ACUTE RETINAL NECROSIS AND IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN A NATALIZUMAB-TREATED PATIENT WITH MULTIPLE SCLEROSIS Vinicius S. Saraiva, MD, PhD
Purpose: To describe a case of acute retinal necrosis and subsequent immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab. Methods: Case report. Results: A 51-year-old man with multiple sclerosis developed acute retinal necrosis during treatment with natalizumab. The patient was successfully managed with natalizumab discontinuation, oral valacyclovir, and prophylactic laser retinal photocoagulation. A few months after natalizumab interruption and 1 month after valacyclovir completion, the patient presented with an episode of presumed noninfectious anterior and intermediate uveitis, which responded well to oral steroid mini-pulse therapy. Conclusion: Natalizumab is a potent immune suppressor used in the treatment of multiple sclerosis and Crohn disease. It has already been linked to herpetic infections and immune reconstitution inflammatory syndrome in the central nervous system. These complications may also affect ocular tissues. RETINAL CASES & BRIEF REPORTS 9:195–197, 2015
areas of retinal whitening, mainly peripheral, with associated vascular involvement and constriction in the right eye (Figure 1). A diagnosis of acute retinal necrosis was made. The patient was started on valacyclovir 1 g orally 3 times a day for 3 months. Prednisolone, atropine, timolol, and dorzolamide drops were also given. Complete blood count, blood urea nitrogen, and creatinine were monitored for side effects. The patient was followed daily during the first week of antiviral therapy. There was a marked decrease in intraocular inflammation and pressure. The areas of retinal necrosis did not progress. Prednisone 60 mg orally once a day was started 4 days after initiation of valacyclovir, with tapering over 4 weeks. Varicella zoster virus serology showed positive IgG and IgM antibodies. Prophylactic laser retinal photocoagulation was performed 14 days after initiation of valacyclovir. Natalizumab was discontinued after Neurology consultation. No other MS treatment was given. Four weeks into antiviral therapy, the retinal lesions faded, leaving atrophic areas. The 3-month course of valacyclovir was completed. Best-corrected visual acuity was 20/30 in both eyes. One month after antiviral therapy, the patient presented with decreased visual acuity and floaters in the right eye. Best-corrected visual acuity was 20/60 in the right eye. Anterior segment biomicroscopy revealed fine keratic precipitates, anterior chamber reaction (2+ cells, 1+ flare), and anterior vitreous reaction (2+ cells)
From the Department of Ophthalmology and Visual Sciences, Federal University of São Paulo, São Paulo, Brazil. Case Report A 51-year-old man with multiple sclerosis (MS) was on natalizumab treatment for the past 6 months and presented with redness and discomfort in the right eye for 2 days. He reported previous episodes of optic neuritis with good recovery. Bestcorrected visual acuity was 20/30 in both eyes. Pupillary reflexes and extraocular motility were intact. Anterior segment biomicroscopy revealed conjunctival injection, anterior chamber reaction (2+ cells, 1+ flare), and anterior vitreous reaction (2+ cells) in the right eye. Intraocular pressure was 23 mmHg in the right eye and 15 mmHg in the left eye. Fundus examination revealed multiple None of the authors have any financial/conflicting interests to disclose. Reprint requests: Vinicius S. Saraiva, MD, PhD, Department of Ophthalmology and Visual Sciences, Federal University of São Paulo, Rua Botucatu, 979—3 andar, São Paulo, SP 04023-062, Brazil; e-mail: [email protected]
195
196
RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 3
Fig. 2. Vitritis in the right eye. Vitreous opacity partially obscuring the view of the fundus and area of retinal atrophy in the temporal aspect of the macula.
Fig. 1. Acute retinal necrosis in the right eye. Top: Area of retinal necrosis in the temporal aspect of the macula. Bottom: Multiple foci of retinal necrosis in the temporal periphery. Identical lesions were found in the other quadrants.
in the right eye. Intraocular pressure was 15 mmHg in the right eye and 11 mmHg in the left eye. Fundus examination revealed vitritis 2+, multiple areas of retinal atrophy, and laser scars in the right eye. There were no signs of vasculitis, retinitis, choroiditis, disk, or macular edema (Figure 2). The anterior and intermediate uveitis was presumably noninfectious and was considered a form of immune reconstitution inflammatory syndrome. After Neurology consultation, the patient was started on oral mini-pulse therapy with dexamethasone 16 mg orally once a day for 5 days followed by prednisone 60 mg orally once a day, with tapering over 4 weeks. Prednisolone and atropine drops were also prescribed. After treatment, best-corrected visual acuity was 20/30 in both eyes, and a significant decrease in the vitreous opacity was observed.
Discussion Natalizumab is an integrin receptor antagonist indicated for the treatment of relapsing MS and Crohn disease with poor response to conventional therapy. Natalizumab is known to cause immunosuppression and increases the risk for opportunistic viral infections,
such as progressive multifocal leukoencephalopathy and herpetic encephalitis/meningitis.1 Acute retinal necrosis is a form of necrotizing herpetic retinitis, and natalizumab-treated patients may be at increased risk for developing acute retinal necrosis, albeit rare.2,3 This patient developed acute retinal necrosis during natalizumab therapy. His positive IgG and IgM antibodies to varicella zoster virus suggested recent viral infection, but latent Varicella zoster virus reactivation cannot be excluded. Natalizumab is a recombinant humanized monoclonal antibody that binds to integrins on the surface of all leukocytes, except neutrophils, disrupting their adhesion to and transmigration across the vascular endothelium.1 Natalizumab substantially decreases the T-cell CD4/CD8 ratio in the cerebrospinal fluid compared with peripheral blood, resulting in impaired immune surveillance in the central nervous system.3 The postmarketing data from the United States Food and Drug Administration’s Adverse Event Reporting System showed an increased incidence of central nervous system herpesvirus infections in natalizumab-treated patients with MS.3 Rebound exacerbations of brain lesions in patients with MS, that is, immune reconstitution inflammatory syndrome, have been described in natalizumabassociated progressive multifocal leukoencephalopathy4 and after natalizumab cessation alone.5 This patient developed an episode of anterior/intermediate uveitis approximately 4 months after natalizumab was discontinued and 1 month after valacyclovir treatment was complete. During this period, no other MS treatment was given. Immune reconstitution inflammatory syndrome, probably due to an enhanced inflammatory response to varicella zoster virus
NATALIZUMAB AND OCULAR INFLAMMATION
antigens in the eye after natalizumab cessation, was the putative cause of his anterior/intermediate uveitis episode. Key words: acute retinal necrosis, immune reconstitution inflammatory syndrome, immune recovery uveitis, multiple sclerosis, natalizumab. References Ò
1. Biogen. Tysabri (natalizumab) injection: full prescribing information. 2012. Available at: http://www.tysabri.com/en_ US/tysb/site/pdfs/TYSABRI-pi.pdf. Accessed March 31, 2014.
197 2. Berger JR, Houff S. Opportunistic infections and other risks with newer multiple sclerosis therapies. Ann Neurol 2009;65:367–377. 3. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis 2013;57:849–852. 4. Tan IL, McArthur JC, Clifford DB, et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011;77:1061–1067. 5. Miravalle A, Jensen R, Kinkel RP. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol 2011;68:186–191.
Purpose: To describe a case of acute retinal necrosis and subsequent immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab. Methods: Case report. Results: A 51-year-old man with multiple sclerosis developed acute retinal necrosis during treatment with natalizumab. The patient was successfully managed with natalizumab discontinuation, oral valacyclovir, and prophylactic laser retinal photocoagulation. A few months after natalizumab interruption and 1 month after valacyclovir completion, the patient presented with an episode of presumed noninfectious anterior and intermediate uveitis, which responded well to oral steroid mini-pulse therapy. Conclusion: Natalizumab is a potent immune suppressor used in the treatment of multiple sclerosis and Crohn disease. It has already been linked to herpetic infections and immune reconstitution inflammatory syndrome in the central nervous system. These complications may also affect ocular tissues. RETINAL CASES & BRIEF REPORTS 9:195–197, 2015
areas of retinal whitening, mainly peripheral, with associated vascular involvement and constriction in the right eye (Figure 1). A diagnosis of acute retinal necrosis was made. The patient was started on valacyclovir 1 g orally 3 times a day for 3 months. Prednisolone, atropine, timolol, and dorzolamide drops were also given. Complete blood count, blood urea nitrogen, and creatinine were monitored for side effects. The patient was followed daily during the first week of antiviral therapy. There was a marked decrease in intraocular inflammation and pressure. The areas of retinal necrosis did not progress. Prednisone 60 mg orally once a day was started 4 days after initiation of valacyclovir, with tapering over 4 weeks. Varicella zoster virus serology showed positive IgG and IgM antibodies. Prophylactic laser retinal photocoagulation was performed 14 days after initiation of valacyclovir. Natalizumab was discontinued after Neurology consultation. No other MS treatment was given. Four weeks into antiviral therapy, the retinal lesions faded, leaving atrophic areas. The 3-month course of valacyclovir was completed. Best-corrected visual acuity was 20/30 in both eyes. One month after antiviral therapy, the patient presented with decreased visual acuity and floaters in the right eye. Best-corrected visual acuity was 20/60 in the right eye. Anterior segment biomicroscopy revealed fine keratic precipitates, anterior chamber reaction (2+ cells, 1+ flare), and anterior vitreous reaction (2+ cells)
From the Department of Ophthalmology and Visual Sciences, Federal University of São Paulo, São Paulo, Brazil. Case Report A 51-year-old man with multiple sclerosis (MS) was on natalizumab treatment for the past 6 months and presented with redness and discomfort in the right eye for 2 days. He reported previous episodes of optic neuritis with good recovery. Bestcorrected visual acuity was 20/30 in both eyes. Pupillary reflexes and extraocular motility were intact. Anterior segment biomicroscopy revealed conjunctival injection, anterior chamber reaction (2+ cells, 1+ flare), and anterior vitreous reaction (2+ cells) in the right eye. Intraocular pressure was 23 mmHg in the right eye and 15 mmHg in the left eye. Fundus examination revealed multiple None of the authors have any financial/conflicting interests to disclose. Reprint requests: Vinicius S. Saraiva, MD, PhD, Department of Ophthalmology and Visual Sciences, Federal University of São Paulo, Rua Botucatu, 979—3 andar, São Paulo, SP 04023-062, Brazil; e-mail: [email protected]
195
196
RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 3
Fig. 2. Vitritis in the right eye. Vitreous opacity partially obscuring the view of the fundus and area of retinal atrophy in the temporal aspect of the macula.
Fig. 1. Acute retinal necrosis in the right eye. Top: Area of retinal necrosis in the temporal aspect of the macula. Bottom: Multiple foci of retinal necrosis in the temporal periphery. Identical lesions were found in the other quadrants.
in the right eye. Intraocular pressure was 15 mmHg in the right eye and 11 mmHg in the left eye. Fundus examination revealed vitritis 2+, multiple areas of retinal atrophy, and laser scars in the right eye. There were no signs of vasculitis, retinitis, choroiditis, disk, or macular edema (Figure 2). The anterior and intermediate uveitis was presumably noninfectious and was considered a form of immune reconstitution inflammatory syndrome. After Neurology consultation, the patient was started on oral mini-pulse therapy with dexamethasone 16 mg orally once a day for 5 days followed by prednisone 60 mg orally once a day, with tapering over 4 weeks. Prednisolone and atropine drops were also prescribed. After treatment, best-corrected visual acuity was 20/30 in both eyes, and a significant decrease in the vitreous opacity was observed.
Discussion Natalizumab is an integrin receptor antagonist indicated for the treatment of relapsing MS and Crohn disease with poor response to conventional therapy. Natalizumab is known to cause immunosuppression and increases the risk for opportunistic viral infections,
such as progressive multifocal leukoencephalopathy and herpetic encephalitis/meningitis.1 Acute retinal necrosis is a form of necrotizing herpetic retinitis, and natalizumab-treated patients may be at increased risk for developing acute retinal necrosis, albeit rare.2,3 This patient developed acute retinal necrosis during natalizumab therapy. His positive IgG and IgM antibodies to varicella zoster virus suggested recent viral infection, but latent Varicella zoster virus reactivation cannot be excluded. Natalizumab is a recombinant humanized monoclonal antibody that binds to integrins on the surface of all leukocytes, except neutrophils, disrupting their adhesion to and transmigration across the vascular endothelium.1 Natalizumab substantially decreases the T-cell CD4/CD8 ratio in the cerebrospinal fluid compared with peripheral blood, resulting in impaired immune surveillance in the central nervous system.3 The postmarketing data from the United States Food and Drug Administration’s Adverse Event Reporting System showed an increased incidence of central nervous system herpesvirus infections in natalizumab-treated patients with MS.3 Rebound exacerbations of brain lesions in patients with MS, that is, immune reconstitution inflammatory syndrome, have been described in natalizumabassociated progressive multifocal leukoencephalopathy4 and after natalizumab cessation alone.5 This patient developed an episode of anterior/intermediate uveitis approximately 4 months after natalizumab was discontinued and 1 month after valacyclovir treatment was complete. During this period, no other MS treatment was given. Immune reconstitution inflammatory syndrome, probably due to an enhanced inflammatory response to varicella zoster virus
NATALIZUMAB AND OCULAR INFLAMMATION
antigens in the eye after natalizumab cessation, was the putative cause of his anterior/intermediate uveitis episode. Key words: acute retinal necrosis, immune reconstitution inflammatory syndrome, immune recovery uveitis, multiple sclerosis, natalizumab. References Ò
1. Biogen. Tysabri (natalizumab) injection: full prescribing information. 2012. Available at: http://www.tysabri.com/en_ US/tysb/site/pdfs/TYSABRI-pi.pdf. Accessed March 31, 2014.
197 2. Berger JR, Houff S. Opportunistic infections and other risks with newer multiple sclerosis therapies. Ann Neurol 2009;65:367–377. 3. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis 2013;57:849–852. 4. Tan IL, McArthur JC, Clifford DB, et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011;77:1061–1067. 5. Miravalle A, Jensen R, Kinkel RP. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol 2011;68:186–191.
