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CASE STUDY

Development of the electroretinogram between 30and 50 weeks after conceptionB

Ruth Hamiltona,*, John Dudgeonb, Michael S. Bradnama, Helen Mactierc

aDepartments of Clinical Physics, Royal Hospital for Sick Children, Dalnair Street, Glasgow G3 8SJ,UK and University of Glasgow, Glasgow G12 8QQ, UKbDepartment of Ophthalmology, Royal Hospital for Sick Children, Dalnair Street, Glasgow G3 8SJ, UKcNeonatal Unit, Princess Royal Maternity, Alexandra Parade, Glasgow G31 2ER,UK and Department of Child Health, University of Glasgow, Glasgow G12 8QQ, UK

Accepted 28 October 2004

0378-3782/$ - see front matter D 200doi:10.1016/j.earlhumdev.2004.10.019

B This work was funded by a grantInstitute for the Blind (ref. 2501.2651* Corresponding author. Tel.: +44 14E-mail address: r.hamilton@clinme

KEYWORDSElectroretinogram;Retina;Retinopathy ofprematurity

Abstract Maturation of the electroretinogram (ERG) reflects retinal development.Serial ERGs recorded from a preterm infant between 30 and 50 weeks afterconception showed rapid maturation. A transient loss of retinal sensitivity coincidedwith clinical signs of stage 2 retinopathy of prematurity (ROP).D 2004 Elsevier Ireland Ltd. All rights reserved.

1. Patient

A female Caucasian singleton was delivered at27+3 weeks’ gestation weighing 1080 g. Twodoses of antenatal steroids had been adminis-tered 10 days previously. Artificial surfactantwas given at delivery and the infant requiredfull assisted ventilation for 4 days before beingextubated to nasal continuous positive airwaypressure. Inotropic support was required in thefirst 24 h and phototherapy was given from

4 Elsevier Ireland Ltd. All right

from the Royal National.42).1 201 6953.d.gla.ac.uk (R. Hamilton).

19 h of age until the fourth day; eye patcheswere worn. Maternal expressed breast milkwas introduced on day 3 and full enteralfeeds established by day 7. Her course there-after was uneventful despite requiring supple-mental inspired oxygen for 50 days and shewas discharged home on day 61 weighing2200 g. She was enrolled in a study ofthe electroretinogram (ERG) in infants at riskfor retinopathy of prematurity (ROP), aspart of which indirect fundoscopy was per-formed twice weekly as soon as she wasclinically stable and until the retinae werefully vascularised. This study was approvedby the Research Ethics Committee of YorkhillNHS Trust, and informed written parentalconsent was obtained.

Early Human Development (2005) 81, 461—464

s reserved.

R. Hamilton et al.462

2. Methods

Six ERG recordings were made at 30, 32+2, 34,36, 37+6, and 50+6 weeks after conception. Theprocedure has previously been described indetail [1]. Briefly, the dark-adapted infantwas placed supine in a modified incubator,which supported the light source over hereyes. A contact lens electrode (Hansen Labo-ratories, Coralville, IA, USA) was used tomaintain eye opening even during sleep andwas placed under local anaesthesia using lubri-cation. The ERG protocol conformed to interna-tional recording standards [2] and included adim (0.02 scot cd s m�2) blue flash rod ERGrecorded as part of a dark-adapted stimulus—response series, dark-adapted oscillatory poten-tials (OPs) using a bright (11.3 scot cd s m�2)white flash, and a light-adapted (10 min to 34phot cd m�2) single white flash photopic ERGusing a flash luminance of 40 phot cd s m�2.The photopic flash was brighter than thestandard clinical flash [2] of 1.5—3.0 phot cds m�2 as we have found photopic ERGs to be

Figure 1 ERG recordings at increasing maturity. (a) Standscotopic oscillatory potentials; (d) stimulus—response curvtriangles: 34; diamonds: 36; inverted triangles: 37+6; hexaresponsivity, Vmax; (f) maturation of retinal sensitivity expresreversed to indicate increasing retinal sensitivity upwards. E

absent at the standard luminance level inpreterm infants.

2.1. Interpretation of data

The relationship between ERG amplitude andstimulus luminance was quantified using theNaka—Rushton equation [3] to determine thesensitivity and responsivity of the retina:

V=Vmax ¼ In= In þ rnÞð

where V=b-wave amplitude (AV), I is trolandvalue (scotopic troland seconds), Vmax=maximalb-wave amplitude (AV), n=a slope parameterusually approximately equal to one, andr=troland value eliciting a half-maximal b-wave[4]. Rod threshold (Ith) quantifies the trolandvalue eliciting a threshold-sized (2.5 AV) ERG.Both r and Ith describe retinal sensitivity, with Ithcorresponding well with psychophysical thresholdsfor adults [5]. Vmax describes the responsivity ofthe underlying signal generators, reflecting photo-receptor and inner retinal function.

ard dim flash rod responses; (b) photopic responses; (c)es at increasing maturity (circles: 30; squares: 32+2;gons: 50+6 weeks after conception); (e) maturation ofsed as logIth (grey circles) and logr (open circles). Axis isrror bars represent standard deviations.

Development of the electroretinogram (ERG) between 30 and 50 weeks after conception 463

3. Results

All recording sessions were completed withoutincident and there were no observed complica-tions. Stage II changes of ROP were noted bilat-erally in the temporal retinae at 36 correctedweeks but had spontaneously resolved 2 weekslater. Ophthalmology and orthoptic assessmentswere normal. At 2-year follow up, there were noneurodevelopmental concerns.

ERGs were robust and measurable even as earlyas 30 weeks after conception. Although rod ERGsto brighter flashes in the stimulus—response serieswere present at this early age, the rod ERG to theclinical standard dim blue flash was not evidentuntil 37+6 weeks; b-wave amplitudes to this flashsubsequently increased from 17 to 87 AV andimplicit time shortened slightly (Fig. 1a). Thesingle flash photopic ERG, which in adults isprimarily a response from the cone system, waspresent at 30 weeks and its b-wave amplitudeincreased from 13 to 167 AV weeks (Fig. 1b). Forthis photopic stimulus, the a-wave was notevident at 30 weeks, but increased from 8 to 60AV between 32+2 and 50+6 weeks. Both a-waveand b-wave implicit times shortened. Threescotopic OPs, conventionally labelled OP2, OP3,and OP4, were first evident at 37+6 weeks. By 50+6

weeks, four (OP2, OP3, OP4, and OP5) wereevident (Fig. 1c).

The six individual stimulus—response functionsare shown in Fig. 1d. Responsivity, Vmax, demon-strated an approximately linear 13-fold increasefrom first to sixth recording (Fig. 1e). Sensitivityincreased as measured by both b-wave threshold(logIth) and b-wave half-maximal luminance (logr):logIth decreased by 2.7 log units and logr decreasedby 1.4 log units. Both logIth and logr increasedbriefly between 34 and 36 weeks, suggesting atransient loss of retinal sensitivity coinciding withsigns of stage 2 ROP.

4. Discussion

The current observations on the maturation of theERG confirm those of previous workers [1,6—10]and extend their findings back to 30 weeks afterconception and on to 10 weeks postterm correctedage. They are in keeping with anatomical observa-tions, which suggest that both rod and cone systemsgenerate a response to light by 30 weeks afterconception.

The dramatic increase in retinal sensitivitybetween 30 and 50 weeks after conception is

caused by a variety of factors including reducingvitreous haze, increasing rhodopsin content [11],maturation of photoreceptor outer segments,increasing numbers of photoreceptors respond-ing, and increasing gain of postreceptor compo-nents. The increase in the maximal size of theERG (retinal responsivity) reflects maturation ofneural processes within the inner retinal layersand was almost linear from 30 to 50 weeksafter conception in this case. The pattern ofincrease in retinal sensitivity (rapid initialincrease) was different from the pattern ofincrease in retinal responsivity (linear increase),suggesting that premature birth may triggermaturation of receptor sensitivity while havingless effect on the development of the neuralretina.

The OPs, thought to reflect radial currentsgenerated by negative feedback pathways in theinner retina, were absent until 37 weeks, in accordwith results from our laboratory [12] and fromGrose et al. [8] and presumably reflect immatureretinal processing.

A contact lens electrode controls eye openingand hence retinal illuminance. Extending ourprevious experience of contact lens electroderecordings [1] back to 30 weeks after conceptionconfirms this as the optimal method for recordingthe ERG in preterm infants. In contrast to theexperience of Berezovsky et al. [13], the proce-dure is well tolerated although time-consuming.To our knowledge, this is the first report ofstimulus—response analysis of retinal function atless than 36 weeks after conception. We havequantified for the first time the increases in dark-adapted retinal sensitivity and responsivity occur-ring in the preterm period and early weeks ofinfancy.

Although a disease of the developing retinalvasculature, ROP adversely affects photoreceptordevelopment as evidenced by ERG changes inlater childhood [14]. Greater understanding ofnormal retinal development is essential foradvancing prevention and treatment of ROP. Ourfinding of a transient loss of retinal sensitivitybetween 34 and 36 weeks, at the time when ROPis manifest clinically, is interesting and meritsfurther study.

Acknowledgements

We are grateful to Professor Daphne McCulloch forhelpful comments during the preparation of thismanuscript.

R. Hamilton et al.464

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