loss may occur, it typically progresses bilaterally in days to weeks. Unilateral tacrolimus optic neuropathy is rare and has been reported in a few cases. Other symptoms involving the afferent pathway including a relative afferent pupillary defect (RAPD), visual field deficits, and loss of color vision are typically seen.1,3-7     
A dilated fundus exam allows for direct visualization of the optic nerve head. Optical coherence tomography (OCT) of the nerve allows for evaluation of the retinal nerve fiber layer thickness. To assess visual field and color vision function, Humphrey visual fields and Ishihara color plates, respectively, may be employed. Fluorescein angiography (FA) may reveal ischemia to the optic disc, suggesting a possible mechanism to explain optic neuropathy secondary to tacrolimus. For example, Yun et al. presented a patient who experienced vision loss after six months of tacrolimus therapy. FA demonstrated delayed blood flow to the optic disc.3 Similarly, Shao et al. described delayed and reduced blood filling of the optic disc on FA in a patient who experienced vision loss after three months of tacrolimus therapy.
Magnetic resonance imaging (MRI) of the brain and orbits may be useful in the setting of tacrolimus optic neuropathy; however, findings are variable. MRI may be normal or demonstrate enhancement of the optic nerves.
Although it is important to measure serum levels of tacrolimus to ensure therapeutic levels, it is not predictive of the development of optic neuropathy. Several studies have described tacrolimus optic neuropathy in patients with therapeutic levels of tacrolimus. Ascaso et al. described a patient who developed unilateral optic neuropathy after six months of tacrolimus use despite serum concentration of 2.6 ng/mL (target range: 5-20 ng/mL). Kessler et al. similarly reported a case after five months of tacrolimus use despite serum concentration of 3.4 ng/mL (target range: 4-6 ng/mL).7 Shao et al. reported a patient with bilateral optic neuropathy after 3 months of tacrolimus use despite serum concentration of 13.9 ng/mL (target range: 12-15 ng/mL).
Other laboratory tests to exclude underlying etiology may include complete blood count, angiotensin converting enzyme (ACE), rheumatoid factor (RF), antineutrophilic cytoplasmic antibody (ANCA), anti-nuclear antibody (ANA), complement levels, venereal disease research laboratory (VDRL), and cerebrospinal fluid (CSF) analysis. Infectious etiologies can be ruled out with laboratory tests for cytomegalovirus, toxoplasmosis, Lyme disease, varicella zoster virus, herpes simplex virus, and fungal and bacterial cultures.1,3-7     
The differential diagnosis for tacrolimus optic neuropathy includes optic neuropathy secondary to other causes such as ischemia, nutritional deficiencies, neoplasm, or infection. It is important to consider patients’ risk factors (age, gender, medical history, medications, etc.) and to rule out other underlying etiologies when making the diagnosis of tacrolimus optic neuropathy.
Early recognition of symptoms related to tacrolimus optic neuropathy is important to prevent potentially irreversible damage. Cessation of tacrolimus is recommended in cases where the benefits of doing so outweigh the risks. Tacrolimus may be critical in maintaining viability of transplanted organs or in managing autoimmune diseases, making discontinuation difficult. Alternative immunosuppressants may be considered. For example, Yun et al. described improvement in visual outcomes after using cyclosporine as an alternative agent to tacrolimus. Kessler et al. similarly used mycophenolate mofetil as an alternative immunosuppressant and reported recovery of visual acuity. Discussion among health care providers regarding safety of discontinuation and alternative therapy options is important in managing this condition.
Medical therapy is not currently established in the treatment of tacrolimus optic neuropathy. Two reports have described the use of corticosteroids, which may help visual outcomes. Gupta et al. reported improvement of visual defects with stable visual acuity with discontinuation of tacrolimus and oral prednisolone therapy. The visual field improvement may be attributed to discontinuation of tacrolimus, addition of prednisolone, or both. In a separate case, the addition of medical therapy was unsuccessful. Ascaso et al. determined the risks of discontinuing tacrolimus in their patient outweighed the benefits. High-dose IV corticosteroids and acetylsalicylic acid were added to the current regimen without improvement in visual outcomes.
No surgical therapy currently exists for tacrolimus optic neuropathy.
Vision loss reversibility in tacrolimus optic neuropathy has been reported in 30% of cases. Visual recovery is variable and may range from complete resolution of visual acuity to baseline to mild improvement. Variable visual field improvements have also been reported.1,3-7      Due to the risk of potentially irreversible vision loss, close surveillance of patients taking tacrolimus may be warranted.
- Rasool N, Boudreault K, Lessell S, Prasad S, Cestari DM. Tacrolimus Optic Neuropathy. J Neuroophthalmol. 2018 Jun;38(2):160-166. doi: 10.1097/WNO.0000000000000635.
- Chen B, Wu Q, Ke G, Bu B. Efficacy and safety of tacrolimus treatment for neuromyelitis optica spectrum disorder. Sci Rep. 2017;7(1):831. Published 2017 Apr 11. doi:10.1038/s41598-017-00860-y
- Ascaso FJ, Mateo J, Huerva V, Cristóbal JA. Unilateral tacrolimus-associated optic neuropathy after liver transplantation. Cutan Ocul Toxicol. 2012 Jun;31(2):167-70. doi: 10.3109/15569527.2011.629325. Epub 2011 Oct 28.
- Yun J, Park KA, Oh SY. Bilateral ischemic optic neuropathy in a patient using tacrolimus (FK506) after liver transplantation. Transplantation. 2010 Jun 27;89(12):1541-2. doi: 10.1097/TP.0b013e3181d2fe83. PubMed PMID: 20559109.
- Shao X, He Z, Tang L, Gao L. Tacrolimus-associated ischemic optic neuropathy and posterior reversible encephalopathy syndrome after small bowel transplantation. Transplantation. 2012 Nov 15;94(9):e58-60. doi: 10.1097/TP.0b013e31826dde21.
- 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. Published 2012 Aug 21. doi:10.1136/bcr-2012-006718
- Kessler L, Lucescu C, Pinget M, Charton MN, Mutschler V, Wolf P, Berney T, Benhamou PY; GRAGIL. Tacrolimus-associated optic neuropathy after pancreatic islet transplantation using a sirolimus/tacrolimus immunosuppressive regimen. Transplantation. 2006 Feb 27;81(4):636-7.'