- Email: [email protected]
Visual Acuity Impairment in Patients with Retinitis Pigmentosa
Visual Acuity Impairment in Patients with Retinitis Pigmentosa Sandeep Grover, MD/ Gerald A. Fishman, MD/ Kenneth R. Alexander, PhD,l Robert J. Anderson, PhD,2 Deborah J. Derlacki, BAl Purpose: The authors evaluated visual acuity impairment in 906 patients from 742 families with either isolated or various identifiable genetic subtypes of retinitis pigmentosa (RP) to determine the severity of their visual acuity impairment. Emphasis was placed on the prevalence of total blindness and visual acuity of 20/200 or worse in this group of patients. Methods: This cross-sectional retrospective study included all patients with RP who met certain entrance criteria and were examined by one of the authors (GAF). The authors analyzed the eye of each patient with the best-corrected visual acuity on their most recent visit. Results: Seventeen patients with a sector form of RP were excluded from the authors' primary analysis. In the remaining group of 889 patients, 710 (80%) had a visual acuity of better than 20/200, 648 (73%) showed a visual acuity of 20170 or better, and 489 (55%) had a visual acuity of 20/40 or better in at least 1 eye. Seventy-five patients (8%) had visual acuity of count fingers or worse in their best eye. There was only one patient with no light perception in each eye. Patients with autosomal dominant RP, as a group, had the least severe and those with X-linked recessive RP had the most severe impairment in visual acuity. Those with autosomal recessive disease were intermediate in severity of visual impairment. Conclusions: Analysis of visual acuity in this large group of patients with RP, which genetically is representative of patients with RP seen in the United States by those who specialize in retinal disease, showed that it was rare for the patients to lose all visual acuity from the disease itself. Further, legal blindness from visual acuity loss, defined as best-corrected visual acuity that is no better than 20/200 in at least one eye, occurred in a relatively small percentage (20%) of our patient population, whereas approximately half of all patients and 42% of those older than 60 years had a visual acuity of 20/40 or better in at least one eye. The extent of impairment in visual acuity was associated with the genetic subtype of the disease. Ophthalmology 1996; 103: 1593-1600
Originally received: November 27, 1995. Revision accepted: May 30, 1996. 1 Department of Ophthalmology and Visual Sciences, University of Illinois, Chicago. 2 Division of Epidemiology-Biostatistics, University of Illinois, Chicago. Presented in part at the ARVO Annual Meeting, Ft. Lauderdale, April 1995, and the Macula Society Annual Meeting, Tucson, February 1996. Supported by a center grant from The Foundation Fighting Blindness, Baltimore, Maryland, and by research grant EY08301 (Dr. Alexander)
Retinitis pigmentosa (RP) defines a spectrum of inherited, progressive retinal degenerations having common features including night blindness, progressive loss of peripheral visual fields, reduced or nondetectable electroretinogram amplitudes, and characteristic pigmentary degenfrom the National Eye Institute, National Institutes of Health, Bethesda, Maryland. Reprint requests to Gerald A. Fishman, MD, UIC Eye Center, University of Illinois at Chicago (M/C 648),1855 W. Taylor St, Chicago, IL 60612.
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Table 1. Age Demographics in Various Genetic Subtypes Age
AD (n = 151)
AD (sect) (n = 17)
AR (n=117)
(n = 81)
XL
ISO (n = 416)
INDET (n = 124)
Mean Range Mean + 1 SD Mean - 1 SD
42 4-88 61.02 23.36
49 19-82 69.83 28.89
46 12-80 63.35 28.36
31 4-77 46.44 15.37
42 3-82 59.76 24.78
39 5-77 56.54 21.16
AD = autosomal dominant; AO(sect) = sectorial; AR = autosomal recessive; XL = X-linked recessive; ISO = isolated; INOET = indeterminate; SO = standard deviation.
erative changes of the retina. The mode of inheritance can be autosomal dominant, autosomal recessive, or Xlinked recessive. Retinitis pigmentosa often has been cited as a blinding di~ease . 1-7 Most of these citations fail to specify the definition of blindness, which could refer to either total blindness or the legal definition of blindness. Although a number of previous studies have documented the natural history of visual impairment in this disease,8-15 limited data are available on the extent of visual acuity loss in a large group of patients with RP. To address this issue of severity in visual acuity loss, we investigated the visual acuity impairment in various genetic subtypes of RP by conducting a retrospective cross-sectional study on 906 such patients, representing data from all patients with RP accessible to the authors that fulfilled certain entrance criteria.
Methods We evaluated the vision of 906 patients from 742 families with various genetic SUbtypes of RP, including autosomal dominant (n = 151), autosomal recessive (n = 117), X-linked recessive (n = 81), and isolated or simplex cases (n = 416) in which the patient was the only known affected family member. Also included were 124 patients with a genetic subtype that was termed indeterminate, because a specific genetic subgroup could not be assigned unambiguously, although at least 2 family members were known to be affected. We identified and separately analyzed data from autosomal dominant patients who had a sector form of RP (n = 17), because these patients often can be predicted to have a good visual prognosis. 12,15 The criteria for assignment into different genetic categories have been described previously by one of the authors. 16 The cases included in this study represent the total number of patients who were seen and diagnosed as having RP by one of the authors (GAF) over a period of 2 decades, and on whom best-corrected visual acuities had been obtained. The patients had been diagnosed as having RP by tests and historic criteria described previously.16 There were 382 men and 524 women in the study. Table 1 lists the mean and the age range of patients within each genetic SUbtype. The total age range was 3 to 88 years with a mean age of 41 years. The mean ages in the
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autosomal dominant, autosomal recessive, and isolated groups were 42, 46, and 42 years, respectively. The Xlinked recessive group had a mean age of 31 years, the indeterminate group had a mean age of 39 years, and the dominant sector group had a mean age of 49 years. The best-corrected monocular visual acuities were obtained from each patient. For the majority of patients in the study, the visual acuities were obtained using Snellen, HOTV, or Feinbloom low vision charts by either of two examiners. The highest acuity value for each patient on the most recent visit was used in the analysis. We note that although a few patients had different visual acuities in the two eyes, as a group, the visual acuities of the two eyes of the patients were correlated significantly (Spearman r = 0.85, P < 0.01). Massof et al 17 also noted bilateral symmetry of visual acuity in patients with RP. An ophthalmologic examination, including slit-lamp biomicroscopy and a detailed retinal examination, was performed by one of us (GAF). Most of the patients had peripheral visual fields measured on a Goldmann perimeter, and the majority underwent electroretinogram testing. Patients with systemic abnormalities associated with RP, such as Usher syndrome or the Bardet-Biedl syndrome, were excluded from the study. We also did not include patients with cone-rod dystrophy. Of 918 patients whose charts were reviewed, 12 patients were excluded, either because a best-corrected visual acuity had not been obtained (n = 9) or because the patients showed bilateral visual acuity loss due to causes other than, or in addition to, RP, such as keratoconus (n = 1), retinal detachment (n = 1), or solar retinopathy (n = 1). However, 24 patients with marked unilateral impairment of vision due to causes other than RP were included because our analysis was performed on the better eye as indicated from the bestcorrected visual acuity results. Patients with lens opacities, pseudophakia, and aphakia were included in the study.
Results Seventeen patients with a sector form of autosomal dominant RP were analyzed separately. An assessment of the visual acuity impairment in the remaining group of 889 patients with RP, irrespective of age and genetic subtype, showed that 710 (80%) had a visual acuity of better than 20/200, 648 (73%) had a visual acuity of 20/70 or better,
Grover et al . Visual Impairment in Patients with RP Table 2. Distribution of Patients with Retinitis Pigmentosa According to Genetic Subtype and Visual Acuity Total*
Visual Acuity 20/40 or better 20/70 or better Better than 20/200 20/200 or worse CF or worse
AD
AD (sect)
AR
INDET
ISO
(n = 889)
(n = 151)
(n = 17)
(n=117)
XL (n = 81)
(n = 416)
(n = 124)
No. (%)
No . (%)
No. (%)
No . (%)
No. (%)
No. (%)
No. (%)
109 120 124 27 10
15 (88) 17 (100) 17 (100) o (0)
45 76 88 29 15
23 44 48 33 11
235 312 349 67 28
77 96 101 23 11
489 648 710 179 75
(55) (73) (80) (20) (8)
AD = autosomal dominant; sect counting fingers.
=
sector; AR
=
(72) (80) (82) (18) (7)
0(0)
autosomal recessive; XL
= X-linked
(39) (65) (75) (25) (13)
recessive; ISO
(28) (54) (59) (41) (14)
=
isolated; INDET
(57) (75) (84) (16) (7)
=
(62) (77) (82) (18) (9)
indeterminate; CF
=
* Excludes the AD sector patients.
and 489 (55%) had a visual acuity of 20/40 or better in at least 1 eye. Seventy-five patients (8%) showed a visual acuity of count fingers or worse in the eye with better vision (Table 2). There was only one patient with no light perception in each eye in the entire group. Analyzing the visual acuity data according to genetic subtypes, without consideration for age, showed that as a group, patients with autosomal dominant RP had less severe impairment of visual acuity, whereas those with Xlinked recessive disease had the most severe impairment, despite the fact that the X-linked group was the youngest group of all the genetic subtypes. For example, 72% of the patients with autosomal dominant, 62% of the indeterminate, 57% of the isolated, 39% of the autosomal recessive, and 28% of the X-linked recessive types of RP had a visual acuity of 20/40 or better in at least one eye (Table 2). Among these five RP subgroups, these rates were significantly different (P < 0.001). Modeling the data with logistic regression, without adjustments for multiple comparisons, showed that the isolated and the indeterminate groups were equivalent to each other but different from the other three subtypes. Additionally, the dominant, recessive, and X-linked groups were different from each other. We also examined other categories of visual acuity across genetic subtypes, still without considering age (Table 2). For the two visual acuity categories of 20170 or better and better than 201200, a higher percentage of patients with autosomal dominant, isolated, and indeterminate RP had visual acuity values within these limits than did patients with autosomal recessive and X-linked recessive RP. Alogistic regression analysis of these data, without adjustment for multiple comparisons, confirmed that the dominant, isolated, and indeterminate groups were similar to each other, but different from the X-linked recessive and the autosomal recessive groups, and that the latter two groups were different from each other. For the visual acuity category of count fingers or worse, the number of patients in each of the genetic subgroups was not sufficient for statistical analysis, but we note that 14% of X-linked recessive, 13% of autosomal recessive, 9% of
indeterminate, and 7% each of the isolated and autosomal dominant groups had this level of visual acuity (Table 2). We then categorized the patients with RP into four arbitrary age groups without considering genetic SUbtype. More than 50% of patients in each of the age groups 120, 21-40, and 41-60 years had a visual acuity of 201 40 or better in at least one eye (Table 3). Of note, 62 (42%) of 149 patients in the age group older than 60 years had a visual acuity of 20/40 or better in at least 1 eye. Analyzing for the prevalence of legal blindness based on a visual acuity criterion alone, we noted that, overall, 179 patients (20%) showed a visual acuity of 20/200 or worse in the eye with better acuity (Table 2). The percentage of patients with visual acuity of 20/200 or worse increased with age, ranging from 10% in the 1- to 20year-old age group to 28% in the 0Ider-than-60-years age group (Table 3). Further analysis considered a comparison of genetic SUbtype and visual acuity within each age group. Because exploration of separate visu¥ acuity dichotomizations compounds the multiple comparisons problem, we chose instead to restrict our analysis to the dichotomization that reflects legal blindness (i.e., visual acuity of 20/200 or worse). An overall comparison of legal blindness rates among the five subgroups was done. We then used a Bonferroni correction for the 10 pairwise comparisons of the legal blindness rates among these genetic subgroups; hence, the P value needed to be less than 0.005 to be considered statistically significant. Table 4 highlights the distribution of patients with RP with a visual acuity of 20/200 or worse by genetic subtype and age group. Irrespective of the genetic subtype, few patients in the age group of 1 to 20 years had a visual acuity of 20/200 or worse in both eyes. Statistically, there was no significant difference among the five genetic subgroups (P = 0.4). In the age group of 41 to 60 years, 80% of the X-linked patients were legally blind, based on a visual acuity criterion, as compared with 12% of autosomal dominant, 17% of isolated, 23% of indeterminate, and 27% of autosomal recessive groups. In this age
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Table 3. Distribution of Patients with Retinitis Pigmentosa by Visual Acuity and Age* 1-20 Yrs
21-40 Yrs
41-60 Yrs
> 60 Yrs
Visual Acuity
No . (%)
No. (%)
No. (%)
No . (%)
20/15-20/40 20/50- > 20/200 20/200- > CF CF-NLP
87 (66) 32 (24) 13 (10)
178 77 40 18
162 66 31 36
62 45 21 21
Total (n CF
= 889)
132
(57) (25) (12) (6)
(55) (22 ) (11) (12)
295
313
(42) (30) (14) (14)
149
= counting fingers; NLP = no light perception.
* Excludes the autosomal d ominant sector patients.
group, there was a highly significant difference among the subtypes (P < 0.001). Pairwise comparisons in this group indicated a significant difference between X-linked recessive and each of the other subtypes (autosomal dominant-X-linked, P < 0.00001; autosomal recessive-Xlinked, P = 0.0004; isolated-X-linked, P < 0.00001; indeterminate-X-linked, P = 0.0001). No other pairwise significant differences were observed. In the older than 60 years age group, approximately one fourth to one third of the patients had a visual acuity of 201200 or worse in each eye. The X-linked group was excluded from statistical analysis because there was only one patient. There was a significant difference among the sUbtypes (P = 0.04), but no pairwise comparisons were statistically significant with a Bonferroni adjustment. We also examined different levels of visual acuities by age groups within each genetic subtype (Table 5). Because of the small sample sizes in many of the subgroups, standard statistical methods could not be used to analyze these data. However, there were certain noteworthy trends. In the 21 to 40 years age group, 78% of the autosomal dominant patients had a visual acuity of 20/40 or better. This compared with 64% in the isolated, 33% in the autosomal recessive, and 20% in the Xlinked recessive groups. In the group of patients with RP who were older than 60 years of age, 53% of the patients with autosomal dominant, 45% of the indeterminate, 42% of the isolated, and 26% of those with
autosomal recessive had a visual acuity of 20/40 or better in at least one eye. A separate analysis of autosomal dominant patients with a sector form of RP (n = 17) showed that all of them had a visual acuity of 20/70 or better. In fact, 15 patients (88%) had a visual acuity of 20/40 or better in at least I eye (Table 2). We also determined the pattern of follow-up in our population of patients with RP (Table 6). The mean number of follow-up visits was 3.2, and the mean duration of followup was 4.5 years. Four hundred six of 906 patients had only one visit. Our pattern of follow-up is on a i-year, or occasionally every 2-year, basis, and so we excluded from our analysis 70 patients who were seen only once within 2 years before the time of the study. We then analyzed the mean ages and visual acuities of the remaining 336 patients, who had 1 visit only with no subsequent follow-up, and compared them with 312 patients who had been seen for 5 years or more (Table 7). The comparison showed that at the time the study was conducted, the mean ages and the mean visual acuities were similar in these two groups (for ages, P = 0.08; for visual acuities, P = 0.68). Additionally, of the 75 patients who had a visual acuity of count fingers or worse, 30 (40%) of them were followed up for a duration of 5 years or more, whereas 36 (48%) of the patients were seen only once. This was similar to the group of 489 patients with a visual acuity of 20/40 or better, where 156 (32%) were seen for a duration of 5 years or more and 230 (47%) were seen only once.
Table 4. Distribution of Patients with Retinitis Pigmentosa with Visual Acuity of 20/200 or Worse by Age .and Genetic Subtype Age (yrs) 1- 20 21-40 41 - 60 >60
AD
AR
XL
ISO
INDET
No . (%)
No. (%)
No. (%)
No . (%)
No. (%)
3 6 6 12
2 9 11 8
3 (12) 13 (37) 16 (80)
4 22 25 16
(14) (12) (12) (38)
(18) (23) (27) (30)
(8) (15) (17) (24)
AD = autosomal dominant; AR = autosomal recessive; XL = X-linked recessive; ISO = isolated; INDET = indeterminate.
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Discussion In the literature, RP is frequently referred to as a blinding disease. I - 7 However, what is not always apparent is whether such references address the issue of total blindness or legal blindness. Although the criterion for legal blindness encompasses both visual acuity and peripheral fields, the present study analyzed visual acuity in these patients to document the severity of visual impairment that can be noted in a group of patients with RP with various genetic subtypes. Although others have commented on visual acuity impairment in such patients, 10.11.15,16.18,19 none have dealt with such a large population of patients with RP. Legal blindness due to visual acuity impairment occurs when best-corrected visual acuity is no better than 201 200 in at least one eye. In our popUlation of 889 patients, 20% would have been considered legally blind by the criterion of visual acuity impairment alone. Conversely, 55% of our patients would have qualified for an unrestricted drivers license based on a visual acuity criterion level of 20/40 or better in at least one eye. Further, 73% of this total group of patients would have qualified for a license restricted to daylight driving in at least half the states in the United States, based on a visual acuity criterion level of 20nO or better in at least 1 eye (27 states; 2 states do not have any legislation for restricted driving licenses).2o Consideration of an acuity criterion in these patients is relevant because even those with considerable peripheral field loss have been shown to pass peripheral field screening procedures for obtaining a drivers license because of flawed testing protocols. 21 We found a notable difference in the visual acuities in certain genetic subtypes. Visual acuity distinctly was less impaired in the autosomal dominant group, with 72% of patients having a visual acuity of 20/40 or better, as compared with 28% in the X-linked recessive group. Those with autosomal recessive disease were intermediate in severity, with 39% having fl visual acuity of 20/40 or better in at least one eye. This trend between genetic SUbtypes also has been noted previously.22,23 Pearlman et af4 found that 52% of 135 patients with RP, including all genetic subtypes, had a visual acuity of better than 20/50, which compares well with our observation of 55% in 489 patients with visual acuity of 20/40 or better. Mannor/ 5 in a study of 179 eyes from 91 patients with either autosomal recessive or autosomal dominant RP, observed that from 60% to 90% of his patients younger than 20 years of age had a visual acuity of 201 40 or better, which is similar to our study, where 55% of autosomal recessive and 72% of autosomal dominant patients in the same age group had a visual acuity of 201 40 or better. Berson et al,25 in a study of 484 patients from 456 families with RP, analyzed the visual acuities (20/40 or better and 20150 or worse in the better eye) of these patients within each genetic subtype. Their three age groups (6-19 years, 20-39 years, and 40+ years) were similar to those included in our study, as were the proportion of patients in each genetic subgroup. From our
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Table 6. Pattern of Follow-up of Patients with Retinitis Pigmentosa* No. of Visits and Years of Follow-up
= 168)
(n
:51 Visit Yr
2-4 Visits Yrs
5-8 Visits Yrs
>12 Visits Yrs Maximum Visits Yrs Mean Visits Yrs Median Visits Yrs
= 117)
(n
ISO
= 81)
(n
= 416)
INDET (0 = 124)
61 68
53 61
31 33
202 244
59 65
66 25
36 16
33 9
127 51
45 22
22 26
14 18
14
13
54 52
15 18
14 21
12 6
0 12
17 36
4 13
5 28
2 16
4 13
16 33
1 6
21 19
16 19
15 22
21 20
15 19
9-12 Visits Yrs
XL
AR
AD
(n
3.73 5.64
3.32 4.50
3.22 5.97
3.17 3.91
2.77 3.80
2 3
2 1
2 4
2 1
2 1
AD = autosomal dominant; AR = autosomal recessive; XL = X-linked recessive; ISO = isolated; INDET = indeterminate. * Rows indicate the number of patients with the corresponding number of visits or duration (years) of follow-up.
analysis of their data, the proportion of their patients with visual acuity of 20/40 or better showed findings consistent with our observations. The number of patients with the sector form of autosomal dominant RP in our study was relatively small (n = 17). However, the observation that 15 (88%) of these 17
patients had 20/40 or better visual acuity in at least 1 eye, and the remaining 2 patients had a visual acuity between 20/50 and 20170 (both patients being older than 60 years of age) confirms previous observations that these patients have a relatively mild impairment of central vision. 12 ,15 As far as total blindness was concerned, in our group
Table 7. Comparison of Mean Visual Acuities and Ages between Patients with Retinitis Pigmentosa Seen Only Once (excluding those seen within 2 years before the study) and Those Seen for a Duration of at Least 5 Years Mean Visual Acuity (IogMAR)
Mean Age
Recent Visitt
AD AR XL ISO INDET
46.9 46.6 34.3 46.3 38.8
(75) (40) (39) (121) (37)
Total
44.0 (312)
1 Visit Only
42.1 46.1 28.4 42.3 41.6
(51) (43) (26) (167) (49)
41.6 (336)
Recent Visitt
0.4 0.7 0.9 0.6 0.6
(75) (40) (39) (121) (37)
0.6 (312)
AD = autosomal dominant; AR = autosomal recessive; XL = X-linked recessive; IS O * Numbers in parentheses indicate the actual number of patients. t Those patients who had .,,5 years of follow-up.
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= isolated;
1 Visit Only
0.4 0.8 1.1 0.5 0.6
% of Patients with 1 Visit Only
(51) (43) (26) (167) (49)
30.4 36.8 32. 1 40.1 39.5
0.6 (336)
37.1
INDET
= indeterminate.
Grover et al . Visual Impairment in Patients with RP of 906 patients, only 1 patient in the isolated group was found to have no light perception in both eyes. As noted, legal blindness from vision loss occurred in 20% of our patients, whereas approximately 50% of this population had a visual acuity of 20/40 or better in at least 1 eye. The proportion of various genetic sUbtypes in the large group of patients with RP included in our present study is consistent with that previously reported from our laboratory.26,27 The genetic percentages (by pedigrees) also are similar to those reported in other cohorts of patients with RP within the United States by Bunker et at2 s and Berson et al. 25 The genetic percentages (by number of patients) is similar to that of other studies done by Heckenlively et al 19 and Heckenlively29 and Boughman and Caldwe1l30 (by probands) in the United States. The mean age of our patients, at the time the study was conducted, was 41 years, whereas in his study of 76 patients with RP, Heckenlivell9 found a mean age of 38.5 years. Our cohort of patients with RP likely represents genetic percentages and an age distribution similar to those seen by retinal specialists in the Unites States who see a substantial number of such patients. Future studies on other cohorts of patients with RP with a markedly different composition of various genetic subgroups or ages could disclose findings that differ from those seen in our population. The cross-sectional nature of our study lends itself to speculation as to any possible referral bias and whether our population is representative of the overall target population of patients with RP in the United States. A longitudinal study on such patients would address the concern that patients with RP with substantial impairment of their vision are no longer motivated to seek ophthalmic consultation. Nevertheless, in this cross-sectional study of our patients with RP, 30 (40%) of 75 patients with visual acuity of counting fingers or worse were followed up for a duration of 5 years or more compared with 156 (32%) of 489 with a visual acuity of 20/40 or better who were followed up for this duration. A number of patients with marked visual acuity impairment were compulsively attentive to their followup commitments, not infrequently because they needed continued attention to numerous documents such as disability, transportation, and medical forms. Further, in our cohort of patients with RP, the mean ages and the visual acuities in the subgroup of patients who had been seen only once and those who had been seen for 5 years or more (visual acuities on their most recent visit) were similar (Table 7). Additionally, as noted in our results, 48% of the patients who had a visual acuity of count fingers or worse were seen only once as compared with 47% of those patients who had a visual acuity of 20/40 or better. We were therefore unable to identify any differences for the number of follow-up visits in patients with the least severe compared with those with the most severe levels of impairment in their visual acuity among our patients with RP. The potential contribution of primarily posterior subcapsular lens opacities to visual acuity impairment in individual patients with RP needs to be considered. This issue was not addressed specifically in the present study or in
most other similar previous studies. It is thus possible that our visual acuity data could represent an underestimation of a patient's visual acuity potential in individual instances. It is our sense that this likely has little impact on the data for patients with visual acuity within the category of 20/200 or less because posterior subcapsular lens opacities severe enough to impact on vision to this level already had been removed. Similarly, those within the category of 20/40 visual acuity or better would not have been placed into another category based on lens opacification. It is possible that within intermediate levels of visual acuity, from approximately 20/50 to 20/80, a likely minor underestimation of visual acuity potential may have been an issue in certain individual patients. It is relevant to recall that even within a Mendelian genetic subtype, heterogeneity in disease-causing mutations can occur. Whether visual prognosis differs among the various mutations within a genetic subgroup would need to be determined by a comprehensive, collaborative study in which all patients being evaluated for visual prognosis are screened for various known disease-causing mutations. Our study represents the most comprehensive attempt to document the prevalence of severe visual acuity impairment within different age groups in a large cohort of patients with RP with various genetic subtypes. Because our sample of patients with RP is genetically similar to other groups of such patients seen by retinal specialists, at least in the United States, the results of this study on our patients should be useful for counseling other patients with RP about their potential for loss of visual acuity.
References 1. Friederich R. Eye disease in the Navajo Indians . Ann Ophthalmol 1982; 14:38-40. 2. Jay B. Prevention of blindness from retinitis pigmentosa. Trans Ophthalmol Soc UK 1978; 98:309-12. 3. Denton MJ, Chen JD, Serravalle S, et al. Analysis of linkage relationships of X-linked retinitis pigmentosa with the following Xp loci: Ll.28, 754, XJ-l.1, pERT87 and C7. Hum Genet 1988;78:60-4. 4. Sieving PA, Richards JE, Naarendorp F, et al. Dark-light: model for nightblindness from the human rhodopsin Gly-90Asp mutation. Proc Nat! Acad Sci USA 1995;92:880-4. 5. Anandakrishnan I, Musarella MA. Genetic counselling in X-linked retinitis pigmentosa. J Pediatr Ophthalmol Strabismus 1989;26:140-5.16. 6. Bloome MA, Garcia CA. Manual of Retinal and Choroidal Dystrophies. New York: Appleton-Century-Ct6fts, 1982;43. 7. Stein HA, Slatt BJ, Stein RM. A Primer in Ophthalmology. St. Louis: Mosby-Year Book, Inc., 1992;142. 8. Sunga RN, Sloan LL. Pigmentary degeneration of the retina: early diagnosis and natural history. Invest Ophthalmol 1967;6:309-27. 9. Tanino T, Olba N, Mishima S. Studies of pigmentary retinal dystrophies, III: a statistical analysis of parametric data. Klin Monatsbl Augenheilkd 1977; 170:808-13. 10. Pearlman JT. Mathematical models of retinitis pigmentosa: study of the rate of progress in different genetic forms. Trans Am Ophthalmol Soc 1979;77:643-56.
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Ophthalmology Volume 103, Number 10 , October 1996 11. Berson EL, Sandberg MA, Rosner B, et al. Natural course of retinitis pigmentosa over a three year interval. Am J OphthalmoI1985;99:240-51. 12. Farber MD, Fishman GA, Weiss RA. Autosomal dominantly inherited retinitis pigmentosa: visual acuity loss by subtype. Arch Ophthalmol 1985; 103:524-28. 13. Massof RW, Finkelstein D. A two stage hypothesis for the natural course of retinitis pigmentosa. In: Zrenner E, Krastel H, Goebels HH, eds. Research in Retinitis Pigmentosa. Elmsford, NY: Pergamon Press, Inc, 1987;62:29-58 . 14. Massof RW, Dagnelie G, Benzschawel T, et a1. First order dynamics of visual field loss in retinitis pigmentosa. Clio Vis Sci 1990;5:1-26. 15. Marmor MF. Visual loss in retinitis pigmentosa. Am J Ophthalmol 1980; 89:692-8. 16. Fishman GA. Retinitis pigmentosa-visual loss. Arch Ophthalmol1978;96:1185-8. 17. Massof RW, Finkelstein D, Starr SJ, et a1. Bilateral symmetry of vision disorders in typical retinitis pigmentosa. Br J Ophthalmol 1979;63:90-6. 18. Madreperla SA, Palmer RW, Massof RW, Finkelstein D. Visual acuity loss in retinitis pigmentosa-relationship to visual field loss. Arch Opbthalmol 1990; 108:358-61. 19. Heckenlively JR, Yoser SL, Friedman LH, Oversier JJ. Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol 1988; 105 :504-11.
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20. Keltner JL, Johnson CA. Visual function, driving safety, and the elderly. Ophthalmology 1987;94:1180-8. 21. Szlyk J, Fishman GA, Master SP, Alexander KR. Peripheral vision screening for driving in retinitis pigmentosa patients. Ophthalmology 1991;98:612-8. 22. Krill AE. Retinitis pigmentosa: a review. Sight Saving Review 1972;42:21-8. 23. Jay B. Hereditary aspects of pigmentary retinopathy. Trans Ophthalmol Soc UK 1972;92:1 73-8. 24. Pearlman JT, Axelrod RN, Tom A. Frequency of central visual impairment in retinitis pigmentosa. Arcb Ophthalmol 1977; 95:894. 25 . Berson EL, Rosner B, Simonoff E. Risk factors for genetic typing and detection in retinitis pigmentosa. Am J Ophthalmol 1980; 89:763-75 . 26. Fishman GA. Retinitis pigmentosa: genetic percentages. Arch Ophthalmol 1978;96:822-6. 27. Boughman JA, Fishman GA. A genetic analysis of retinitis pigmentosa. Br J Ophthalmol 1983;67:449-54. 28. Bunker CH, Berson EL, Bromley WC, et al. Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol 1984;97:357-65. 29. Heckenlively JR. RP cone-rod degeneration. Trans Am Ophtbalmol Soc 1987; 85:438-70. 30. Boughman JA, Caldwell RJ. Genetic and clinical characterization of a survey population with retinitis pigmentosa. Prog Clin BioI Res 1982;82:1 47-66.
Originally received: November 27, 1995. Revision accepted: May 30, 1996. 1 Department of Ophthalmology and Visual Sciences, University of Illinois, Chicago. 2 Division of Epidemiology-Biostatistics, University of Illinois, Chicago. Presented in part at the ARVO Annual Meeting, Ft. Lauderdale, April 1995, and the Macula Society Annual Meeting, Tucson, February 1996. Supported by a center grant from The Foundation Fighting Blindness, Baltimore, Maryland, and by research grant EY08301 (Dr. Alexander)
Retinitis pigmentosa (RP) defines a spectrum of inherited, progressive retinal degenerations having common features including night blindness, progressive loss of peripheral visual fields, reduced or nondetectable electroretinogram amplitudes, and characteristic pigmentary degenfrom the National Eye Institute, National Institutes of Health, Bethesda, Maryland. Reprint requests to Gerald A. Fishman, MD, UIC Eye Center, University of Illinois at Chicago (M/C 648),1855 W. Taylor St, Chicago, IL 60612.
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Table 1. Age Demographics in Various Genetic Subtypes Age
AD (n = 151)
AD (sect) (n = 17)
AR (n=117)
(n = 81)
XL
ISO (n = 416)
INDET (n = 124)
Mean Range Mean + 1 SD Mean - 1 SD
42 4-88 61.02 23.36
49 19-82 69.83 28.89
46 12-80 63.35 28.36
31 4-77 46.44 15.37
42 3-82 59.76 24.78
39 5-77 56.54 21.16
AD = autosomal dominant; AO(sect) = sectorial; AR = autosomal recessive; XL = X-linked recessive; ISO = isolated; INOET = indeterminate; SO = standard deviation.
erative changes of the retina. The mode of inheritance can be autosomal dominant, autosomal recessive, or Xlinked recessive. Retinitis pigmentosa often has been cited as a blinding di~ease . 1-7 Most of these citations fail to specify the definition of blindness, which could refer to either total blindness or the legal definition of blindness. Although a number of previous studies have documented the natural history of visual impairment in this disease,8-15 limited data are available on the extent of visual acuity loss in a large group of patients with RP. To address this issue of severity in visual acuity loss, we investigated the visual acuity impairment in various genetic subtypes of RP by conducting a retrospective cross-sectional study on 906 such patients, representing data from all patients with RP accessible to the authors that fulfilled certain entrance criteria.
Methods We evaluated the vision of 906 patients from 742 families with various genetic SUbtypes of RP, including autosomal dominant (n = 151), autosomal recessive (n = 117), X-linked recessive (n = 81), and isolated or simplex cases (n = 416) in which the patient was the only known affected family member. Also included were 124 patients with a genetic subtype that was termed indeterminate, because a specific genetic subgroup could not be assigned unambiguously, although at least 2 family members were known to be affected. We identified and separately analyzed data from autosomal dominant patients who had a sector form of RP (n = 17), because these patients often can be predicted to have a good visual prognosis. 12,15 The criteria for assignment into different genetic categories have been described previously by one of the authors. 16 The cases included in this study represent the total number of patients who were seen and diagnosed as having RP by one of the authors (GAF) over a period of 2 decades, and on whom best-corrected visual acuities had been obtained. The patients had been diagnosed as having RP by tests and historic criteria described previously.16 There were 382 men and 524 women in the study. Table 1 lists the mean and the age range of patients within each genetic SUbtype. The total age range was 3 to 88 years with a mean age of 41 years. The mean ages in the
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autosomal dominant, autosomal recessive, and isolated groups were 42, 46, and 42 years, respectively. The Xlinked recessive group had a mean age of 31 years, the indeterminate group had a mean age of 39 years, and the dominant sector group had a mean age of 49 years. The best-corrected monocular visual acuities were obtained from each patient. For the majority of patients in the study, the visual acuities were obtained using Snellen, HOTV, or Feinbloom low vision charts by either of two examiners. The highest acuity value for each patient on the most recent visit was used in the analysis. We note that although a few patients had different visual acuities in the two eyes, as a group, the visual acuities of the two eyes of the patients were correlated significantly (Spearman r = 0.85, P < 0.01). Massof et al 17 also noted bilateral symmetry of visual acuity in patients with RP. An ophthalmologic examination, including slit-lamp biomicroscopy and a detailed retinal examination, was performed by one of us (GAF). Most of the patients had peripheral visual fields measured on a Goldmann perimeter, and the majority underwent electroretinogram testing. Patients with systemic abnormalities associated with RP, such as Usher syndrome or the Bardet-Biedl syndrome, were excluded from the study. We also did not include patients with cone-rod dystrophy. Of 918 patients whose charts were reviewed, 12 patients were excluded, either because a best-corrected visual acuity had not been obtained (n = 9) or because the patients showed bilateral visual acuity loss due to causes other than, or in addition to, RP, such as keratoconus (n = 1), retinal detachment (n = 1), or solar retinopathy (n = 1). However, 24 patients with marked unilateral impairment of vision due to causes other than RP were included because our analysis was performed on the better eye as indicated from the bestcorrected visual acuity results. Patients with lens opacities, pseudophakia, and aphakia were included in the study.
Results Seventeen patients with a sector form of autosomal dominant RP were analyzed separately. An assessment of the visual acuity impairment in the remaining group of 889 patients with RP, irrespective of age and genetic subtype, showed that 710 (80%) had a visual acuity of better than 20/200, 648 (73%) had a visual acuity of 20/70 or better,
Grover et al . Visual Impairment in Patients with RP Table 2. Distribution of Patients with Retinitis Pigmentosa According to Genetic Subtype and Visual Acuity Total*
Visual Acuity 20/40 or better 20/70 or better Better than 20/200 20/200 or worse CF or worse
AD
AD (sect)
AR
INDET
ISO
(n = 889)
(n = 151)
(n = 17)
(n=117)
XL (n = 81)
(n = 416)
(n = 124)
No. (%)
No . (%)
No. (%)
No . (%)
No. (%)
No. (%)
No. (%)
109 120 124 27 10
15 (88) 17 (100) 17 (100) o (0)
45 76 88 29 15
23 44 48 33 11
235 312 349 67 28
77 96 101 23 11
489 648 710 179 75
(55) (73) (80) (20) (8)
AD = autosomal dominant; sect counting fingers.
=
sector; AR
=
(72) (80) (82) (18) (7)
0(0)
autosomal recessive; XL
= X-linked
(39) (65) (75) (25) (13)
recessive; ISO
(28) (54) (59) (41) (14)
=
isolated; INDET
(57) (75) (84) (16) (7)
=
(62) (77) (82) (18) (9)
indeterminate; CF
=
* Excludes the AD sector patients.
and 489 (55%) had a visual acuity of 20/40 or better in at least 1 eye. Seventy-five patients (8%) showed a visual acuity of count fingers or worse in the eye with better vision (Table 2). There was only one patient with no light perception in each eye in the entire group. Analyzing the visual acuity data according to genetic subtypes, without consideration for age, showed that as a group, patients with autosomal dominant RP had less severe impairment of visual acuity, whereas those with Xlinked recessive disease had the most severe impairment, despite the fact that the X-linked group was the youngest group of all the genetic subtypes. For example, 72% of the patients with autosomal dominant, 62% of the indeterminate, 57% of the isolated, 39% of the autosomal recessive, and 28% of the X-linked recessive types of RP had a visual acuity of 20/40 or better in at least one eye (Table 2). Among these five RP subgroups, these rates were significantly different (P < 0.001). Modeling the data with logistic regression, without adjustments for multiple comparisons, showed that the isolated and the indeterminate groups were equivalent to each other but different from the other three subtypes. Additionally, the dominant, recessive, and X-linked groups were different from each other. We also examined other categories of visual acuity across genetic subtypes, still without considering age (Table 2). For the two visual acuity categories of 20170 or better and better than 201200, a higher percentage of patients with autosomal dominant, isolated, and indeterminate RP had visual acuity values within these limits than did patients with autosomal recessive and X-linked recessive RP. Alogistic regression analysis of these data, without adjustment for multiple comparisons, confirmed that the dominant, isolated, and indeterminate groups were similar to each other, but different from the X-linked recessive and the autosomal recessive groups, and that the latter two groups were different from each other. For the visual acuity category of count fingers or worse, the number of patients in each of the genetic subgroups was not sufficient for statistical analysis, but we note that 14% of X-linked recessive, 13% of autosomal recessive, 9% of
indeterminate, and 7% each of the isolated and autosomal dominant groups had this level of visual acuity (Table 2). We then categorized the patients with RP into four arbitrary age groups without considering genetic SUbtype. More than 50% of patients in each of the age groups 120, 21-40, and 41-60 years had a visual acuity of 201 40 or better in at least one eye (Table 3). Of note, 62 (42%) of 149 patients in the age group older than 60 years had a visual acuity of 20/40 or better in at least 1 eye. Analyzing for the prevalence of legal blindness based on a visual acuity criterion alone, we noted that, overall, 179 patients (20%) showed a visual acuity of 20/200 or worse in the eye with better acuity (Table 2). The percentage of patients with visual acuity of 20/200 or worse increased with age, ranging from 10% in the 1- to 20year-old age group to 28% in the 0Ider-than-60-years age group (Table 3). Further analysis considered a comparison of genetic SUbtype and visual acuity within each age group. Because exploration of separate visu¥ acuity dichotomizations compounds the multiple comparisons problem, we chose instead to restrict our analysis to the dichotomization that reflects legal blindness (i.e., visual acuity of 20/200 or worse). An overall comparison of legal blindness rates among the five subgroups was done. We then used a Bonferroni correction for the 10 pairwise comparisons of the legal blindness rates among these genetic subgroups; hence, the P value needed to be less than 0.005 to be considered statistically significant. Table 4 highlights the distribution of patients with RP with a visual acuity of 20/200 or worse by genetic subtype and age group. Irrespective of the genetic subtype, few patients in the age group of 1 to 20 years had a visual acuity of 20/200 or worse in both eyes. Statistically, there was no significant difference among the five genetic subgroups (P = 0.4). In the age group of 41 to 60 years, 80% of the X-linked patients were legally blind, based on a visual acuity criterion, as compared with 12% of autosomal dominant, 17% of isolated, 23% of indeterminate, and 27% of autosomal recessive groups. In this age
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Table 3. Distribution of Patients with Retinitis Pigmentosa by Visual Acuity and Age* 1-20 Yrs
21-40 Yrs
41-60 Yrs
> 60 Yrs
Visual Acuity
No . (%)
No. (%)
No. (%)
No . (%)
20/15-20/40 20/50- > 20/200 20/200- > CF CF-NLP
87 (66) 32 (24) 13 (10)
178 77 40 18
162 66 31 36
62 45 21 21
Total (n CF
= 889)
132
(57) (25) (12) (6)
(55) (22 ) (11) (12)
295
313
(42) (30) (14) (14)
149
= counting fingers; NLP = no light perception.
* Excludes the autosomal d ominant sector patients.
group, there was a highly significant difference among the subtypes (P < 0.001). Pairwise comparisons in this group indicated a significant difference between X-linked recessive and each of the other subtypes (autosomal dominant-X-linked, P < 0.00001; autosomal recessive-Xlinked, P = 0.0004; isolated-X-linked, P < 0.00001; indeterminate-X-linked, P = 0.0001). No other pairwise significant differences were observed. In the older than 60 years age group, approximately one fourth to one third of the patients had a visual acuity of 201200 or worse in each eye. The X-linked group was excluded from statistical analysis because there was only one patient. There was a significant difference among the sUbtypes (P = 0.04), but no pairwise comparisons were statistically significant with a Bonferroni adjustment. We also examined different levels of visual acuities by age groups within each genetic subtype (Table 5). Because of the small sample sizes in many of the subgroups, standard statistical methods could not be used to analyze these data. However, there were certain noteworthy trends. In the 21 to 40 years age group, 78% of the autosomal dominant patients had a visual acuity of 20/40 or better. This compared with 64% in the isolated, 33% in the autosomal recessive, and 20% in the Xlinked recessive groups. In the group of patients with RP who were older than 60 years of age, 53% of the patients with autosomal dominant, 45% of the indeterminate, 42% of the isolated, and 26% of those with
autosomal recessive had a visual acuity of 20/40 or better in at least one eye. A separate analysis of autosomal dominant patients with a sector form of RP (n = 17) showed that all of them had a visual acuity of 20/70 or better. In fact, 15 patients (88%) had a visual acuity of 20/40 or better in at least I eye (Table 2). We also determined the pattern of follow-up in our population of patients with RP (Table 6). The mean number of follow-up visits was 3.2, and the mean duration of followup was 4.5 years. Four hundred six of 906 patients had only one visit. Our pattern of follow-up is on a i-year, or occasionally every 2-year, basis, and so we excluded from our analysis 70 patients who were seen only once within 2 years before the time of the study. We then analyzed the mean ages and visual acuities of the remaining 336 patients, who had 1 visit only with no subsequent follow-up, and compared them with 312 patients who had been seen for 5 years or more (Table 7). The comparison showed that at the time the study was conducted, the mean ages and the mean visual acuities were similar in these two groups (for ages, P = 0.08; for visual acuities, P = 0.68). Additionally, of the 75 patients who had a visual acuity of count fingers or worse, 30 (40%) of them were followed up for a duration of 5 years or more, whereas 36 (48%) of the patients were seen only once. This was similar to the group of 489 patients with a visual acuity of 20/40 or better, where 156 (32%) were seen for a duration of 5 years or more and 230 (47%) were seen only once.
Table 4. Distribution of Patients with Retinitis Pigmentosa with Visual Acuity of 20/200 or Worse by Age .and Genetic Subtype Age (yrs) 1- 20 21-40 41 - 60 >60
AD
AR
XL
ISO
INDET
No . (%)
No. (%)
No. (%)
No . (%)
No. (%)
3 6 6 12
2 9 11 8
3 (12) 13 (37) 16 (80)
4 22 25 16
(14) (12) (12) (38)
(18) (23) (27) (30)
(8) (15) (17) (24)
AD = autosomal dominant; AR = autosomal recessive; XL = X-linked recessive; ISO = isolated; INDET = indeterminate.
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(4) (19) (23) (25)
Grover et al
Visual Impairment in Patients with RP
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Discussion In the literature, RP is frequently referred to as a blinding disease. I - 7 However, what is not always apparent is whether such references address the issue of total blindness or legal blindness. Although the criterion for legal blindness encompasses both visual acuity and peripheral fields, the present study analyzed visual acuity in these patients to document the severity of visual impairment that can be noted in a group of patients with RP with various genetic subtypes. Although others have commented on visual acuity impairment in such patients, 10.11.15,16.18,19 none have dealt with such a large population of patients with RP. Legal blindness due to visual acuity impairment occurs when best-corrected visual acuity is no better than 201 200 in at least one eye. In our popUlation of 889 patients, 20% would have been considered legally blind by the criterion of visual acuity impairment alone. Conversely, 55% of our patients would have qualified for an unrestricted drivers license based on a visual acuity criterion level of 20/40 or better in at least one eye. Further, 73% of this total group of patients would have qualified for a license restricted to daylight driving in at least half the states in the United States, based on a visual acuity criterion level of 20nO or better in at least 1 eye (27 states; 2 states do not have any legislation for restricted driving licenses).2o Consideration of an acuity criterion in these patients is relevant because even those with considerable peripheral field loss have been shown to pass peripheral field screening procedures for obtaining a drivers license because of flawed testing protocols. 21 We found a notable difference in the visual acuities in certain genetic subtypes. Visual acuity distinctly was less impaired in the autosomal dominant group, with 72% of patients having a visual acuity of 20/40 or better, as compared with 28% in the X-linked recessive group. Those with autosomal recessive disease were intermediate in severity, with 39% having fl visual acuity of 20/40 or better in at least one eye. This trend between genetic SUbtypes also has been noted previously.22,23 Pearlman et af4 found that 52% of 135 patients with RP, including all genetic subtypes, had a visual acuity of better than 20/50, which compares well with our observation of 55% in 489 patients with visual acuity of 20/40 or better. Mannor/ 5 in a study of 179 eyes from 91 patients with either autosomal recessive or autosomal dominant RP, observed that from 60% to 90% of his patients younger than 20 years of age had a visual acuity of 201 40 or better, which is similar to our study, where 55% of autosomal recessive and 72% of autosomal dominant patients in the same age group had a visual acuity of 201 40 or better. Berson et al,25 in a study of 484 patients from 456 families with RP, analyzed the visual acuities (20/40 or better and 20150 or worse in the better eye) of these patients within each genetic subtype. Their three age groups (6-19 years, 20-39 years, and 40+ years) were similar to those included in our study, as were the proportion of patients in each genetic subgroup. From our
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Volume 103, Number 10, October 1996
Table 6. Pattern of Follow-up of Patients with Retinitis Pigmentosa* No. of Visits and Years of Follow-up
= 168)
(n
:51 Visit Yr
2-4 Visits Yrs
5-8 Visits Yrs
>12 Visits Yrs Maximum Visits Yrs Mean Visits Yrs Median Visits Yrs
= 117)
(n
ISO
= 81)
(n
= 416)
INDET (0 = 124)
61 68
53 61
31 33
202 244
59 65
66 25
36 16
33 9
127 51
45 22
22 26
14 18
14
13
54 52
15 18
14 21
12 6
0 12
17 36
4 13
5 28
2 16
4 13
16 33
1 6
21 19
16 19
15 22
21 20
15 19
9-12 Visits Yrs
XL
AR
AD
(n
3.73 5.64
3.32 4.50
3.22 5.97
3.17 3.91
2.77 3.80
2 3
2 1
2 4
2 1
2 1
AD = autosomal dominant; AR = autosomal recessive; XL = X-linked recessive; ISO = isolated; INDET = indeterminate. * Rows indicate the number of patients with the corresponding number of visits or duration (years) of follow-up.
analysis of their data, the proportion of their patients with visual acuity of 20/40 or better showed findings consistent with our observations. The number of patients with the sector form of autosomal dominant RP in our study was relatively small (n = 17). However, the observation that 15 (88%) of these 17
patients had 20/40 or better visual acuity in at least 1 eye, and the remaining 2 patients had a visual acuity between 20/50 and 20170 (both patients being older than 60 years of age) confirms previous observations that these patients have a relatively mild impairment of central vision. 12 ,15 As far as total blindness was concerned, in our group
Table 7. Comparison of Mean Visual Acuities and Ages between Patients with Retinitis Pigmentosa Seen Only Once (excluding those seen within 2 years before the study) and Those Seen for a Duration of at Least 5 Years Mean Visual Acuity (IogMAR)
Mean Age
Recent Visitt
AD AR XL ISO INDET
46.9 46.6 34.3 46.3 38.8
(75) (40) (39) (121) (37)
Total
44.0 (312)
1 Visit Only
42.1 46.1 28.4 42.3 41.6
(51) (43) (26) (167) (49)
41.6 (336)
Recent Visitt
0.4 0.7 0.9 0.6 0.6
(75) (40) (39) (121) (37)
0.6 (312)
AD = autosomal dominant; AR = autosomal recessive; XL = X-linked recessive; IS O * Numbers in parentheses indicate the actual number of patients. t Those patients who had .,,5 years of follow-up.
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= isolated;
1 Visit Only
0.4 0.8 1.1 0.5 0.6
% of Patients with 1 Visit Only
(51) (43) (26) (167) (49)
30.4 36.8 32. 1 40.1 39.5
0.6 (336)
37.1
INDET
= indeterminate.
Grover et al . Visual Impairment in Patients with RP of 906 patients, only 1 patient in the isolated group was found to have no light perception in both eyes. As noted, legal blindness from vision loss occurred in 20% of our patients, whereas approximately 50% of this population had a visual acuity of 20/40 or better in at least 1 eye. The proportion of various genetic sUbtypes in the large group of patients with RP included in our present study is consistent with that previously reported from our laboratory.26,27 The genetic percentages (by pedigrees) also are similar to those reported in other cohorts of patients with RP within the United States by Bunker et at2 s and Berson et al. 25 The genetic percentages (by number of patients) is similar to that of other studies done by Heckenlively et al 19 and Heckenlively29 and Boughman and Caldwe1l30 (by probands) in the United States. The mean age of our patients, at the time the study was conducted, was 41 years, whereas in his study of 76 patients with RP, Heckenlivell9 found a mean age of 38.5 years. Our cohort of patients with RP likely represents genetic percentages and an age distribution similar to those seen by retinal specialists in the Unites States who see a substantial number of such patients. Future studies on other cohorts of patients with RP with a markedly different composition of various genetic subgroups or ages could disclose findings that differ from those seen in our population. The cross-sectional nature of our study lends itself to speculation as to any possible referral bias and whether our population is representative of the overall target population of patients with RP in the United States. A longitudinal study on such patients would address the concern that patients with RP with substantial impairment of their vision are no longer motivated to seek ophthalmic consultation. Nevertheless, in this cross-sectional study of our patients with RP, 30 (40%) of 75 patients with visual acuity of counting fingers or worse were followed up for a duration of 5 years or more compared with 156 (32%) of 489 with a visual acuity of 20/40 or better who were followed up for this duration. A number of patients with marked visual acuity impairment were compulsively attentive to their followup commitments, not infrequently because they needed continued attention to numerous documents such as disability, transportation, and medical forms. Further, in our cohort of patients with RP, the mean ages and the visual acuities in the subgroup of patients who had been seen only once and those who had been seen for 5 years or more (visual acuities on their most recent visit) were similar (Table 7). Additionally, as noted in our results, 48% of the patients who had a visual acuity of count fingers or worse were seen only once as compared with 47% of those patients who had a visual acuity of 20/40 or better. We were therefore unable to identify any differences for the number of follow-up visits in patients with the least severe compared with those with the most severe levels of impairment in their visual acuity among our patients with RP. The potential contribution of primarily posterior subcapsular lens opacities to visual acuity impairment in individual patients with RP needs to be considered. This issue was not addressed specifically in the present study or in
most other similar previous studies. It is thus possible that our visual acuity data could represent an underestimation of a patient's visual acuity potential in individual instances. It is our sense that this likely has little impact on the data for patients with visual acuity within the category of 20/200 or less because posterior subcapsular lens opacities severe enough to impact on vision to this level already had been removed. Similarly, those within the category of 20/40 visual acuity or better would not have been placed into another category based on lens opacification. It is possible that within intermediate levels of visual acuity, from approximately 20/50 to 20/80, a likely minor underestimation of visual acuity potential may have been an issue in certain individual patients. It is relevant to recall that even within a Mendelian genetic subtype, heterogeneity in disease-causing mutations can occur. Whether visual prognosis differs among the various mutations within a genetic subgroup would need to be determined by a comprehensive, collaborative study in which all patients being evaluated for visual prognosis are screened for various known disease-causing mutations. Our study represents the most comprehensive attempt to document the prevalence of severe visual acuity impairment within different age groups in a large cohort of patients with RP with various genetic subtypes. Because our sample of patients with RP is genetically similar to other groups of such patients seen by retinal specialists, at least in the United States, the results of this study on our patients should be useful for counseling other patients with RP about their potential for loss of visual acuity.
References 1. Friederich R. Eye disease in the Navajo Indians . Ann Ophthalmol 1982; 14:38-40. 2. Jay B. Prevention of blindness from retinitis pigmentosa. Trans Ophthalmol Soc UK 1978; 98:309-12. 3. Denton MJ, Chen JD, Serravalle S, et al. Analysis of linkage relationships of X-linked retinitis pigmentosa with the following Xp loci: Ll.28, 754, XJ-l.1, pERT87 and C7. Hum Genet 1988;78:60-4. 4. Sieving PA, Richards JE, Naarendorp F, et al. Dark-light: model for nightblindness from the human rhodopsin Gly-90Asp mutation. Proc Nat! Acad Sci USA 1995;92:880-4. 5. Anandakrishnan I, Musarella MA. Genetic counselling in X-linked retinitis pigmentosa. J Pediatr Ophthalmol Strabismus 1989;26:140-5.16. 6. Bloome MA, Garcia CA. Manual of Retinal and Choroidal Dystrophies. New York: Appleton-Century-Ct6fts, 1982;43. 7. Stein HA, Slatt BJ, Stein RM. A Primer in Ophthalmology. St. Louis: Mosby-Year Book, Inc., 1992;142. 8. Sunga RN, Sloan LL. Pigmentary degeneration of the retina: early diagnosis and natural history. Invest Ophthalmol 1967;6:309-27. 9. Tanino T, Olba N, Mishima S. Studies of pigmentary retinal dystrophies, III: a statistical analysis of parametric data. Klin Monatsbl Augenheilkd 1977; 170:808-13. 10. Pearlman JT. Mathematical models of retinitis pigmentosa: study of the rate of progress in different genetic forms. Trans Am Ophthalmol Soc 1979;77:643-56.
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Ophthalmology Volume 103, Number 10 , October 1996 11. Berson EL, Sandberg MA, Rosner B, et al. Natural course of retinitis pigmentosa over a three year interval. Am J OphthalmoI1985;99:240-51. 12. Farber MD, Fishman GA, Weiss RA. Autosomal dominantly inherited retinitis pigmentosa: visual acuity loss by subtype. Arch Ophthalmol 1985; 103:524-28. 13. Massof RW, Finkelstein D. A two stage hypothesis for the natural course of retinitis pigmentosa. In: Zrenner E, Krastel H, Goebels HH, eds. Research in Retinitis Pigmentosa. Elmsford, NY: Pergamon Press, Inc, 1987;62:29-58 . 14. Massof RW, Dagnelie G, Benzschawel T, et a1. First order dynamics of visual field loss in retinitis pigmentosa. Clio Vis Sci 1990;5:1-26. 15. Marmor MF. Visual loss in retinitis pigmentosa. Am J Ophthalmol 1980; 89:692-8. 16. Fishman GA. Retinitis pigmentosa-visual loss. Arch Ophthalmol1978;96:1185-8. 17. Massof RW, Finkelstein D, Starr SJ, et a1. Bilateral symmetry of vision disorders in typical retinitis pigmentosa. Br J Ophthalmol 1979;63:90-6. 18. Madreperla SA, Palmer RW, Massof RW, Finkelstein D. Visual acuity loss in retinitis pigmentosa-relationship to visual field loss. Arch Opbthalmol 1990; 108:358-61. 19. Heckenlively JR, Yoser SL, Friedman LH, Oversier JJ. Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol 1988; 105 :504-11.
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20. Keltner JL, Johnson CA. Visual function, driving safety, and the elderly. Ophthalmology 1987;94:1180-8. 21. Szlyk J, Fishman GA, Master SP, Alexander KR. Peripheral vision screening for driving in retinitis pigmentosa patients. Ophthalmology 1991;98:612-8. 22. Krill AE. Retinitis pigmentosa: a review. Sight Saving Review 1972;42:21-8. 23. Jay B. Hereditary aspects of pigmentary retinopathy. Trans Ophthalmol Soc UK 1972;92:1 73-8. 24. Pearlman JT, Axelrod RN, Tom A. Frequency of central visual impairment in retinitis pigmentosa. Arcb Ophthalmol 1977; 95:894. 25 . Berson EL, Rosner B, Simonoff E. Risk factors for genetic typing and detection in retinitis pigmentosa. Am J Ophthalmol 1980; 89:763-75 . 26. Fishman GA. Retinitis pigmentosa: genetic percentages. Arch Ophthalmol 1978;96:822-6. 27. Boughman JA, Fishman GA. A genetic analysis of retinitis pigmentosa. Br J Ophthalmol 1983;67:449-54. 28. Bunker CH, Berson EL, Bromley WC, et al. Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol 1984;97:357-65. 29. Heckenlively JR. RP cone-rod degeneration. Trans Am Ophtbalmol Soc 1987; 85:438-70. 30. Boughman JA, Caldwell RJ. Genetic and clinical characterization of a survey population with retinitis pigmentosa. Prog Clin BioI Res 1982;82:1 47-66.