Tacrolimus (FK506) is a calcineurin phosphatase inhibitor produced by Streptomyces tsukubensis2). It suppresses T-cell function and cytokine/interleukin synthesis, and is widely used to prevent rejection after solid organ transplantation and to treat autoimmune diseases (such as myasthenia gravis, ulcerative colitis, and lupus nephritis). In Japan, it is marketed under the brand names Prograf and Graceptor.
Tacrolimus optic neuropathy (TON) is a rare complication, with only about 16 cases reported in the literature as of 20222). In a retrospective study of 65 ophthalmology consultations in post-lung transplant patients, TON was identified in 3 cases (4.6%), suggesting it may be more common than previously thought1).
The onset of TON ranges from 2 months to 10 years after starting tacrolimus, with a median of several months1). The earliest case report of TON was by Brazis et al. (2000) in a 58-year-old man after liver transplantation.
Ocular side effects of tacrolimus include, in addition to TON, decreased tear production, trichiasis, cytomegalovirus retinitis, cortical blindness, and maculopathy.
Although extremely rare with only about 16 cases reported in the literature, one study identified TON in 3 of 65 consultations (4.6%) after lung transplantation1), suggesting that the actual incidence may have been underestimated.
The causative agent of TON is tacrolimus (a calcineurin inhibitor) itself. The following risk factors have been identified.
Blood concentration is not a predictor of onset. Multiple cases have been reported within the therapeutic range (5–20 ng/mL) (e.g., Ascaso et al. 2.6 ng/mL, Kessler et al. 3.4 ng/mL, Shao et al. 13.9 ng/mL), and because the half-life varies widely (3.5–40.5 hours), plasma concentration may not accurately reflect actual body burden1).
It can occur. Several cases have been reported even within the therapeutic target range, and blood concentration monitoring alone cannot prevent the onset of optic neuropathy 1). This is because the half-life of tacrolimus varies widely from 3.5 to 40.5 hours, and plasma concentration may not accurately reflect the actual body burden.
TON is a diagnosis of exclusion, made after ruling out infectious, inflammatory, and neoplastic optic neuropathies 1).
The principle of treatment for toxic optic neuropathy is discontinuation of the toxic substance; if discontinuation or withdrawal of the drug is delayed, there is a risk of irreversible visual dysfunction.
Discontinuation is recommended when the benefits outweigh the risks, but it may be difficult to stop tacrolimus due to the need for graft survival or autoimmune disease management. In such cases, careful discussion among the medical team is necessary.
Discontinuation
First-line approach: Once TON is diagnosed, promptly consider discontinuing tacrolimus.
The decision should be made in consultation with the primary medical team, taking into account the status of the transplanted organ and the activity of the autoimmune disease.
Switching to an alternative drug
Cyclosporine: The most commonly reported switch. In the case by Hussein et al., after switching from tacrolimus 3 mg BID to cyclosporine 150 mg BID, visual acuity improved to 20/25 (both eyes) at 12 months, and RNFL thickness normalized 2).
Mycophenolate mofetil: Used as an alternative drug, with reported visual recovery (Kessler et al.).
Steroid adjunct
Not an established treatment. Gupta et al.: Discontinuation of tacrolimus plus oral prednisolone stabilized vision and improved visual field.
Limitations if not discontinued: Ascaso et al.: High-dose steroid pulse therapy was performed while continuing tacrolimus, but no improvement was observed.
Discontinuation can be expected to result in at least partial visual improvement in about half (approximately 50%) of cases1). However, some cases continue to worsen after discontinuation or have irreversible visual impairment. Early intervention tends to lead to better outcomes2).
The pathogenesis of TON is proposed to involve multiple mechanisms including vascular, demyelinating, and direct toxicity, which may vary among individual cases.
Vascular (ischemic) mechanism
Elevated thromboxane A2: Tacrolimus increases thromboxane A2 levels, causing vasoconstriction and leading to optic nerve ischemia.
Fluorescein angiography findings: FA has reported blood flow defects in the optic disc (Yun et al.) and delayed filling or decreased perfusion (Shao et al.).
Mechanism: Vasoconstriction and relative tissue ischemia due to modification of the interaction between prostacyclin and thromboxane A22).
Demyelination and Direct Toxicity Mechanism
Affinity for myelin: Tacrolimus is lipophilic and has affinity for myelin, which has a high lipid content, causing damage to oligodendrocytes.
Histological evidence: Optic nerve biopsy revealed marked demyelination with preserved axons and no ischemic changes (Rasool et al.)2).
Direct neurotoxicity: Causes axonal edema, increased water content, and neural tissue edema2).
Blood-brain barrier disruption: Transient disruption of the blood-brain barrier due to GVHD or meningitis (e.g., VZV) may increase CNS penetration of tacrolimus1). Genetic polymorphisms in ABCB1 (P-glycoprotein multidrug efflux pump) reduce tacrolimus efflux from the CNS, increasing CNS toxicity susceptibility independent of plasma concentration1,2).
Association with PRES: TON may precede PRES (posterior reversible encephalopathy syndrome). TON has been suggested to be an early sign of vascular dysregulation and blood-brain barrier dysfunction1).
Pharmacokinetic factors: Tacrolimus maintains biological activity after hepatic metabolism. Its half-life ranges widely from 3.5 to 40.5 hours, and normal plasma concentrations may not accurately reflect actual tacrolimus load1).
It is considered a different condition. Tacrolimus, which is highly lipophilic, has a high affinity for myelin sheaths, and findings predominantly of demyelination have been reported in optic nerve biopsies 2). Since there are reports of visual improvement after switching to cyclosporine, the toxic mechanisms of the two drugs are thought to be different.
Nanda et al. (2021) reported three cases of TON after lung transplantation and compiled the clinical features of 16 previously reported cases (including their own three cases) into a table 1). The frequency of 3 cases out of 65 consultations was higher than expected, and they proposed the need for routine ophthalmologic follow-up after lung transplantation. Currently, there are no guidelines for regular ophthalmologic follow-up after lung transplantation.
Hussein et al. (2022) reported a case of TON presenting with the largest reported papilledema on OCT, with a retinal nerve fiber layer thickness of 442 μm 2). Although the findings resembled papilledema, lumbar puncture showed normal intracranial pressure. This case, which showed marked improvement after switching to cyclosporine, highlights the importance of differentiating between papilledema and TON.
