Acta Ophthalmologica 2015
Rome, Italy; 2Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy; 3Department of Ophthalmology, Hospital Conegliano Veneto, Conegliano Veneto, Italy doi: 10.1111/aos.12677
Editor, espite extensive use of antivascular endothelial growth factor (anti-VEGF), the optimal treatment for choroidal neovascularization associated with pathologic myopia (mCNV) is still a matter of debate, centring on a Pro re nata regimen (PRN, initial single dose plus additional doses in case of CNV activity) and a loading dose+PRN regimen (three consecutive monthly injections+PRN). However, one protocol is not clearly superior to the other in terms of efficacy or safety (Neelam et al. 2012). This 18-month prospective study evaluated the outcomes of a treatment algorithm guided by the initial response to the first ranibizumab injection. The loading dose was given in cases of persistent CNV activity at the 1-month examination, with a PRN strategy reserved for silent CNV. CNV activity was defined as persistent leakage on fluorescein angiography, persistent intraretinal/subretinal fluid on optical coherence tomography, visual acuity loss of at least five ETDRS letters or increased metamorphosia. The research adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board. Fifteen patients were included in the PRN Group and 12 in the LOAD+PRN Group (Table 1). The median BCVA improved in the PRN group from its baseline value over the subsequent 3 months, registering a continuous statistically significant BCVA gain, which was preserved thereafter. The LOAD+PRN Group failed to maintain the improvement registered at 1 month, with the gains stabilizing from the 3-month examination on. At the 18-month examination, a greater proportion of eyes with an improvement of >1 and >3 lines was registered in the PRN group (86% versus 58%, 73% versus 25%, Chi-square test, p: 0.02). Statistically significant reductions in the CMT and CNV areas were
D
(A)
(B)
(C)
Fig. 1. Brain magnetic resonance images. Axial T2-FLAIR image (A) demonstrating a hyper intense signal of the left oculomotor nerve at its exit point from the mesencephalon. Coronal (B) and sagittal (C) gadolinium-enhanced T1-weighted images showing the enhancement of the lesion (arrows).
The pathogenic mechanism explaining how EBV infection can affect neurological structures remains unclear. The possibility of a direct viral invasion to neural tissues and/or of an indirect post-infectious immunological mediated mechanism is debated (Tselis 2014). The combination of both mechanisms is highly probable making the descriptive term ‘parainfectious’ the most appropriate (Tselis 2014). Concerning the treatment, the use of corticosteroids in patients with neurological manifestations related to IM remains controversial (Odumade et al. 2011). It has been argued that steroids may enhance replication of herpesviruses. However, corticosteroids may be beneficial in patients with impending airway obstruction and when severe neurological or haematological (thrombocytopenia and haemolytic anaemia) complications occur (Brazis & Miller 2005). It appears that in most of the cases, the prognosis is good with a spontaneous recovery of the cranial nerve palsy over weeks to months, only with supportive measures (Erben et al. 2008). Epstein–Barr virus infection should be considered when confronted to an oculomotor palsy, mainly when it occurs in adolescents or young adults. Usually, the prognosis is good.
References Brazis W & Miller NR (2005): Viruses (except retrovirus) and viral diseases. In: Miller NR (ed.). Walsh and Hoyt’s clinical neuro-ophthalmology. Philadelphia, PA: Lippincott Williams & Wilkins 3176–3183.
Erben Y, Gonzalez Hofmann C, Steinmetz H & Ziemann U (2008): [Isolated neuritis of the oculomotor nerve in infectious mononucleosis]. Nervenarzt 79: 462–464. Odumade OA, Hogquist KA & Balfour HH Jr (2011): Progress and problems in understanding and managing primary EpsteinBarr virus infections. Clin Microbiol Rev 24: 193–209. Silverstein A, Steinberg G & Nathanson M (1972): Nervous system involvement in infectious mononucleosis. The heralding and-or major manifestation. Arch Neurol 26: 353–358. Tselis AC (2014): Epstein-Barr virus infections of the nervous system. Handb Clin Neurol 123: 285–305.
Correspondence: Dr Damien Biotti, MD Department of Neurology H^ opital Neurologique Pierre Wertheimer 59 boulevard Pinel 69394 Lyon, France Tel: +33 4 72 35 78 82 Fax: +33 4 72 35 73 51 Email: [email protected] The authors report no conflict of interest.
A new treatment algorithm for the management of myopic choroidal neovascularization using intravitreal ranibizumab Pierluigi Iacono,1 Maurizio Battaglia Parodi,2 Alexandros Papayannis,3 Carlo La Spina,2 Monica Varano1 and Francesco Bandello2 1
G. B. Bietti Foundation for study and research in ophthalmology, IRCCS,
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Acta Ophthalmologica 2015
noted in both groups from the 1-month examination on. The baseline features of the two groups differed significantly in median age at the time of inclusion, symptom duration and CNV area. The mean number of injections administered was 1.3 0.5 in the PRN Group and 4.4 1 in the LOAD+PRN Group. During the follow-up, five patients received 1 additional injection in the PRN Group, whereas 10 patients required additional injections after the loading dose (5, 3 and 2 eyes requiring 1, 2 and 3 injections, respectively). These results are consistent with recent studies of IVRI, showing a mean visual improvement from 1.5 to 4 lines (Vadala et al. 2011; Iacono et al. 2012). The difference between the two groups in BCVA outcomes, baseline
characteristics, mean number of injections administered and high retreatment rate noted in the LOAD+PRN Group are likely the result of the treatment algorithm, which included eyes with higher CNV activity in the LOAD+PRN Group. As already highlighted in the studies employing anti-VEGF therapy for mCNV, the most favourable functional results are generally obtained in patients under 55, with shorter symptom duration and smaller CNV (RuizMoreno et al. 2013) – all characteristics encountered in patients in the PRN Group. A continuous statistically significant improvement in the BCVA occurred during the first 3 months, whereas it was not seen in the LOAD+PRN Group. Our data cast some doubt on the reinforcing effect of the loading
Table 1. Demographic and clinical characteristics of the two groups at the baseline and during the 18-month follow-up (PRN Group: eyes receiving ranibizumab injection according to Pro re nata strategy; LOAD+PRN Group: eyes receiving loading phase + pro re nata strategy). Baseline characteristics
PRN group
Number of patients 15/27 (55%) Median age (range) 60 (38–72) Gender 10 F (66%)-5 M (34%) Median time elapsed 10 (5–20) between onset of symptoms and diagnosis (days, range) Median BCVA (logMAR, CI 95%) Baseline 0.70 (0.62–0.90) 1 month 0.50 (0.40–0.77)* [p: 0.0002] 3 months 0.50 (0.22–0.70)* [p: 0.0002] 6 months 0.50 (0.22–0.70)* [p: 0.0002] 12 months 0.40 (0.22–0.70)* [p: 0.0002] 18 months 0.40 (0.22–0.70)* [p: 0.0002] Median CMT (lm, CI 95%) Baseline 333 (265–408) 1 month 267 (216–298)* [p: 0.001] 3 months 267 (203–286)* [p: 0.0004] 6 months 244 (196–282)* [p: 0.0002] 12 months 250 (174–274)* [p: 0.0001] 18 months 233 (176–253)* [p: 0.0001] Median AREA (mm2, CI 95%) Baseline 0.80 (0.6–1.3) 1 month 0.75 (0.3–1.3)* [p: 0.001] 3 months 0.60 (0.2–1.2)* [p: 0.001] 6 months 0.54 (0.2–1.2)* [p: 0.009] 12 months 0.38 (0.2–1.0)* [p: 0.0002] 18 months 0.38 (0.2–0.9)* [p: 0.0002]
LOAD+PRN group
pValue
12/27 67.5 9 27.5
0.01† 0.07† 0.0009†
(45%) (56–81) F (66%)/3 M (34%) (5–40)
0.70 0.65 0.70 0.70 0.70 0.70
(0.60–0.90) (0.40–0.78)* (0.21–0.96)* (0.20–0.96)* (0.20–0.98)* (0.20–0.98)*
415 296 281 301 271 270
(190–490) (183–370)* (171–332)* (173–349)* (173–344)* (170–344)*
2.28 2.18 2.00 1.81 1.77 1.65
(0.9–3.9) (0.8–2.9)* (0.8–3.0)* (0.8–3.0)* (0.7–3.1)* (0.6–2.7)*
0.64† [p: 0.007] [p:0.08] [p:0.08] [p:0.12] [p: 0.13] 0.30†
[p: [p: [p: [p: [p:
0.002] 0.001] 0.001] 0.001] 0.0005] 0.03†
[p: [p: [p: [p: [p:
0.0005] 0.001] 0.001] 0.006] 0.0006]
BCVA = best-corrected visual acuity, CMT = central macular thickness, CNV = choroidal neovascularization, PRN = pro re nata strategy, LOAD+PRN = loading phase + pro re nata strategy. At the baseline, a statistically significant difference between the two groups was observed with regard to age, area of the CNV, and time elapsed between onset of symptoms and diagnosis (days). * Wilcoxon test (data compared with baseline value). † Mann–Whitney test.
e520
dose, as previously described by other authors (Kung et al. 2014). On the contrary, the importance of treating early-stage, small CNV seems crucial. The main shortcomings of this study are the small sample size and the short-term follow-up. It was not designed to establish the superiority of the PRN strategy over the loading dose followed by a Pro re nata treatment. In essence, our data confirm that an early diagnosis is associated with a small CNV with reduced activity, allowing a simple PRN strategy in a subgroup of younger patients and avoiding potential overtreatment through the loading phase.
References Iacono P, Parodi MB, Papayannis A, Kontadakis S, Sheth S, Cascavilla ML & Bandello F (2012): Intravitreal ranibizumab versus bevacizumab for treatment of myopic choroidal neovascularization. Retina 32: 1539–1546. Kung YH, Wu TT & Huang YH (2014): Oneyear outcome of two different initial dosing regimens of intravitreal ranibizumab for myopic choroidal neovascularization. Acta Ophthalmol 92: e615–e620. Neelam K, Cheung CM, Ohno-Matsui K, Lai TY & Wong TY (2012): Choroidal neovascularization in pathological myopia. Prog Retin Eye Res 31: 495–525. Ruiz-Moreno JM, Arias L, Montero JA, Carneiro A & Silva R (2013): Intravitreal anti-VEGF therapy for choroidal neovascularisation secondary to pathological myopia: 4-year outcome. Br J Ophthalmol 97: 1447– 1450. Vadala M, Pece A, Cipolla S, Monteleone C, Fasolino G, Casuccio A & Cillino S (2011): Is ranibizumab effective in stopping the loss of vision for choroidal neovascularisation in pathologic myopia? A long-term follow-up study. Br J Ophthalmol 95: 657–661.
Correspondence: Pierluigi Iacono, MD Fondazione G. B. Bietti per l’Oftalmologia IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Via Livenza 3 Rome, Italy Tel: +39 06 77052834 Fax: +39 06 77052833 Email: [email protected] The research for this paper was supported by Ministry of Health and Fondazione Roma.
Rome, Italy; 2Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy; 3Department of Ophthalmology, Hospital Conegliano Veneto, Conegliano Veneto, Italy doi: 10.1111/aos.12677
Editor, espite extensive use of antivascular endothelial growth factor (anti-VEGF), the optimal treatment for choroidal neovascularization associated with pathologic myopia (mCNV) is still a matter of debate, centring on a Pro re nata regimen (PRN, initial single dose plus additional doses in case of CNV activity) and a loading dose+PRN regimen (three consecutive monthly injections+PRN). However, one protocol is not clearly superior to the other in terms of efficacy or safety (Neelam et al. 2012). This 18-month prospective study evaluated the outcomes of a treatment algorithm guided by the initial response to the first ranibizumab injection. The loading dose was given in cases of persistent CNV activity at the 1-month examination, with a PRN strategy reserved for silent CNV. CNV activity was defined as persistent leakage on fluorescein angiography, persistent intraretinal/subretinal fluid on optical coherence tomography, visual acuity loss of at least five ETDRS letters or increased metamorphosia. The research adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board. Fifteen patients were included in the PRN Group and 12 in the LOAD+PRN Group (Table 1). The median BCVA improved in the PRN group from its baseline value over the subsequent 3 months, registering a continuous statistically significant BCVA gain, which was preserved thereafter. The LOAD+PRN Group failed to maintain the improvement registered at 1 month, with the gains stabilizing from the 3-month examination on. At the 18-month examination, a greater proportion of eyes with an improvement of >1 and >3 lines was registered in the PRN group (86% versus 58%, 73% versus 25%, Chi-square test, p: 0.02). Statistically significant reductions in the CMT and CNV areas were
D
(A)
(B)
(C)
Fig. 1. Brain magnetic resonance images. Axial T2-FLAIR image (A) demonstrating a hyper intense signal of the left oculomotor nerve at its exit point from the mesencephalon. Coronal (B) and sagittal (C) gadolinium-enhanced T1-weighted images showing the enhancement of the lesion (arrows).
The pathogenic mechanism explaining how EBV infection can affect neurological structures remains unclear. The possibility of a direct viral invasion to neural tissues and/or of an indirect post-infectious immunological mediated mechanism is debated (Tselis 2014). The combination of both mechanisms is highly probable making the descriptive term ‘parainfectious’ the most appropriate (Tselis 2014). Concerning the treatment, the use of corticosteroids in patients with neurological manifestations related to IM remains controversial (Odumade et al. 2011). It has been argued that steroids may enhance replication of herpesviruses. However, corticosteroids may be beneficial in patients with impending airway obstruction and when severe neurological or haematological (thrombocytopenia and haemolytic anaemia) complications occur (Brazis & Miller 2005). It appears that in most of the cases, the prognosis is good with a spontaneous recovery of the cranial nerve palsy over weeks to months, only with supportive measures (Erben et al. 2008). Epstein–Barr virus infection should be considered when confronted to an oculomotor palsy, mainly when it occurs in adolescents or young adults. Usually, the prognosis is good.
References Brazis W & Miller NR (2005): Viruses (except retrovirus) and viral diseases. In: Miller NR (ed.). Walsh and Hoyt’s clinical neuro-ophthalmology. Philadelphia, PA: Lippincott Williams & Wilkins 3176–3183.
Erben Y, Gonzalez Hofmann C, Steinmetz H & Ziemann U (2008): [Isolated neuritis of the oculomotor nerve in infectious mononucleosis]. Nervenarzt 79: 462–464. Odumade OA, Hogquist KA & Balfour HH Jr (2011): Progress and problems in understanding and managing primary EpsteinBarr virus infections. Clin Microbiol Rev 24: 193–209. Silverstein A, Steinberg G & Nathanson M (1972): Nervous system involvement in infectious mononucleosis. The heralding and-or major manifestation. Arch Neurol 26: 353–358. Tselis AC (2014): Epstein-Barr virus infections of the nervous system. Handb Clin Neurol 123: 285–305.
Correspondence: Dr Damien Biotti, MD Department of Neurology H^ opital Neurologique Pierre Wertheimer 59 boulevard Pinel 69394 Lyon, France Tel: +33 4 72 35 78 82 Fax: +33 4 72 35 73 51 Email: [email protected] The authors report no conflict of interest.
A new treatment algorithm for the management of myopic choroidal neovascularization using intravitreal ranibizumab Pierluigi Iacono,1 Maurizio Battaglia Parodi,2 Alexandros Papayannis,3 Carlo La Spina,2 Monica Varano1 and Francesco Bandello2 1
G. B. Bietti Foundation for study and research in ophthalmology, IRCCS,
e519
Acta Ophthalmologica 2015
noted in both groups from the 1-month examination on. The baseline features of the two groups differed significantly in median age at the time of inclusion, symptom duration and CNV area. The mean number of injections administered was 1.3 0.5 in the PRN Group and 4.4 1 in the LOAD+PRN Group. During the follow-up, five patients received 1 additional injection in the PRN Group, whereas 10 patients required additional injections after the loading dose (5, 3 and 2 eyes requiring 1, 2 and 3 injections, respectively). These results are consistent with recent studies of IVRI, showing a mean visual improvement from 1.5 to 4 lines (Vadala et al. 2011; Iacono et al. 2012). The difference between the two groups in BCVA outcomes, baseline
characteristics, mean number of injections administered and high retreatment rate noted in the LOAD+PRN Group are likely the result of the treatment algorithm, which included eyes with higher CNV activity in the LOAD+PRN Group. As already highlighted in the studies employing anti-VEGF therapy for mCNV, the most favourable functional results are generally obtained in patients under 55, with shorter symptom duration and smaller CNV (RuizMoreno et al. 2013) – all characteristics encountered in patients in the PRN Group. A continuous statistically significant improvement in the BCVA occurred during the first 3 months, whereas it was not seen in the LOAD+PRN Group. Our data cast some doubt on the reinforcing effect of the loading
Table 1. Demographic and clinical characteristics of the two groups at the baseline and during the 18-month follow-up (PRN Group: eyes receiving ranibizumab injection according to Pro re nata strategy; LOAD+PRN Group: eyes receiving loading phase + pro re nata strategy). Baseline characteristics
PRN group
Number of patients 15/27 (55%) Median age (range) 60 (38–72) Gender 10 F (66%)-5 M (34%) Median time elapsed 10 (5–20) between onset of symptoms and diagnosis (days, range) Median BCVA (logMAR, CI 95%) Baseline 0.70 (0.62–0.90) 1 month 0.50 (0.40–0.77)* [p: 0.0002] 3 months 0.50 (0.22–0.70)* [p: 0.0002] 6 months 0.50 (0.22–0.70)* [p: 0.0002] 12 months 0.40 (0.22–0.70)* [p: 0.0002] 18 months 0.40 (0.22–0.70)* [p: 0.0002] Median CMT (lm, CI 95%) Baseline 333 (265–408) 1 month 267 (216–298)* [p: 0.001] 3 months 267 (203–286)* [p: 0.0004] 6 months 244 (196–282)* [p: 0.0002] 12 months 250 (174–274)* [p: 0.0001] 18 months 233 (176–253)* [p: 0.0001] Median AREA (mm2, CI 95%) Baseline 0.80 (0.6–1.3) 1 month 0.75 (0.3–1.3)* [p: 0.001] 3 months 0.60 (0.2–1.2)* [p: 0.001] 6 months 0.54 (0.2–1.2)* [p: 0.009] 12 months 0.38 (0.2–1.0)* [p: 0.0002] 18 months 0.38 (0.2–0.9)* [p: 0.0002]
LOAD+PRN group
pValue
12/27 67.5 9 27.5
0.01† 0.07† 0.0009†
(45%) (56–81) F (66%)/3 M (34%) (5–40)
0.70 0.65 0.70 0.70 0.70 0.70
(0.60–0.90) (0.40–0.78)* (0.21–0.96)* (0.20–0.96)* (0.20–0.98)* (0.20–0.98)*
415 296 281 301 271 270
(190–490) (183–370)* (171–332)* (173–349)* (173–344)* (170–344)*
2.28 2.18 2.00 1.81 1.77 1.65
(0.9–3.9) (0.8–2.9)* (0.8–3.0)* (0.8–3.0)* (0.7–3.1)* (0.6–2.7)*
0.64† [p: 0.007] [p:0.08] [p:0.08] [p:0.12] [p: 0.13] 0.30†
[p: [p: [p: [p: [p:
0.002] 0.001] 0.001] 0.001] 0.0005] 0.03†
[p: [p: [p: [p: [p:
0.0005] 0.001] 0.001] 0.006] 0.0006]
BCVA = best-corrected visual acuity, CMT = central macular thickness, CNV = choroidal neovascularization, PRN = pro re nata strategy, LOAD+PRN = loading phase + pro re nata strategy. At the baseline, a statistically significant difference between the two groups was observed with regard to age, area of the CNV, and time elapsed between onset of symptoms and diagnosis (days). * Wilcoxon test (data compared with baseline value). † Mann–Whitney test.
e520
dose, as previously described by other authors (Kung et al. 2014). On the contrary, the importance of treating early-stage, small CNV seems crucial. The main shortcomings of this study are the small sample size and the short-term follow-up. It was not designed to establish the superiority of the PRN strategy over the loading dose followed by a Pro re nata treatment. In essence, our data confirm that an early diagnosis is associated with a small CNV with reduced activity, allowing a simple PRN strategy in a subgroup of younger patients and avoiding potential overtreatment through the loading phase.
References Iacono P, Parodi MB, Papayannis A, Kontadakis S, Sheth S, Cascavilla ML & Bandello F (2012): Intravitreal ranibizumab versus bevacizumab for treatment of myopic choroidal neovascularization. Retina 32: 1539–1546. Kung YH, Wu TT & Huang YH (2014): Oneyear outcome of two different initial dosing regimens of intravitreal ranibizumab for myopic choroidal neovascularization. Acta Ophthalmol 92: e615–e620. Neelam K, Cheung CM, Ohno-Matsui K, Lai TY & Wong TY (2012): Choroidal neovascularization in pathological myopia. Prog Retin Eye Res 31: 495–525. Ruiz-Moreno JM, Arias L, Montero JA, Carneiro A & Silva R (2013): Intravitreal anti-VEGF therapy for choroidal neovascularisation secondary to pathological myopia: 4-year outcome. Br J Ophthalmol 97: 1447– 1450. Vadala M, Pece A, Cipolla S, Monteleone C, Fasolino G, Casuccio A & Cillino S (2011): Is ranibizumab effective in stopping the loss of vision for choroidal neovascularisation in pathologic myopia? A long-term follow-up study. Br J Ophthalmol 95: 657–661.
Correspondence: Pierluigi Iacono, MD Fondazione G. B. Bietti per l’Oftalmologia IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Via Livenza 3 Rome, Italy Tel: +39 06 77052834 Fax: +39 06 77052833 Email: [email protected] The research for this paper was supported by Ministry of Health and Fondazione Roma.
