April 2015
Volume 56, Issue 4
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Eye Movements, Strabismus, Amblyopia and Neuro-ophthalmology  |   April 2015
Functional Loss of the Inner Retina in Childhood Optic Gliomas Detected by Photopic Negative Response
Author Affiliations & Notes
  • Edoardo Abed
    Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy
  • Marco Piccardi
    Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy
  • Daniela Rizzo
    Department of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy
  • Antonio Chiaretti
    Department of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy
  • Lucia Ambrosio
    Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy
  • Sergio Petroni
    Department of Ophthalmology, Bambino Gesù Children's Hospital, Rome, Italy
  • Rosa Parrilla
    Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy
  • Anna Dickmann
    Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy
  • Riccardo Riccardi
    Department of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy
  • Benedetto Falsini
    Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy
  • Correspondence: Edoardo Abed, Department of Ophthalmology, Catholic University, Largo Agostino Gemelli, 8, Rome, Italy; edoardoabed@yahoo.it
Investigative Ophthalmology & Visual Science April 2015, Vol.56, 2469-2474. doi:10.1167/iovs.14-16235
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      Edoardo Abed, Marco Piccardi, Daniela Rizzo, Antonio Chiaretti, Lucia Ambrosio, Sergio Petroni, Rosa Parrilla, Anna Dickmann, Riccardo Riccardi, Benedetto Falsini; Functional Loss of the Inner Retina in Childhood Optic Gliomas Detected by Photopic Negative Response. Invest. Ophthalmol. Vis. Sci. 2015;56(4):2469-2474. doi: 10.1167/iovs.14-16235.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To determine whether the Ganzfeld ERG photopic negative response (PhNR), an assay of inner retinal activity, is altered in childhood optic glioma (OPG).

Methods.: Seventeen pediatric patients with a diagnosis of OPG, established on neuro-ophthalmologic and brain/orbit magnetic resonance imaging (MRI) criteria, were enrolled. The examination protocol included determination of visual acuity (VA), fundus examination, retinal nerve fiber layer (RNFL) measurement with spectral-domain optical coherence tomography (SD-OCT) and photopic ERG. Fifteen normal children served as control group. Ten of the 17 OPG patients were retested 1 to 3 months after the first examination. Photopic ERGs were recorded after 10 minutes of light adaptation in response to a Ganzfeld flash presented on a steady light–adapting background. Amplitude and peak-time of b-wave and PhNR were measured.

Results.: Compared with normal values, PhNR amplitude was significantly reduced (P < 0.0001) in the OPG group. Peak-time of PhNR as well as b-wave amplitude and peak-time were similar in both patients and controls. Losses of PhNR were found in patients with involvement of either anterior or retro-chiasmatic optic pathways. Linear regression analysis showed significant positive correlation between RNFL thickness and PhNR amplitude (r2 = 0.34, P = 0.008). Mean percentage test–retest difference for PhNR amplitude and peak-time was 12% and 6%, respectively.

Conclusions.: These findings indicate that flash ERG PhNR can detect a loss of inner retinal function in childhood OPGs supporting the use of this technique, as an adjunct to standard psychophysical and electrophysiological tests, to monitor visual function in OPG.

Optic glioma (OPG) is the most frequent tumor of the optic pathways in childhood.1 It is relatively common in children with neurofibromatosis type 1 (NF-1) and is most often a pilocytic astrocytoma.2 The neoplasm may be confined to the optic nerve (ON), or may be localized to the chiasm (CM) with a tendency to involve posterior visual pathways.13 Optic gliomas may show a rapid clinical progression with profound vision loss, optic atrophy, and proptosis, but more frequently, these tumors tend to have an indolent growth pattern or remain stable for many years.2,4,5 Spontaneous regression of OPG has also been observed.6,7 Only optic gliomas with an aggressive growth or causing a progressive vision loss are candidate for treatment so that a precise assessment of visual function is essential in the follow-up of these patients. 
However, visual acuity (VA) measurement or visual field examination is often difficult in young children and patients with NF-1 due to low cooperation and/or cognitive impairment810 leading to the need of more objective and repeatable visual function tests. Several authors1013 investigated flash and/or pattern visual evoked potentials as objective and noninvasive functional tests in patients suffering from OPGs. However, earlier and more direct indicators of ON axonal damage may be needed in order to develop more effective therapeutic strategies of the OPG-associated visual loss, or to document the effectiveness of new drugs.14 
Experimental studies in a mouse model of NF-1, expressing a mutated gene product neurofibromin and developing OPGs,15 have begun to elucidate the mechanism underlying the concomitant visual loss. In particular, it has been shown that, early in the disease process, a substantial loss by apoptosis of retinal ganglion cells (RGC) occurs in concomitance to OPG development.15 
Recently, there has been increasing interest in the photopic negative response (PhNR) of the primate cone-mediated electroretinogram (ERG), a slow negative potential that follows the b-wave, as a functional probe of inner retinal activity. In the monkey, PhNR is severely reduced or abolished by intravitreal injection of tetrodotoxin, or by ganglion cell damage induced by experimental glaucoma.16 In humans, significant and selective losses of the PhNR have been reported in eyes with early glaucoma.17,18 These findings support a proximal retinal origin for the PhNR, whose generation has been ascribed to the spiking activity of retinal ganglion cells and/or glial cells.16 
The photopic negative response appears to be a potentially effective assay of inner retina/retinal ganglion cell function in pediatric OPG, adding direct information about development of peripheral damage associated with OPG involving more central visual pathways. 
The aim of the present study was to evaluate the PhNR of the Ganzfeld ERG in children with OPG with or without NF-1. We sought to determine whether PhNR losses were associated with OPGs and, secondarily, whether these losses showed a relationship with the severity of optic disc damage. To these purposes, a special pediatric protocol for PhNR recording, allowing collection of fast and reproducible results, was developed. 
Materials and Methods
Subjects
Seventeen pediatric patients (nine males and eight females, median age 8 years, range, 3.5–18) affected by OPG were included in the study. Exclusion criteria were amblyopia, cataract, retinopathy of prematurity, glaucoma, and any ocular or neurologic condition other than OPG that may affect vision or ON function. The diagnosis of OPG was established on neuro-ophthalmologic and brain/orbit magnetic resonance imaging (MRI) criteria; MRI scans were reviewed by one neuroradiologist to determine the extent and location of tumor within the afferent visual pathways. Signal abnormality and enhancement were used to indicate the presence of tumor. The neuroradiologist was masked to the presence and severity of visual loss. Chiasm location was defined as involvement of optic chiasm with or without involvement of the ONs; postchiasm location was defined as involvement of postchiasmal visual pathways (including hypothalamus) with or without involvement of the chiasm and ONs. Clinical details of individual patients are reported in Table 1. All patients had been followed up clinically every 6 months and with MRI every year for a 1- to 3-year period before testing. In these patients, no significant clinical or MRI changes were noted during the observation period. Seven out of the 17 patients had a clinical diagnosis of NF-1. Before examination, six patients had undergone one or more cycles of chemotherapy (CT; with an induction cycle of carboplatin and vincristine, followed by maintenance treatment with the same drugs alternated with vincristine/1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea [CCNU]/procarbazine/dexamethasone). Seven patients had undergone one or more surgeries for partial excision of the tumor; in three of them, a ventriculus-peritoneal shunt procedure had been also performed. 
Table 1
 
Demographic and Clinical Findings of OPG Patients
Table 1
 
Demographic and Clinical Findings of OPG Patients
Sixteen normal subjects, with age (mean: 6 years, range, 0.5–16) and sex (eight males, eight females) distribution comparable with that of patients, were also evaluated. 
Each patient underwent a complete neuro-ophthalmologic examination, including VA measurement, extrinsic and intrinsic ocular motility testing, anterior segment biomicroscopy, direct ophthalmoscopy, spectral-domain optical coherence tomography (SD-OCT, Cirrus; Carl Zeiss Meditec, Inc., Dublin, CA, USA), retinal nerve fiber layer (RNFL) measurement, and photopic ERG. Visual acuity testing was made, when possible, with a standard adult Snellen chart. In patients in whom acuity testing with a standard Snellen chart was not possible, pediatric acuity charts with symbols (Allen figures) were employed to estimate acuity. Diagnostic grading of OPG in individual patients was based on the above-reported clinical criteria. 
Ten patients underwent repeated electrophysiological testing within 1 to 3 months from the first examination in order to evaluate test–retest changes in the measurements. Informed consent to participate in the study was obtained from all patients or controls, or their parents, after the aims and modalities of the investigation were fully explained. The study followed the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Institution. 
OCT Examination
After pupil dilation, RNFL was measured using the SD-OCT device (Carl Zeiss Meditec, Inc.) with the optic disc cube 200 × 200 standard examination protocol. This protocol elaborates a cube of data covering a 6-mm square area by acquiring a series of 200 horizontal b-scans each composed of 200 a-scans. The analysis software (Carl Zeiss Meditec, Inc.) then identifies optic disc center and calculates a 3.46-mm diameter circular scan centered on the optic disc. The anterior and posterior boundaries of the RNFL are automatically recognized all along this circle and used to calculate RNFL thickness at each point. The mean RNFL value was then recorded and used for data analysis. 
In case of low scan quality (signal strength < 5), decentration, segmentation failure, or motion artifacts scans were repeated and, if not improving, excluded from the analysis. 
ERG Recordings
Electroretinogram responses were recorded in response to Ganzfeld flash stimulation after 10 minutes of preadaptation to a steady background of 20 cd/m2. Then white 50-ms stimuli with an intensity of 2 cd/m2 were presented on a steady white background of 20 cd/m2. The interstimulus interval was 1 second. 
Electroretinograms were recorded by skin electrodes following a pediatric protocol first proposed by Fulton et al.19 Silver chloride electrodes (0.8 mm) were taped on the skin of the lower eyelids, just 2.5 mm below the inferior lid rim, in the vertical axis passing through the corneal apex. An interocular reference was used20 that minimized noise coming for blink and conjugate eye movement artifacts. 
Signals were amplified (50 K), filtered (0.3–250 Hz), digitized at 2 KHz, and averaged (40 events) with automatic artifact rejection. Forty events for each run were collected. Two runs were typically performed for each eye. The peak-to-peak noise level was estimated on line from the sum of events and odd events obtained for the averaging process. 
The amplitude and peak-time of the b-wave and PhNR were measured as previously described.18 
Statistical Analysis
The measurements derived from the right eyes of each normal control subject, and from the eye that was functionally/anatomically more affected of each patient, were included in the main statistical analysis. In patients with similar involvement in both eyes, the study eye was randomly selected. Two-tailed unpaired t-test was performed to compare PhNR and b-wave amplitude and latency between the OPG and the control group. 
Test–retest results from OPG patients (one randomly selected eye for each patient was included in the analysis) were evaluated by calculating the absolute and percentage amplitude difference between the two test results (i.e., first–second test) for each patient. Coefficient of repeatability was estimated based on the methods reported by Fleiss21 and Bland and Altman.22 Parametric Pearson's correlations were employed to correlate PhNR amplitude with RNFL thickness in OPG patients. In all the analyses a P value < 0.05 was considered statistically significant. 
Results
Demographics and clinical data of individual patients of the OPG group are reported in Table 1. Median VA in OPG patients was 20/100 and ranged between 20/20 and light perception. Visual acuity examination could not be performed in 6 of the 17 patients (29.4%). High quality SD-OCT scans of the ON were obtained in 11 patients of the OPG group (64.7%), allowing an accurate measurement of RNFL thickness. The remaining six patients (35.3%) were unable to fixate during the examination resulting in motion artifacts and segmentation errors. Mean RNFL thickness in the OPG group was 55.4 ± 12.1 μm. 
Photopic ERG responses were successfully recorded in all patients of the OPG and control group. Representative examples of ERG PhNR signals recorded from a normal control and a patient with OPG are displayed in Figures 1A and 1B, respectively. While in control subjects there was a highly significant intereye correlation for both PhNR amplitude and implicit time (r2 = 0.7, P < 0.01), in patients the PhNR amplitude parameters recorded from the right and left eyes were not significantly correlated (r2 = 0.06, P = 0.34) Similarly, RNFL thickness measurements obtained from right and left eyes of patients were not correlated (r2 = 0.005; P = 0.84). The electroretinogram examination showed a good intratest reproducibility with a mean percentage test–retest difference of 6% and 12% for PhNR amplitude and peak-time, respectively. 
Figure 1
 
Representative examples of photopic ERG recorded from a healthy control and a patient with OPG. Compared with a normal patient, the PhNR amplitude is considerably reduced in the OPG patient while no significant differences are appreciable in b-wave amplitude and latency.
Figure 1
 
Representative examples of photopic ERG recorded from a healthy control and a patient with OPG. Compared with a normal patient, the PhNR amplitude is considerably reduced in the OPG patient while no significant differences are appreciable in b-wave amplitude and latency.
Electroretinograms from 10 eyes of 10 patients were obtained in two separate occasions 1 to 3 months apart. Results of this test–retest analysis are shown in Figure 2 in the form of a Bland-Altman plot. In the plot, the absolute difference between the two measurements is reported. The horizontal lines indicate the limits derived from the coefficient of repeatability. In this sample of affected eyes, the coefficient of repeatability—expressed as percentage of the mean amplitude value—was 15% (95% CI: 13.92%–16.08%). 
Figure 2
 
Bland-Altman plot showing the results of test–retest analysis for PhNR amplitude. The absolute differences of the two measurements are reported for each of the 10 patients retested. The horizontal lines indicate the limits derived from the coefficient of repeatability.
Figure 2
 
Bland-Altman plot showing the results of test–retest analysis for PhNR amplitude. The absolute differences of the two measurements are reported for each of the 10 patients retested. The horizontal lines indicate the limits derived from the coefficient of repeatability.
As shown in Table 2, mean amplitude of PhNR was reduced by 56% in patients of the OPG group compared with the control group (8.60 ± 3.26 μV and 19.16 ± 5.04 μV, respectively; P < 0.0001). Conversely, no significant differences were seen between the two study groups regarding PhNR latency and b-wave amplitude and peak time (P = 0.58, P = 0.54, and P = 0.98, respectively). Linear regression analysis with Pearson's coefficient showed a significant positive correlation between RNFL and PhNR amplitude (r2 = 0.34, P = 0.008) as showed in the scatterplot (Fig. 3). In the figure, individual PhNR values recorded from right and left eyes are plotted, as scattergrams, for patients with a retrochiasmatic or an anterior OPG. Photopic negative response amplitude was lower in the worse, compared with the less affected eye, as determined by RNFL, in 89% of patients. When only the PhNR amplitudes of the study patients that had had no previous treatment (chemo or surgery) were compared with values from normal eyes, the difference between patients and controls still remained significant (10.40 ± 2.84 μV and 19.16 ± 5.04 μV, P < 0.001). 
Table 2
 
Photopic ERG Results in OPG Patients and Controls
Table 2
 
Photopic ERG Results in OPG Patients and Controls
Figure 3
 
Scatterplot illustrating the significant positive correlation between PhNR amplitude and RNFL thickness in OPG patients.
Figure 3
 
Scatterplot illustrating the significant positive correlation between PhNR amplitude and RNFL thickness in OPG patients.
Diagnostic accuracy of PhNR for detecting inner retina dysfunction in OPG patients was determined by receiver operating characteristics (ROC) analysis. The results are reported in Figure 4, which shows a ROC curve for PhNR amplitude. The resulting area under the curve was 0.86 (95% CI: 0.82–0.93). 
Figure 4
 
The results of the ROC analysis for the diagnostic accuracy of PhNR amplitude in detecting RGC dysfunction in OPG patients are shown. The area under the ROC curve is 0.86 (95% CI: 0.82–0.93).
Figure 4
 
The results of the ROC analysis for the diagnostic accuracy of PhNR amplitude in detecting RGC dysfunction in OPG patients are shown. The area under the ROC curve is 0.86 (95% CI: 0.82–0.93).
Discussion
In this study, we found a substantial reduction of Ganzfeld ERG PhNR amplitude (P < 0.0001) of patients with OPG. Compared with controls, PhNR amplitude was decreased by 56% in the OPG group, which is largely greater than the mean test–retest percentage difference, confirming the clinical significance of our findings. Conversely, no significant alterations were seen in PhNR latency and in b-wave amplitude and peak time. 
Test–retest variability of PhNR amplitude in OPG patients was determined in a subgroup of 10 patients evaluated in two separate occasions. We found that the estimated coefficient of repeatability corresponded to 15% of the mean amplitude value, indicating a reasonably good reproducibility of this ERG component in diseased eyes, and its potential use in longitudinal studies. 
While a- and b-waves of the ERG originate from the proximal retinal processing,23,24 a large body of evidence indicates that PhNR selectively reflects the activity of RGCs and their axons. In primates, blocking voltage-gated Na+ channels by intravitreal injection of tetrodotoxin causes disappearance of the PhNR without altering other ERG components.16 In the retina, voltage-gated Na+ channels are mainly expressed in RGCs and their axons and amacrine cells25 suggesting that these cells are the generators of PhNR. 
Furthermore, clinical studies reported a significant decrease of PhNR amplitude in a large number of ON diseases including glaucoma,18,26,27 multiple sclerosis,28 and chiasmal compression.29 Thus, the selective reduction of PhNR amplitude in patients affected by OPG indicates that this tumor induces a functional impairment of RGCs. Potential confounding factors in our study could have been the chemo or surgery that were administered to 10 out of 17 patients. These treatments may have affected the outcome variable of the study independent of the tumor. However, a significant PhNR amplitude loss, compared with normal values, was found also in untreated OPG patients, suggesting that the tumor per se may be associated with inner retina dysfunction. 
This finding agrees with a case report by Moradi et al.30 describing an alteration of pattern ERG N95:P50 ratio in a 15-year-old girl with an OPG involving the optic nerve. 
The current findings are also consistent with the results of experimental studies15 on murine models of NF-1 showing a progressive loss of RGCs in early phases of OPG development. The authors suggest that RGCs apoptosis may be caused by a retrograde degeneration, an abnormal signaling by mutated astrocytes with loss of neurofibromin function or a combination of these two mechanisms.15 
Recently, the advent of OCT imaging technology allowed the researchers to document in vivo the alteration of RGC and their axons in OPG. In particular, it has been demonstrated that both macular ganglion cell complex31 and RNFL thickness32,33 is significantly reduced in OPG patients. Furthermore, Fard et al.34 showed that RNFL thinning may be predictive for the progression of OPG suggesting that OCT examination may be a useful tool to monitor these patients. However, without eye tracking systems35 or sedation,36 the acquisition of OCT scans may be difficult in young children and in case of severe vision impairment, which may limit patient fixation capability.31 
Accordingly, in our study, even if OCT showed a remarkable reduction of RNFL thickness in OPG patients compared with normative values reported in the literature,37 RNFL measurement was not possible in approximately one-third of patients due to motion artifacts and/or poor scan quality. Conversely, photopic ERG examination with skin taped electrodes does not require fixation stability or high cooperation and, in this study, was successfully recorded in all patients tested, suggesting that this test could be particularly useful to evaluate visual function in young children and patients with profound vision loss. Additionally, PhNR recording may be advantageous in case of OPG involving the ON or the chiasm presenting with nerve swelling that may lead to a false increase of RNFL thickness. 
In this study, we also found a significant positive correlation between PhNR amplitude and mean RNFL thickness (P < 0.008). We decided to measure RNFL mean thickness because Ganzfeld PhNR is likely to reflect the activity of RGCs throughout the ocular fundus. This linear relationship between PhNR amplitude and RNFL thickness was already described in glaucoma,25,26 optic atrophy,38 and multiple sclerosis,27 and indicates that RGCs function declines proportionately with neural loss. 
In conclusion, photopic flash ERG with PhNR measurement can detect inner retinal dysfunction in childhood OPG, suggesting that this technique may play a relevant role in the assessment of visual impairment in these patients. The current results on test–retest variability indicate a relatively good reproducibility (coefficient of repeatability of 15%) of our measure. On the other hand, the main limitation of this study is the small number of patients included which may reduce the reliability of statistical analysis. It also remains to be determined whether PhNR amplitude alterations may be predictive for OPG growth pattern. Large prospective longitudinal studies are warranted to validate our results and to elucidate the prognostic value of PhNR alterations in OPG progression. 
Acknowledgments
Supported by the Project Grant “Translational Study on Neuroprotective Role of Conjunctivally Applied Nerve Growth Factor in Childhood Optic Gliomas” (Grant #2009-1536140) by Ministero della Salute – Direzione Generale della Ricerca Scientifica e Tecnologica – Roma, Italy. 
Disclosure: E. Abed, None; M. Piccardi, None; D. Rizzo, None; A. Chiaretti, None; L. Ambrosio, None; S. Petroni, None; R. Parrilla, None; A. Dickmann, None; R. Riccardi, None; B. Falsini, None 
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Figure 1
 
Representative examples of photopic ERG recorded from a healthy control and a patient with OPG. Compared with a normal patient, the PhNR amplitude is considerably reduced in the OPG patient while no significant differences are appreciable in b-wave amplitude and latency.
Figure 1
 
Representative examples of photopic ERG recorded from a healthy control and a patient with OPG. Compared with a normal patient, the PhNR amplitude is considerably reduced in the OPG patient while no significant differences are appreciable in b-wave amplitude and latency.
Figure 2
 
Bland-Altman plot showing the results of test–retest analysis for PhNR amplitude. The absolute differences of the two measurements are reported for each of the 10 patients retested. The horizontal lines indicate the limits derived from the coefficient of repeatability.
Figure 2
 
Bland-Altman plot showing the results of test–retest analysis for PhNR amplitude. The absolute differences of the two measurements are reported for each of the 10 patients retested. The horizontal lines indicate the limits derived from the coefficient of repeatability.
Figure 3
 
Scatterplot illustrating the significant positive correlation between PhNR amplitude and RNFL thickness in OPG patients.
Figure 3
 
Scatterplot illustrating the significant positive correlation between PhNR amplitude and RNFL thickness in OPG patients.
Figure 4
 
The results of the ROC analysis for the diagnostic accuracy of PhNR amplitude in detecting RGC dysfunction in OPG patients are shown. The area under the ROC curve is 0.86 (95% CI: 0.82–0.93).
Figure 4
 
The results of the ROC analysis for the diagnostic accuracy of PhNR amplitude in detecting RGC dysfunction in OPG patients are shown. The area under the ROC curve is 0.86 (95% CI: 0.82–0.93).
Table 1
 
Demographic and Clinical Findings of OPG Patients
Table 1
 
Demographic and Clinical Findings of OPG Patients
Table 2
 
Photopic ERG Results in OPG Patients and Controls
Table 2
 
Photopic ERG Results in OPG Patients and Controls
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