Doc Ophthalmol (2014) 129:203–207 DOI 10.1007/s10633-014-9461-y
CLINICAL CASE REPORT
Intravitreal dexamethasone implant [Ozurdex] for the treatment of nonarteritic anterior ischaemic optic neuropathy Florian Alten • Christoph R. Clemens Peter Heiduschka • Nicole Eter
•
Received: 23 June 2014 / Accepted: 25 September 2014 / Published online: 2 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To evaluate structural and functional outcomes of intravitreal dexamethasone implant (IDI) in three patients presenting with nonarteritic anterior ischaemic optic neuropathy. Methods IDI was administered once in three patients. Best-corrected visual acuity (BCVA), perimetry, volume spectral-domain optical coherence tomography scan of the optic disc (ODV), retinal nerve fibre layer (RNFL) scan and visually evoked potential (VEP) measurements were assessed at baseline and after one and 3 months. Results Mean BCVA was 20/100 in patient 1 (patient 2: 20/100; patient 3: 20/50) at baseline, 20/60 (patient 2: 20/400) at 1 month and 20/80 (20/400; 20/60) at 3 months. Mean deviation in perimetry developed from -4.90 dB (-22.09 dB; -8.68 dB) to -7.60 dB (-30.75 dB) and -14.23 dB (-30.59 dB; -7.17 dB). ODV and RNFL decreased during followup. VEP measurements showed a reduction in amplitudes during the entire observation period. Conclusions All patients showed a reduction in papilla oedema over time. A functional improvement was not observed.
F. Alten (&) C. R. Clemens P. Heiduschka N. Eter Department of Ophthalmology, University of Muenster Medical Centre, Domagkstrasse 15, 48149 Muenster, Germany e-mail: [email protected]; [email protected]
Keywords Visually evoked potential NAION Ozurdex Dexamethasone
Introduction Today, there is still no well-established treatment for patients with nonarteritic anterior ischaemic optic neuropathy (NAION), the most common acute optic neuropathy. The Ischemic Optic Neuropathy Decompression Trial reported no benefit from surgical intervention [1]. The effectiveness of oral steroids is still a matter of ongoing debate in the literature; yet, a very large study including over 600 patients showed unambiguously that treating NAION patients with high-dose systemic corticosteroids results in a significantly higher probability of improvement in both visual acuity and visual fields [2, 3]. Intravitreal injections of triamcinolon acetonide (TA), an off-label corticosteroid for ophthalmology use, and anti-vascular endothelial growth factor (VEGF) agents have been proposed for NAION treatment showing rather heterogeneous results [4–6]. Recently, an intravitreal dexamethasone implant (IDI) (OzurdexÒ; Allergan Inc., Irvine, CA) has been demonstrated to be safe and effective in treating macular oedema secondary to retinal vein occlusion or noninfectious uveitis [7]. We hypothesized that a treatment with an IDI in patients with acute NAION may be beneficial based on the rationale that intravitreal steroids decrease vascular
123
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Doc Ophthalmol (2014) 129:203–207
leakage at the optic disc, facilitate the resolution of disc oedema, reduce compression of capillary vessels and eventually improve the survival rate of hypoxic retinal nerve fibres [2]. We treated three consecutive patients with NAION with a single IDI and report the results of a three-month follow-up period.
Materials and methods Informed and written consent emphasizing the offlabel character of IDI in NAION was obtained, and the study was conducted in agreement with the Declaration of Helsinki. Prior to injection, best-corrected visual acuity (BCVA), intraocular pressure (IOP), standard automated perimetry using a 30-2 central threshold test (Humphrey 740i, Zeiss Meditec, Germany), colour fundus photography of the optic disc (Visucam, Carl Zeiss Meditech, Germany), volume spectral-domain optical coherence tomography (SDOCT) scan of the optic disc (Spectralis, Heidelberg Engineering, Germany), a retinal nerve fibre layer (RNFL) SD-OCT scan and visually evoked potential (VEP) measurements according to ISCEV standard (RetiPort System, Roland Consult, Germany) were assessed. Follow-up visits were scheduled at 1 and 3 months after treatment and included the same examinations as performed prior to injection.
Results Patients reported unilateral vision loss four (three, seven) days prior to presentation. All patients were
treated with a high dosage of systemic steroids for 3 days, and IDI injection was performed ten (five, twelve) days after onset of symptoms. Patient three could not attend 1-month follow-up for personal reasons and showed an increased IOP of 23 mmHg at 3 months which was controlled by local treatment. No cataract progression was observed in any patient. Functional and morphologic data are shown in Table 1 and Figs. 1 and 2.
Discussion Compared to intravenous or oral corticosteroid treatment, intravitreal IDI offers the advantage that systemic side effects do not occur. However, transient increase in IOP is a well-known side effect of intraocular corticosteroids which may have even more serious consequences in patients with acute NAION. Application of a slow-release drug in an acute pathology does not seem reasonable at first sight. However, looking closely at pharmacodynamics of IVI, two phases of drug release after implant administration were demonstrated [8]. The first phase provides high concentrations followed by a second phase of decreasing concentrations. Thus, using IVI we can achieve high dexamethasone concentration levels immediately after drug release, which seems relevant in this acute pathology. In contrast to the off-label use of TA, OzurdexÒ is approved for use in ophthalmology and showed a better risk profile regarding cataract progression and increases in IOP [7]. Additionally, its sustained release nature avoids possibly multiple TA injections and
Table 1 Functional and morphologic data of patients one through three Perimetry [dB]
VEP 1° [lV]
VEP 150 [lV]
BCVA
RNFL [lm]
ODV [mm3]
Baseline
20/100
204
11.73
-4.90
2.74
2.82
1 Month 3 Month
20/60 20/80
121 77
10.03 8.52
-7.60 -14.23
4.32 1.37
1.72 5.15
Baseline
20/100
258
13.9
-22.09
8.95
9.39
1 Month
20/400
172
11.62
-30.75
3.10
1.05
3 Month
20/400
77
8.6
-30.59
4.30
0.65
Baseline
20/50
175
12.82
-8.68
11.00
11.60
3 Month
20/60
83
8.97
-7.17
10.50
10.70
Patient 1
Patient 2
Patient 3
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Doc Ophthalmol (2014) 129:203–207
205
Fig. 1 a–c Morphologic results at baseline, one-month and threemonth follow-up examination of patient one. a Colour fundus photography. b Spectral-domain optical coherence tomography volume scan of the optic disc shows the colour-coded decrease in disc swelling. c Absolute values of volumetric measurements within the EDTRS grid also prove the reduction in disc volume
therefore reduces the risk of endophthalmitis. Another substantial advantage of IDI over TA is the antiinflammatory activity of dexamethasone which is sixfold greater than that of TA [9]. Jonas and colleagues found no effect in increasing visual acuity in three patients treated with TA, while Kaderli et al. report a visual gain in four treated patients [4, 5]. Yet, visual improvement must be interpreted cautiously in NAION patients as it may well be attributed to the improved ability of eccentric fixation [1]. Besides, it must be pointed out that visual acuity improves spontaneously in about one-third of NAION patients within 6 months and that optic disc oedema resolves within 8 weeks without any treatment [10]. Recently, Rootman et al. presented results from a nonrandomized controlled clinical trial on
intravitreal bevacizumab. No difference between bevacizumab and natural history for change in visual field, visual acuity and optic nerve thickness in OCT was found [6]. Our VEP results are similar to previous findings reporting a reduction in amplitude after NAION reflecting the hypoxic and malfunctioning portion of the optic disc [11]. Similar to patients without intravitreal treatment in a study by Bellusci et al. [12], we observed a dramatic increase in average RNFL thickness at the acute event and a strong decrease during follow-up. Our presented, well-documented data reveal a reduction of optic disc oedema after intravitreal dexamethasone implantation in NAION patients, which corresponds to the natural course of the pathology. Functional parameters did not show any improvement
123
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Doc Ophthalmol (2014) 129:203–207
Fig. 2 a–c Functional results at baseline, onemonth and three-month follow-up examination of patient one. a Standard automated perimetry shows an increase in sensitivity loss. b Waveforms of standard pattern VEP measurements obtained for a resolution of 1° (upper traces) and 150 (lower traces) at the time points as indicated above. The responses are considerably delayed and reduced in their amplitudes. c Diagrams show values of the amplitudes. Grey shaded areas indicate amplitude ranges measured in healthy controls
during the observation period. Obviously, our data are limited by the small number of patients as well as the confounding factor of additional intravenous corticosteroid therapy. Given the ischaemic cause of NAION, an intravitreal treatment performed immediately after NAION onset may result in a better functional outcome. This report shall mainly demonstrate the feasibility of the treatment without obvious iatrogenic worsening of the condition. Doubtlessly, larger studies are certainly required to reliably state on its efficacy and safety in this indication. Conflict of interest The authors have full control of all primary data and they agree to allow the journal to review their data if requested.
References 1. The Ischemic Optic Neuropathy Decompression Trial Research Group (1995) Optic nerve decompression surgery for the non-arteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA 273:625–632
123
2. Hayreh SS, Zimmerman MB (2008) Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol 246:1029–1046 3. Rebolleda G, Pe´rez-Lo´pez M, Casas-LLera P, Contreras I, Mun˜oz-Negrete FJ (2013) Visual and anatomical outcomes of non-arteritic anterior ischemic optic neuropathy with high-dose systemic corticosteroids. Graefes Arch Clin Exp Ophthalmol 251:255–260 4. Jonas JB, Spandau UH, Harder B, Sauder G (2007) Intravitreal triamcinolone acetonide for treatment of acute nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol 245:749–750 5. Kaderli B, Avci R, Yucel A, Guler K, Gelisken O (2007) Intravitreal triamcinolone improves recovery of visual acuity in nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol 27:164–168 6. Rootman DB, Gill HS, Margolin EA (2013) Intravitreal bevacizumab for the treatment of nonarteritic anterior ischemic optic neuropathy: a prospective trial. Eye (Lond) 27:538–544 7. Haller JA, Bandello F, Belfort R Jr et al Ozurdex GENEVA Study Group (2011) Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 118:2453–2460 8. Chang-Lin JE, Attar M, Acheampong AA et al (2011) Pharmacokinetics and pharmacodynamics of a sustainedrelease dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 52:80–86
Doc Ophthalmol (2014) 129:203–207 9. Goldfien A (1995) Adrenocorticosteroids and adrenocortical antagonists. In: Katzung BG (ed) Basic and clinical pharmacology, 6th edn. Prentice Hall International, London, pp 592–607 10. Hayreh SS, Zimmerman MB (2008) Non-arteritic anterior ischemic optic neuropathy—natural history of visual outcome. Ophthalmology 115:298–305 11. Atilla H, Tekeli O, Ornek K, Batioglu F, Elhan AH, Eryilmaz T (2009) Pattern electroretinography and visual evoked potentials in optic nerve diseases. J Clin Neurosci 13:55–59
207 12. Bellusci C, Savini G, Carbonelli M, Carelli V, Sadun AA, Barboni P (2008) Retinal nerve fiber layer thickness in nonarteritic anterior ischemic optic neuropathy: oCT characterization of the acute and resolving phases. Graefes Arch Clin Exp Ophthalmol 246:641–647
123
CLINICAL CASE REPORT
Intravitreal dexamethasone implant [Ozurdex] for the treatment of nonarteritic anterior ischaemic optic neuropathy Florian Alten • Christoph R. Clemens Peter Heiduschka • Nicole Eter
•
Received: 23 June 2014 / Accepted: 25 September 2014 / Published online: 2 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To evaluate structural and functional outcomes of intravitreal dexamethasone implant (IDI) in three patients presenting with nonarteritic anterior ischaemic optic neuropathy. Methods IDI was administered once in three patients. Best-corrected visual acuity (BCVA), perimetry, volume spectral-domain optical coherence tomography scan of the optic disc (ODV), retinal nerve fibre layer (RNFL) scan and visually evoked potential (VEP) measurements were assessed at baseline and after one and 3 months. Results Mean BCVA was 20/100 in patient 1 (patient 2: 20/100; patient 3: 20/50) at baseline, 20/60 (patient 2: 20/400) at 1 month and 20/80 (20/400; 20/60) at 3 months. Mean deviation in perimetry developed from -4.90 dB (-22.09 dB; -8.68 dB) to -7.60 dB (-30.75 dB) and -14.23 dB (-30.59 dB; -7.17 dB). ODV and RNFL decreased during followup. VEP measurements showed a reduction in amplitudes during the entire observation period. Conclusions All patients showed a reduction in papilla oedema over time. A functional improvement was not observed.
F. Alten (&) C. R. Clemens P. Heiduschka N. Eter Department of Ophthalmology, University of Muenster Medical Centre, Domagkstrasse 15, 48149 Muenster, Germany e-mail: [email protected]; [email protected]
Keywords Visually evoked potential NAION Ozurdex Dexamethasone
Introduction Today, there is still no well-established treatment for patients with nonarteritic anterior ischaemic optic neuropathy (NAION), the most common acute optic neuropathy. The Ischemic Optic Neuropathy Decompression Trial reported no benefit from surgical intervention [1]. The effectiveness of oral steroids is still a matter of ongoing debate in the literature; yet, a very large study including over 600 patients showed unambiguously that treating NAION patients with high-dose systemic corticosteroids results in a significantly higher probability of improvement in both visual acuity and visual fields [2, 3]. Intravitreal injections of triamcinolon acetonide (TA), an off-label corticosteroid for ophthalmology use, and anti-vascular endothelial growth factor (VEGF) agents have been proposed for NAION treatment showing rather heterogeneous results [4–6]. Recently, an intravitreal dexamethasone implant (IDI) (OzurdexÒ; Allergan Inc., Irvine, CA) has been demonstrated to be safe and effective in treating macular oedema secondary to retinal vein occlusion or noninfectious uveitis [7]. We hypothesized that a treatment with an IDI in patients with acute NAION may be beneficial based on the rationale that intravitreal steroids decrease vascular
123
204
Doc Ophthalmol (2014) 129:203–207
leakage at the optic disc, facilitate the resolution of disc oedema, reduce compression of capillary vessels and eventually improve the survival rate of hypoxic retinal nerve fibres [2]. We treated three consecutive patients with NAION with a single IDI and report the results of a three-month follow-up period.
Materials and methods Informed and written consent emphasizing the offlabel character of IDI in NAION was obtained, and the study was conducted in agreement with the Declaration of Helsinki. Prior to injection, best-corrected visual acuity (BCVA), intraocular pressure (IOP), standard automated perimetry using a 30-2 central threshold test (Humphrey 740i, Zeiss Meditec, Germany), colour fundus photography of the optic disc (Visucam, Carl Zeiss Meditech, Germany), volume spectral-domain optical coherence tomography (SDOCT) scan of the optic disc (Spectralis, Heidelberg Engineering, Germany), a retinal nerve fibre layer (RNFL) SD-OCT scan and visually evoked potential (VEP) measurements according to ISCEV standard (RetiPort System, Roland Consult, Germany) were assessed. Follow-up visits were scheduled at 1 and 3 months after treatment and included the same examinations as performed prior to injection.
Results Patients reported unilateral vision loss four (three, seven) days prior to presentation. All patients were
treated with a high dosage of systemic steroids for 3 days, and IDI injection was performed ten (five, twelve) days after onset of symptoms. Patient three could not attend 1-month follow-up for personal reasons and showed an increased IOP of 23 mmHg at 3 months which was controlled by local treatment. No cataract progression was observed in any patient. Functional and morphologic data are shown in Table 1 and Figs. 1 and 2.
Discussion Compared to intravenous or oral corticosteroid treatment, intravitreal IDI offers the advantage that systemic side effects do not occur. However, transient increase in IOP is a well-known side effect of intraocular corticosteroids which may have even more serious consequences in patients with acute NAION. Application of a slow-release drug in an acute pathology does not seem reasonable at first sight. However, looking closely at pharmacodynamics of IVI, two phases of drug release after implant administration were demonstrated [8]. The first phase provides high concentrations followed by a second phase of decreasing concentrations. Thus, using IVI we can achieve high dexamethasone concentration levels immediately after drug release, which seems relevant in this acute pathology. In contrast to the off-label use of TA, OzurdexÒ is approved for use in ophthalmology and showed a better risk profile regarding cataract progression and increases in IOP [7]. Additionally, its sustained release nature avoids possibly multiple TA injections and
Table 1 Functional and morphologic data of patients one through three Perimetry [dB]
VEP 1° [lV]
VEP 150 [lV]
BCVA
RNFL [lm]
ODV [mm3]
Baseline
20/100
204
11.73
-4.90
2.74
2.82
1 Month 3 Month
20/60 20/80
121 77
10.03 8.52
-7.60 -14.23
4.32 1.37
1.72 5.15
Baseline
20/100
258
13.9
-22.09
8.95
9.39
1 Month
20/400
172
11.62
-30.75
3.10
1.05
3 Month
20/400
77
8.6
-30.59
4.30
0.65
Baseline
20/50
175
12.82
-8.68
11.00
11.60
3 Month
20/60
83
8.97
-7.17
10.50
10.70
Patient 1
Patient 2
Patient 3
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205
Fig. 1 a–c Morphologic results at baseline, one-month and threemonth follow-up examination of patient one. a Colour fundus photography. b Spectral-domain optical coherence tomography volume scan of the optic disc shows the colour-coded decrease in disc swelling. c Absolute values of volumetric measurements within the EDTRS grid also prove the reduction in disc volume
therefore reduces the risk of endophthalmitis. Another substantial advantage of IDI over TA is the antiinflammatory activity of dexamethasone which is sixfold greater than that of TA [9]. Jonas and colleagues found no effect in increasing visual acuity in three patients treated with TA, while Kaderli et al. report a visual gain in four treated patients [4, 5]. Yet, visual improvement must be interpreted cautiously in NAION patients as it may well be attributed to the improved ability of eccentric fixation [1]. Besides, it must be pointed out that visual acuity improves spontaneously in about one-third of NAION patients within 6 months and that optic disc oedema resolves within 8 weeks without any treatment [10]. Recently, Rootman et al. presented results from a nonrandomized controlled clinical trial on
intravitreal bevacizumab. No difference between bevacizumab and natural history for change in visual field, visual acuity and optic nerve thickness in OCT was found [6]. Our VEP results are similar to previous findings reporting a reduction in amplitude after NAION reflecting the hypoxic and malfunctioning portion of the optic disc [11]. Similar to patients without intravitreal treatment in a study by Bellusci et al. [12], we observed a dramatic increase in average RNFL thickness at the acute event and a strong decrease during follow-up. Our presented, well-documented data reveal a reduction of optic disc oedema after intravitreal dexamethasone implantation in NAION patients, which corresponds to the natural course of the pathology. Functional parameters did not show any improvement
123
206
Doc Ophthalmol (2014) 129:203–207
Fig. 2 a–c Functional results at baseline, onemonth and three-month follow-up examination of patient one. a Standard automated perimetry shows an increase in sensitivity loss. b Waveforms of standard pattern VEP measurements obtained for a resolution of 1° (upper traces) and 150 (lower traces) at the time points as indicated above. The responses are considerably delayed and reduced in their amplitudes. c Diagrams show values of the amplitudes. Grey shaded areas indicate amplitude ranges measured in healthy controls
during the observation period. Obviously, our data are limited by the small number of patients as well as the confounding factor of additional intravenous corticosteroid therapy. Given the ischaemic cause of NAION, an intravitreal treatment performed immediately after NAION onset may result in a better functional outcome. This report shall mainly demonstrate the feasibility of the treatment without obvious iatrogenic worsening of the condition. Doubtlessly, larger studies are certainly required to reliably state on its efficacy and safety in this indication. Conflict of interest The authors have full control of all primary data and they agree to allow the journal to review their data if requested.
References 1. The Ischemic Optic Neuropathy Decompression Trial Research Group (1995) Optic nerve decompression surgery for the non-arteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA 273:625–632
123
2. Hayreh SS, Zimmerman MB (2008) Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol 246:1029–1046 3. Rebolleda G, Pe´rez-Lo´pez M, Casas-LLera P, Contreras I, Mun˜oz-Negrete FJ (2013) Visual and anatomical outcomes of non-arteritic anterior ischemic optic neuropathy with high-dose systemic corticosteroids. Graefes Arch Clin Exp Ophthalmol 251:255–260 4. Jonas JB, Spandau UH, Harder B, Sauder G (2007) Intravitreal triamcinolone acetonide for treatment of acute nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol 245:749–750 5. Kaderli B, Avci R, Yucel A, Guler K, Gelisken O (2007) Intravitreal triamcinolone improves recovery of visual acuity in nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol 27:164–168 6. Rootman DB, Gill HS, Margolin EA (2013) Intravitreal bevacizumab for the treatment of nonarteritic anterior ischemic optic neuropathy: a prospective trial. Eye (Lond) 27:538–544 7. Haller JA, Bandello F, Belfort R Jr et al Ozurdex GENEVA Study Group (2011) Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 118:2453–2460 8. Chang-Lin JE, Attar M, Acheampong AA et al (2011) Pharmacokinetics and pharmacodynamics of a sustainedrelease dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 52:80–86
Doc Ophthalmol (2014) 129:203–207 9. Goldfien A (1995) Adrenocorticosteroids and adrenocortical antagonists. In: Katzung BG (ed) Basic and clinical pharmacology, 6th edn. Prentice Hall International, London, pp 592–607 10. Hayreh SS, Zimmerman MB (2008) Non-arteritic anterior ischemic optic neuropathy—natural history of visual outcome. Ophthalmology 115:298–305 11. Atilla H, Tekeli O, Ornek K, Batioglu F, Elhan AH, Eryilmaz T (2009) Pattern electroretinography and visual evoked potentials in optic nerve diseases. J Clin Neurosci 13:55–59
207 12. Bellusci C, Savini G, Carbonelli M, Carelli V, Sadun AA, Barboni P (2008) Retinal nerve fiber layer thickness in nonarteritic anterior ischemic optic neuropathy: oCT characterization of the acute and resolving phases. Graefes Arch Clin Exp Ophthalmol 246:641–647
123
