Immune-Mediated Optic Neuropathy in Chronically Immunosuppressed Transplant Patients

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Immune-Mediated Optic Neuropathy in Chronically Immunosuppressed Transplant Patients Sarah M. Kamal, MD, Jacob M. Winters, MD, Bayan A. Al Othman, MD, Ashwini T. Kini, MD, Hilary A. Beaver, MD, Andrew G. Lee, MD C hronic immunosuppression is critical in solid organ transplant patients to prevent graft rejection. Although it would seem logical to assume that these chronic and aggressive immunosuppressive regimens would suppress or prevent acute inflammatory disease producing visual loss, we report 4 such cases of acute inflammatory optic neuropathy in chronically immunosuppressed patients. To the best of our knowledge, these are the first such reports in the English language ophthalmic literature. These cases raise the question of whether immune-specific regimens can worsen other immunologic mechanisms of disease that are not being suppressed. CASE 1 A 74-year-old Caucasian woman presented with acute painless loss of vision in the left eye. The medical history was significant for liver transplant and chronic immunosuppressive therapy with tacrolimus. On examination, the visual acuity was no light perception (NLP) in the right eye due to previous long standing and stable herpetic infection with secondary retinal detachment several years ago. The vision measured 20/80 in the left eye and was decreased from her previous baseline of 20/30 vision in the left eye. Humphrey visual field testing (24-2 HVF) demonstrated a superior and inferior arcuate defect in the left eye. The right anterior segment showed a markedly thickened cornea because of chronic stromal edema with an intact corneal epithelium in the right eye. The anterior chamber was flat and there was a dense iris membrane and marked chronic posterior synechiae in the right eye. The slit-lamp examination in the left eye was normal. There was no view of the fundus in the McGovern Medical School (SK), Houston, Texas; Texas Tech University Health Sciences Center (JW), El Paso Paul L. Foster School of Medicine, El Paso, Texas; Department of Ophthalmology (BAO, AK, HB, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Department of Ophthalmology (HB, AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (HB, AGL), University of Texas Medical Branch, Galveston, Texas; Departments of Neurology and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Suite 450, Houston, TX 77030; E-mail: [e-mail] e180 right eye. Dilated fundus examination in the left eye showed multifocal dot and blot hemorrhages and vascular narrowing with a cup-to-disc ratio of 0.8. The optic nerve was sharp and there was no edema or pallid edema. Fundus fluorescein angiogram showed markedly delayed arteriovenous transit time, intraretinal hemorrhages, venous dilation, and multifocal cotton wool spots in the left eye. This was believed to be consistent with an ocular ischemic image of the left eye. No Hollenhorst plaques were seen. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) measured 26 mm/hour and 0.53 mg/ dL, respectively. She was admitted to the hospital and received intravenous methylprednisolone (IVMP), and a temporal artery biopsy showed disruption of the internal elastic lamina and CD68+ histiocytes consistent with giant cell arteritis (GCA). The patient was discharged after 5 doses of IVMP on oral prednisolone and on follow-up examination 3 months later had 20/20 vision in the left eye with resolution of the posterior segment findings (and a stable NLP vision in the right eye). She was continued on a tapering dose of long-term steroids for biopsy proven GCA. CASE 2 A 68-year-old Caucasian man presented with chronic and progressive visual loss in both eyes. He had been on chronic immunosuppressive therapy with tacrolimus, mycophenolate, and a low-dose prednisone status after bilateral lung transplant for 6 years. The lung transplant was performed for idiopathic pulmonary fibrosis. In addition to the progressive vision loss, he had hearing loss, ataxia, neurogenic bladder, and peripheral neuropathy worse on the left. Subsequent MRI demonstrated longitudinally extensive transverse myelitis (LETM) with T2 hyperintensity across 3 vertebral segments (C3, C4, and C5) and subtle enhancement in the posterior cervical cord at the lower C3 to upper C4 levels. The patient was referred for neuro-ophthalmology evaluation 7 months after the onset of visual loss. On examination, his visual acuity was 20/125 in the right eye and 20/100 in the left eye. Humphrey visual field (24-2 HVF) showed generalized depression in the right eye and a temporal nerve fiber defect in the left eye (Fig. 1). External, anterior segment and intraocular pressure examinations were normal in both eyes. Dilated fundus examination Kamal et al: J Neuro-Ophthalmol 2021; 41: e180-e183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Humphrey visual fields (24-2 HVF), Case 2. Note generalized depression in the right eye and a greater temporal visual field defect than a nasal visual field defect in the left eye. showed bilateral diffuse optic atrophy. The patient was admitted to the hospital and continued with 5-mg oral prednisone and 2.5-mg oral tacrolimus. Electromyography (EMG) was performed and suggested overall moderately severe axonal sensory-motor neuropathy with preference to the right. Lumbar puncture demonstrated an elevated protein level of 60 mg/ dL (normal range 15–45 mg/dL) in the cerebrospinal fluid (CSF). Antimyelin oligodendrocyte glycoprotein and neuromyelitis optica (NMO) antibodies (i.e., aquaporin-4 antibodies) were negative. An MRI of the orbit with gadolinium showed potential left optic nerve atrophy that was confirmed with an ophthalmoscope. Other causes of optic neuropathy and LETM were ruled out—specifically vitamin B12, varicella zoster virus, neurosyphilis, and CSF cell count with differential were all normal or negative. A paraneoplastic panel including CRMP5 antibody was checked and came back negative. He received a five-day course of IVMP and intravenous immunoglobulin (IVIg). At his most recent neurology appointment 9 months after presentation, the neurogenic bladder, hearing loss, and neuropathic symptoms seemed stable; however, his ataxia had progressed to a nonambulatory state. Potential causes of the hearing loss and axonal sensory-motor peripheral neuropathy were explored—laboratory results showed a normal B12, hemoglobin A1c, B1, anti-nuclear antibody, and thyroidstimulating hormone. However, there was a significant alcohol use history. He was transferred to a rehabilitation unit, and Kamal et al: J Neuro-Ophthalmol 2021; 41: e180-e183 tacrolimus and mycophenolate were discontinued, and cyclosporine was initiated for a seronegative NMO spectrum disorder (1). CASE 3 A 54-year-old Caucasian man presented with bilateral, painless, progressive visual loss. The medical history was significant for biopsy-proven sarcoidosis status after pulmonary transplantation with chronic rejection on chronic immunosuppression with tacrolimus and 10 mg of prednisone daily and graftvs-host disease status after plasmapheresis and stem cell transplantation. He was treated with IV steroids, but his vision did not improve. On referral to the neuroophthalmology service, his visual acuity was hand motions in each eye. The pupils were poorly reactive bilaterally. Slit-lamp examination showed pseudophakia and no evidence for anterior or posterior uveitis. No intraocular granulomatous disease was seen. Ophthalmoscopy showed diffuse optic atrophy in both eyes. The patient was readmitted to the hospital with initiation of high-dose IV steroids. MRI of the brain and orbits with and without contrast showed increased T2 signal in the optic chiasm and bilateral optic tracts. Chest x-ray showed scarring and granulomatous calcifications adjacent to the left hilum. The patient received IVIg for 4 days and the vision remained stable. e181 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence CASE 4 A 76-year-old African American woman on chronic immunosuppression with sirolimus and tacrolimus status after heart transplant 8 years before due to extensive coronary artery disease presented to the ophthalmology clinic with painful, bilateral, progressive blurring of vision, headache, weight loss, and scalp tenderness for the past 4 months. Examination showed visual acuity of 20/25 in the right eye and 20/40 in the left eye with no anisocoria or relative afferent pupillary defect. Fields were full to confrontation. Dilated fundus examination demonstrated mild pallor of both optic nerves. The ESR and CRP were within normal limits. She underwent a left temporal artery biopsy that showed irregular intimal hyperplasia associated with the focal absence of internal elastic lamina. There was no lymphocytic or giant cell infiltrate in the wall of the artery. The Movat pentachrome staining showed a focal segmental absence of the elastic lamina and focal fibrosis of the muscularis under this area. CD68 IHC staining showed few associated histiocytes at the level of the internal elastic lamina. Diagnostic features for active GCA were not seen. However, the features present were suggestive of a healing or treated temporal arteritis. The patient was started on a high-dose prednisone with long-term tapering in addition to her existing immunosuppressive regimen. DISCUSSION Our 4 patients presented with acute presumed inflammatory visual loss despite chronically suppressed immune systems. The chronic immunosuppression failed to prevent the emergence of the following diagnoses: GCA, presumed NMO, and sarcoidosis. This highlights the importance of understanding the mechanisms of action of various immunosuppressive agents and their effects on different autoimmune pathologies. GCA is a chronic granulomatous inflammatory condition that affects medium to large size vessels. The T helper 1 (Th1)-mediated pathway and release of inflammatory mediators (e.g., IFNg) activate macrophages and lead to subsequent release of additional inflammatory cytokines (e.g., interleukin 1 (IL1), TNFa, and IL6). Release of these cytokines leads to tissue infiltration by leukocytes and an inflammatory cascade that may eventually lead to blindness in GCA (2). NMO is an autoimmune antibody– mediated disorder that affects the optic nerve and the spinal cord. It is activated peripherally by an unknown trigger and results in an IgG autoantibody against the aquaporin-4 water channel. It is believed that the etiology of NMO is founded on a Th17-mediated pathway with subsequent activation of IL6 (3). Interestingly, in recent years, GCA has also been found to have a Th17-mediated immune response (2). The treatment for both GCA and NMO in the acute phase is corticosteroids. Corticosteroids decrease the transcription of many cytokines by working on the nuclear e182 factor of activated T-cells pathway (4). This inhibits the production of key cytokines involved in GCA and NMO including IL1, TNFa, and IL6. Other immunosuppressive agents target the inflammatory pathway in a different manner, and thus the mechanism for suppression of the immune system for solid organ transplantation is different than the immunosuppressive regimens used for GCA and NMO. In our case series specifically, sirolimus, mycophenolate, and tacrolimus were used to prevent transplant rejection. Tacrolimus functions as a calcineurin inhibitor by binding to the FKBP (FK506binding protein) and preventing transcription of IL-2 (5). Sirolimus functions as an mammalian target of rapamycin inhibitor also by binding to the FKBP and blocks the response to IL2 (6). Finally, mycophenolate is an inosine monophoshate dehydrogenase inhibitor and prevents the synthesis of B and T cells (7). All function to inhibit or deplete B and T cells but none specifically target cytokines as corticosteroids do. Subsequently, it has been proposed that no immunosuppressive agent (with the exception of corticosteroids) can suppress the emergence of some inflammatory diseases, such as GCA and NMO, 2 cytokine-mediated inflammatory conditions. Sarcoidosis is a noncaseating granulomatous disorder with a predilection for the eye and lung. Like GCA and NMO, the mechanisms underlying these inflammatory disorders may differ from the immunologic mechanisms of organ transplant rejection, and thus immunosuppression in this setting may not prevent reactivated inflammatory disease elsewhere. To the best of our knowledge, only 2 previous case reports have discussed this phenomenon. In 2015, Arlow and Sergott reported a patient with rheumatoid arthritis on chronic immunosuppression who presented with visual field loss in one eye. This patient was seropositive for aquaporin-4 NMO (8). Kim et al in 2016 reported a patient on chronic immunosuppression with tacrolimus, mycophenolate, and prednisone for a cardiac transplant who also met diagnostic criteria for seronegative NMO (9). In a similar vein, Simsek et al conducted a literature search in 2007 and found that 15 patients receiving antitumor necrosis factor alpha therapy developed optic neuritis (10). This only further exemplifies how suppression of one arm of the immune system may either fail to suppress or even release another arm. In this article, we have presented a four-patient case series describing patients in whom chronic immunosuppression for organ transplant rejection failed to prevent the emergence of GCA, presumed NMO, and sarcoidosisrelated optic neuropathy. Of note, 2 of our patients were on low-dose oral prednisone as a part of their immunosuppressive regimen; however, it is likely that the low dose and oral route were unable to prevent GCA and NMO from occurring. It is also important to highlight that ESR and CRP may be depressed in chronic immunosuppression. ESR and CRP secretion is largely cytokine dependent, and thus, they should not be relied on as diagnostic markers for GCA or NMO, especially in the setting of a chronically immunosuppressed patient (11). Kamal et al: J Neuro-Ophthalmol 2021; 41: e180-e183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence We believe that these cases may reflect an emerging trend for reactivation of inflammatory disease causing optic neuropathy through different immunologic mechanisms than graft rejection and that immunosuppression in this setting may not prevent disease occurrence in other organ systems. Clinicians should be aware that chronic immunosuppression does not protect patients from acute inflammatory optic neuropathy with mechanisms that differ from the inflammatory and immunologic pathways that require suppression for prevention of organ transplant rejection. REFERENCES 1. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66:1485–1489. 2. Cid MC. 3. Pathogenesis of giant cell arteritis, Rheumatology. 2014;53:i2–i3. 3. Bukhari W, Barnett MH, Prain K, Broadley SA. Molecular pathogenesis of neuromyelitis optica. Int J Mol Sci. 2012;13:12970–12993. 4. Rogatsky I, Ivashkiv LB. 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