Tacrolimus (FK506, Prograf) is an immunosuppressive agent often used in patients after bone marrow and solid organ transplantation to reduce the risk of rejection. It irreversibly inhibits T-cell development and function and inhibits cytokine synthesis (1–3). The most common central nervous system toxicity of tacrolimus is posterior reversible leukoencephalopathy syndrome (PRES), which typically presents with bilateral white matter lesions predominately affecting the parieto-occipital lobes and can result in seizures, confusion, and significant visual and neurologic compromise (4,5). Rarely, tacrolimus has been reported to cause optic neuropathy, although its diverse clinical and radiologic manifestations make this entity difficult to diagnose. We report 3 cases of tacrolimus optic neuropathy after bone marrow transplant and review the literature related to this topic.
A 55-year-old man reported a 1-week history of a “gray film” over his right eye. He denied any associated systemic or neurologic symptoms. He had a history of rheumatoid arthritis, diabetes mellitus, and hypertension. Four years previously, he was diagnosed with a right scapular plasmacytoma and light-chain multiple myeloma. One year before presentation, he developed myelodysplastic syndrome with refractory cytopenia and multilineage dysplasia that are believed to be related to acute graft-vs-host disease (GVHD). He was on tacrolimus 2 mg twice a day, melphalan, and prednisone. At the time of his visual symptoms, his tacrolimus level was 8 ng/mL (therapeutic range: > 2.0 ng/mL), and his renal function was within normal limits. Five months before onset of visual symptoms, the patient's creatinine was elevated at 2.13 mg/dL (normal: 06–1.2 mg/dL), with an elevation in his tacrolimus level to 23 ng/mL.
On examination, visual acuity was 20/200 in the right eye and 20/25 in the left eye. Color vision was reduced in the right eye and normal in the left eye. He had a right relative afferent pupillary defect (RAPD). Visual field testing in the right eye disclosed diffuse depression with sparing of the superonasal field and superior and inferior nasal field loss in the left eye (Fig. 1A). The right optic disc was swollen, and the left disc appeared normal (Fig. 1A). Postcontrast magnetic resonance imaging (MRI) of the orbits and brain was unremarkable. Lumbar puncture demonstrated a lymphocytic pleocytosis (27 WBCs, 93% lymphocytes), protein of 75 mg/dL (normal: < 44 mg/dL), and a normal glucose level. Cerebrospinal fluid analysis was negative for Epstein barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), John Cunningham (JC) virus, varicella zoster virus (VZV), Cryptococcus, and syphilis. A second lumbar puncture confirmed an elevated cell count (19 WBCs, 89% lymphocytes) and protein level of 76 mg/dL. Cytology of both samples was negative for malignant cells. The patient's tacrolimus dose was decreased to 1 mg twice a day.
One month later, visual acuity was 20/20 in the right eye and 20/25 in the left eye. Color vision was normal in the right eye and slightly reduced in the left eye. He had some progression of field loss in both eyes (Fig. 1B). The right optic disc was pale, and the left disc was swollen (Fig. 1B). Repeat MRI was unremarkable, and the tacrolimus dose was lowered to 0.5 mg twice a day and subsequently discontinued. The patient was followed for 3 years, and his visual function has remained stable.
A 66-year-old man reported a 3-month history of declining vision initially involving his left eye and then his right eye. He had a complicated history of acute myeloid leukemia and 2 peripheral blood stem cell transplants with GVHD followed by chemotherapy (mitoxantrone, etoposide, and Ara-C), intravenous immunoglobulin (IVIg), interleukin-2, mycophenolate mofetil, imatinib mesylate and, finally, rituximab and had been in remission for 5 years. When he experienced his visual symptoms, he was taking tacrolimus 0.5 mg/day, prednisone, tacrolimus (0.1%) ophthalmic drops, and cyclosporine ophthalmic drops.
His visual acuity was 20/25 in the right eye and 20/100 in the left eye. Color vision was reduced bilaterally but greater in the left eye. There was no RAPD, and visual field loss was present in each eye (Fig. 2A). Examination of the anterior and posterior segments was normal bilaterally. Brain MRI demonstrated nonenhancing hyperintensities involving the optic nerves, chiasm, and anterior brainstem (Fig. 2B, C) extending to involve the right internal capsule. Hematologic studies were negative for EBV, CMV, HSV, JC virus, Lyme, VZV, Leber hereditary optic neuropathy, and neuromyelitis optica. Lumbar puncture revealed elevated protein at 68.6 mg/dL (normal: < 44 mg/dL) with 3 WBCs and normal glucose. His tacrolimus level was 10 ng/mL (therapeutic range: > 2 ng/mL), and creatinine was within normal limits. The patient's tacrolimus dose was tapered and discontinued, and 2 months later, his acuity was 20/60 in the right eye and counting fingers in the left eye. However, over the next 2 years, his vision stabilized at 20/30 in the right eye and 20/60 in the left eye, and a follow-up brain MRI was normal in appearance.
A 63-year-old man presented with a 3-day history of a “gray cloud” in the vision of his left eye. He had a history of myelofibrosis/myelodysplasia, had a bone marrow transplant, and was taking tacrolimus 0.5 mg/day and sirolimus 4 months before the onset of his visual symptoms. He developed GVHD soon thereafter and mycophenolate mofetil was added to his regimen. Visual acuity was 20/20 in the right eye and 20/50 in the left eye. There was a left RAPD and reduced color vision in the left eye. He had diffuse visual field loss in the left eye and nasal field loss in the right eye (Fig. 3A). Both optic discs were swollen (Fig. 3B). Magnetic resonance imaging demonstrated subtle enhancement of both optic nerves. Studies were negative for EBV, CMV, HSV, JC virus, Lyme disease, VZV, Cryptococcus, syphilis, and toxoplasmosis. His tacrolimus level was 5 ng/mL, and his creatinine was within normal limits. However, 2 months before the onset of his visual symptoms, his creatinine had risen to 4.7 mg/dL (normal: 0.6–1.2 mg/dL) with an elevation in his tacrolimus level to 23 ng/mL. Tacrolimus was discontinued, and his examination remained stable over the next 8 months.
Tacrolimus is produced from the fungus Streptomyces tsukbaensis, and its mechanism of action is similar to cyclosporine, preventing T-cell activation and signaling by inhibiting calcineurin phosphatase. This reduces the production of interleukins and cytokines necessary for a robust immune response. Tacrolimus is primarily metabolized by the liver and intestinal mucosa by cytochrome P4503A enzymes and excreted through biliary excretion (6). The drug's half-life can vary from 3.5 to 40.5 hours, and breakdown products of the drug can retain biologic activity. As a result, plasma concentrations of the medication are not good indicators of the total amount of active drug in the body (7–11). Nephrotoxicity secondary to tacrolimus therapy has been reported and often associated with tacrolimus blood concentrations more than 20 ng/mL. Although there is an association with increased creatinine and higher blood concentrations of tacrolimus, the medication is not renally eliminated and this association remains unclear (12,13).
Tacrolimus optic neuropathy is rare, with few previously published cases (Table 1). Patients may present with slightly subnormal visual acuity or may progress to significant vision loss including complete blindness. Most patients developed bilateral optic neuropathy; a number of these initially experienced unilateral symptoms, which became bilateral within days to weeks. Optic nerve appearance is variable and can vary from normal to optic disc edema (with or without peripapillary hemorrhages) to optic disc pallor. The appearance of the disc likely depends on the timing of the examination in relation to the development of visual symptoms.
The reported time of exposure to tacrolimus has varied from a number of months to 2 years, and there is no correlation between the development of optic nerve toxicity and the concomitant treatment with additional immunosuppressants. It is unclear why some patients developed optic nerve toxicity within 2 months of being on the medication, whereas others developed it years later. To our knowledge, there is no evidence that the drug is stored in the fat or liver, making cumulative dose toxicity over time unlikely. However, 2 of our patients demonstrated elevated tacrolimus levels in the context of elevated creatinine levels months before the onset of visual symptoms, but normal drug levels in proximity to the development of visual dysfunction. This raises the possibility that the medication may be stored or may have caused subclinical damage, thereby predisposing the optic nerve to further damage over time.
Central nervous system pharmacokinetics have been found to contribute to tacrolimus toxicity, with gene polymorphisms making certain patients more sensitive to the medication (14,15). These factors, however, do not explain the diverse range of time of exposure to the drug before toxicity. It is possible, that in conjunction with a genetic predisposition, patients may become more susceptible to the effects of the medication because of a factor yet unknown. Furthermore, in our 3 patients, the presence of GVHD may have led to a breakdown of the blood–brain barrier thereby making the optic nerves more susceptible to the effects of tacrolimus. In addition, studies have shown that GVHD decreases tacrolimus clearance by approximately 20% independent of creatinine or bilirubin values and likely secondary to hepatocyte injury (4). This also may have been a contributing factor in our patients.
Magnetic resonance imaging of the brain and orbits may demonstrate either no changes or enhancement and/or T2 hyperintensity of the optic nerves (Table 1) (16). One of our patients also demonstrated significant enhancement and T2 hyperintensity of the anterior brainstem, which has not previously been identified in conjunction with the optic neuropathy. The toxic effects of tacrolimus on the brainstem have been reported in 2 patients and both experienced reversibility of their neurologic findings after discontinuation of the medication (9,17). Similarly, our patient's brainstem findings gradually improved on cessation of his medication. Reversibility of visual loss in tacrolimus optic neuropathy has been reported in 30% of cases demonstrating the importance of early recognition of the disorder (18–22).
The mechanism of CNS and optic nerve toxicity by tacrolimus remains unknown. It is believed to cause PRES is some patients by causing dysautoregulation of vascular endothelial cells in the posterior cerebral circulation (23). It also may have a direct neurotoxic effect resulting in axonal swelling with resultant cerebral edema (24,25). With respect to its effects on the optic nerve, the presence of optic disc swelling and peripapillary hemorrhages is similar to nonarteritic anterior ischemic optic neuropathy. This may be in keeping with the vascular hypothesis of augmentation of thromboxane A2 production resulting in vasoconstriction and ischemia seen with cyclosporine toxicity. Possibly a similar mechanism occurs with tacrolimus (18,24,26,27). However, Venneti et al (16) reported a patient with bilateral visual loss to hand motion, right eye, and no light perception, left eye, secondary to tacrolimus toxicity. Left optic nerve biopsy demonstrated no vascular changes but rather significant loss of myelin with preservation of axons and a few perivascular inflammatory cells. These findings suggest that the toxicity is, in part, related to damage to oligodendroglial cells, similar to other inhibitors of calcineurin (28).
Given that tacrolimus is often critical in maintaining the viability of transplanted organs and decreasing or discontinuing it may have significant systemic consequences, it is essential that other infectious, inflammatory, and neoplastic etiologies are excluded. Clinicians should be aware of concurrent medications influencing the cytochrome P4503A enzyme complexes, which may alter the pharmacokinetics of tacrolimus.
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