A RELATIVE AFFERENT PUPILLARY DEFECT IS AN EARLY SIGN OF OPTIC NERVE DAMAGE IN GLAUCOMA

BERTIL LINDBLOM

Göteborg University, Institute of Clinical Neuroscience, Ophthalmology Section,

Göteborg, Sweden

Introduction

By alternately illuminating the two eyes, the reactions of the pupils to light can be compared. A relative afferent pupillary defect (RAPD) is present when the light reaction is asymmetrical between the eyes. The eye with the more sluggish reaction is said to have a RAPD. This is caused by a difference in afferent neural signals between the eyes due to a lesion somewhere along the neural pathway from the photoreceptors to the retinal ganglion cell axons synapsing in pre-tectal nuclei in the midbrain. An RAPD can be caused by a unilateral retinal or optic nerve lesion, or by bilateral but asymmetrical lesions. It may also be caused by a lesion of the optic chiasm or the optic tract proximal to the pre-tectal nuclei.1 In humans, a few such optic tract lesions have been reported.2 These are interesting because they give a clue to the degree of asymmetry needed to produce an RAPD. In humans, it has been estimated that 53% of the axons in one optic nerve decussate to join the contralateral optic tract, while 47% join the ipsilateral optic tract.3 Thus, a cross-sectional lesion to the optic tract results in a difference in afferent neural input of approximately 13% ((0.53/0.47)/100), with the larger input from the eye ipsilateral to the lesion. Such optic tract lesions have been reported to produce a RAPD in the contralateral eye.2

In comparison, it has been estimated that it takes 25-30% of axonal loss before a visual field defect can be demonstrated with standard automated perimetry.4 Considering the fact that chronic open-angle glaucoma seldom starts simultaneously and symmetrically in both eyes, an RAPD may, on theoretical grounds, be a more sensitive test of glaucomatous optic nerve lesion than standard perimetry. It has the additional huge advantage that it requires a minimum of cooperation from the patient.

This pilot study was conducted to address the hypothesis that the presence of an RAPD can be used as a means of detecting early glaucomatous optic neuropathy. A pupillometer for the quantification of RAPDs is under construction.

Address for correspondence: Professor Bertil Lindblom, MD, PhD, Department of Ophthalmology, Sahlgrenska University Hospital, SE 431 80 Mölndal, Sweden. Email: bertil.lindblom@neuro.gu.se

Perimetry Update 2002/2003, pp. 371–375

Proceedings of the XVth International Perimetric Society Meeting, Stratford-upon-Avon, England, June 26–29, 2002

edited by David B. Henson and Michael Wall

© 2004 Kugler Publications, The Hague, The Netherlands

372 B. Lindblom

Subjects and methods

Forty-three patients with manifest or suspected open-angle glaucoma were enrolled in the study. Patients scheduled for an ordinary glaucoma follow-up visit at the glaucoma clinic at the Sahlgrenska University Hospital were recruited. Inclusion criteria were: 1. A diagnosis of manifest or suspected chronic open-angle glaucoma as stated in the patient’s file; pseudoexfoliative or pigmentary glaucoma were considered variants of open-angle glaucoma and patients with these glaucoma types were included. 2. An age of 80 years or younger. Exclusion criteria were: 1. Visual acuity of less than 0.5 for any reason. 2. Other ocular conditions capable of causing visual field defects, including diabetic retinopathy and retinal vascular occlusion. 3. The inability to perform reliable visual field testing.

After tests of visual acuity with refraction and tonometry, all patients underwent high-pass resolution perimetry (HRP) using the Ophthimus instrument (HighTech Vision, Göteborg) in both eyes. A trained technician performed the examinations according to the manufacturer’s instructions. The majority of patients had previous perimetric experience. No attempt was made to compensate for any training effect. The results used in this study were the calculated neural capacity and the overall rating of the visual field made by the instrument (normal or not normal, the latter included borderline or abnormal results). The same technician then performed scanning laser optic disc imaging with Heidelberg Retina Tomograph (HRT) (Heidelberg Engineering GmbH, Heidelberg, Germany). Three scans were made in each eye, and the mean values were calculated by the instrument (software version 2.01). The technician then manually outlined the optic disc border, defined as the inner edge of the scleral ring. The glaucoma classification made by the instrument (normal or glaucoma) was used in further comparisons. The author then assessed RAPD by swinging flashlight technique. Pupil reactions were observed through the ophthalmoscope against the red fundus reflex as the light illuminated the eyes alternately. No attempt was made to grade the RAPD with neutral filters – only the presence or absence of RAPD was noted. The examiner was unaware of the results of HRP and HRT when performing the swinging light test.

The final diagnosis (glaucoma or not glaucoma) was then made based primarily on optic disc and retinal nerve fiber layer photographs, but also on available perimetric data. In many cases, long-term follow-up photographs were available.

Results

There were different combinations of test results from the three examinations. The RAPD test, as performed in this study, could only be used to detect a difference in afferent input between the eyes, but was unable to show whether an optic nerve damage was present in one or both eyes. Therefore, comparisons between the tests were restricted to the worst eye of each patient. The majority of patients had only subtle glaucomatous changes.

Agreement

For 18 of the 43 subjects (42%), there was agreement between all three diagnostic methods. In 17 of these, all three tests showed abnormal results and all these patients were judged to have glaucoma. In one subject, judged as normal, all three tests were normal. The remaining subjects showed abnormal results in one or two diagnostic tests in different combinations.

HRP abnormal, HRT normal, no RAPD

This group included six subjects, only one of whom was judged to have glaucoma (see comment). The reasons for false positive results were lens sclerosis (one subject), supernormal HRP thresholds (one subject), and unknown (three subjects), the latter showing normal optic disc and retinal nerve fiber findings on fundus photography.

HRT abnormal, HRP normal, no RAPD

This group contained four subjects, none of whom were judged to have glaucoma, based on photographic documentation of a normal retinal nerve fiber layer, in two subjects with long-term follow-up photographs.

RAPD, HRT and HRP normal

One patient was found to have RAPD with normal HRP and HRT. After scrutinizing old patient records, it was revealed that this male had been treated with oral steroids because of polymalgia rheumatica with a suspicion of anterior optic neuropathy many years earlier.

HRP and HRT abnormal, no RAPD

This group included four subjects, one of whom was judged to have glaucoma, while the other three were judged as being normal. One patient had normal HRP after retest, one had supernormal HRP thresholds, and one had a very large optic disc with normal retinal nerve fiber layer.

HRP abnormal, RAPD, HRT normal

Seven subjects showed this result, six of whom were judged to have glaucoma, based on progressive glaucomatous damage (four subjects), optic disc hemorrhage (one subject), and photographic documentation of optic disc damage (one subject). One subject was judged to be normal, and HRP normalized on retesting.

HRT abnormal, RAPD, HRP normal

Only one patient showed this combination. Photographic documentation revealed typical glaucomatous damage.

Contralateral RAPD, abnormal HRP and HRT

Two patients with abnormal HRT and HRP showed RAPD in the eye contralateral to the most damaged eye, according to HRP and HRT results.

Table 1 shows the overall results. Of the three tests, the presence of RAPD seemed to be the most reliable sign of optic nerve damage.

Table 1. Overall number of patients with and without glaucoma showing abnormal results with the three tests

Discussion

The presence of an RAPD means that there is an imbalance of neural input between the eyes. Simply by comparing the pupillary responses in the two eyes, it is not possible to decide whether one or both eyes or optic nerves are affected. Thus, the presence of an RAPD in a patient with glaucoma provides no information on whether the disease is unior bilateral. Clinically, however, the most important decision is whether the patient has glaucoma in either of his eyes. This decision is crucial for the future handling of the patient,

All studies of glaucoma are hampered by the lack of a diagnostic technique sensitive and specific enough to serve as gold standard reference. Usually, conventional perimetry using the Humphrey Field Analyzer is used as a gold standard in comparative studies. However, using a subjective test that places high demands on patient cooperation, demands that are not always fulfilled in a clinical setting, is far from ideal. This is illustrated by the different criteria for diagnosing glaucoma that are being used in different studies. In the present study, all available information was used to diagnose glaucomatous damage with emphasis on the analysis of optic disc and nerve fiber layer photographs, especially when long-term follow-up photographs were available. A bias favoring HRP was deliberately introduced in that perimetric data were also used to verify the diagnosis of glaucoma. However, the aim of this study was not primarily to compare HRP and HRT as diagnostic tools, but rather to see if a test of RAPD could be used as a test for glaucoma.

What difference in HRP neural capacity between the eyes will produce a clinically discernable RAPD? In the present study, the largest intraocular difference in neural capacity in subjects without RAPD was 24%. Patients with RAPD had differences in neural capacities of various magnitudes, including two subjects with RAPD in the eye with the higher neural capacity. However, neural capacity is an index influenced by factors other than optic nerve damage, including media opacities. The amount of optic nerve axon loss producing RAPD has been studied in monkeys, and has been reported to be between 25 and 50%.5

We could argue that the present comparison between diagnostic methods is unfair

to HRP and HRT, since both these methods were judged solely on the basis of a single index (neural capacity in HRP, glaucoma classification in HRT). An experienced examiner uses additional information, such as the form of the threshold surface in HRP, and the contour of the peripapillary nerve fiber layer in HRP. However, by so doing, a subjective component is introduced. The purpose of this ongoing study of RAPD is to find an objective way to diagnose glaucoma.

This pilot study showed that it was indeed uncommon for a patient with glaucomatous optic neuropathy to have symmetrically reacting pupils. RAPD in glaucoma has already been reported,6 also in glaucoma patients without visual field defects.7 RAPD in glaucoma has also been quantified.8 So, faced with the common task of deciding whether or not a patient has glaucoma, the ophthalmologist should carefully investigate pupil reactions. In the absence of RAPD, the diagnosis of glaucoma should be challenged, provided of course that the ophthalmologist has the necessary skills to detect a subtle RAPD.

This small study did not systematically study the specificity of RAPD testing. However, it is my clinical experience that a false positive RAPD is a very uncommon finding.

References

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2.Newman SA, Miller NR: Optic tract syndrome: neuro-ophthalmologic consideration. Arch Ophthalmol 101:1241-1250, 1983

3.Kupfer C, Chumbley L, Downer J: Quantitative histology of optic nerve, optic tract and lateral geniculate nucleus in man. J Anat 101:393-401, 1967

4.Kerrigan-Baumlind LA, Quigley HA, Pease ME, Kerigan DF, Mitchell RS: Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci 41:741-748, 2000

5.Kerrison JB, Buchanan K, Rosenberg ML, Clark R, Andreason K, Alfaro DV, Grossnikolaus HE, Kerrigan-Baumrind LA, Kerrigan DF, Miller NR, Quigley HA: Quantification of optic nerve axon loss associated with a relative afferent pupillary defect in the monkey. Arch Ophthalmol 119:13331341, 2001

6.Brown RH, Zilis JD, Lynch MG, Sanborn GE: The afferent pupillary defect in asymmetric glaucoma. Arch Ophthalmol 105:1540-1543, 1987

7.Kohn AN, Moss AP, Podos SM: Relative afferent pupillary defects in glaucoma without characteristics field loss. Arch Ophthalmol 97:294-296, 1979

8.Jonas JB, Zäch F-M, Naumann GOH: Quantitative pupillometry of relative afferent defects in glaucoma. Arch Ophthalmol 108:479-480, 1990