Didier Chabaud
email: didier.chabaud@univ-paris1.fr

Jean-François Sattin
email: jean-francois.sattin@univ-paris1.fr

Back to the roots! Testing Miller's entrepreneurial orientation construct using Sono-Leontief conditions

Keywords: Methodology, Entrepreneurial orientation, SME JEL: M13, C10 Methodology, Entrepreneurial orientation, SME JEL: M13, C10

Using a new database of 391 interviews of French SME managers, this paper investigates the consistency of the Miller indicator of entrepreneurial orientation by relying on Sono-Leontief conditions. The main results suggest that Miller's construct is impacted by internal effects that cast doubts on its internal reliability, and that multidimensional assessments of entrepreneurial orientation should be preferred in empirical research

Introduction

Entrepreneurial orientation (EO) 1 is a vibrant research topic [START_REF] Covin | Crafting high-impact entrepreneurial orientation research: some suggested guidelines[END_REF], leading to a proliferation of research questions and studies [START_REF] Wales | Entrepreneurial orientation: A review and synthesis of promising research directions[END_REF], which encourage us to consider that EO is a "predominant construct of interest in strategic entrepreneurship research" [START_REF] Anderson | Reconceptualizing entrepreneurial orientation[END_REF](Anderson et al., : 1579) ) and even in management sciences [START_REF] Gupta | The concept of entrepreneurial orientation[END_REF]. However, there is still no consensus among scholars on how to measure EO [START_REF] Covin | Entrepreneurial orientation theory and research: reflections on a needed construct[END_REF]Covin andWales, 2012, 2018;[START_REF] George | Entrepreneurial orientation: a theoretical and empirical examination of the consequences of differing construct representations[END_REF].

Following [START_REF] Miller | The correlates of entrepreneurship in three types of firms[END_REF] and [START_REF] Covin | Strategic management of small firms in hostile and benign environments[END_REF], prior empirical research has mainly assessed EO as a unidimensional construct 2 derived from three primary dimensions: innovativeness, risk-taking, and proactiveness [START_REF] Saeed | On cultural and macroeconomic contingencies of the entrepreneurial orientation-performance relationship[END_REF]. Since [START_REF] Covin | Strategic management of small firms in hostile and benign environments[END_REF] it has generally been posited that these three dimensions could be aggregated (i.e. summed with equal weights) in order to assess the overall level of a firm's EO. [START_REF] George | Entrepreneurial orientation: a theoretical and empirical examination of the consequences of differing construct representations[END_REF]George ( : 1293) ) emphasizes that 34 out of the 39 empirical studies he has found on this topic use this aggregative measure. This approach has nevertheless been strongly challenged over the years, mainly because it assumes that these three components of EO (innovativeness, risk-taking, and proactiveness) can be conceptualized as substitutes for the construct. [START_REF] Lumpkin | Clarifying the entrepreneurial orientation construct and linking it to performance[END_REF], for instance, have suggested that EO is a multidimensional construct, in which each of the five dimensions they differentiate 3 can vary independently. Following this line, Hughes and Morgan (2007) emphasize that "proactiveness and innovativeness have a positive influence on business 1 According to [START_REF] Miller | The correlates of entrepreneurship in three types of firms[END_REF], "An entrepreneurial firm is one that engages in product-market innovation, undertakes somewhat risky ventures, and is first to come up with 'proactive' innovations, beating competitors to the punch" (p. 771). 2 In this paper we use the terms construct, aggregate and indicator synonymously. 3 They add competitive aggressiveness and autonomy to the canonical Miller model: innovation, risk-taking, proactiveness. performance while risk-taking has a negative relationship," challenging Miller's conceptualization of EO [START_REF] George | The epistemology of entrepreneurial orientation: conceptual formation, modeling, and operationalization[END_REF] and opening the way for measurement models [START_REF] George | Entrepreneurial orientation: a theoretical and empirical examination of the consequences of differing construct representations[END_REF]Covin and Wales, 2011). Several scholars even stress the need to "reconceptualize EO," for instance by distinguishing between entrepreneurial behaviors (that encompass innovativeness and proactiveness) and managerial attitude toward risk (risktaking) [START_REF] Anderson | Reconceptualizing entrepreneurial orientation[END_REF], or by taking into account the contextual dimensions of the firm and the need to focus more on configurations of EO than on a single generic construct (Hughes et al., 2007[START_REF] Kearney | Examining facilitative configurations of entrepreneurially oriented growth: an information processing perspective[END_REF].

We propose to test the reliability of Miller's construct to address these debates about EO indicators. In management research, the reliability of composite indicators is usually assessed using empirical procedures [START_REF] Chandler | Issues of research design and construct measurement in entrepreneurship research: the past decade[END_REF], such as Cronbach alphas or confirmatory data analysis, which mainly investigate the correlations among items. As such, most of the existing indicators currently suffer from a lack of methodological foundation, as they do not indicate anything about the way the items included in the construct actually interact together. From this perspective, we think that a better assessment of the reliability of these constructs will be useful in order to check the internal consistency of past and future research that relies on these constructs and, from a broader perspective, to enhance "transparency in management research" [START_REF] Aguinis | What you see is what you get? Enhancing methodological transparency in management research[END_REF].

The question of the validity of composite indicators was raised-and answered-a long time ago in economics during the controversy about the nature of capital aggregates [START_REF] Cohen | Whatever happened to the Cambridge capital theory controversies[END_REF]. A common way to assess if an aggregated indicator holds is to evaluate whether the Sono-Leontief conditions are met [START_REF] Sono | The effect of prices changes on the demand and supply of separable goods[END_REF]Leontief, 1947aLeontief, , 1947b)). The aim is to assess if all the information carried by sub-indicators (or items) can be summarized in the composite or if, to some extent, sub-indicators still convey information independently, even when these dimensions are conflated. Thus the aim of this paper is to evaluate if Miller's construct passes the Sono-Leontief conditions and should be considered valid from a methodological point of view.

Our paper follows a conventional structure. Section two introduces our methodology. Section three presents the collected dataset and variables and the empirical strategy. Econometric estimates are presented in section four. The final section suggests avenues for future research and concludes.

Methodology

The Sono-Leontief conditions hold that, in order for a composite indicator to be valid, it is necessary that its impact on a chosen dependent variable remains constant whatever its internal composition. In our case, this would mean, for instance, that when dealing with firm performance, a change in the relative composition of EO (among innovativeness, risk-taking, and proactiveness) should have no impact on firm performance, taking the overall level of EO constant. 4 Previous literature has mainly tested the validity of EO indicators by focusing only on the impact of their level on a chosen dependent variable. We propose here to develop an alternative perspective that tests the impact of both the level and the internal structure of EO indicators on the dependent variable in order to challenge their validity.

Formally, the Sono-Leontief conditions (also known as separability conditions) state that, with Y(x 1 , x 2 ,…,x n ) a function that is continuously twice differentiable, A(x 1 , …, x k ) and 5 G(A(x 1 , …, xk), x k+1 ,..., x n ), can be defined such that Y(x 1 ,…, x k ,…, x n )=G(A(x 1 , …, xk), x k+1 ,..., x n ) if and only if Y has the property ( )

z j i x Y Y n k z k i j k i , , , 0 ] , 1 [ ] , 1 [ ] , 1 [ ∀ = ∂ ∂ + ∈ ∈ ≠ ∈
, where the subscripts denote differentiation [START_REF] Sono | The effect of prices changes on the demand and supply of separable goods[END_REF]Leontief, 1947a;1947b).

In order to check empirically if the Sono-Leontief conditions are met for an existing aggregate, [START_REF] Aizcorbe | Testing the validity of aggregates[END_REF] suggests reshaping the function Y by including some mix functions M m in order to recover the information lost due to aggregation, and then to test the validity of the associated coefficients using regression models.

More precisely, Y can be restated as Y=H(

A(x 1 , …, x k ), M 1 ,…, M k-1 , x k+1 ,..., x n ) where the mix functions M 1 = M l (x 1 , x k ), M 2 =M 2 (x 2 , x k ),…, M k-1 = M k-1 (x k-1 , x k )
have been included as independent variables next to A(.). [START_REF] Aizcorbe | Testing the validity of aggregates[END_REF] shows that if the indicator function A(.) is increasing in all inputs and the mix functions M m , m Є [1, k-1] are differentiable, homogeneous-of-degree-zero functions with non-zero first partials that are specified so as to be independent from each other and from A(.), then the separability condition holds if and only if

] 1 , 1 [ , 0 - ∈ ∀ = ∂ ∂ k m M H m
This condition suggests that the indicator is valid from a methodological point of view if and only if the coefficients of the mix variables incorporated in a valid empirical model are not significant, regardless of the functional forms used for them.

Put differently, these conditions state that an aggregate is valid if and only if the explained outcome Y is impacted by the aggregate A but not by the mix effects M m . This also means that the value of Y should not vary when the respective contributions of the sub-indicators are changed, while the value of the aggregate remains unchanged. Moreover this result should hold whatever the nature of the effects of the mix variables on Y [START_REF] Aizcorbe | Testing the validity of aggregates[END_REF].

It follows that the aggregate is valid if variables that assess the internal structure of the aggregate, understood as the way components may interact together (complementarity or substitutability), are never significant in valid empirical models.

Turning back to EO assessment, the Sono-Leontief conditions require Miller's construct to encompass all the information on EO level and structure, and that its effect on a chosen dependent variable should not vary when one change is made to its internal structure by replacing one component with another (for instance, by replacing some proactiveness with the "same amount" of innovativeness, so as to keep the value of the aggregate unchanged).

Empirical model, data, and variables

Empirical model

In order to investigate the internal consistency of Miller's EO construct, we focus on the following model, which aims to explain firm performance [START_REF] Wiklund | Entrepreneurial orientation and small business performance: a configurational approach[END_REF] and where two mix functions M 1 (Risk, Innovation) and M 2 (Proactiveness, Innovation) have been added 5 :

5 As Miller's indicator encompasses three items, only two mix variables can be incorporated in the model to assess the composition effects. As an example, we have chosen to focus on the relationships between Risk and Innovation and Proactiveness and Innovation. The results remain the same with models that also encompass M 3 = (Risk/Proactiveness). These results are available on request from the authors.

Firm Performance

= β 1 Firm Size+ β 2 Firm Age + β 3 Miller's EO construct + β 4 Industrial Dynamism + β 5 Financial Constraints + β 6 M 1 + β 7 M 2 + γ+ ε
where γ denotes the sectoral effects and ε is a random error.

At first glance, all the estimations are performed here using the OLS method. If the aggregate is valid, then the proposition H 0 : β 6 = β 7 = 0 should hold whatever functional form is used for the mix variables.

Data and variables

The data come from the Association Ariane Compétences et Management (Ariane CM), which launched a robustly methodological survey in connection with the Fondation Nationale pour l'Enseignement de la Gestion des Entreprises (FNEGE)6 in 2011 in order to investigate the characteristics of French SME managers and to compare them with their European counterparts.

The survey was elaborated by a steering committee formed from members of Ariane CM (former CEOs and board representatives of French firms), FNEGE (senior scholars in management sciences), and TNS SOFRES 7 to highlight manager profiles, management practices and performance in French SMEs. Emphasis was placed on the EO of SMEs, as it seemed important to understand the internal dynamics of a firm. It was decided to measure EO using the seven-item index developed and validated by [START_REF] Miller | The correlates of entrepreneurship in three types of firms[END_REF], which has been widely used and seen as reliable, specifically in the context of SMEs [START_REF] Zahra | Entrepreneurship in medium-size companies: exploring the effects of ownership and governance systems[END_REF][START_REF] Zahra | Entrepreneurship in family vs. non-family firms: a resource-based analysis of the effect of organizational culture[END_REF]. The questionnaire was pre-tested on an initial sample to check for the clarity and relevance of its content. We deleted the question from the survey that SME managers generally reported that they didn't understand".

We assembled a sample of independent SMEs with 10 to 249 employees, representative of the whole population of French SMEs, as identified by the French National Institute of Statistics (INSEE). SMEs were selected using strata on regions and firm size.

Data were collected by TNS SOFRES through telephone calls to SME managers between April 18 and May 23, 2012. 8 The database encompassed more than 450 observations but the final sample was reduced to 391 observations, due to missing variables. Possible nonresponse bias was checked and the final sample appeared to be random.

An important point to note is that respondents were firms' owners or general managers of SMEs, who appeared to be "key managers" (Miller, 1983, Covin and[START_REF] Covin | International entrepreneurial orientation: conceptual considerations, research themes, measurement issues, and future research directions[END_REF]. These managers were in a central position in the SME, and constituted "the key determinant of the strategic posture of the firm" (Miller, 1983: 94, quoted in Covin andMiller, 2014: 17). On this basis, we assume that their answers give an accurate depiction of the EO of their firm.

All the variables and descriptive statistics are summarized in Table 1.

Results

Due to the need for homogeneous-of-degree-zero functions, the mix functions of Miller's EO construct can only be derived from ratios of items chosen between the Risk, Innovation and Proactiveness items. As an example we focus here on M 1 = f 1 (Risk/Innovation) and M 2 = f 2 (Proactiveness/Innovation), f 1 and f 2 being functions to be defined. 9

First the test is displayed using three kinds of functional forms for f 1 and f 2 (identity, log and exponential) that assess respectively constant, decreasing and increasing returns in the way sub-indicators interact together. Table 2 shows that the requirement to pass the F-test of H 0 is never met, whatever the functional form is chosen for the mix variables. But if there is not enough evidence here to reject the assumption that Miller's construct is valid, Model 3 also suggests that the mix variables fit better with exponential functional forms. 9 Other formulations, such as item percentages, lead to similar results that are available on request from the authors. -0,004 -0,005 -0,004 -0,005 0,003 0,003 0,003 0,003 To verify this point, the test was again displayed using a more general exponential form. M 1 = (Risk/Innovation) α and M 2 = (Proactiveness/Innovation) α were defined and the test was computed for α ranging from 0.1 to 15. Figure 1 shows the evolution of the F-statistic associated with H 0 , as well as its significance level.

Table 2. Regression results

Variables

The results of the simulation suggest that the coefficients of M 1 and M 2 both turn out to be significant for α higher than 6, the first being negative and the second positive. This last point suggests that, independently of the firm's EO level, high levels of risk-taking may have an adverse effect on firm performance if they do not lead to high levels of innovation. The opposite appears to be true for the relationship between levels of proactiveness and innovation. A key point is that the effect on firm performance is significant when the three items do not covary. Up to a point these results suggest some weak complementarity between the three dimensions incorporated in Miller's indicator. As H 0 is validated, Miller's EO indicator no longer appears to meet the separability conditions and there is enough evidence to cast doubt on its methodological consistency. Enhancing methodological transparency remains a clear issue in management research [START_REF] Aguinis | What you see is what you get? Enhancing methodological transparency in management research[END_REF]. While it is usual to test statistically the reliability of composite indicators in managerial studies (e.g., with Cronbach alphas), it is now necessary to go beyond empirical approaches to challenge the methodological foundations of these constructs.

Sono-Leontief conditions are of obvious interest here, because they directly address the ability of the indicators to summarize all the information deriving from their components. Applied to EO, our empirical results suggest that while Miller's EO indicator may meet some theoretical issues, the separability conditions are not met, signifying that the Miller index neither properly nor completely addresses the EO phenomenon. More precisely, the significance of the mix variables indicates that some combinations of components can have an additional impact on firm performance, outside Miller's indicator.

It is necessary to go one step further to understand the reasons and consequences of our results. The three components--proactiveness, innovation, and risk-taking -do not appear to be substitute elements of EO. 10 In view of this, a better understanding of their true nature appears to be essential.

But "reconceptualizing EO" [START_REF] Anderson | Reconceptualizing entrepreneurial orientation[END_REF] appears equally necessary in order to highlight both the connections between proactiveness, innovation and risk-taking, possibly by differentiating the elements (see [START_REF] Anderson | Reconceptualizing entrepreneurial orientation[END_REF], and the connection between EO and firm performance. Contingency factors (Hughes and Morgan, 2007, Hughes et al., 2007[START_REF] Lumpkin | Linking two dimensions of entrepreneurial orientation to firm performance: the moderating role of environment and industry life cycle[END_REF], and configurational dimensions that can have an impact [START_REF] Linton | Configurations of entrepreneurial orientation and competitive strategy for high performance[END_REF]Kask, 2017, Kearney et al., 2018) need to be scrutinized to understand better the nature and the consequences of EO for firms.

Our research is not without limitations. First, testing for Sono-Leontief conditions requires choosing a valid empirical model where the indicator has an acknowledged impact on the dependent variable. Results should then be robust when switching from one model to another, and it would be interesting to see if our conclusions hold when focusing on the impact of EO on, for example, innovation or firm governance. Moreover, the empirical test proposed here relies on a rather simple formalization of the relationship between EO and performance, with only a few moderator variables. It would be informative to see if our conclusions remain unchanged after the inclusion of variables that refer, for instance, to the characteristics of top management teams (Richard et al., 2009), leadership behavior [START_REF] Saeed | On cultural and macroeconomic contingencies of the entrepreneurial orientation-performance relationship[END_REF], or the environment of the firm [START_REF] Dess | Entrepreneurial strategy making and firm performance: tests of contingency and configurational models[END_REF], Zhara, 1991). Estimation methods could also be refined, especially when dealing with complex (non-linear) mix variables.

Last but not least, testing all the possible functional forms for the mixed variables can be problematic when the number of items in the indicator becomes significant, as the number of mixed variables will grow exponentially. The Sono-Leontief method is better adapted to testing simple aggregates that encompass only a limited number of items.

Conclusion

Assessing organizational phenomena for conducting empirical research can sometimes be problematic. We provide here a simple procedure to check the reliability of composite indicators, as well as an application of Miller's EO empirical construct. From this perspective, we believe that our research leads to a deeper understanding of the true nature of composite indicators, and opens new perspectives for scholars involved in EO research.

While our results-which emphasize that the Miller index does not pass the Sono-Leontief conditions-may be puzzling, considering past research on this topic, it should be regarded

Figure

  Figure 1. F statistics and significance levels of the mix variables

Table 1 . Variables and descriptive statistics (N = 391)

 1

	Name of the variable	Description	Mean	sd	Min	Max
	Firm Performance	Sum of the answers from the four following items (quoted 1: false, 2: true)	6.38	1.35	4	8
		1. Our sales have increased over the past 3 years
		2. Our market share has increased over the past 3 years
		3. We have hired new wage earners over the past 3 years
		4. Our profitability has increased over the past 3 years
	Firm Size	Number of wage earners in the company	64.7	63.98	10	249
	Firm Age	Firm age in years	36.33 31.05	1	338
	Miller's EO construct Sum of Risk, Innovation and Proactiveness	14.57	2.61	6	23
	Industrial Dynamism	Sum of the answers from the four following items (quoted 1: totally false, 2: somewhat false, 3: somewhat	1.44	2.06	6	16
		true, 4: totally true)
		1. In our industrial sector, competitors often change their tactics
		2. In our industrial sector, clients demand change rapidly
		3. In our industrial sector, legal changes are common
		4. In our industrial sector, innovation is important
	Financial Constraints Answer to the following proposition (quoted 1: totally false, 2: somewhat false, 3: somewhat true, 4:	2.97	0.76	1	4
		totally true)
		My company can easily finance the development of a new project.
	Risk	Sum of answers from the two following items (quoted 1: totally false, 2: somewhat false, 3: somewhat true,	4.49	1.36	2	8
		4: totally true)
		1. Our company accepts to deal with very risky projects
		2. Our company rewards calculated risk-taking
	Proactiveness	Sum of the answers from two following items (quoted 1: totally false, 2: somewhat false, 3: somewhat true,	5.71	1.20	2	8
		4: totally true)
		1. Our company attacks competitors on their market
		2. Our company targets long-term goals
	Innovation	Sum of answers from the two following items (quoted 1: totally false, 2: somewhat false, 3: somewhat true,	4.36	1.16	2	8
		4: totally true)
		1. Our company is the first one to introduce new products on the market
		2. Our company only uses well-known procedures and methods (reverse coding)

Composition effects should be assessed in both linear and non-linear ways.

The French Foundation for Management Education. TNS SOFRES (now Kantar TNS) is the leading data collection firm in the French market.

Note that TNS SOFRES arranged telephone appointments with SME managers to plan the administration of the questionnaire. Scholars were able to access the administration platform to obtain guarantees about the quality of the data collection process.

It would also be interesting to provide additional analysis of the variables metric in order to refine the conclusions.

more as a way to refine our understanding of the EO phenomenon than as a radical critique of its interest.

But if previous EO research has conveyed first-hand results regarding the entrepreneurial position of the firm, we also need to be aware that focusing on the Miller index may be somewhat misleading, as it conveys the risk of missing some important issues in the way EO components interact together.

Our results open new perspectives for future research as they suggest that multidimensional assessments of EO should be considered, as well as contingency and configurational effects (Lumpkin andDess, 1996, Anderson et al., 2015). Our findings also call for a reexamination of a large part of the empirical literature that includes EO as a strategic determinant of organizational behavior by relying on Miller's construct [START_REF] Rauch | Entrepreneurial orientation and business performance: an assessment of past research and suggestions for the future[END_REF], Seed et al., 2014).


MD Adriane Mailhac

MD José Labarere

MD Florent Aptel

MD Sylvie Berthemy-Pellet

MD Laurence Bouillet

MD, PhD Christophe Chiquet

Prof Christophe Chiquet

Five-year trends in multifocal electroretinogram for patients with birdshot chorioretinopathy

INTRODUCTION

Birdshot chorioretinopathy (BSCR) is a posterior autoimmune uveitis, usually symmetric, and strongly associated with human leukocyte antigen A 29. BSCR accounts for 0.5 to 1.5% of uveitis, with a higher prevalence in female and a mean age of symptom onset of 53 years. [START_REF] Shah | Birdshot chorioretinopathy[END_REF] BSCR has an insidious progression and can cause a significant visual loss due to various complications, including macular edema, diffuse retinal atrophy, epiretinal membrane, and/or choroidal neovascularization.

Because visual acuity (VA) may remain stable despite steadily progressive deterioration of retinal function, [START_REF] Tomkins-Netzer | Long-term clinical and anatomic outcome of birdshot chorioretinopathy[END_REF] it lacks sensitivity for detecting or monitoring patients with BSCR. Several functional and imaging technologies have been proposed for monitoring BSCR, [START_REF] Comander | Diagnostic testing and disease monitoring in birdshot chorioretinopathy[END_REF] including visual field, [START_REF] Gordon | Longitudinal cohort study of patients with birdshot chorioretinopathy. IV. Visual field results at baseline[END_REF] color vision, [START_REF] Holland | Longitudinal cohort study of patients with birdshot chorioretinopathy II: color vision at baseline[END_REF] standard electroretinography (ERG), [START_REF] Comander | Diagnostic testing and disease monitoring in birdshot chorioretinopathy[END_REF][START_REF] Holder | Electrophysiological characterisation and monitoring in the management of birdshot chorioretinopathy[END_REF][START_REF] Sobrin | Electroretinographic monitoring in birdshot chorioretinopathy[END_REF][START_REF] Zacks | Electroretinograms as an indicator of disease activity in birdshot retinochoroidopathy[END_REF] fluorescein (FA) and indocyanine green (ICGA) angiography, and optical coherence tomography (OCT). [START_REF] Symes | Quantitative Assessment of Retinal Degeneration in Birdshot Chorioretinopathy Using Optical Coherence Tomography[END_REF][START_REF] Teussink | Multimodal imaging of the disease progression of birdshot chorioretinopathy[END_REF] Yet these tests yield limited accuracy or reliability for assessing disease activity. This explains why monitoring BSCR patient remains challenging in routine practice.

Because electrophysiological testing may detect early functional changes, its use has been advocated for monitoring disease progression in uveitis. [START_REF] Gouliopoulos | Electrophysiological examination in uveitis: a review of the literature[END_REF] Three types of electroretinogramm are currently used in the clinical setting: full field, pattern, and multifocal ERGs. Multifocal ERG (mfERG) is a non-invasive method for objectively measuring retinal function within localized patches, especially the central retina, that is, up to 45° of eccentricity around the central foveal area. Multifocal ERG waveform can be understood as a combination of overlapping ON-and OFF-bipolar cell contributions combined with smaller contributions from inner retina and photoreceptors. [START_REF] Hood | Retinal origins of the primate multifocal ERG: implications for the human response[END_REF] Many studies have reported on the diagnostic and prognostic values of full field ERG parameters for BSCR, including the light adapted 30-HZ flicker response. [START_REF] Holder | Electrophysiological characterisation and monitoring in the management of birdshot chorioretinopathy[END_REF][START_REF] Sobrin | Electroretinographic monitoring in birdshot chorioretinopathy[END_REF][START_REF] Zacks | Electroretinograms as an indicator of disease activity in birdshot retinochoroidopathy[END_REF] In contrast, only two cross-sectional studies investigated the value of mfERG in BSCR. [START_REF] Birch | Macular atrophy in birdshot retinochoroidopathy: an optical coherence tomography and multifocal electroretinography analysis[END_REF][START_REF] Chiquet | MULTIFOCAL ELECTRORETINOGRAM IN BIRDSHOT CHORIORETINOPATHY[END_REF] Birch et al. [START_REF] Birch | Macular atrophy in birdshot retinochoroidopathy: an optical coherence tomography and multifocal electroretinography analysis[END_REF] reported 1) lower mfERG responses for 6 eyes with macular atrophy compared to 8 eyes without macular thinning and 2) abnormal mfERG responses for patients with BSCR evolving for 10 years or more.

Using a cross sectional study design, Chiquet et al. [START_REF] Chiquet | MULTIFOCAL ELECTRORETINOGRAM IN BIRDSHOT CHORIORETINOPATHY[END_REF]

METHODS

Study design

As part of a prospective observational case series of BSCR, the present analysis focused on consecutive adult patients who were monitored at baseline, 3 and 5 years of FU, using mfERG in Grenoble Alpes University Hospital. This study complied with the declaration of Helsinki guidelines for research involving human subjects and was approved by the local Institutional Review board (IRB 00008855).

All study participants provided written informed consent for conducting all ophthalmologic examinations.

Patients

All patients met the 2006 International consensus conference research criteria for diagnosis of BSCR, [START_REF] Levinson | Research Criteria for the Diagnosis of Birdshot Chorioretinopathy: Results of an International Consensus Conference[END_REF] were older than 18 years, had no medical contraindications for performing FA and ICGA. They were recruited between January 2008 and December 2010.

Data collection

Baseline characteristics and FU data were prospectively collected, including measurement of VA (ETDRS chart), a 30-2 Swedish Interactive Threshold Algorithm (SITA) standard program on the Humphrey Field Analyzer (Carl Zeiss Meditec Inc., Dublin, CA) and a Lanthony desaturated panel D-15 test for color vision under standardized conditions of ambient illumination, with calculation of the total error score. [START_REF] Lanthony | Evaluation of the desaturated Panel D-15. I. Method of quantification and normal scores[END_REF][START_REF] Török | Farnsworth-munsell FM 100-Hue, Farnsworth D-15 and lanthony D-15-WEB-based scoring[END_REF] All patients had a reliable visual field test, defined as a false positive error < 15%, a false negative error <15%, and a fixation loss < 20%. Quality of life (QoL) was assessed using the cross-cultural adaptation of the NEI Visual Function Questionnaire (VFQ-25) in French. [START_REF] Mangione | Development of the 25-item National Eye Institute Visual Function Questionnaire[END_REF] Anatomical testing was based on FA, ICGA (Heidelberg, Germany) and optical coherence tomography (OCT) (Spectral domain Carl Zeiss Meditec Inc., or Spectral domain Heidelberg, Germany). Angiographic data were evaluated, in a blinded fashion by two independent investigators, [START_REF] Priem | Birdshot chorioretinopathy: clinical characteristics and evolution[END_REF][START_REF] Fardeau | Indocyanine green angiography in birdshot chorioretinopathy[END_REF] and included optic disk hyperfluorescence, macular edema, retinal vascular staining and/or leakage (with an extension varying between 0 and 4 related quadrants), peripheral capillary leakage (extension: 0-4 quadrants), and posterior capillary leakage. Retinal vasculitis was defined as fluorescein staining of any retinal vessels proximal to the third bifurcation. [START_REF] Monnet | Longitudinal cohort study of patients with birdshot chorioretinopathy. I. Baseline clinical characteristics[END_REF] ICGA criteria were presence of hypocyanescence areas at the intermediate frame (10 min after the ICG injection). [START_REF] Fardeau | Indocyanine green angiography in birdshot chorioretinopathy[END_REF] OCT data collected were central macular thickness (CMT), alteration of outer retina, and macular edema (ME). We defined ME in TD-OCT as CMT over 260 µm and in SD-OCT as CMT over 295 µm. [START_REF] Fiore | Repeatability and Reproducibility of Retinal Thickness Measurements in Diabetic Patients with Spectral Domain Optical Coherence Tomography[END_REF][START_REF] Browning | Optical Coherence Tomography Measurements and Analysis Methods in Optical Coherence Tomography Studies of Diabetic Macular Edema[END_REF] Other ME features included cystoid macular edema (CME), consisting of low-reflective intra-retinal spaces, clearly defined and separated by thin, high-reflective retinal tissue; diffuse ME consisting of increased macular thickness; small low-reflective areas with spongy appearance of the retinal layers. We defined alterations of the outer retina by the presence of a defects of at least one of four hyper-reflective outer retinal bands: the external limiting membrane (ELM); the ellipsoid portion of the inner segments (ellipsoid band); the cone outer segment/contact cylinder region (cone OS) and the RPE. [START_REF] Spaide | ANATOMICAL CORRELATES TO THE BANDS SEEN IN THE OUTER RETINA BY OPTICAL COHERENCE TOMOGRAPHY: Literature Review and Model[END_REF][START_REF] Nazari | Morphometric spectraldomain optical coherence tomography features of epiretinal membrane correlate with visual acuity in patients with uveitis[END_REF] CMT was defined as the mean retinal thickness within the 1-mm central subfield.

Each patient was followed using the same OCT machine. Patients initially included in 2008 had TD-OCT at baseline and were followed by TD-OCT over 5 years and SD-OCT from 2010. Cirrus measurement was defined as the reference measurement, and we used the conversion table to convert stratus (Cirrus = Stratus × 1 + 55.6) and Heidelberg measurements (Cirrus = Spectralis x 0.8 + 36.4) into cirrus CMT. [START_REF] Roh | Foveal Thickness between Stratus and Spectralis Optical Coherence Tomography in Retinal Diseases[END_REF] Severity of the disease and progression of inflammation were based on anatomical (fluorescein and ICG angiography, OCT) and functional (VA, visual field parameters) examinations.

Multifocal ERG (Vision Monitor; Métrovision, Pérenchies, France) was performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol, [START_REF] Hood | ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition)[END_REF] using a 61 hexagon strategy and scaled hexagons.

Stimulations were generated on a cathode ray tube monitor with a 120-Hz frame rate. The luminance of white hexagons was 400 cd/m 2 and that of black hexagons 4 cd/m 2 . The electrode used was the ERG-jet corneal electrode™. Dark frames were inserted after the white frames to achieve an 18-Hz stimulus frequency. The surrounding luminance was set at 30 cd/m 2 . The stimulus was calibrated following the ISCEV guidelines. [START_REF] Hood | ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition)[END_REF] After pupil dilation using phenylephrine 5% (Europhta, Monaco) and tropicamide (Thea, Clermont-Ferrand, France), patient positioning, good fixation, best optical correction for near vision, and constant moderate room light for at least 15 minutes were ensured for each patient. Care was taken to eliminate any reflections from lens surfaces and to keep any bright light sources out of the patient's direct view. The first-order kernel mfERG responses were analyzed.

Individual mfERG responses for the hexagons were grouped into five concentric rings centered on the fovea for analysis (2, 2-5, 5-10, 10-15, and beyond 15 degrees of visual angle). Mathematically, the first order kernel is obtained by adding all the records that follow the presentation of a white hexagon (luminance, 400 cd/m 2 ) and subtracting all the records that follow a black hexagon. The following data were collected: the root mean square values (RMS), implicit time (IT) and AMP of N1, P1, and N2 waves. The N1 response was measured from the starting baseline to the base of the N1 trough; the P1 response AMP was measured from the N1 trough to the P1 peak. IT was measured from the onset of the stimulation to the trough or peak. Only averaged data including five rings were presented in the Results section.

Normative values (obtained from the manufacturer Métrovision) are (mean ±SD): -915 ±260 nV for N1 AMP, 1633 ±395 NV for P1 AMP, 23.2 ±1.3 msec for N1 IT and 42.2 ±1.6 msec for P1 IT. The reliability using the Metrovision device has been previously reported. in this study. [START_REF] Thimonier | Multifocal ERG using ERG-jet and Gold Foil electrodes in normal subjects: comparison and reproducibility[END_REF] For N1 and P1 waves, the percentage change for the intraindividual reproducibility study was 9.1% and 6.7%, respectively, with the ERG-jet electrode and 18.2% and 13.5%, respectively, using the same electrode. These published data have been used in the present study to categorize evolution of mfERG parameters into unchanged/ improved / deteriorated evolution from baseline.

Statistical analysis

Gender, treatments at baseline, evidence of photoreceptor alteration, ME and ERM on OCT, fluorescein and indocyanine green angiography findings were reported as numbers and percentages. Age, disease duration, VA, QoL score, foveal threshold, VF parameters, color vision score, CMT and ERG data (i.e. N1 and P1 implicit times and amplitudes) were summarized with means and standard deviation.

Because of skewed distribution, disease duration and total error score were summarized with the median and 25th-75th percentiles. Time trends in continuous mfERG parameters were modeled using linear regression for longitudinal data with time to FU visit entered as an independent variable. The linear time trend reflected the long-run tendency of mfERG parameter values to increase or decrease over time.

Temporal trends in continuous mfERG parameters were modelled using linear regression for longitudinal data with time to FU visit entered as an independent variable. To investigate univariate associations of mfERG parameters, we performed longitudinal regression modeling for continuous dependent variables, with characteristics and time to FU entered as independent covariates. We assessed the linearity assumption for continuous independent variables by using fractional polynomial functions. First-order interactions involving time to FU and each independent covariate were systematically tested for statistical significance. If a significant interaction was found, coefficient estimates were stratified by time to FU.

To account for the hierarchical data structure, we used generalized estimated equations with the eye and FU observations nested within participants. [START_REF] Thimonier | Multifocal ERG using ERG-jet and Gold Foil electrodes in normal subjects: comparison and reproducibility[END_REF][START_REF] Glynn | Regression methods when the eye is the unit of analysis[END_REF] Regression coefficient point estimates were reported along with 95% confidence intervals. Regression coefficients represent the variation in predicted mfERG parameter value for a one-unit increase in the covariate value. In longitudinal analysis, changes in mfERG parameter values were reported as "per year of FU". Two-sided p-values of <0.05 were considered statistically significant. All analyses were performed using Stata Special Edition version 14.0 (Stata Corporation, College Station, TX, USA).

RESULTS

Overall, 16 patients with a mean age of 60.2 (standard deviation, 7.8) were enrolled between 2008 and 2010 and underwent FU visits at 3.2 years (standard deviation 0.3) and 5.1 years (standard deviation, 0.2) of enrolment. Baseline characteristics are reported in Table 1. The mean time from diagnosis to enrolment was 4.8 ±4 years. Eight eyes (25%) had a cataract and none was pseudophakic at baseline while four eyes (12.5%) underwent cataract surgery during the FU period.

No significant temporal trend was found for VA (increase of 0.46 letter per year of FU, 95% confidence interval [CI], -0.51 to 1.44, P=.35), color vision score (decrease of -9 per year of FU, 95% CI, -20 to 2, P=.12), foveal threshold (increase of 0.19 dB per year of FU, 95% CI, -0.14 to 0.52, P=.26) and mean deviation of visual field (increase of 0.07 dB per year of FU, 95% CI, -0.19 to 0.33, P=.60), and quality of life score (increase of 0.71 per year of FU, 95% CI, -0.89 to 2.31, P=.39) over the 5-year FU period.

The percentage of patients receiving corticosteroids alone or in combination with immunosuppressive treatment was 62% (10/16) and 56% (9/16) at baseline and 5 years of FU, respectively (P=.72). The percentage of patients with corticosteroids alone decreased over time (from 50% at baseline to 25% at the 5-year FU) and the proportion of patients with corticosteroids and immunosuppressants increased (from 0% at baseline to 31%). Over the 5-year period, two out of 16 patients were newly treated, 3 out 16 did not change their treatment, 3 out 16 stopped their previous treatment and 4 out 16 had no treatment.

A significant decreasing temporal trend was observed over the 5-year FU period for N1 (37 nV, 95% CI, 24 to 51, p<.001), P1 (61 nV, 95% CI, 38 to 84, p<.001), and N2 (35 nV, 95% CI, 11 to 58, p=.003) amplitudes. Over the same period, P1 implicit time increased (0.68 ms, 95% CI, 0.41 to 0.94, p<.001) while N1 (0.24 ms, 95% CI, -0.04 to 0.51, p=.08) and N2 (0.89 ms, 95% CI, -5.20 to 6.98, p=.78) implicit times did not vary significantly. Taken into account the intraindividual reproducibility of the mfERG, we reported that N1 AMP and P1 AMP deteriorated in 25/32 eyes (78%) between baseline and FU3 (last visit, Supplementary material, Table 4).

Increasing N1 and P1 IT were both associated with increasing values of EDTRS score (in letters), foveal threshold, and quality of life and with increasing color vision score, mean deviation of visual field over the 5-year FU period (Table 2).

A significant relationship was observed between decreasing P1 AMP values and increasing MD of visual field. Increased N2 AMP and longer N2 IT were associated with decreasing values of mean deviation of visual field over the 5-year FU period (Table 2) whereas longer N2 IT was also associated with increasing values of VA (EDTRS letters).

Over the 5-year FU period, longer N1 and P1 IT were both associated with macular edema (Table 3). Additionally P1 IT was also associated with optic disk hyperfluorescence and peripapillary hypocyanescence. Univariate associations were found between reduced N1 AMP values and the presence of venous vasculitis and peripheral capillary leakage. Reduced P1 AMP values were associated with the presence of photoreceptor layer alteration. No significant association was found between mfERG variables with posterior capillary leakage. Reduced N2 AMP and lower IT were significantly associated with photoreceptor alteration in OCT.

DISCUSSION

This prospective observational case series study showed that mfERG parameters worsen in BSCR patients during a 5-year FU period, with decreasing N1 and P1 AMP values and increasing P1 IT. Importantly, these temporal trends in mfERG parameter values were not paralleled by changes in classical functional parameters such as VA and visual field. However, substantial associations were found between N1 AMP and venous vasculitis and peripheral capillary leakage, whereas P1 AMP reflected alterations of the outer retina in OCT, after adjusting for time to FU. Waves amplitudes were well correlated to the visual field parameters whereas IT was well correlated to quality of life, VA and visual field parameters.

We confirmed that BSCR patients exhibit reduced AMP of P1 and N1 waves and increased IT of P1 over time. These data are consistent with our previous findings in a cross-sectional study, showing that BSCR eyes differed significantly from healthy eyes by a decrease in P1 (-17%) and N2 AMP (-27%) and an increase in N1 (9%) and P1 (5%) IT. [START_REF] Chiquet | MULTIFOCAL ELECTRORETINOGRAM IN BIRDSHOT CHORIORETINOPATHY[END_REF] In presence of macular atrophy in long-standing (> 10 years) BSCR patients, foveal mfERG amplitudes [START_REF] Birch | Macular atrophy in birdshot retinochoroidopathy: an optical coherence tomography and multifocal electroretinography analysis[END_REF] are reduced by 2.3 when compared to BSCR eyes without anatomic thinning.

To our knowledge, the present study is the first to investigate trends in mfERG in patients with BSCR over a 5 year-period. The reduction in N1 and P1 AMP and increase in P1 IT suggest a worsening of retinal function across time whereas classical functional parameters such as VA, color vision and visual field parameters did not vary significantly. A previous study reporting standard ERG [START_REF] Murdoch | People and eyes: statistical approaches in ophthalmology[END_REF] showed that 70% of the patients had a loss of inner and/or outer retinal functions over prolonged FU. Previous studies reporting the full-field cone system 30-Hz flicker ERG peak time, [START_REF] Holder | Electrophysiological characterisation and monitoring in the management of birdshot chorioretinopathy[END_REF] the scotopic bright flash amplitudes (combined rods and cones), reduction in the a-wave and b-wave amplitudes, [START_REF] Oh | Birdshot retinochoroiditis: long term follow-up of a chronically progressive disease[END_REF][START_REF] Hirose | Retinal function in birdshot retinochoroidopathy[END_REF] reduction in cone-b-wave implicit times and reduction in scotopic rod b-wave amplitudes 7 illustrated that both the rod and cone systems are involved in BSCR.

Previous studies showed that VA did not reflect accurately disease severity, [START_REF] Priem | Electrophysiologic studies in birdshot chorioretinopathy[END_REF] was stable 2 or yielded a slow decline over time. [START_REF] Murdoch | People and eyes: statistical approaches in ophthalmology[END_REF] Color vision is impaired in BSCR, [START_REF] Holland | Longitudinal cohort study of patients with birdshot chorioretinopathy II: color vision at baseline[END_REF][START_REF] Chiquet | MULTIFOCAL ELECTRORETINOGRAM IN BIRDSHOT CHORIORETINOPATHY[END_REF] with 55-61% of patients abnormal color confusion scores. However the color vision score remained stable over 5 years in our study. There is more information in the literature concerning the abnormalities of the visual field, including peripheral constriction, generalized diminished sensitivity, enlarged blind spot, and central or paracentral scotoma. [START_REF] Touhami | Visual Acuity in Birdshot Retinochoroidopathy Evaluation[END_REF][START_REF] Shah | Birdshot chorioretinopathy[END_REF] Recent studies showed that MD might be stable 2 whereas PSD possibly reflecting sectorial changes increases, especially in patients who received short-term treatment. Pointwise linear regression analysis of luminance sensitivity can identify visual field loss despite a stable MD. [START_REF] Shah | Birdshot chorioretinopathy[END_REF] These data highlight the need of complementary functional tests, which can reliably estimate the evolution of the retinal function.

Our data show a positive correlation between mfERG and other functional tests despite the absence of temporal changes of VA, color vision, and visual field parameters over a 5-year period. Waves AMP were well correlated to the visual field sensitivity whereas ITs were well correlated to quality of life, VA and visual field parameters. An original finding of this study is the worsening of mfERG responses while VA and MD of visual field remains stable over time. There are several potential explanations for this discrepancy. First, changes in N1 and P1 AMP and/or IT may be early markers of worsening clinical outcomes that may not be captured over a 5year FU period. Second, we cannot exclude that this study was underpowered to detect any significant time trends in visual acuity, quality of life, visual field or color vision. A perspective of this work will consist to investigate the prognostic value of mfERG responses at baseline for the prediction of visual function in the long-term.

BSCR has a high impact on vision-related quality of life, especially for general health and near vision, difficulties with activities and depression, [START_REF] Chiquet | MULTIFOCAL ELECTRORETINOGRAM IN BIRDSHOT CHORIORETINOPATHY[END_REF] with a mean global VFQ-25 score around 70 consistent with previous study. [START_REF] Arya | Pointwise linear regression analysis of serial Humphrey visual fields and a correlation with electroretinography in birdshot chorioretinopathy[END_REF] In this study taking into account both eyes of each patient, we showed for the first time that (1) the reduced QoL score was not modified significantly during a 5-year period and (2) QoL score was significantly associated with N1 and P1 IT. This finding is interesting since previous report showed only a weak correlation between composite scores and VA. [START_REF] Arya | Pointwise linear regression analysis of serial Humphrey visual fields and a correlation with electroretinography in birdshot chorioretinopathy[END_REF] P1 wave abnormalities suggest a lesion at the cone receptor site and ONbipolar cells, with a delayed response from both neurons. [START_REF] Levinson | Longitudinal cohort study of patients with birdshot chorioretinopathy. V. Quality of life at baseline[END_REF] The P1 IT is also known to be a very sensitive measure of outer retinal function. [START_REF] Levinson | Longitudinal cohort study of patients with birdshot chorioretinopathy. V. Quality of life at baseline[END_REF] In BSCR patients, the outer retina damages, such as photoreceptor layer alteration and presence of macular edema were respectively correlated with decreased AMP and longer IT of P1. This finding confirms the pilot study of Birch who showed that BSCR patients with OCT macular thinning exhibit a significantly altered mfERG. [START_REF] Birch | Macular atrophy in birdshot retinochoroidopathy: an optical coherence tomography and multifocal electroretinography analysis[END_REF] These data highlights the importance of analyzing the outer retina. Loss of OFF-bipolar cells is known to decrease the amplitude of N1. [START_REF] Levinson | Longitudinal cohort study of patients with birdshot chorioretinopathy. V. Quality of life at baseline[END_REF] We found that venous vasculitis and capillary leakage were specifically associated with a reduction in N1 AMP, probably by a deleterious effect on the inner retina, especially on bipolar cells. The origin of N2 wave remains uncertain. [START_REF] Hood | Retinal origins of the primate multifocal ERG: implications for the human response[END_REF] A recent study indicated that the activity of retinal ganglion cells contributed to the amplitude of the N2 of the mfERG. [START_REF] Kato | Correlation between N2 amplitude of multifocal ERGs and retinal sensitivity and retinal nerve fiber layer thickness in glaucomatous eyes[END_REF] The univariate analysis done in our study shows that N2 AMP was associated with photoreceptor alterations but it was not possible to identify confounding factors and contributions of other retinal layers, such as the retinal ganglion cell layer. Contribution of N2 for the FU of uveitis patients should be confirmed by further studies, while association with VF and VA were found in this study.

The implicit times of the N1 and P1 response are also known to be a very sensitive measure of outer retinal function, [START_REF] Levinson | Longitudinal cohort study of patients with birdshot chorioretinopathy. V. Quality of life at baseline[END_REF] and were correlated to the presence of macular edema. This finding is consistent with the correlation between CMT or macular edema and longer IT found previously in BSCR [START_REF] Chiquet | MULTIFOCAL ELECTRORETINOGRAM IN BIRDSHOT CHORIORETINOPATHY[END_REF] and diabetic patients. [START_REF] Hood | Assessing retinal function with the multifocal technique[END_REF][START_REF] Kato | Correlation between N2 amplitude of multifocal ERGs and retinal sensitivity and retinal nerve fiber layer thickness in glaucomatous eyes[END_REF] We did not find any correlations between mfERG parameters and ICGA data, such as the number of quadrants with hypocyanescent dots at the intermediate phase. This finding could be due to the relative independence between choroidal and retinal involvement. [START_REF] Fortune | Multifocal electroretinogram delays reveal local retinal dysfunction in early diabetic retinopathy[END_REF][START_REF] Leozappa | Prognostic prediction ability of postoperative multifocal ERG after vitrectomy for diabetic macular edema[END_REF] P1 IT was correlated with peripapillary hypocyanescence, which is a frequent finding in BSCR. [START_REF] Herbort | Differential inflammatory involvement in retina and choroïd in birdshot chorioretinopathy[END_REF][START_REF] Koizumi | Fundus autofluorescence in birdshot chorioretinopathy[END_REF] Future studies are needed to correlate choroidal thinning with changes of mfERG. [START_REF] Piffer | Relevance of wide-field autofluorescence imaging in Birdshot retinochoroidopathy: descriptive analysis of 76 eyes[END_REF] The limitations of our study deserve mention. First, our study might be underpowered in detecting clinically significant temporal trends, due to the relatively limited sample size. Second, we investigated univariate associations only. Indeed, too few observations were available relative to the number of predictors included in multivariate analysis of mfERG. Hence, the multivariable model would fit the data set too closely and be likely to perform less well in new patients -a statistical phenomenon called overfitting. Furthermore the limited series of patients did not allow statistical comparisons for each ring separately. Third, five patients of the cohort were followed using TD-OCT since they were examined at baseline using TD-OCT in 2008. For this reason, analysis of the outer retina was done according the IS/OS disruption and not systematically considering the four bands well described in SD-OCT (ELM, EZ, CIZ, RPE). We used a published formula in order to reduce the effect of using different OCT machines. We estimate that the range of error is slight and that CME detection was not affected by these calculations. Fourth, four eyes (12.5%) were operated on for cataract during the study and the surgery was done between baseline and the first visit. The change in lens status may have changed the mfERG parameters. Cataract may reduce N1 and P1 amplitudes [START_REF] Young | Choroidal degeneration in birdshot chorioretinopathy[END_REF] and cataract surgery may increase mfERG responses. [START_REF] Birnbaum | Correlation between clinical signs and optical coherence tomography with enhanced depth imaging findings in patients with birdshot chorioretinopathy[END_REF] Finally, mfERG is limited to the central 30 degrees, much less than standard ERG. Our previous study [START_REF] Chiquet | MULTIFOCAL ELECTRORETINOGRAM IN BIRDSHOT CHORIORETINOPATHY[END_REF] showed that the degree of eccentricity (five rings) modulated the values for RMS, P1 and N2 amplitude, and P1 implicit time. These differences were found essentially between ring 1+2 and the other rings, suggesting that the macula is more sensitive to inflammation than the extrafoveal retina. This topographic information was not used statistically in the present study due to statistical limitations. We can therefore these exams are time consuming and necessitates cooperation of the patient.

In conclusion, this longitudinal study of BSCR patients provides for the first time the evidence of worsening of mfERG responses in patients who were stable for other standard visual tests. MfERG, which is considered a reliable and accurate functional test, [START_REF] Tam | Effects of different degrees of cataract on the multifocal electroretinogram[END_REF] was able to detect variations in N1 and P1 AMP and P1 IT over the 5-year FU period. Longer N1 and P1 IT at each visit were associated with functional worsening and macular edema. On the other hand, waves AMP were associated with presence of venous vasculitis and peripheral capillary leakage for N1 and photoreceptor layer alteration for P1. Although our findings deserve replication, our study supports the use of mfERG for initial assessment and subsequent monitoring of BSCR activity.

TABLES LEGENDS

Table 4 (supplementary material):

Eye status according to intra-individual relative variation from baseline to the last follow-up (5-year FU) in N1 and P1 amplitude.

Intra-individual relative change was computed as (baseline value -FU3 value) / baseline value. For example, P1 AMP was defined as stable if the change between baseline visit and follow-up 3 (FU3) was comprised between -6 ;7% and +6,7%, improved (increased AMP) if increased by 6.7% or more, and deteriorated (decreased AMP) if decreased by 6.7% or more.

* Eye status at follow-up was determined using an intra-individual relative variation threshold of 9.1% for N1 amplitude and 6.7% for P1 amplitude, respectively. [START_REF] Thimonier | Multifocal ERG using ERG-jet and Gold Foil electrodes in normal subjects: comparison and reproducibility[END_REF] venous vasculitis and a macular edema, and was initially treated by steroids and mycophenolate mofetil. In 2010, the patient was free of macular edema and vasculitis, under treatment with mycophenolate mofetil. Visual field was stable within the 5-year period with MD varying between -1.94 dB and -0.92 dB. Foveal sensitivity and visual acuity were stable (37 dB and 20/20, respectively). This case illustrates

FIGURES LEGENDS

  showed that amplitudes (AMP) and implicit times (IT) of the mfERG parameters were impaired in BSCR patients and were associated with other anatomical and functional test findings. In contrast to fullfield ERG, mfERG explores cone-driven light-adapted retinal function and provides objective assessment of central retinal function in different retinal areas within a short time frame. Furthermore, the multifocal technique may provide useful insights into the mechanisms of BSCR since the N1 wave represents the hyperpolarization of cones, and the P1 wave represents the depolarization of bipolar cells. Yet the value of mfERG for monitoring BSCR patients remains to be established and prospective longitudinal studies are warranted for this purpose.This prospective cohort study of BSCR patients with a 5-year follow-up (FU) period aimed to investigate temporal trends in mfERG parameter values and elucidate their relationships with anatomical and functional tests.

Figure 3

 3 Figure 3 illustrates one case with a typical reduction of N1 and P1 AMP over

Table 3 :

 3 Abbreviations: CI = confidence interval; ms = millisecond; deg= degree; VA = visual

Figure 1 :Figure 2 :Figure 3 :

 123 Figure 1: Trends in average values of mfERG parameter values at baseline (BL),

Table 1 :

 1 Baseline patient and eye characteristics. Data are expressed as mean (standard deviation) or numbers (%). CMT was defined as the mean retinal thickness within the 1-mm central subfield.

Table 2 :

 2 Longitudinal analysis of univariate associations between mfERG variables

Table 1 .

 1 Baseline characteristics.

the worsening of mfERG parameters within the 5-year period: decrease in N1 amplitudes (from -865 nV to -738 nV) and P1 amplitudes (from 1398 nV to 1197 nV).

Note that N1 amplitudes are illustrated in positive absolute values in the 3D graph.

Association for Research and Teaching in Ophthalmology (ARFO, Grenoble, France). The sponsor of the funding organization had no role in the design or conduct of this research.

No conflicting relationship exists for any author.