Objective characterization of the relative afferent pupillary defect in MS

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Abstract

Objective

To develop an objective and precise neurophysiologic method from which to identify and characterize the presence and magnitude of relative afferent pupillary defects (RAPD) in patients with MS.

Methods

Binocular infrared pupillometry was performed in 40 control subjects and 32 MS patients with RAPDs, using two precisely defined sequences of alternating light flashes (right–left and left–right). We analyzed three distinct pupillary metrics in response to light stimulation. These included percent diameter change (DC), constriction curve area (CCA), which measures change in diameter over time, and the phase-plane curve area (PCA) which measures change in diameter with change in velocity. Direct and consensual response ratios (for each eye) were computed and analyzed for each metric in response to both the first flash (i.e. first phase) and second flash (i.e. second phase) of the ‘swinging flashlight’ test.

Results

Second flash pupillary response metric asymmetry ratios yielded the highest discriminatory power for RAPD detection. Receiver operating characteristic areas under the curve for each of the pupillary metric response asymmetry ratios were as follows: diameter change: 0.97; constriction curve area: 0.96; phase-plane curve area: 0.95 (p < 0.0001 for all comparisons compared to normal subjects). The sum of these three squared ratios (SSR) yielded a combined metric with the greatest discriminatory power (receiver operator characteristic area under the curve = 0.99).

Conclusions

Second flash (i.e. the second phase of the swinging light test) pupillary metric response asymmetry ratios are highly sensitive and specific for the confirmation and characterization of an RAPD in patients with MS. This objective neurophysiologic method may be useful for studying the relationship between a stereotyped reflex, and nervous system architecture, with potential ramifications for detecting and monitoring neuroprotective and restorative effects of novel agents in MS treatment trials.

Introduction

Pupillary testing is perhaps the most important bedside examination technique in suspected acute optic neuritis [1], [2]. Initially, each pupil is illuminated individually and the constriction responses are evaluated and compared. The affected side in unilateral acute optic neuritis will usually reveal a diminished pupillary response to direct illumination, indicating altered afferent transmission along the optic nerve, but a normal consensual response in the affected eye upon illumination of the contralateral eye, signifying an intact efferent response on the side of the acute optic neuritis. Then the swinging flashlight test is employed where illumination of the normal eye results in brisk direct and consensual pupillary responses, whereas swinging the light to the affected eye results in either dilation (i.e. pupillary escape from constriction) of both pupils, or a brief period of constriction followed by dilation; confirming the presence of a relative afferent pupillary defect (RAPD). The strength of the RAPD can be semi-quantitatively characterized (as log units) at the bedside using neutral density light filters placed in front of the healthy or less affected eye, and adjusting the light transmittance via changes in the filter, until the abnormal eye responds identically to a direct and consensual response [3]. In general, an RAPD should be present in acute optic neuritis, on the affected side, unless there is commensurate involvement of the fellow eye [4], [5]. Post-chiasmal lesions can be associated with an RAPD, generally on the side of greater visual field loss. In particular, when contralateral to a tract lesion, the greater crossing of pupillary light reflex fibers in the chiasm, than those that remain homolateral in the optic tract, has been proposed as an etiologic mechanism [2], [6], [7]. The pathophysiology of the RAPD results from slowed or blocked transmission of light information to the pretectal olivary nucleus, leading to delayed and/or reduced activation of the Edinger and Westphal parasympathetic nuclei on both sides of the midbrain tegmentum [6].

Kardon and colleagues have demonstrated that computerized infrared pupillometry methods can provide objective parameters for the purpose of standardizing the swinging flashlight test, and to optimize the accuracy of detecting and quantifying the RAPD [8], [9]. The application of pupillometry has facilitated the diagnosis of optic neuropathy associated with glaucoma, where measurements of pupil area amplitude have been found to exhibit greater diagnostic utility when compared to constriction velocity [10]. Additionally, a significant correlation has been confirmed between retinal ganglion cell loss, and the presence of an RAPD in patients with unilateral involvement of the optic nerve [11]. In quantifying the relationship between retinal nerve fiber layer degeneration and the development of an RAPD, studies in rhesus monkeys have shown that the pupillary defect does not occur until about 25 to 50% of retinal ganglion cell neurons have degenerated [12].

The goal of this study was to develop an objective, sensitive and highly specific method to identify and characterize the magnitude of RAPDs in MS patients, when compared to the gold standard bedside neurological examination, the swinging flashlight test. The development of highly precise pupillary metrics may facilitate the study of structure–function relationships in the visual system of MS and related disorders such as neuromyelitis optica (NMO). Further, in conjunction with low contrast letter acuity and sensitivity, optical coherence tomography, multifocal visual evoked potentials, and multifocal electroretinography, sophisticated pupillometry testing may advance our ability to detect and monitor the therapeutic properties of putative protective and restorative agents in treatment trials.

Section snippets

Study subjects

We studied the pupillary responses of 40 control subjects (mean age 35.08 ± 9.74 years; 68% female), as well as 32 MS patients (mean age; 43.51 ± 9.66 years; 84% female). All MS patients were confirmed to have experienced an attack of unilateral optic neuritis within 6 months of testing, and bedside examination revealed a corresponding RAPD on the affected side (all confirmed by a single examiner; EMF). Subjects were between 18 and 65 years of age, were recruited from the Clinical Center for Multiple

Swinging flashlight test

We investigated the metrics of constriction and pupillary dilation in both normal subjects [Fig. 1], and in MS patients who had an RAPD [Fig. 2]. The first half of the waveform corresponds to the pupillary reflex in response to the direct first flash stimulus. The consensual second flash stimulus of the swinging flashlight test generates analogous transmission properties and measured metrics, as the light is transitioned to the opposite side [Fig. 1, Fig. 2].

The two protocols – each with a

Discussion

With the application of infrared, binocular pupillometry, our principal objective was to develop a reproducible and objective method to detect and characterize the magnitude of the RAPD in patients with MS. Our method confirms the superiority of utilizing the second phase pupillary response ratios instead of first flash response ratio metrics. We demonstrated that three measurements constituted robust metrics in differentiating normal subjects from those with an RAPD, and were based on

Limitations

In those patients without clinical evidence of an RAPD, but who had SSR values above the 11.20 threshold for RAPD confirmation, the failure to identify this cardinal sign at the bedside may be related to the limitation of the examiner to subjectively detect discrepancies in the pupillary response characteristics of the mildest RAPDs. Alternately, while we suspect that the use of neutral density filters would likely increase the clinical recognition of subtle RAPDs, this method is rarely used in

Future directions

The second flash asymmetry response ratios, and SSR method for analyzing pupillary metrics can provide information on the magnitude of the RAPD, with greater values signifying more extensive asymmetry; a finding which could be used to longitudinally monitor changes in pupillary function over time, or in response to therapeutic interventions. Given that the RAPD is a functional signature of tissue injury within an eloquent CNS tract system, the second flash composite asymmetry ratio (the SSR),

Author contributions

Paul Blazek was involved in the formulation, design, and execution of the study. He participated in the analysis of the data, preparing the manuscript and its final revision.

Scott Davis was involved in the formulation, design, and execution of the study. He participated in the analysis of the data, preparing of the manuscript and its final revision.

Amy and Darrel Conger contributed to the study through data collection and analysis and with respect to assistance with the editing and revision of

Conflict of interest

None of the authors have a conflict with respect to financial interest concerning the work reported in this paper. The following represent general financial disclosures:

  • Paul Blazek has nothing to declare.

  • Scott Davis has nothing to declare.

  • Amy and Darrel Conger have nothing to declare.

  • Steven Vernino has received consulting fees from Athena Diagnostics and Chelsea Therapeutics.

  • Shin Beh has nothing to declare.

  • Olaf Stuve has received speaker honoraria from Teva Neuroscience and consulting fees from

Study funding

The UT Southwestern Medical Center STARS Program (PB), National Multiple Sclerosis Society (RG 3780A3/3 to Elliot M. Frohman, RG 4091A3/1 to Robert Fox subcontracted to E.M.F., TR 3760-A-3 to P.A.C. and RG 4212-A-4 to Laura J. Balcer subcontracted to P.A.C. and E.M.F.). National Eye Institute (R01 EY 014993 and R01 EY 019473 to Laura J. Balcer subcontracted to P.A.C. and E.M.F.). Braxton Debbie Angela Dillon and Skip (DADS) Donor Advisor Fund (to Elliot M. Frohman subcontracted to P.A.C., and

Acknowledgments

We would like to thank our dedicated patients for participating in our studies.

References (19)

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