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676 BritishlournalofOphthalmology, 1990,74,676-680

Pupillary responses in Br J Ophthalmol: first published as 10.1136/bjo.74.11.676 on 1 November 1990. Downloaded from

Alison Y Firth

Abstract light was then alternatively switched from one Relative afferent pupillary defects (RAPD) to the other, giving a period of stimulation of were detected in 32*3% ofpatients with ambly- 1 to 2 seconds, and the initial pupillary con- opia by a modification ofthe swinging flashlight striction was observed. The light was then left in test and the synoptophore. After consideration front ofeach eye for a count of3 and the pupillary ofvarious clinical investigations the significant escape noted. factors identified in patients showing a RAPD If a pupillary defect was observed, a neutral were: , early age of onset where density filter was placed in the arm of the was present, level of visual acuity synoptophore in front of the eye without the following treatment, longer period ofocclusion defect. In practice it was not found possible to therapy. These points bear similarities to the quantify the defect to within 0-1 log unit as has results of pattern electroretinograms (PERG) previously been reported,5 but merely to confirm in amblyopes, and the possibility of the its presence. Where no defect was initially causative defect being at ganglion cell level is apparent, a 0-3 log unit NDF was placed in discussed. The effect of occlusion treatment either arm in turn to produce a difference in cannot be predicted from the presence or response. In some cases this revealed a subtle absence of a RAPD. defect, as the was still present but to a lesser extent in one eye while completely absent in the other. During the examination An afferent or relative afferent pupillary defect refractive correction was worn, the interpupillary has been reported to be present in between 9% distance corrected, and the tubes set at the and 93% of amblyopes.'' The main criticism of objective angle of deviation by rotating each arm these findings is that poor fixation in the ambly- equally, thus ensuring similar stimulation in opic eye may result in the light stimulus striking either eye. The patient fixed simultaneous different retinal areas.7 macular perception slides throughout. Routine orthoptic examination does not Where possible this test was performed blind, include a test capable of detecting small afferent but casual observation - as in cases of obvious or relative afferent pupillary defects. When anisometropia or strabismus, wearing of attempting to assess the latter, the swinging occlusion, comment on suppression - meant that flashlight test89 is used, but this has drawbacks the amblyopic eye was known to the examiner in for the examination of The child will some cases. children. http://bjo.bmj.com/ often look at the light causing constriction of the After the assessment of the pupillary reaction due to the near , which obscures the on the synoptophore the density of any response to light,'0 or the reaction may be suppression present was measured at the objec- blocked in excitable children." In addition other tive angle by dimming the rheostat in front ofthe disadvantages to the test include: confusion due non-suppressing eye until the 'suppressed' to hippus7 (one pupil being observed on the image could be seen and the rheostat number upswing and the other on the downswing), noted. The and were subjective objective angles on September 23, 2021 by guest. Protected copyright. presence of ,9 and the danger of using compared to elicit the type of retinal correspon- too bright a light, as an after image can keep the dence. small and so prevent the pupillary Visual acuity was assessed (with the patient escape." 12 wearing refractive correction) by a linear test Pupillomotor changes have also been reported (Snellen or Snellen with key card). Some patients in suppression.'3 had their acuity tested with single optotypes The implication of the presence of a relative (Sheridan Gardiner), fixation by the Visuscope afferentpupillarydefectin diagnosis and manage- and contrast sensitivity by the American Optical mentofamblyopia has not beenfullydetermined. System (which is based on Arden's gratings). The purpose ofthis study was to discover factors The size ofpupilswasmeasured, as anyanisocoria common to amblyopes who display a defect with or more than 2 mm could make the testing of a view to ascertaining whether assessment of the pupillary responses inaccurate.9 pupillary response is of clinical value during the Further details were taken from the hospital treatment of amblyopia. records. These included: age at date of test, type of amblyopia, age at onset of strabismus, visual acuity prior to occlusion therapy (and test used), Methods and patients age at first occlusion, types of occlusion therapy Welsh School of Orthoptics, University To observe any asymmetry in pupillary response undergone, continuity of occlusion, best pre- Hospital of Wales, Heath the synoptophore was used with modification of vious visual acuity (if higher than on day of Park, Cardiff CF4 4XW the bright light source normally used for the testing), refractive correction, and fundus AY Firth production of after images. The light intensity examination. When any lesion of the fundus or Correspondence to: Alison Y Firth. was reduced by fitting neutral density filters media was present the patient was excluded. Accepted for publication (NDF) of 0-4 log units into the same rubber Since the study was of necessity conducted 7 June 1990 holder as each eye piece . The after image during normal clinical sessions, the selection of Pupillary responses in amblyopia 677

patients was haphazard. They were examined * RAPD Present Br J Ophthalmol: first published as 10.1136/bjo.74.11.676 on 1 November 1990. Downloaded from

during their routine orthoptic examinations. o RAPD Absent Initially only patients with amblyopia were 601 (12) examined, but later all patients examined with no prior knowledge of whether or not amblyopia was present. No attempt was made to examine 50 patients under the age of 3 years. Nine children were followed up through occlusion therapy. A group of 25 children from a local junior ? 40 c0 school were used as controls. m9 z 30 Results Seventy six patients were examined with ages ranging from 3 years 2 months to 13 years 10 20 months. Sixty five had amblyopia, this being defined as any difference in linear visual acuity. The type ofamblyopia is shown in Table 1. 10 Of the patients with equal visual acuity four had previously had strabismic amblyopia which had responded to treatment, five had intermittent (0) or alternating deviations, and two had equal but Idiopathic Ansio Strab+Ansio Strab reduced visual acuity due to ametropic ambly- Type of Ambyopia opia. Figure 1 Relativefrequencies ofdifferent types of The pupillary responses in 72% of patients amblyopia: idiopathic, anisometropic (aniso), combination of strabismic and anisometropic (strab+aniso) and strabismic were examined blind. (strab) in patients with (shaded) and without (unshaded) a Of the 65 amblyopic patients 21 had a relative relative afferent pupilary defect (RAPD). Actual patient afferent pupillary defect in their amblyopic eye numbers shown in brackets. and two in their non-amblyopic eye. Of 25 controls tested a subtle defect was found in one of 26 without a defect were anisometropic, it was child. considered that this may have caused a bias. Contraction anisocoria is estimated to occur to Unfortunately the numbers were too small to an extent which is clinically visible in 5% of the analyse in the pure strabismic amblyopes, but in population." This may explain the finding of a a comparison of patients with anisometropia and defect in the control and non-amblyopic . strabismus (Fig 2) the age at onset of the However, it could have been observer error. The strabismus was found by the Mann-Whitney U two patients with the defect in their non ambly- test to be significant at the p<005 level. opic eye were excluded from further consider- Various factors concerning occlusion were ation. considered: (a) age at first occlusion; (b) the http://bjo.bmj.com/ The type of amblyopia of the remaining 63 delay from onset of strabismus to start of patients was first considered (Fig 1). For statis- occlusion; (c) type and continuity (d) period of tical evaluation the idiopathic group was occlusion; and (e) time lapse from the last excluded because of the low number. By means occlusion to the date of testing. Of these, the of the likelihood ratio criterion the type of period ofocclusion (Fig 3) was the only significant amblyopia was shown to be significant at the p<0 02 level, and further grouping of patients Table 2 Presence or absence ofrelative afferent pupillary on September 23, 2021 by guest. Protected copyright. into those with or without anisometropia (Table defect (RAPD) in amblyopia involving anisometropia and 2) and those with or without strabismus (Table 3) amblyopia without anisometropia. Statistical evaluation showed only the difference in the former group given to be The amount significant (p<001). actual of Type ofamblyopia anisometropia, however, did not prove to be significant. Aniso and An accurate age at onset in those with strabis- Strab+Aniso Pure strab Total mus was given in 35 patients. The Mann- RAPD present 17 4 21 Whitney U test showed the age at onset to be at a RAPD absent 18 22 40 significantly younger age in those with a relative Total 35 26 61 afferent pupillary defect (p=0 0294). However, df= as eight out of the nine patients with a pupillary XL'=7-7297883, 1, p

Table I Number ofpatients with each type ofamblyopia in the presence or absence ofa Type ofamblyopia relative afferent pupillary defect (RAPD) Pure Aniso+strab Type ofamblyopia Aniso and strab Total Idiopathic Aniso Stab+Aniso Strab Total RAPD present 5 16 21 RAPD absent 6 34 40 RAPD present 0 5 12 4 21 Total 11 50 61 RAPD absent 2 6 12 22 42 Total 2 11 24 26 63 XL'=0-7011637, df= 1, not significant 678 Firth

* RAPD Present

o RAPD Absent Br J Ophthalmol: first published as 10.1136/bjo.74.11.676 on 1 November 1990. Downloaded from

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0-1 1:1-2 2:1 andover A B C D Age of onset of Strabismus (Years:Months) Visual acuity range Figure 2 Relativefrequencies ofthe age ofonset of Figure 4 Relative frequencies ofthe range ofvisual acuity strabismus in anisometropic patients with (shaded) and ofthe amblyopic eye in patients who had undergone occlusion without (unshaded) a relative afferent pupillary defect therapy with (shaded) and without (unshaded) a relative (RAPD). Actual patient numbers shown in brackets. afferentpupillary defect (RAPD). A: up to 6/9; B: 6/10 5 to 6118; C: 6/21 to 6136; D: 6/48 and below. Actual patient numbers shown in brackets. factor (p=0-0188). This suggests that in patients with a relative afferent pupillary defect it was acuity was lower in those with a relative afferent either more difficult to gain an improvement or was their acuity was more difficult to stabilise. pupillary defect. (The level of visual acuity Statistical examination of the results of retinal not significant prior to occlusion.) correspondence, state of fixation, density of Finally nine patients were followed up through suppression, and contrast sensitivity showed no treatment. Three had a relative afferent pupillary significant differences. defect and had not had prior treatment. In two of Different aspects of visual acuity were these the defect disappeared, but in the third it examined including: (a) linear acuity in patients persisted. Three of the nine had a defect but had who had undergone occlusion and those who had already undergone some occlusion; in one the

defect disappeared, and three showed no relative http://bjo.bmj.com/ not; (b) presence of crowding; and (c) the inci- afferent pupillary defect and had not been dence of visual acuity being at less than its best occluded. In one ofthese a defect was never seen, level. The only significant factor (p=00054) but in the other two a defect appeared in the non- found was the level of visual acuity in patients amblyopic eye which disappeared after occlusion who had undergone occlusion (Fig 4). Visual was stopped. on September 23, 2021 by guest. Protected copyright. . RAPD Present Discussion

l ~~~~o0 RAPD Abse~iAbsent AFFERENT OR EFFERENT? The present study, owing to the method of testing used, does not answer this question.

0 However, the defect has been shown to occur u 30- (9) only on stimulation of the central area of the 0 and not the periphery, and not by stimu- 4 0 _ lation with blue light.'4 Further, there is no delay in the consensual reaction' on stimulation of the non-amblyopic eye.

(2)(2 (3) (3) CAUSE A defect prior to the lateral geniculate nucleus (LGN) is the most likely explanation, though 1) other reasons may be considered. Inhibition either of the retina or the o-10--1:1-2 2:1-3 3:1-4 4:1+4:1+ nucleus may occur. Evidence Edinger-Westphalfor the presence of Period of Occlusion (Years:Months) centrifugal fibres in the has been w:published,"6 17 but doubt is now expressed about Figure 3 Relativefrequencies ofthe period ofocclusion M tubipsed, e'bThdou trisnow vxprssdsaou patients w ith (shaded) and without (unshaded) a relative their presence. The afferent psupillary defect (RAPD). Actualpatient numbers (CNS) has been shown to be capable ofinhibition shown in Ibrackets. at the level of the Edinger-Westphal nucleus.' Pupillary responses in amblyopia 679

This may play a part in pupillomotor changes in metropia in newborn babies screened with suppression, but in the testing of amblyopes the photorefraction,4517 and the incidence in 6- to 9- Br J Ophthalmol: first published as 10.1136/bjo.74.11.676 on 1 November 1990. Downloaded from stimulated eye is observed, and no effort of a month olds appears far less than in school age psychosensory nature to prevent the reaction is children.484' In fact between the ages of 1 and being made. 31/2 years anisometropia may either develop or A similar sized RAPD has been reported in resolve.50 Anisohypermetropia has been pro- hemianopia," where midnasal pallor duced by radial keratotomy in kittens,5' and axial of the in the ipsilateral eye is present. length changes have compensated for this pro- Experimentally, cutting of the optic tract (in vided accommodative function is intact and monkeys) produces a similar afferent pupillary there is normal visual experience. defect and pattern of atrophy.2' It is extremely Accommodative function may be abnormal in unlikely that postchiasmal changes in amblyopia anisometropic amblyopia. Although defective would cause such a pupillary defect in the has been reported in ambly- presence of a normal disc appearance. opia,52 the consensual response when the non- If the retina is considered at the site for the amblyopic eye is stimulated is normal.53 Unsteady cause, then again several suggestions may be fixation, perceptual difficulties, or lack of foveal made. Retinal haemorrhages at birth could cause function may be the cause of this apparent an undetectable retinal defect.2' However, from defect.5456 a series of babies followed up to an age at which If accommodative function is normal, then a visual acuity could be measured, these haemor- lack of normal visual experience in one eye may rhages did not appear to have any detrimental be the cause of the lack of emmetropisation and effect on the normal development ofvision.22 the resultant anisometropia. If the cause of such Malorientation of the retinal receptors has is an undetectable defect in the retina (post- been suggested as a cause oforganic amblyopia;23 receptor level or ganglionic level), this may be the 24 this would result in less light being absorbed. explanation for the differences in CSF between However, the findings of malorientation of the anisometropic and strabismic amblyopes57-'" and receptors is disputed,25 and normal cone electro- be the cause of the RAPD and abnormal PERG retinogram recordings, suggestive of normal responses. preganglionic cell function, have been reported in amblyopia.26 Pattern electroretinograms (PERG), which TREATMENT reflect the integrity ofthe ganglion cell layer, are During occlusion there may be some reversi- abnormal in amblyopia,272`0 though this has not bility of the RAPD, or it may be that a defect is been confirmed by every study.3 132 Ifthe cause of beingproduced in theoccluded eye, thus masking the abnormal pupillary response lies at ganglion that in the amblyopic eye. As mentioned above,2' cell level, then some similarities in the type of the PERG reduces in the occluded eye and patient having a RAPD and showing an abnormal disruption of the orientation of retinal receptors PERG may be expected. Where an analysis ofthe occurs.'3 Further study is needed to quantify the PERG response has been related to different pupillary reactions of each eye to determine the categories of patients and treatment,2' it was answer to this question. It has been reported3 http://bjo.bmj.com/ found that the greatest defects occurred in that increased latencies of contraction become anisometropes and those patients who did not more normal with treatment. As the level of respond well to treatment. Furthermore, reduc- visual acuity prior to occlusion therapy is not tion in the amplitude of the PERG in the significant to the presence of a RAPD, this test occluded, non-amblyopic eye, occurred, which cannot be used as an indicator of the outcome of reversed with the cessation oftreatment.2' occlusion therapy in amblyopia. X and Yganglion cell function has been shown on September 23, 2021 by guest. Protected copyright. to be abnormal in cats raised with strabismus,33" I would like to thank the consultant ophthalmologists at the there is the University Hospital ofWales for allowing me to use their patients. though again dispute.35 Often Thanks also go to the headmaster and children ofTirphil Primary strabismus (or anisometropia) is produced in the School; Mr A K W Henn for translations; the Department of animal at around 3 to 4 weeks of Medical Illustrations; Dr T J Peters for advice and help with the age,3"3-3 though statistics; Miss J V Plenty for helpful comments on the paper; my sometimes this has varied."' The lower spatial colleagues at work; and Dr J M Woodhouse for overseeing the frequencies (in the cat) are unaffected where project. strabismus is produced after eight weeks,39 and 1 Dolenek A. Bietrag zur pupillographie. Ophthalmologica 1960; in infants the low frequency end of the contrast 139: 77-83. sensitivity function (CSF) curve does seem to 2 Kruger KE. Pupillenstorungen und amblyopie. Ber Dutsch Ophthalmol Ges I9%0; 63: 275-8. develop to an adult-like shape earlier than the 3 Dolenek A, Kristek A, Nemec J, Komenda S. Uber Verander- high frequency end. unden der Pupillenreaktion nach erfolgreicher Amblyopie- behandlung. Klin MonatsblAugenheilkd 1962; 141: 353-7. The Y and W cells are probably responsible 4 Greenwald MJ, Folk ER. Afferent pupillary defects in ambly- for the detection of low to medium spatial opia. J Pediatr Ophthalmol Strabismus 1983; 20: 63-7. 5 Portnoy JZ, Thompson HS, Lennarson L, Corbett JJ. frequencies.42 It has been suggested that the Pupillary defects in amblyopia. Am J Ophthalmol 1983; 96: luminance detectors originally identified43 which 609-14. 6 Cremers H. Pupillary abnormalities in amblyopia. AustOrthopt showed a regularly increasing frequency of dis- J 1986; 23: 47 (abstr). charge with an increase in level are W 7 Thompson HS. Afferent pupillary defects. (Pupillary findings associated with defects of the afferent arm of the pupillary cells." Thus it is plausible that early-onset light reflex arc). AmJ Ophthalmol 1966; 62: 860-73. strabismics are more likely to show changes 8 Levatin P. Pupillary escape in disease of the retina or optic nerve. Arch Ophthalmol 1959; 62: 768-79. which result in a RAPD. However, the case for 9 Thompson HS, Corbett JJ, Cox TA. How to measure the anisometropes is less clear, as it cannot be relative afferent pupillary defect. Surv Ophthalmol 1981; 26: 39-42. assumed that the difference in is 10 Cox TA. Pupillary testing using the direct ophthalmolscope. present at birth. There is no mention of aniso- AmJ Ophthalmol 1988; 105: 427-8. 680 Firth

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