- Email: [email protected]
Relative afferent pupillary defects in patients with Leber hereditary optic neuropathy and unilateral visual loss
Relative Afferent Pupillary Defects in Patients With Leber Hereditary Optic Neuropathy and Unilateral Visual Loss DANIEL M. JACOBSON, MD, EDWIN M. STONE, MD, PHD, NEIL R. MILLER, MD, STEPHEN C. POLLOCK, MD, WILLIAM A. FLETCHER, MD, FRCPC, PATRICIA JOHNSTON MCNUSSEN, MD, AND TIMOTHY J. MARTIN, MD
● PURPOSE:
It has been suggested that the pupillary light reaction is relatively preserved in the affected eyes of patients with Leber hereditary optic neuropathy (LHON). To test the hypothesis that visual-pupillomotor dissociation exists in LHON, we performed a retrospective study to evaluate the magnitude of the relative afferent pupillary defect (RAPD) in patients who had experienced monocular visual loss. We also compared the size of the measured RAPD with the size of the RAPD that would be expected on the basis of documented visual field loss. ● METHODS: We identified a cohort of patients with LHON and monocular visual loss, whose pupillary reactions had been quantified using neutral density filters. From a review of the case records, we determined whether an RAPD was present, as well as the magnitude of the documented RAPDs. We also calculated the expected size of the RAPD for each patient, using previ-
Accepted for publication Dec 15, 1997. From the Departments of Neurology and Ophthalmology, Marshfield Clinic, Marshfield, Wisconsin (Dr Jacobson); the Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa (Dr Stone); Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland (Dr Miller); the Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina (Dr Pollock); the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (Dr Fletcher); the Division of Neurosciences, Carle Clinic, Urbana, Illinois (Dr McNussen); and the Department of Ophthalmology, Bowman Gray School of Medicine, Winston-Salem, North Carolina (Dr Martin). Reprint requests to Daniel M. Jacobson, MD, Neuroophthalmology (4F-2), Marshfield Clinic, 1000 N Oak Ave, Marshfield, WI 54449; fax: (715) 387-5727; e-mail [email protected]
0002-9394/98/$19.00 PII S0002-9394(98)00152-4
©
1998 BY
ously established templates that correlated the size of the RAPD with the degree of visual field loss. ● RESULTS: An RAPD was identified in all 10 patients in this study. There was no significant difference between the size of the measured and predicted RAPD, nor did the size of the RAPD correlate with visual acuity or the time interval between the onset of visual loss and evaluation. ● CONCLUSION: The results of this study do not support the hypothesis that visual-pupillomotor dissociation is a common feature of LHON. (Am J Ophthalmol 1998;126:291–295. © 1998 by Elsevier Science Inc. All rights reserved.)
L
EBER HEREDITARY OPTIC NEUROPATHY (LHON) IS
a maternally inherited disorder that typically causes severe visual loss in one eye that is followed weeks to months later by similar visual loss in the opposite eye.1–3 Specific point mutations within the portions of mitochondrial DNA that code for respiratory chain proteins are identified in at least 90% of symptomatic members of multigeneration pedigrees.4 Certain clinical features in symptomatic individuals favor the peripapillary retina as the site of initial injury to the visual system, although the precise location and mechanism responsible for the visual loss in this condition remains unknown.5–7 Three lines of evidence suggest that the neuropathic process associated with symptomatic LHON may spare some or all of the retinal ganglion cell
ELSEVIER SCIENCE INC. ALL
RIGHTS RESERVED.
291
METHODS
bodies, or their axonal projections, subserving the afferent limb of the pupillary light reflex. Many investigators have observed that the pupillary light reaction is surprisingly brisk in affected eyes.8 –10 In fact, Bynke and associates10 did not observe a relative afferent pupillary defect (RAPD) in a carefully studied patient with LHON who presented with monocular involvement. Furthermore, Wakakura and Yokoe11 found that the constriction amplitude of the direct pupillary light response, which was recorded with video pupillography, was no different in affected eyes from patients with LHON than in normal controls. Finally, Nakamura and associates12 found that the latency of the early response of the photic blink reflex, which was thought to be mediated by visual afferent fibers that project to the midbrain pretectum, in most affected eyes of patients with LHON was similar to that in normal controls. Bynke and associates10 consider that relative preservation of the pupillary light reaction supports the peripapillary retina, not the optic nerve, as being the primary site of injury in LHON. Nikoskelainen and associates9 suggest that a brisk pupillary light reaction differentiates LHON from other optic neuropathies. In clinical practice, the integrity of the afferent pupillomotor pathway is objectively assessed by performing the swinging flashlight test to identify an RAPD.13 The size of the RAPD is proportional to the degree of visual field loss present in unilateral disorders and to the disparity in the degree of visual field loss between the two eyes in bilateral conditions.14 –16 If the retinal ganglion cells or their axonal projections that subserve the pupillary light reaction were selectively spared in LHON, as has been suggested by some investigators,11,12 either no RAPD or a smaller than expected RAPD would be observed in patients with unilateral involvement. On the other hand, if this hypothesis were incorrect, an RAPD would consistently be found in such a patient, the size of which would be proportional to the degree of visual field loss. A retrospective clinical study was conducted to further assess the hypothesis that visual-pupillomotor dissociation exists in patients with LHON. 292
AMERICAN JOURNAL
WE REVIEWED CASE RECORDS OF PATIENTS WHO FUL-
filled all of the following entry criteria: (1) the presence of a primary mitochondrial DNA mutation at nucleotide position 11778, 3460, or 14484; (2) symptoms of visual loss in only one eye; (3) normal visual acuity and visual field in the asymptomatic eye; (4) no concurrent or previous ocular (for example, glaucoma), neurologic (for example, multiple sclerosis), or systemic (for example, diabetes) disorder that might cause an optic neuropathy or retinopathy or that could adversely influence the ability to detect an RAPD; and, (5) an RAPD was sought by an examiner who routinely uses neutral density filters during the swinging light test. The last criterion was included because a quantified measurement of the RAPD was desired, if one were present, to compare with the visual field loss in an affected patient. Although this was a retrospective study, assessment of pupillary reactions and quantification of an identified RAPD were performed by all the coinvestigators using the technique advocated by Thompson and associates.17,18 In brief, the technique involves introduction of neutral density filters of successively greater strength (in log units) before the unaffected eye during the swinging light test. At some point, the amount of light stimulus to the unaffected eye was dimmed sufficiently so that the RAPD was no longer apparent. The size of the RAPD in that patient was then defined as the number of log units required to neutralize that sign. Because of the stringent entry criteria, we had to rely on different sources to collect a sufficient number of case records for this study. One case was evaluated by the principal investigator (D.M.J.). Four cases were identified by reviewing the medical records of all patients evaluated at the University of Iowa Hospital and Clinics who underwent molecular assay confirmation by one of us (E.M.S.). Two cases were identified by contacting neuro-ophthalmologists who had received their fellowship training with H. Stanley Thompson, MD (Iowa City, Iowa), a long-standing advocate of measuring the RAPD with neutral density filters.17,18 Finally, three cases were identified by advertising our interest in collecting such cases on NANOSNET, the internet elecOF
OPHTHALMOLOGY
AUGUST 1998
tronic-mail group sponsored by the North American Neuro-ophthalmology Society. One of these patients (Case 8) had been previously reported.19 The following information was abstracted from the medical records: age and gender; time interval from onset of visual loss to neuro-ophthalmologic examination; mitochondrial DNA mutation; visual acuity of the symptomatic and asymptomatic eye; visual fields; and whether an RAPD had been identified and, if so, its size as determined using neutral density filters. These variables were entered into a commercially available database and statistical analysis software system (Prism, GraphPad Software, San Diego, California). In addition to identifying whether RAPDs existed in this population of patients, we were also interested in determining how the size of the measured RAPD, if present, compared with the size of the RAPD predicted on the basis of documented visual field loss. For patients who underwent testing of their visual field using a Goldmann perimeter, we used the visual field template derived by Thompson and associates14 to estimate the predicted size of their RAPD. Two patients underwent visual field testing using Program 30-2 of the Humphrey Field Analyzer (Humphrey-Zeiss, San Leandro, California). For these patients, the linear regression line determined by Kardon and associates16 was used for predicting the RAPD. We used the Wilcoxon signed rank test (two-tailed) to compare the size of the measured and predicted RAPD. Linear regression was used to further analyze the relationship between these two variables. We used the Spearman rank correlation test (two-tailed) to determine whether a relationship existed between visual acuity and the measured RAPD, and between the time interval from the onset of visual loss to examination and the measured RAPD. When analyzing the visual acuity relationship, we converted the Snellen measurement to log (MAR)21, where MAR equaled the minimum angle of resolution, which was determined by dividing the numerator by the denominator. We arbitrarily assigned a Snellen acuity of 20/800 for patients whose visual acuity was in the counting fingers range and 20/1600 if it was in the hand motions range. VOL. 126, NO. 2
TABLE. Clinical Variables of 10 Patients With Leber Hereditary Optic Neuropathy and Unilateral Visual Loss Patient No., Age (yrs), Sex
1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
36, F 31, M 37, F 17, M 9, M 49, M 19, M 34, M 38, F 24, F
Interval* (wk)
DNA Mutation
Snellen Visual Acuity
Measured
Predicted†
7 36 6 6 10 48 10 24 12 40
3460 11778 11778 3460 11778 14484 3460 11778 11778 11778
20/300 CF 2 ft CF 3 ft 20/200 20/200 20/400 CF 3 ft CF 8 ft 20/400 HM
1.4 1.8 1.0 0.9 0.3 0.6 0.8 0.6 0.8 1.8
0.9 2.2 0.9 0.6 0.9 0.6 1.1 0.9 1.7 2.5
RAPD (log units)
RAPD 5 relative afferent pupillary defect; CF 5 counting fingers; HM 5 hand motions. *Time from visual loss to evaluation. † Derived from Goldmann visual field defects in all patients except patients 6 and 7, who were tested with automated perimetry.
RESULTS THE TABLE SUMMARIZES THE MAJOR CLINICAL FEA-
tures of the 10 patients who were included in this study. All patients had an RAPD that ranged in size from 0.3 to 1.8 log units (median, 0.9 log units; mean, 1.0 log units). The size of the predicted RAPD (that is, based on degree of visual field loss) in the 10 study patients ranged in size from 0.6 to 2.5 log units (median, 0.9 log units; mean, 1.2 log units). There was no significant difference (P 5 .13) between the size of the measured RAPD and the predicted RAPD. Linear regression (Figure 1) identified a significant relationship between the measured and predicted RAPD (r2 5 0.55; P 5 .014). No correlation existed between the size of the measured RAPD and visual acuity (r 5 0.44; P 5 .20) or the time interval from onset of visual loss to evaluation (r 5 20.04; P 5 .92).
DISCUSSION IN THIS STUDY POPULATION OF PATIENTS WITH LHON
and monocular visual loss, we found that an RAPD was universally present and that its size was propor-
RELATIVE AFFERENT PUPILLARY DEFECTS
293
sized RAPDs have not often been recognized in symptomatic patients with LHON. When a patient is evaluated at the onset of visual loss in the first eye, the diagnosis of LHON often is not initially suspected, because many affected individuals do not have a positive family history and the characteristic peripapillary microangiopathy is either absent or not recognized.1–3 Because the area of impaired visual field is relatively small in this condition during the early phase,5 the direct pupillary light reaction of the affected eye appears brisk. However, a pupil can still react briskly yet demonstrate a sizable RAPD during the swinging flashlight test when the direct pupillary reactions and the latency and degree of escape can be compared between the two eyes.17 Unless a careful comparison is made of the pupillary reactions of the two eyes during the swinging flashlight test, an RAPD may not be identified during the early stage of LHON. It is often not until the patient develops visual loss in his or her second eye that LHON becomes a suspected diagnosis. At that point, however, the visual loss in the two eyes is more in balance, so the preexisting RAPD is either reduced in size or completely neutralized. It is also possible that during the early phase of LHON (that is, when the visual loss appears to be unilateral) subclinical optic nerve or retinal dysfunction in the fellow eye could reduce the magnitude of the afferent pupillary defect in the symptomatic eye. Our results do not support the hypothesis that some critical period of time must elapse before injury to the pupillomotor fibers is sufficient to result in a clinically detectable RAPD; there was no correlation between the size of the RAPD in our patients and the time interval between the onset of visual loss and evaluation. Because our sample size was small, we cannot state that pupillomotor input is impaired in all cases of LHON. It is still possible that some affected patients have a relative sparing of pupillomotor function that is defined by variables that we did not assess or remain unknown. However, it seems counterintuitive that selective sparing of a certain population of retinal ganglion cells or their axonal projections would occur in a disorder that causes marked generalized injury to fibers of the papillomacular bundle and their central projections.21,22
FIGURE. Linear regression analysis shows a significant relationship (r2 5 0.55) between the measured and predicted relative afferent pupillary defect (RAPD). The slope (0.97) of the regression line (solid line) is significantly different than zero (P 5 .014). The 95% confidence intervals (broken lines) of the slope (0.25– 1.69) are shown above and below the regression line.
tional to the degree of associated visual field loss. We found no evidence to support the hypothesis that a visual-pupillomotor dissociation of retinal ganglion cell function occurs in patients with symptomatic LHON. Accordingly, our data do not support the notion that the presence of a brisk direct pupillary light reaction or the absence of a RAPD in a patient with unilateral unexplained visual loss should, by itself, necessarily prompt consideration of a diagnosis of LHON. Yoshitomi and associates20 used pupil perimetry to evaluate a patient with LHON and monocular visual loss, and they were also unable to demonstrate visual-pupillomotor dissociation. They used an infrared camera to record and measure the change of pupillary area that occurred in response to light stimulation delivered by a modified Goldmann perimeter at various target locations throughout the visual field. They found impaired pupillary reactions in target locations that corresponded to the patient’s central scotoma. We can only speculate as to why appropriately 294
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
AUGUST 1998
ACKNOWLEDGMENT
We dedicate this project to H. Stanley Thompson, MD (Iowa City, Iowa), in honor of his retirement. During his 30-year career in the Department of Ophthalmology at the University of Iowa Hospitals and Clinics, Dr Thompson quietly taught us the value of watching and measuring the pupil in order to gain insight into the function of the afferent and efferent visual system.
9.
10. 11. 12.
REFERENCES
13.
1. Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991;111: 750 –762. 2. Johns DR, Smith KH, Miller NR. Leber’s hereditary optic neuropathy: clinical manifestations of the 3460 mutation. Arch Ophthalmol 1992;110:1577–1581. 3. Johns DR, Heher KL, Miller NR, Smith KH. Leber’s hereditary optic neuropathy: clinical manifestations of the 14484 mutation. Arch Ophthalmol 1993;111:495– 498. 4. Mackey DA, Oostra R-J, Rosenberg T, et al. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 1996;59:481– 485. 5. Nikoskelainen E, Sogg RL, Rosenthal R, Friberg TR, Dorfman LJ. The early phase in Leber hereditary optic atrophy. Arch Ophthalmol 1977;95:969 –978. 6. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditary optic neuropathy, II: the fundus findings in the affected family members. Arch Ophthalmol 1983;101:1059 –1068. 7. Nikoskelainen E, Hoyt WF, Nummelin K, Schatz H. Fundus findings in Leber’s hereditary optic neuroretinopathy, III: fluorescein angiographic studies. Arch Ophthalmol 1984;102:981–989. 8. Nikoskelainen E. The clinical findings in Leber’s hereditary
14. 15. 16. 17. 18. 19. 20. 21.
22.
optic neuroretinopathy: Leber’s disease. Trans Ophthalmol Soc UK 1985;104:845– 852. Nikoskelainen EK, Huoponen K, Juvonen V, Lamminen T, Nummelin K, Savontaus M-L. Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology 1996;103:504 –514. Bynke H, Bynke G, Rosenberg T. Is Leber’s hereditary optic neuropathy a retinal disorder? Report of a case. Neuro-ophthalmology 1996;16:115–123. Wakakura M, Yokoe J. Evidence for preserved direct pupillary light response in Leber’s hereditary optic neuropathy. Br J Ophthalmol 1995;79:442– 446. Nakamura M, Sekiya Y, Yamamoto M. Preservation of photic blink reflex in Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 1996;37:2736 –2743. Levatin P. Pupillary escape in disease of the retina or optic nerve. Arch Ophthalmol 1959;62:768 –779. Thompson HS, Montague P, Cox TA, Corbett JJ. The relationship between visual acuity, pupillary defect, and visual field loss. Am J Ophthalmol 1982;93:681– 688. Johnson LN, Hill RA, Bartholomew MJ. Correlation of afferent pupillary defect with visual field loss on automated perimetry. Ophthalmology 1988;95:1649 –1655. Kardon RH, Haupert CL, Thompson HS. The relationship between static perimetry and the relative afferent pupillary defect. Am J Ophthalmol 1993;115:351–356. Thompson HS, Corbett JJ, Cox TA. How to measure the relative afferent pupillary defect. Surv Ophthalmol 1981; 26:39 – 42. Thompson HS, Corbett JJ. Swinging flashlight test. [letter]. Neurology 1989;38:154 –156. Flanigan KM, Johns DR. Association of the 11778 mitochondrial DNA mutation and demyelinating disease. Neurology 1993;43:2720 –2722. Yoshitomi T, Matsui T, Mukuno K, Ishikawa S. Objective visual field measurement using “pupil perimetry.” J Jpn Ophthalmol Soc 1996;100:825– 831. Kerrison JB, Howell N, Miller NR, Hirst L, Green WR. Leber hereditary optic neuropathy: electron microscopy and molecular genetic analysis of a case. Ophthalmology 1995;102:1509 –1516. Wilson J. Leber’s hereditary optic atrophy: some clinical and aetiological considerations. Brain 1963;86:347–362.
Authors Interactivet We encourage questions and comments regarding this article via the Internet on Authors Interactivet at http://www.ajo.com/ Questions, comments, and author responses are posted.
VOL. 126, NO. 2
RELATIVE AFFERENT PUPILLARY DEFECTS
295
● PURPOSE:
It has been suggested that the pupillary light reaction is relatively preserved in the affected eyes of patients with Leber hereditary optic neuropathy (LHON). To test the hypothesis that visual-pupillomotor dissociation exists in LHON, we performed a retrospective study to evaluate the magnitude of the relative afferent pupillary defect (RAPD) in patients who had experienced monocular visual loss. We also compared the size of the measured RAPD with the size of the RAPD that would be expected on the basis of documented visual field loss. ● METHODS: We identified a cohort of patients with LHON and monocular visual loss, whose pupillary reactions had been quantified using neutral density filters. From a review of the case records, we determined whether an RAPD was present, as well as the magnitude of the documented RAPDs. We also calculated the expected size of the RAPD for each patient, using previ-
Accepted for publication Dec 15, 1997. From the Departments of Neurology and Ophthalmology, Marshfield Clinic, Marshfield, Wisconsin (Dr Jacobson); the Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa (Dr Stone); Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland (Dr Miller); the Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina (Dr Pollock); the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (Dr Fletcher); the Division of Neurosciences, Carle Clinic, Urbana, Illinois (Dr McNussen); and the Department of Ophthalmology, Bowman Gray School of Medicine, Winston-Salem, North Carolina (Dr Martin). Reprint requests to Daniel M. Jacobson, MD, Neuroophthalmology (4F-2), Marshfield Clinic, 1000 N Oak Ave, Marshfield, WI 54449; fax: (715) 387-5727; e-mail [email protected]
0002-9394/98/$19.00 PII S0002-9394(98)00152-4
©
1998 BY
ously established templates that correlated the size of the RAPD with the degree of visual field loss. ● RESULTS: An RAPD was identified in all 10 patients in this study. There was no significant difference between the size of the measured and predicted RAPD, nor did the size of the RAPD correlate with visual acuity or the time interval between the onset of visual loss and evaluation. ● CONCLUSION: The results of this study do not support the hypothesis that visual-pupillomotor dissociation is a common feature of LHON. (Am J Ophthalmol 1998;126:291–295. © 1998 by Elsevier Science Inc. All rights reserved.)
L
EBER HEREDITARY OPTIC NEUROPATHY (LHON) IS
a maternally inherited disorder that typically causes severe visual loss in one eye that is followed weeks to months later by similar visual loss in the opposite eye.1–3 Specific point mutations within the portions of mitochondrial DNA that code for respiratory chain proteins are identified in at least 90% of symptomatic members of multigeneration pedigrees.4 Certain clinical features in symptomatic individuals favor the peripapillary retina as the site of initial injury to the visual system, although the precise location and mechanism responsible for the visual loss in this condition remains unknown.5–7 Three lines of evidence suggest that the neuropathic process associated with symptomatic LHON may spare some or all of the retinal ganglion cell
ELSEVIER SCIENCE INC. ALL
RIGHTS RESERVED.
291
METHODS
bodies, or their axonal projections, subserving the afferent limb of the pupillary light reflex. Many investigators have observed that the pupillary light reaction is surprisingly brisk in affected eyes.8 –10 In fact, Bynke and associates10 did not observe a relative afferent pupillary defect (RAPD) in a carefully studied patient with LHON who presented with monocular involvement. Furthermore, Wakakura and Yokoe11 found that the constriction amplitude of the direct pupillary light response, which was recorded with video pupillography, was no different in affected eyes from patients with LHON than in normal controls. Finally, Nakamura and associates12 found that the latency of the early response of the photic blink reflex, which was thought to be mediated by visual afferent fibers that project to the midbrain pretectum, in most affected eyes of patients with LHON was similar to that in normal controls. Bynke and associates10 consider that relative preservation of the pupillary light reaction supports the peripapillary retina, not the optic nerve, as being the primary site of injury in LHON. Nikoskelainen and associates9 suggest that a brisk pupillary light reaction differentiates LHON from other optic neuropathies. In clinical practice, the integrity of the afferent pupillomotor pathway is objectively assessed by performing the swinging flashlight test to identify an RAPD.13 The size of the RAPD is proportional to the degree of visual field loss present in unilateral disorders and to the disparity in the degree of visual field loss between the two eyes in bilateral conditions.14 –16 If the retinal ganglion cells or their axonal projections that subserve the pupillary light reaction were selectively spared in LHON, as has been suggested by some investigators,11,12 either no RAPD or a smaller than expected RAPD would be observed in patients with unilateral involvement. On the other hand, if this hypothesis were incorrect, an RAPD would consistently be found in such a patient, the size of which would be proportional to the degree of visual field loss. A retrospective clinical study was conducted to further assess the hypothesis that visual-pupillomotor dissociation exists in patients with LHON. 292
AMERICAN JOURNAL
WE REVIEWED CASE RECORDS OF PATIENTS WHO FUL-
filled all of the following entry criteria: (1) the presence of a primary mitochondrial DNA mutation at nucleotide position 11778, 3460, or 14484; (2) symptoms of visual loss in only one eye; (3) normal visual acuity and visual field in the asymptomatic eye; (4) no concurrent or previous ocular (for example, glaucoma), neurologic (for example, multiple sclerosis), or systemic (for example, diabetes) disorder that might cause an optic neuropathy or retinopathy or that could adversely influence the ability to detect an RAPD; and, (5) an RAPD was sought by an examiner who routinely uses neutral density filters during the swinging light test. The last criterion was included because a quantified measurement of the RAPD was desired, if one were present, to compare with the visual field loss in an affected patient. Although this was a retrospective study, assessment of pupillary reactions and quantification of an identified RAPD were performed by all the coinvestigators using the technique advocated by Thompson and associates.17,18 In brief, the technique involves introduction of neutral density filters of successively greater strength (in log units) before the unaffected eye during the swinging light test. At some point, the amount of light stimulus to the unaffected eye was dimmed sufficiently so that the RAPD was no longer apparent. The size of the RAPD in that patient was then defined as the number of log units required to neutralize that sign. Because of the stringent entry criteria, we had to rely on different sources to collect a sufficient number of case records for this study. One case was evaluated by the principal investigator (D.M.J.). Four cases were identified by reviewing the medical records of all patients evaluated at the University of Iowa Hospital and Clinics who underwent molecular assay confirmation by one of us (E.M.S.). Two cases were identified by contacting neuro-ophthalmologists who had received their fellowship training with H. Stanley Thompson, MD (Iowa City, Iowa), a long-standing advocate of measuring the RAPD with neutral density filters.17,18 Finally, three cases were identified by advertising our interest in collecting such cases on NANOSNET, the internet elecOF
OPHTHALMOLOGY
AUGUST 1998
tronic-mail group sponsored by the North American Neuro-ophthalmology Society. One of these patients (Case 8) had been previously reported.19 The following information was abstracted from the medical records: age and gender; time interval from onset of visual loss to neuro-ophthalmologic examination; mitochondrial DNA mutation; visual acuity of the symptomatic and asymptomatic eye; visual fields; and whether an RAPD had been identified and, if so, its size as determined using neutral density filters. These variables were entered into a commercially available database and statistical analysis software system (Prism, GraphPad Software, San Diego, California). In addition to identifying whether RAPDs existed in this population of patients, we were also interested in determining how the size of the measured RAPD, if present, compared with the size of the RAPD predicted on the basis of documented visual field loss. For patients who underwent testing of their visual field using a Goldmann perimeter, we used the visual field template derived by Thompson and associates14 to estimate the predicted size of their RAPD. Two patients underwent visual field testing using Program 30-2 of the Humphrey Field Analyzer (Humphrey-Zeiss, San Leandro, California). For these patients, the linear regression line determined by Kardon and associates16 was used for predicting the RAPD. We used the Wilcoxon signed rank test (two-tailed) to compare the size of the measured and predicted RAPD. Linear regression was used to further analyze the relationship between these two variables. We used the Spearman rank correlation test (two-tailed) to determine whether a relationship existed between visual acuity and the measured RAPD, and between the time interval from the onset of visual loss to examination and the measured RAPD. When analyzing the visual acuity relationship, we converted the Snellen measurement to log (MAR)21, where MAR equaled the minimum angle of resolution, which was determined by dividing the numerator by the denominator. We arbitrarily assigned a Snellen acuity of 20/800 for patients whose visual acuity was in the counting fingers range and 20/1600 if it was in the hand motions range. VOL. 126, NO. 2
TABLE. Clinical Variables of 10 Patients With Leber Hereditary Optic Neuropathy and Unilateral Visual Loss Patient No., Age (yrs), Sex
1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
36, F 31, M 37, F 17, M 9, M 49, M 19, M 34, M 38, F 24, F
Interval* (wk)
DNA Mutation
Snellen Visual Acuity
Measured
Predicted†
7 36 6 6 10 48 10 24 12 40
3460 11778 11778 3460 11778 14484 3460 11778 11778 11778
20/300 CF 2 ft CF 3 ft 20/200 20/200 20/400 CF 3 ft CF 8 ft 20/400 HM
1.4 1.8 1.0 0.9 0.3 0.6 0.8 0.6 0.8 1.8
0.9 2.2 0.9 0.6 0.9 0.6 1.1 0.9 1.7 2.5
RAPD (log units)
RAPD 5 relative afferent pupillary defect; CF 5 counting fingers; HM 5 hand motions. *Time from visual loss to evaluation. † Derived from Goldmann visual field defects in all patients except patients 6 and 7, who were tested with automated perimetry.
RESULTS THE TABLE SUMMARIZES THE MAJOR CLINICAL FEA-
tures of the 10 patients who were included in this study. All patients had an RAPD that ranged in size from 0.3 to 1.8 log units (median, 0.9 log units; mean, 1.0 log units). The size of the predicted RAPD (that is, based on degree of visual field loss) in the 10 study patients ranged in size from 0.6 to 2.5 log units (median, 0.9 log units; mean, 1.2 log units). There was no significant difference (P 5 .13) between the size of the measured RAPD and the predicted RAPD. Linear regression (Figure 1) identified a significant relationship between the measured and predicted RAPD (r2 5 0.55; P 5 .014). No correlation existed between the size of the measured RAPD and visual acuity (r 5 0.44; P 5 .20) or the time interval from onset of visual loss to evaluation (r 5 20.04; P 5 .92).
DISCUSSION IN THIS STUDY POPULATION OF PATIENTS WITH LHON
and monocular visual loss, we found that an RAPD was universally present and that its size was propor-
RELATIVE AFFERENT PUPILLARY DEFECTS
293
sized RAPDs have not often been recognized in symptomatic patients with LHON. When a patient is evaluated at the onset of visual loss in the first eye, the diagnosis of LHON often is not initially suspected, because many affected individuals do not have a positive family history and the characteristic peripapillary microangiopathy is either absent or not recognized.1–3 Because the area of impaired visual field is relatively small in this condition during the early phase,5 the direct pupillary light reaction of the affected eye appears brisk. However, a pupil can still react briskly yet demonstrate a sizable RAPD during the swinging flashlight test when the direct pupillary reactions and the latency and degree of escape can be compared between the two eyes.17 Unless a careful comparison is made of the pupillary reactions of the two eyes during the swinging flashlight test, an RAPD may not be identified during the early stage of LHON. It is often not until the patient develops visual loss in his or her second eye that LHON becomes a suspected diagnosis. At that point, however, the visual loss in the two eyes is more in balance, so the preexisting RAPD is either reduced in size or completely neutralized. It is also possible that during the early phase of LHON (that is, when the visual loss appears to be unilateral) subclinical optic nerve or retinal dysfunction in the fellow eye could reduce the magnitude of the afferent pupillary defect in the symptomatic eye. Our results do not support the hypothesis that some critical period of time must elapse before injury to the pupillomotor fibers is sufficient to result in a clinically detectable RAPD; there was no correlation between the size of the RAPD in our patients and the time interval between the onset of visual loss and evaluation. Because our sample size was small, we cannot state that pupillomotor input is impaired in all cases of LHON. It is still possible that some affected patients have a relative sparing of pupillomotor function that is defined by variables that we did not assess or remain unknown. However, it seems counterintuitive that selective sparing of a certain population of retinal ganglion cells or their axonal projections would occur in a disorder that causes marked generalized injury to fibers of the papillomacular bundle and their central projections.21,22
FIGURE. Linear regression analysis shows a significant relationship (r2 5 0.55) between the measured and predicted relative afferent pupillary defect (RAPD). The slope (0.97) of the regression line (solid line) is significantly different than zero (P 5 .014). The 95% confidence intervals (broken lines) of the slope (0.25– 1.69) are shown above and below the regression line.
tional to the degree of associated visual field loss. We found no evidence to support the hypothesis that a visual-pupillomotor dissociation of retinal ganglion cell function occurs in patients with symptomatic LHON. Accordingly, our data do not support the notion that the presence of a brisk direct pupillary light reaction or the absence of a RAPD in a patient with unilateral unexplained visual loss should, by itself, necessarily prompt consideration of a diagnosis of LHON. Yoshitomi and associates20 used pupil perimetry to evaluate a patient with LHON and monocular visual loss, and they were also unable to demonstrate visual-pupillomotor dissociation. They used an infrared camera to record and measure the change of pupillary area that occurred in response to light stimulation delivered by a modified Goldmann perimeter at various target locations throughout the visual field. They found impaired pupillary reactions in target locations that corresponded to the patient’s central scotoma. We can only speculate as to why appropriately 294
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ACKNOWLEDGMENT
We dedicate this project to H. Stanley Thompson, MD (Iowa City, Iowa), in honor of his retirement. During his 30-year career in the Department of Ophthalmology at the University of Iowa Hospitals and Clinics, Dr Thompson quietly taught us the value of watching and measuring the pupil in order to gain insight into the function of the afferent and efferent visual system.
9.
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