Acta Ophthalmologica 2015
Peripapillary retinal vessel diameter correlates with mfERG alterations in retinitis pigmentosa Lisette T. Lopez Torres,* Cengiz T€ urksever,* Andreas Sch€ otzau, Selim Org€ ul and Margarita G. Todorova Department of Ophthalmology, University of Basel, Basel, Switzerland
ABSTRACT. Purpose: To investigate relationship between the peripapillary retinal vessel diameter and the residual retinal function, measured by mfERG, in patients with retinitis pigmentosa (RP). Patients and Methods: A cross-sectional study based on 23 patients with RP (43 eyes) and 20 controls (40 eyes) was performed. Retinal vessel diameters were measured using a computer-based program of the retinal vessel analyser (RVA; IMEDOS Systems UG, Jena, Germany). We evaluated the mean diameter in all four major retinal arterioles (D-A) and venules (D-V) within 1.0–1.5 optic disc diameters from the disc margin. The data were compared with the N1 amplitudes (measured from the baseline to the trough of the first negative wave), with the N1P1 amplitudes (measured from the trough of the first negative wave to the peak of the first positive wave) of the mfERG overall response and with the mfERG responses averaged in zones [zone 1 (0°–3°), zone 2 (3°–8°), zone 3 (8°–15°) and zone 4 (15°–24°)]. Results: Mean (SD) D-A and D-V were narrower in patients with RP [84.86 lm (13.37 lm) and 103.35 lm (13.65 lm), respectively] when compared to controls [92.81 lm (11.49 lm) and 117.67 lm (11.93 lm), respectively; the p-values between groups were p = 0.003 for D-A and p < 0.001 for D-V, linear mixed-effects model]. The RP group revealed clear differences compared to the controls: D-A and D-V became narrower with reduced mfERG responses. D-V correlated significantly with the overall mfERG N1 amplitudes (p = 0.013) and with N1P1 amplitudes (p = 0.016). D-V correlated with the mfERG amplitudes averaged in zones: (zone 2, 3 and 4; p ≤ 0.040) and N1P1 mfERG amplitudes (zones 1, 2, 3 and 4; p ≤ 0.013). Conclusions: Peripapillary retinal vessel diameter is reduced in RP proportionally to functional alterations. Key words: mfERG – retinal function – retinal vessel diameter – retinitis pigmentosa
Acta Ophthalmol. 2015: 93: e527–e533 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12707
*These authors contributed equally to this work
Introduction Retinitis pigmentosa (RP) is the most commonly recognized hereditary progressive photoreceptor degeneration
that affects ~1/4000 people worldwide. The hallmarks of RP are nyctalopia and progressive visual field constriction, which in some cases are followed by central vision deterioration (Ammann
et al. 1965; Hamel 2006; Hartong et al. 2006). An almost universal finding in eyes with RP is the attenuation in retinal vessels (Merin & Auerbach 1976; Hartong et al. 2006; Ma et al. 2012), which is mainly thought to reflect decreased metabolic demand of the degenerating retina (Grunwald et al. 1996; Marc & Jones 2003; Cottet & Schorderet 2009). Histopathological studies have reported sclerosis and atrophy of the retinal vasculature in extreme cases (Blanks & Johnson 1986; Milam et al. 1998). In addition, the regions underlying the retinal pigment epithelium destruction have revealed a lack of choroidal capillaries (Henkind & Gartner 1983; Korte et al. 1986; Milam et al. 1998; Penn et al. 2000). In case of compromised outer retina function: following retinal pigment epithelium apoptosis in RP (Milam et al. 1998; Marc & Jones 2003; Jones & Marc 2005; Panfoli et al. 2009), adjacent photoreceptors are destroyed and replaced by glial tissue. This is also the case following argon laser photocoagulation for treatment of diabetic retinopathy (Stef ansson et al. 1986; Stefansson 1990; Gottfredsd ottir et al. 1993) where histological studies confirmed secondary attenuation of the retinal vasculature (Stef ansson et al. 1986; Stefansson 1990). The previously described clinical feature of attenuated retinal vessel diameter (Merin & Auerbach 1976; Hartong et al. 2006; Ma et al. 2012) has been confirmed in recent studies applying a computer-based program of the retinal vessel analyser (RVA; IMEDOS Systems UG, Jena, Germany) (Eysteinsson et al. 2014; Nakagawa et al. 2014). Full-field ERG is accepted as a gold standard for clinical diagnosis and
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Acta Ophthalmologica 2015
monitoring of patients with inherited retina diseases (Gouras & Carr 1964; Fishman 1985; Birch & Sandberg 1987; Falsini et al. 1999; Alexander et al. 2003; Tzekov et al. 2003). Nonetheless, in some patients with only central visual fields, the full-field ERG may not be sensitive enough to detect the still preserved responses from the central retina. In such cases, localized responses may still be obtained using the multifocal ERG (mfERG) (Hood & Zhang 2000; Gr€ anse et al. 2004; Nagy et al. 2008). Since the development of the mfERG by Sutter and Tran in 1992 the method is introduced for an objective topographical evaluation of retinal function (Sutter & Tran 1992; Bearse & Sutter 1996; Hood 2000; Sutter 2001). Many studies using mfERG in patients with RP revealed abnormal delayed and reduced responses beyond the paracentral regions (Hood & Zhang 2000; Gr€ anse et al. 2004; Greenstein et al. 2004; Gerth et al. 2007). Other studies have found associations between functional and psychophysical determinants in patients with RP, (Sandberg et al. 1996; Gr€anse et al. 2004; Gerth et al. 2007; Nagy et al. 2008; Ma et al. 2012; Wen et al. 2012), using mainly the methods described above. Moreover, in a group of children with retinal degenerations, a positive association between the degree of diminution of the arteriolar diameter and the dark adapted visual thresholds, measured by the preferential looking test, has been disclosed, thus confirming the natural progressive course of the disease (Hansen et al. 2008). However, simple and feasible application of a combined analysis for a comprehensive routine diagnosis is lacking. The aim of this study was therefore to investigate the relationship between the structural (i.e. peripapillary retinal vessel diameters) and the functional (i.e. mfERG) alterations in patients with RP.
Material and Methods A cross-sectional consecutive study based on 23 patients with RP (43 eyes) and 20 controls (40 eyes) was performed. The study protocol was approved by the Ethics Committee of the University of Basel and adhered to the tenets of the Declaration of Helsinki. All study subjects provided informed consent before enrolment in the study.
e528
Subjects
All controls and the patients with RP completed a standard ophthalmologic examination, including best corrected visual acuity (Snellen charts), Goldmann applanation tonometry measurement, biomicroscopy and fundoscopy. The clinical phenotype of patients with RP was characterized following clinical and electrophysiological assessment. Inclusion criteria for patients with RP were as follows: Caucasian origin, characteristic fundoscopic findings of RP, reduced or non-detectable a- and b-wave amplitudes of the scotopic fullfield ERG. Inclusion criteria for controls were as follows: Caucasian origin, best corrected Snellen visual acuity at distance ≥ 0.8. Exclusion criteria for patients and controls were as follows: the above-mentioned inclusion criteria not fulfilled, the presence of ocular and/or systemic pathology other than RP (for instance diabetes mellitus, hypertension, or other metabolic and neurodegenerative diseases potentially affecting the vessel diameter and mfERG measurements), unstable fixation, and fundus images with inadequate quality. Retinal vessel imaging
Both pupils of each subject were dilated (7.0–8.0 mm) using tropicamide 0.5% and phenylephrine 1% eye drops (Vandewalle et al. 2013). After a minimum of 20 minutes, four test–retest fundus images were obtained, as described previously (Todorova et al. 2014; T€ urksever et al. 2014, 2015). Briefly, 50° field optic disc-centred fundus were taken per eye using the retinal vessel analyser (RVA: Imedos UG, Jena, Germany) which was connected to the fundus camera FF450 (Carl Zeiss Meditec, Jena, Germany). We evaluated the mean diameter in all first and second branch retinal arterioles (D-A; lm) and venules (D-V; lm) within the peripapillary annulus, (1.0– 1.5 optic disc diameters). Representative images of a control and a patient with RP are given in Fig. 1.
MfERG stimulus, recordings and analysis
MfERGs were performed on VERIS Science 6.1.2TM unit (Visual Evoked Response Imaging System, Electrodiagnostic Imaging; EDI, San Matheo,
CA, USA) according to ISCEV 2012 Standards (Hood et al. 2012). For mfERG recording, patients were adapted to ambient room light for 30 minutes. Recording was performed on FMS III stimulator. During the recording session, hexagons flickered between black and white according to m-sequence of 215 (frame rate: 75 Hz). The stimulus array consisted of 103 hexagons. The central 50° of the retina were stimulated. During the light phase, the maximal luminance of the hexagons (Lmax) was 200 cd/m2, and during the dark phase, (Lmin)
Peripapillary retinal vessel diameter correlates with mfERG alterations in retinitis pigmentosa Lisette T. Lopez Torres,* Cengiz T€ urksever,* Andreas Sch€ otzau, Selim Org€ ul and Margarita G. Todorova Department of Ophthalmology, University of Basel, Basel, Switzerland
ABSTRACT. Purpose: To investigate relationship between the peripapillary retinal vessel diameter and the residual retinal function, measured by mfERG, in patients with retinitis pigmentosa (RP). Patients and Methods: A cross-sectional study based on 23 patients with RP (43 eyes) and 20 controls (40 eyes) was performed. Retinal vessel diameters were measured using a computer-based program of the retinal vessel analyser (RVA; IMEDOS Systems UG, Jena, Germany). We evaluated the mean diameter in all four major retinal arterioles (D-A) and venules (D-V) within 1.0–1.5 optic disc diameters from the disc margin. The data were compared with the N1 amplitudes (measured from the baseline to the trough of the first negative wave), with the N1P1 amplitudes (measured from the trough of the first negative wave to the peak of the first positive wave) of the mfERG overall response and with the mfERG responses averaged in zones [zone 1 (0°–3°), zone 2 (3°–8°), zone 3 (8°–15°) and zone 4 (15°–24°)]. Results: Mean (SD) D-A and D-V were narrower in patients with RP [84.86 lm (13.37 lm) and 103.35 lm (13.65 lm), respectively] when compared to controls [92.81 lm (11.49 lm) and 117.67 lm (11.93 lm), respectively; the p-values between groups were p = 0.003 for D-A and p < 0.001 for D-V, linear mixed-effects model]. The RP group revealed clear differences compared to the controls: D-A and D-V became narrower with reduced mfERG responses. D-V correlated significantly with the overall mfERG N1 amplitudes (p = 0.013) and with N1P1 amplitudes (p = 0.016). D-V correlated with the mfERG amplitudes averaged in zones: (zone 2, 3 and 4; p ≤ 0.040) and N1P1 mfERG amplitudes (zones 1, 2, 3 and 4; p ≤ 0.013). Conclusions: Peripapillary retinal vessel diameter is reduced in RP proportionally to functional alterations. Key words: mfERG – retinal function – retinal vessel diameter – retinitis pigmentosa
Acta Ophthalmol. 2015: 93: e527–e533 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12707
*These authors contributed equally to this work
Introduction Retinitis pigmentosa (RP) is the most commonly recognized hereditary progressive photoreceptor degeneration
that affects ~1/4000 people worldwide. The hallmarks of RP are nyctalopia and progressive visual field constriction, which in some cases are followed by central vision deterioration (Ammann
et al. 1965; Hamel 2006; Hartong et al. 2006). An almost universal finding in eyes with RP is the attenuation in retinal vessels (Merin & Auerbach 1976; Hartong et al. 2006; Ma et al. 2012), which is mainly thought to reflect decreased metabolic demand of the degenerating retina (Grunwald et al. 1996; Marc & Jones 2003; Cottet & Schorderet 2009). Histopathological studies have reported sclerosis and atrophy of the retinal vasculature in extreme cases (Blanks & Johnson 1986; Milam et al. 1998). In addition, the regions underlying the retinal pigment epithelium destruction have revealed a lack of choroidal capillaries (Henkind & Gartner 1983; Korte et al. 1986; Milam et al. 1998; Penn et al. 2000). In case of compromised outer retina function: following retinal pigment epithelium apoptosis in RP (Milam et al. 1998; Marc & Jones 2003; Jones & Marc 2005; Panfoli et al. 2009), adjacent photoreceptors are destroyed and replaced by glial tissue. This is also the case following argon laser photocoagulation for treatment of diabetic retinopathy (Stef ansson et al. 1986; Stefansson 1990; Gottfredsd ottir et al. 1993) where histological studies confirmed secondary attenuation of the retinal vasculature (Stef ansson et al. 1986; Stefansson 1990). The previously described clinical feature of attenuated retinal vessel diameter (Merin & Auerbach 1976; Hartong et al. 2006; Ma et al. 2012) has been confirmed in recent studies applying a computer-based program of the retinal vessel analyser (RVA; IMEDOS Systems UG, Jena, Germany) (Eysteinsson et al. 2014; Nakagawa et al. 2014). Full-field ERG is accepted as a gold standard for clinical diagnosis and
e527
Acta Ophthalmologica 2015
monitoring of patients with inherited retina diseases (Gouras & Carr 1964; Fishman 1985; Birch & Sandberg 1987; Falsini et al. 1999; Alexander et al. 2003; Tzekov et al. 2003). Nonetheless, in some patients with only central visual fields, the full-field ERG may not be sensitive enough to detect the still preserved responses from the central retina. In such cases, localized responses may still be obtained using the multifocal ERG (mfERG) (Hood & Zhang 2000; Gr€ anse et al. 2004; Nagy et al. 2008). Since the development of the mfERG by Sutter and Tran in 1992 the method is introduced for an objective topographical evaluation of retinal function (Sutter & Tran 1992; Bearse & Sutter 1996; Hood 2000; Sutter 2001). Many studies using mfERG in patients with RP revealed abnormal delayed and reduced responses beyond the paracentral regions (Hood & Zhang 2000; Gr€ anse et al. 2004; Greenstein et al. 2004; Gerth et al. 2007). Other studies have found associations between functional and psychophysical determinants in patients with RP, (Sandberg et al. 1996; Gr€anse et al. 2004; Gerth et al. 2007; Nagy et al. 2008; Ma et al. 2012; Wen et al. 2012), using mainly the methods described above. Moreover, in a group of children with retinal degenerations, a positive association between the degree of diminution of the arteriolar diameter and the dark adapted visual thresholds, measured by the preferential looking test, has been disclosed, thus confirming the natural progressive course of the disease (Hansen et al. 2008). However, simple and feasible application of a combined analysis for a comprehensive routine diagnosis is lacking. The aim of this study was therefore to investigate the relationship between the structural (i.e. peripapillary retinal vessel diameters) and the functional (i.e. mfERG) alterations in patients with RP.
Material and Methods A cross-sectional consecutive study based on 23 patients with RP (43 eyes) and 20 controls (40 eyes) was performed. The study protocol was approved by the Ethics Committee of the University of Basel and adhered to the tenets of the Declaration of Helsinki. All study subjects provided informed consent before enrolment in the study.
e528
Subjects
All controls and the patients with RP completed a standard ophthalmologic examination, including best corrected visual acuity (Snellen charts), Goldmann applanation tonometry measurement, biomicroscopy and fundoscopy. The clinical phenotype of patients with RP was characterized following clinical and electrophysiological assessment. Inclusion criteria for patients with RP were as follows: Caucasian origin, characteristic fundoscopic findings of RP, reduced or non-detectable a- and b-wave amplitudes of the scotopic fullfield ERG. Inclusion criteria for controls were as follows: Caucasian origin, best corrected Snellen visual acuity at distance ≥ 0.8. Exclusion criteria for patients and controls were as follows: the above-mentioned inclusion criteria not fulfilled, the presence of ocular and/or systemic pathology other than RP (for instance diabetes mellitus, hypertension, or other metabolic and neurodegenerative diseases potentially affecting the vessel diameter and mfERG measurements), unstable fixation, and fundus images with inadequate quality. Retinal vessel imaging
Both pupils of each subject were dilated (7.0–8.0 mm) using tropicamide 0.5% and phenylephrine 1% eye drops (Vandewalle et al. 2013). After a minimum of 20 minutes, four test–retest fundus images were obtained, as described previously (Todorova et al. 2014; T€ urksever et al. 2014, 2015). Briefly, 50° field optic disc-centred fundus were taken per eye using the retinal vessel analyser (RVA: Imedos UG, Jena, Germany) which was connected to the fundus camera FF450 (Carl Zeiss Meditec, Jena, Germany). We evaluated the mean diameter in all first and second branch retinal arterioles (D-A; lm) and venules (D-V; lm) within the peripapillary annulus, (1.0– 1.5 optic disc diameters). Representative images of a control and a patient with RP are given in Fig. 1.
MfERG stimulus, recordings and analysis
MfERGs were performed on VERIS Science 6.1.2TM unit (Visual Evoked Response Imaging System, Electrodiagnostic Imaging; EDI, San Matheo,
CA, USA) according to ISCEV 2012 Standards (Hood et al. 2012). For mfERG recording, patients were adapted to ambient room light for 30 minutes. Recording was performed on FMS III stimulator. During the recording session, hexagons flickered between black and white according to m-sequence of 215 (frame rate: 75 Hz). The stimulus array consisted of 103 hexagons. The central 50° of the retina were stimulated. During the light phase, the maximal luminance of the hexagons (Lmax) was 200 cd/m2, and during the dark phase, (Lmin)
