Abstract
Purpose
Tacrolimus is a commonly used immunosuppressant medication after lung transplantation. In rare cases, tacrolimus causes a medication-induced optic neuropathy (TON) that can lead to significant vision loss.
Observations
In this series, we describe three cases of TON, 1–10 years after medication use. Two patients were young (22yr and 33yr) females with cystic fibrosis. The last case was a 65yr male with idiopathic pulmonary fibrosis. In 2/3 cases tacrolimus serum levels were normal. Visual acuity ranged from 20/20 to 20/300, and vision loss occurred acutely to sub-acutely, over a span of 2–3 months.
Conclusions and importance
As presented here, TON can be highly variable. MRI findings are often non-specific, from normal brain findings to extensive white matter changes. There remains an unclear association with graft-versus-host disease and reduced kidney function. Visual findings are often subtle, including color vision aberration and peripheral visual field deficits, both of which usually require an ophthalmologic evaluation. When diagnosed in a timely fashion, TON is at least partially reversible in up to half of all cases. While rare, the cases described here support post-lung transplant ophthalmologic evaluation in those taking high-risk medications.
Introduction
Since its approval in 1997 tacrolimus is now used in upwards of 93% of all post-lung transplant patients for maintenance immunosuppression. Tacrolimus induced optic neuropathy (TON) remains an extremely rare and elusive diagnosis, with only 13 cases published in the literature. Due to its infrequency, it remains a diagnosis of exclusion, after infectious, inflammatory, and neoplastic causes are evaluated. In many cases, the diagnosis remains presumptive. The exact mechanism remains unclear. Some authors support the possibility of an ischemic process, with two studies finding a delay or absence in vascular circulation on fluorescein angiography. In contrast, biopsy of the optic nerve has demonstrated extensive demyelination without ischemic insult, and cortical cultures have shown direct oligodendritic toxicity and death. , TON is likely distinct from cyclosporine-induced optic neuropathy, as patients who have been switched to cyclosporine due to suspected TON have demonstrated visual improvement.
Clinically, TON usually presents as a slow reduction in visual acuity, progressive visual field deficits, and/or dyschromatopsia, though acute changes have also been described. MRI can show optic nerve and other white matter lesions, even in the context of normal tacrolimus levels. , While tacrolimus can also affect the visual system from posterior involvement of the visual tracts or occipital lobes, due to tacrolimus-induced posterior reversible encephalopathy syndrome (PRES), TON is usually associated with optic nerve edema or pallor. Through an institutional review board-approved process (AAAS6456), we reviewed all post-lung transplant inpatient consults performed at our institution between 2014 and 2019. Of 65 consultations, 3 patients were found to have tacrolimus-induced optic neuropathy. This report does not contain any personal information that could lead to the identification of these 3 patients.
Findings
Case 1
A 33-year-old female with a past medical history of diabetes and cystic fibrosis, status post double lung transplant 11 years prior, presented to the neurology service for non-specific headache, vision loss (blurriness, darkness, loss of peripheral vision), weakness, and lethargy. She had several prior admissions for headache, neck pain, and subjective fever. During these admissions, repeat lumbar punctures, along with extensive encephalitis panels, were unremarkable. A previous MRI, however, demonstrated new T2/FLAIR abnormalities along the optic chiasm and proximal optic tracts, hypothalamus, and cerebellum. Based on these findings her tacrolimus dose of 0.5mg/day was discontinued, even though she had remained within therapeutic range (5–20ng/ml). Her creatinine (Cr) function at that time was consistent with acute kidney injury (AKI) of 2.51.
3 months later, on presentation to our institution, she reported continued worsening of her visual symptoms over the course of 2–3 months. On exam, her visual acuity was 20/300 in the right eye and 20/200 in the left eye. She had severe dyschromatopsia on Hardy-Rand-Rittler color plates (0/12 in both eyes). A 24–2 visual field ( Fig. 1 ) demonstrated poor reliability, but suggested bitemporal field loss with significant field constriction. Dilated fundus examination was notable for optic nerve pallor and atrophy. This was confirmed on optical coherence tomography (OCT), which demonstrated diffuse ganglion cell layer loss.
During this admission she was diagnosed and treated for a superficial cellulitis of the hand, which improved after intravenous vancomycin. A broader infectious examination – including coccidiomycosis, syphilis, tuberculosis, John Cunningham virus, cytomegalovirus, and bartonella – was negative. Inflammatory and neoplastic evaluation, including a PET scan, were unremarkable. Kidney function improved from her prior admissions (Cr of 1.50) and she underwent a repeat brain, orbit, and spinal MRI. Her MRI abnormalities remained unchanged, with persistent hyperintensity of the optic chiasm ( Fig. 2 ). Her visual symptoms, which persisted after treatment of her cellulitis, along with her neuroradiologic findings, were deemed most consistent with a severe and atypical tacrolimus-induced toxicity.
Case 2
A 65-year-old male with a history of idiopathic pulmonary fibrosis complicated by pulmonary hypertension, underwent a single left lung transplantation 2 years prior to admission. His immediate post-transplant course was complicated by cryptococcal meningitis, which resolved after treatment, with no residual deficits. His immunosuppressive regimen included tacrolimus at an alternating dose of 0.5mg and 0.25mg twice a day, prednisone 10mg daily, and cellcept 500mg three times a day. On admission, he presented with an acute change in mental status and slurring of speech and was found to have maculopapular lesions respecting the midline, consistent with varicella zoster virus (VZV) in the trigeminal V1 distribution.
At the time the patient also complained of blurry vision in his left eye, which warranted an ophthalmology consultation. On exam, vision was 20/50 in both eyes and was otherwise unremarkable, notable only for tilted optic discs, a benign finding. CT imaging was negative for stroke, but a lumbar puncture was VZV polymerase chain reaction positive, confirming CNS involvement. MRI brain revealed diffuse pachymeningeal enhancement. His titers resolved on intravenous anti-viral treatment with acyclovir, yet he remained lethargic and deconditioned. On treatment, he had a persistently mild AKI (Cr of 1.30–1.60). After several weeks, his condition improved and the patient returned to baseline.
One month later, however, he was reexamined for a subjective worsening of vision, now in the right eye. At this point, there was a decrease in right eye vision, from 20/50 to 20/70, a new right afferent pupillary defect, and a new temporal visual field deficit. Optic nerve exam demonstrated newfound pallor in both eyes, consistent with a sub-acute to chronic process. Color vision was reduced on Ishihara color plates, 1.5/14 right eye and 11.5/14 left eye. Optic nerve atrophy was confirmed on OCT, which demonstrated diffuse, asymmetric, nerve fiber layer loss (right > left) ( Fig. 3 ). There was no evidence of vasculitis, or any MRI findings suggestive of leptomeningeal spread involving the optic nerves. Systemic infectious work-up remained negative and metabolic causes such as folate or vitamin B12 deficiency were excluded. Kidney function had normalized with fluid management, Cr 1.10–1.20, while being maintained on intravenous acyclovir 500mg twice a day. The interdisciplinary teams agreed that these findings were most consistent with TON, and his tacrolimus dosing was discontinued.
Case 3
A 23-year-old female with cystic fibrosis, status post bilateral lung transplant one-year prior, was transferred to our medical intensive care unit due to acute on chronic respiratory failure. Prior to admission, her home dose of tacrolimus was 0.5mg daily and prednisone 10mg daily. On admission, she was intubated for acute respiratory distress syndrome. Infectious work up (including bronchoalveolar lavage cultures) remained negative, prompting a diagnosis of acute cellular rejection (ACR). Her tacrolimus level rose from 17 to 53 ng/ml acutely and was held. Of note, she’d had a prior admission one year ago for acute tacrolimus toxicity resulting in AKI, which had resolved. Creatinine on this admission was 2.37, consistent with AKI.
She was treated with pulse dose steroids, intravenous immunoglobulin and plasma exchange, and Thymoglobulin with eventual clinical improvement. She was extubated 5 days later. At one month, she reported a new right temporal visual field deficit. On exam, vision was 20/20 in both eyes. Visual field was full ( Fig. 4 A–B). Her dilated exam demonstrated temporal nerve pallor in the right eye and diffuse optic atrophy in the left eye. This was confirmed on optical coherence tomography, which demonstrated asymmetric nerve loss (left > right) and appeared consistent with TON ( Fig. 4 C–D).
She was scheduled for a wider visual field test (Goldmann) to assess for far temporal visual field deficits but developed bifrontal seizures and altered mental status requiring admission to the neuro-intensive care unit. MRI brain demonstrated white matter changes consistent with PRES. Tacrolimus was discontinued with eventual improvement in both her symptoms and brain lesions. She remained hospitalized for another month due to the re-development of ACR requiring further medication management. She was subsequently discharged home on cyclosporine 375mg twice a day and oral prednisone 50mg daily, after a 3-month hospital stay.
Discussion
The diagnosis of tacrolimus induced optic neuropathy is clinically challenging. Previous cases report the development of TON anywhere from 2 months to 5 years after initiation. Toxicity usually occurs at a plasma level >20 ng/ml but can occur at normal or even sub-therapeutic levels ( Table 1 ). Vision loss can be sudden, over a few days, or gradual (>1 year). Like the cases described herein, in which one patient maintained 20/20 vision while another declined to the 20/200–300 range, prior studies have reported 20/20 to light perception vision. Usually, TON is a bilateral process, but can affect one optic nerve prior to the other, as with case 2. Similar to case 1, visual deterioration can continue, even after tacrolimus discontinuation.
