Clin Rheumatol DOI 10.1007/s10067-014-2623-1
CASE BASED REVIEW
Bilateral dexamethasone intravitreal implant in a young patient with Vogt-Koyanagi-Harada disease and refractory uveitis Maria Eugenia Latronico & Donato Rigante & Francesco Caso & Luca Cantarini & Luisa Costa & Laura Nieves-Martín & Claudio Traversi & Rossella Franceschini
Received: 15 March 2014 / Revised: 2 April 2014 / Accepted: 7 April 2014 # Clinical Rheumatology 2014
Abstract Vogt-Koyanagi-Harada disease (VKHD) is a multisystemic disorder characterized by granulomatous panuveitis with exudative retinal detachments, often associated with neurologic and cutaneous manifestations. Therapy relies mainly on the use of corticosteroids, administrated as oral or intravenous high-dose pulses, and immunosuppressants. However, since macular edema and retinal detachment can often be refractory to systemic therapies, intravitreal triamcinolone acetate has been used successfully. Herein, we report the first case of refractory bilateral panuveitis in a young patient with VKHD successfully treated with dexamethasone intravitreal implant. Keywords Prednisone . Therapy . Uveitis . Vogt-Koyanagi-Harada disease (VKHD) M. E. Latronico : C. Traversi : R. Franceschini Ophthalmology and Neurosurgery Department, University of Siena, Siena, Italy D. Rigante Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy F. Caso : L. Cantarini (*) : L. Nieves-Martín Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Siena, Italy e-mail: [email protected] F. Caso Rheumatology Unit, Department of Medicine DIMED, University of Padua, Padua, Italy L. Costa Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy L. Nieves-Martín Rheumatology Service, Hospital Regional Universitario Carlos Haya, University of Málaga, Málaga, Spain
Introduction Vogt-Koyanagi-Harada disease (VKHD) is a multisystemic disorder characterized by granulomatous panuveitis with exudative retinal detachments, often associated with neurologic and cutaneous manifestations. Although its etiopathogenesis remains unraveled, a T cell-mediated autoimmune response to melanin-associated antigens is hypothesized, in which viral agents might trigger an immune response inducing the failure of self-tolerance in genetically susceptible individuals [1]. Its onset is characterized by flu-like features and nonspecific ocular signs, often in the form of blurred vision and photophobia, followed by progressive panuveitis, variably associated with unilateral or bilateral involvement of auditory and sensorineural nerves, causing progressive hearing loss, tinnitus, and vertigo. In a small subset of patients, neurological and cutaneous signs, respectively, meningitis and vitiligo, poliosis, or alopecia, might occur [2]. Therapy relies mainly on the use of corticosteroids, usually administrated as intravenous highdose pulses (1 g/day of methylprednisolone for 3 to 5 days), followed by oral high-dose prednisone [3]. Additional use of immunosuppressants, anti-tumor necrosis factor-alpha agents, or intravenous immunoglobulins can be useful in severely affected patients as steroid-sparing agents. However, since macular edema and retinal detachment can often be refractory to systemic therapies, intravitreal triamcinolone acetate has been used successfully [4]. Dexamethasone intravitreal implant (Ozurdex®; Allergan, Inc., Irvine, CA, USA) is a biodegradable drug delivery system (DDS), injected into the vitreous cavity to treat macular edema, caused by noninfectious posterior uveitis or central retinal vein occlusion, releasing 700 μg of preservative-free dexamethasone to the retina and vitreous [5, 6]. To the best of our knowledge, its use has been reported in two cases of adult patients diagnosed with a probable diagnosis of VKHD [7, 8]. Herein, we report the first case of refractory bilateral
Clin Rheumatol Table 1 Ocular examination findings for our patient with VogtKoyanagi-Harada disease at time of onset and during the follow-up period Time
BVCA
CRT (μm) (SD-OCT)
OR
OL
OR
OL
0 1 2 3 4 5
20/40 20/20 10/20 2/20 20/200 16/20
20/200 16/20 6/20 16/20 20/200 20/32
905 381 624 326 442 715
602 309 776 273 798 259
6
20/25
20/32
390
252
BCVA best-corrected visual acuity, CRT central retinal thickness, OL left eye, OR right eye, SD-OCT spectral domain-ocular coherence tomography
panuveitis in a young patient with VKHD successfully treated with dexamethasone DDS.
Patients and methods Case report A 15-year-old girl consulted us for bilateral blurred vision, following an episode of flu-like disease with fever, malaise, and headache. The patient presented acute loss of vision (visual acuity of 20/40 in the right eye, with a correction of +2.25sf, and 20/200 in the left eye, with a correction of +0.50 sf). Bilateral granulomatous anterior uveitis associated with supraciliary effusions, vitritis, granulomatous keratitic precipitates, and edema of the optic nerve head were found, while scotomas and decreased mean retinal sensitivity were observed at the visual field test. The patient also showed progressive eyelash whitening. Spectral domain-ocular coherence tomography (SD-OCT) showed an increased central retinal thickness, due to macular edema associated with superficial bilateral exudative retinal detachment in both eyes (Table 1; time 0). Fluorescein angiography showed bilateral disc hyperfluorescence with optic nerve head leakage and diffuse late staining (Fig. 1a, b). After having ruled out traumatic lesions, viral and bacterial infectious diseases, and Blau syndrome [2, 9, 10], diagnosis of VKH disease was made. Thus, within 1 week of presentation, the patient had received not only topical dexamethasone and systemic nonsteroidal anti-inflammatory drugs but also cycles
of intravenous methylprednisolone (1 g/day for 5 days, followed by 25 mg/day of oral prednisone). A notable improvement in visual acuity and reduction in both retinal exudation and thickness were observed within 1 month (Table 1; time 1), continued 2 months later, when a further relapse occurred (Table 1; time 2). At that time, while taking 15 mg prednisolone daily, the patient presented again vision loss: the SD-OCT showed increased central retinal thickness and macular edema. The patient also referred hearing loss in the left ear, confirmed by audiology evaluation. Thus, intravenous pulses of methylprednisolone were restarted for 5 days, followed by oral prednisone and cyclosporine (150 mg/day), leading to auditory and ocular improvement (Table 1; time 3). However, after 1 month, a further flare of bilateral uveitis occurred (left>right eye) (Fig. 1c, d) (Table 1; time 4). In addition to intravenous pulses of methylprednisolone for 3 days, we inserted an intravitreal left eye Ozurdex® device, after obtaining patient’s parents’ informed consent. Three weeks after implantation (Table 1; time 5), left eye visual acuity showed improvement and the anterior chamber showed no flare. No vitreous cellular infiltration or keratitic precipitates were detected. Left eye visual field showed improvement of both scotomas and mean sensitivity. The cornea was clear and macular thickness was decreased, with complete resolution of subretinal fluid accumulation and intraretinal edema on OCT scans (Fig. 1e). On the contrary, despite use of intravenous pulses of methylprednisolone, the right eye worsened (Table 1; time 5). Therefore, 2 weeks later, we also implanted Ozurdex® in the right eye. Two weeks after this new implantation (Table 1; time 6), right eye visual acuity also improved. The anterior chamber did not flare, and the same success was seen on the visual field test and OCT scan (Fig. 1f). Examination of the fundus showed no papillitis. Furthermore, at this time, left eye examination also confirmed a stable improvement (Table 1; time 6). Fluorescein angiography was also bilaterally improved. (Fig. 1g, h). Neither anterior nor posterior complications were reported in both eyes, and prednisone was gradually tapered. Visual acuity remained stable. An increased intraocular pressure (27 mmHg) was detected in the left eye, and therapy with topical acetazolamide successfully administered (still in course).
Discussion Our experience with intravitreal use of dexamethasone implant in both eyes of this young girl with refractory VKHD has been successful. To date, only two cases—a 49-year-old man and a 45-year-old woman [7, 8] with a probable diagnosis of VKHD treated with intravitreal Ozurdex®—have been
Clin Rheumatol Fig. 1 Fluorescein angiograms and spectral domain-ocular coherence tomography before and after the use of Ozurdex® implant. Right eye (a) and left eye (b): the late-phase fluorescein angiograms at the time of uveitis onset, showing bilateral hyperfluorescence of the optic disc and retinal vessels, marked peripheral hypopigmentation of the choroid, associated hyperpigmented patches of retinal pigment epithelium, leaking points, macular edema, and exudative retinal detachments. Right eye (c) and left eye (d): spectral domainocular coherence tomography images before the use of Ozurdex® implant, showing bilateral exudative retinal detachments and alteration of the normal profile and morphology associated with increase of foveal area thickness, caused by edema (hypoechoic areas). Right eye (e) and left eye (f): spectral domainocular coherence tomography images after the use of Ozurdex® implant, showing complete regression of edema (hypoechoic areas), with recovery of normal morphology and thickness of the fovea. Detection of a few cells is just visible in the right eye (e). Right eye (g) and left eye (h): the late-phase fluorescein angiograms after the use of Ozurdex® implant, showing respectively reduction in the fluorescence of retinal vessels and no macular edema
reported. Hence, to the best of our knowledge, our case represents the first report of VKHD in a young patient. Our experience lets us suggest that intravitreal dexamethasone implants might have an effective role in the treatment of refractory uveitis with retinal complications of VKHD, also to prevent side effects of long-term corticosteroid administration.
Disclosures None.
References 1. Tagawa Y, Sugiura S, Yakura H, Wakisaka A, Aizawa M (1976) HLA and Vogt-Koyanagi-Harada syndrome. N Engl J Med 295:173 2. Greco A, Fusconi M, Gallo A, Turchetta R, Marinelli C, Macri GF, De Virgilio A, de Vincentiis M (2013) Vogt-Koyanagi-Harada syndrome. Autoimmun Rev 12:1033–1038 3. Yamanaka E, Ohguro N, Yamamoto S, Nakagawa Y, Imoto Y, Tano Y (2002) Evaluation of pulse corticosteroid therapy for VogtKoyanagi-Harada disease assessed by optical coherence tomography. Am J Ophthalmol 134:454–456 4. Andrade RE, Muccioli C, Farah ME, Nussenblatt RB, Belfort R Jr (2004) Intravitreal triamcinolone in the treatment of serous retinal
Clin Rheumatol detachment in Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 137:572–574 5. Haller JA, Bandello F, Belfort R Jr, Blumenkranz MS, Gillies M, Heier J, Loewenstein A, Yoon YH, Jacques ML, Jiao J, Li XY, Whitcup SM, OZURDEX GENEVA Study Group (2010) Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 117:1134–1146(e3) 6. Kuppermann BD, Blumenkranz MS, Haller JA, Williams GA, Weinberg DV, Chou C, Whitcup SM, Dexamethasone DDS Phase II Study Group (2007) Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 125:309–317
7. Chuang CT, Huang PS, Chen SC, Sheu SJ (2013) Reversible alopecia in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. J Ophthalmic Inflamm Infect 3:41 8. Myung JS, Aaker GD, Kiss S (2010) Treatment of noninfectious posterior uveitis with dexamethasone intravitreal implant. Clin Ophthalmol 4:1423–1426 9. Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L (2012) Blau syndrome, clinical and genetic aspects. Autoimmun Rev 12: 44–51 10. Caso F, Wouters CH, Rose CD, Costa L, Tognon S, Sfriso P, Cantarini L, Rigante D, Punzi L (2014) Blau syndrome and latent tubercular infection: an unresolved partnership. Int J Rheum Dis. doi: 10.1111/1756-185X.12330
CASE BASED REVIEW
Bilateral dexamethasone intravitreal implant in a young patient with Vogt-Koyanagi-Harada disease and refractory uveitis Maria Eugenia Latronico & Donato Rigante & Francesco Caso & Luca Cantarini & Luisa Costa & Laura Nieves-Martín & Claudio Traversi & Rossella Franceschini
Received: 15 March 2014 / Revised: 2 April 2014 / Accepted: 7 April 2014 # Clinical Rheumatology 2014
Abstract Vogt-Koyanagi-Harada disease (VKHD) is a multisystemic disorder characterized by granulomatous panuveitis with exudative retinal detachments, often associated with neurologic and cutaneous manifestations. Therapy relies mainly on the use of corticosteroids, administrated as oral or intravenous high-dose pulses, and immunosuppressants. However, since macular edema and retinal detachment can often be refractory to systemic therapies, intravitreal triamcinolone acetate has been used successfully. Herein, we report the first case of refractory bilateral panuveitis in a young patient with VKHD successfully treated with dexamethasone intravitreal implant. Keywords Prednisone . Therapy . Uveitis . Vogt-Koyanagi-Harada disease (VKHD) M. E. Latronico : C. Traversi : R. Franceschini Ophthalmology and Neurosurgery Department, University of Siena, Siena, Italy D. Rigante Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy F. Caso : L. Cantarini (*) : L. Nieves-Martín Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Siena, Italy e-mail: [email protected] F. Caso Rheumatology Unit, Department of Medicine DIMED, University of Padua, Padua, Italy L. Costa Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy L. Nieves-Martín Rheumatology Service, Hospital Regional Universitario Carlos Haya, University of Málaga, Málaga, Spain
Introduction Vogt-Koyanagi-Harada disease (VKHD) is a multisystemic disorder characterized by granulomatous panuveitis with exudative retinal detachments, often associated with neurologic and cutaneous manifestations. Although its etiopathogenesis remains unraveled, a T cell-mediated autoimmune response to melanin-associated antigens is hypothesized, in which viral agents might trigger an immune response inducing the failure of self-tolerance in genetically susceptible individuals [1]. Its onset is characterized by flu-like features and nonspecific ocular signs, often in the form of blurred vision and photophobia, followed by progressive panuveitis, variably associated with unilateral or bilateral involvement of auditory and sensorineural nerves, causing progressive hearing loss, tinnitus, and vertigo. In a small subset of patients, neurological and cutaneous signs, respectively, meningitis and vitiligo, poliosis, or alopecia, might occur [2]. Therapy relies mainly on the use of corticosteroids, usually administrated as intravenous highdose pulses (1 g/day of methylprednisolone for 3 to 5 days), followed by oral high-dose prednisone [3]. Additional use of immunosuppressants, anti-tumor necrosis factor-alpha agents, or intravenous immunoglobulins can be useful in severely affected patients as steroid-sparing agents. However, since macular edema and retinal detachment can often be refractory to systemic therapies, intravitreal triamcinolone acetate has been used successfully [4]. Dexamethasone intravitreal implant (Ozurdex®; Allergan, Inc., Irvine, CA, USA) is a biodegradable drug delivery system (DDS), injected into the vitreous cavity to treat macular edema, caused by noninfectious posterior uveitis or central retinal vein occlusion, releasing 700 μg of preservative-free dexamethasone to the retina and vitreous [5, 6]. To the best of our knowledge, its use has been reported in two cases of adult patients diagnosed with a probable diagnosis of VKHD [7, 8]. Herein, we report the first case of refractory bilateral
Clin Rheumatol Table 1 Ocular examination findings for our patient with VogtKoyanagi-Harada disease at time of onset and during the follow-up period Time
BVCA
CRT (μm) (SD-OCT)
OR
OL
OR
OL
0 1 2 3 4 5
20/40 20/20 10/20 2/20 20/200 16/20
20/200 16/20 6/20 16/20 20/200 20/32
905 381 624 326 442 715
602 309 776 273 798 259
6
20/25
20/32
390
252
BCVA best-corrected visual acuity, CRT central retinal thickness, OL left eye, OR right eye, SD-OCT spectral domain-ocular coherence tomography
panuveitis in a young patient with VKHD successfully treated with dexamethasone DDS.
Patients and methods Case report A 15-year-old girl consulted us for bilateral blurred vision, following an episode of flu-like disease with fever, malaise, and headache. The patient presented acute loss of vision (visual acuity of 20/40 in the right eye, with a correction of +2.25sf, and 20/200 in the left eye, with a correction of +0.50 sf). Bilateral granulomatous anterior uveitis associated with supraciliary effusions, vitritis, granulomatous keratitic precipitates, and edema of the optic nerve head were found, while scotomas and decreased mean retinal sensitivity were observed at the visual field test. The patient also showed progressive eyelash whitening. Spectral domain-ocular coherence tomography (SD-OCT) showed an increased central retinal thickness, due to macular edema associated with superficial bilateral exudative retinal detachment in both eyes (Table 1; time 0). Fluorescein angiography showed bilateral disc hyperfluorescence with optic nerve head leakage and diffuse late staining (Fig. 1a, b). After having ruled out traumatic lesions, viral and bacterial infectious diseases, and Blau syndrome [2, 9, 10], diagnosis of VKH disease was made. Thus, within 1 week of presentation, the patient had received not only topical dexamethasone and systemic nonsteroidal anti-inflammatory drugs but also cycles
of intravenous methylprednisolone (1 g/day for 5 days, followed by 25 mg/day of oral prednisone). A notable improvement in visual acuity and reduction in both retinal exudation and thickness were observed within 1 month (Table 1; time 1), continued 2 months later, when a further relapse occurred (Table 1; time 2). At that time, while taking 15 mg prednisolone daily, the patient presented again vision loss: the SD-OCT showed increased central retinal thickness and macular edema. The patient also referred hearing loss in the left ear, confirmed by audiology evaluation. Thus, intravenous pulses of methylprednisolone were restarted for 5 days, followed by oral prednisone and cyclosporine (150 mg/day), leading to auditory and ocular improvement (Table 1; time 3). However, after 1 month, a further flare of bilateral uveitis occurred (left>right eye) (Fig. 1c, d) (Table 1; time 4). In addition to intravenous pulses of methylprednisolone for 3 days, we inserted an intravitreal left eye Ozurdex® device, after obtaining patient’s parents’ informed consent. Three weeks after implantation (Table 1; time 5), left eye visual acuity showed improvement and the anterior chamber showed no flare. No vitreous cellular infiltration or keratitic precipitates were detected. Left eye visual field showed improvement of both scotomas and mean sensitivity. The cornea was clear and macular thickness was decreased, with complete resolution of subretinal fluid accumulation and intraretinal edema on OCT scans (Fig. 1e). On the contrary, despite use of intravenous pulses of methylprednisolone, the right eye worsened (Table 1; time 5). Therefore, 2 weeks later, we also implanted Ozurdex® in the right eye. Two weeks after this new implantation (Table 1; time 6), right eye visual acuity also improved. The anterior chamber did not flare, and the same success was seen on the visual field test and OCT scan (Fig. 1f). Examination of the fundus showed no papillitis. Furthermore, at this time, left eye examination also confirmed a stable improvement (Table 1; time 6). Fluorescein angiography was also bilaterally improved. (Fig. 1g, h). Neither anterior nor posterior complications were reported in both eyes, and prednisone was gradually tapered. Visual acuity remained stable. An increased intraocular pressure (27 mmHg) was detected in the left eye, and therapy with topical acetazolamide successfully administered (still in course).
Discussion Our experience with intravitreal use of dexamethasone implant in both eyes of this young girl with refractory VKHD has been successful. To date, only two cases—a 49-year-old man and a 45-year-old woman [7, 8] with a probable diagnosis of VKHD treated with intravitreal Ozurdex®—have been
Clin Rheumatol Fig. 1 Fluorescein angiograms and spectral domain-ocular coherence tomography before and after the use of Ozurdex® implant. Right eye (a) and left eye (b): the late-phase fluorescein angiograms at the time of uveitis onset, showing bilateral hyperfluorescence of the optic disc and retinal vessels, marked peripheral hypopigmentation of the choroid, associated hyperpigmented patches of retinal pigment epithelium, leaking points, macular edema, and exudative retinal detachments. Right eye (c) and left eye (d): spectral domainocular coherence tomography images before the use of Ozurdex® implant, showing bilateral exudative retinal detachments and alteration of the normal profile and morphology associated with increase of foveal area thickness, caused by edema (hypoechoic areas). Right eye (e) and left eye (f): spectral domainocular coherence tomography images after the use of Ozurdex® implant, showing complete regression of edema (hypoechoic areas), with recovery of normal morphology and thickness of the fovea. Detection of a few cells is just visible in the right eye (e). Right eye (g) and left eye (h): the late-phase fluorescein angiograms after the use of Ozurdex® implant, showing respectively reduction in the fluorescence of retinal vessels and no macular edema
reported. Hence, to the best of our knowledge, our case represents the first report of VKHD in a young patient. Our experience lets us suggest that intravitreal dexamethasone implants might have an effective role in the treatment of refractory uveitis with retinal complications of VKHD, also to prevent side effects of long-term corticosteroid administration.
Disclosures None.
References 1. Tagawa Y, Sugiura S, Yakura H, Wakisaka A, Aizawa M (1976) HLA and Vogt-Koyanagi-Harada syndrome. N Engl J Med 295:173 2. Greco A, Fusconi M, Gallo A, Turchetta R, Marinelli C, Macri GF, De Virgilio A, de Vincentiis M (2013) Vogt-Koyanagi-Harada syndrome. Autoimmun Rev 12:1033–1038 3. Yamanaka E, Ohguro N, Yamamoto S, Nakagawa Y, Imoto Y, Tano Y (2002) Evaluation of pulse corticosteroid therapy for VogtKoyanagi-Harada disease assessed by optical coherence tomography. Am J Ophthalmol 134:454–456 4. Andrade RE, Muccioli C, Farah ME, Nussenblatt RB, Belfort R Jr (2004) Intravitreal triamcinolone in the treatment of serous retinal
Clin Rheumatol detachment in Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 137:572–574 5. Haller JA, Bandello F, Belfort R Jr, Blumenkranz MS, Gillies M, Heier J, Loewenstein A, Yoon YH, Jacques ML, Jiao J, Li XY, Whitcup SM, OZURDEX GENEVA Study Group (2010) Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 117:1134–1146(e3) 6. Kuppermann BD, Blumenkranz MS, Haller JA, Williams GA, Weinberg DV, Chou C, Whitcup SM, Dexamethasone DDS Phase II Study Group (2007) Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 125:309–317
7. Chuang CT, Huang PS, Chen SC, Sheu SJ (2013) Reversible alopecia in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. J Ophthalmic Inflamm Infect 3:41 8. Myung JS, Aaker GD, Kiss S (2010) Treatment of noninfectious posterior uveitis with dexamethasone intravitreal implant. Clin Ophthalmol 4:1423–1426 9. Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L (2012) Blau syndrome, clinical and genetic aspects. Autoimmun Rev 12: 44–51 10. Caso F, Wouters CH, Rose CD, Costa L, Tognon S, Sfriso P, Cantarini L, Rigante D, Punzi L (2014) Blau syndrome and latent tubercular infection: an unresolved partnership. Int J Rheum Dis. doi: 10.1111/1756-185X.12330
