JAMA Ophthalmology

Smith, Janine A.; Vitale, Susan; Reed, George F.; Grieshaber, Shirley A.; Goodman, Linda A.; Vanderhoof, Vien H.; Calis, Karim A.; Nelson, Lawrence M.

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.151pmid: 14769589

ObjectiveTo examine whether women with premature ovarian failure (POF) have abnormal findings in ocular surface or tear parameters and whether they report symptoms of ocular discomfort compared with age-matched controls.MethodsSixty-five patients with POF and 36 age-matched healthy controls were examined for signs and symptoms of dry eye. The Ocular Surface Disease Index questionnaire and the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) were administered to the participants. Assessments of ocular surface damage (Oxford and van Bijsterveld scores of vital dye staining) and tear status (Schirmer tests 1 [without anesthesia] and 2 [with anesthesia] and tear breakup time) were performed.ResultsWomen with POF scored significantly worse than controls on all ocular surface damage parameters: Oxford score (3.2 vs 1.7; P= .001), conjunctival lissamine green (2.1 vs 1.3; P= .02), corneal fluorescein staining (1.2 vs 0.4; P= .005), and van Bijsterveld score (2.1 vs 1.3; P= .02). Further, the proportion of patients with POF meeting the dry eye diagnostic criterion of a van Bijsterveld score greater than or equal to 4 was significantly greater among women with POF than among controls (20% vs 3%; P= .02). The POF group also tended to have worse scores than controls on self-reported symptoms, as measured by the overall Ocular Surface Disease Index (12.5 vs 2.1; P<.001) and the overall NEI-VFQ (94 vs 98; P= .001) after adjustment for age and race. Schirmer test scores and tear breakup time did not differ.ConclusionsWomen with POF were more likely to exhibit ocular surface damage and symptoms of dry eye than age-matched controls. They were not, however, more likely to have reduced tear production. To our knowledge, this association between ocular surface disease and POF has not been previously reported. These data provide further evidence of the multifaceted role of sex hormones in the health and disease of the ocular surface.Premature ovarian failure (POF) is defined as cessation of normal ovarian function in women younger than 40 years and affects 1% of women as determined by a large cohort study of Minnesota women followed up for date and type of menopause.In addition to amenorrhea, women with POF exhibit hypoandrogenemia, hypoestrogenemia, and elevated gonadotropin levels. Women with POF experience the same symptoms of estrogen deficiency as do postmenopausal women, including hot flashes, night sweats, fatigue, and mood swings and have an increased risk of cardiovascular disease and osteoporosis.Although chemotherapy, irradiation, and chromosomal abnormalities can cause POF, an autoimmune origin is also well recognized. Women with autoimmune POF are at increased risk of potentially fatal autoimmune adrenal insufficiency.In addition, women with POF demonstrate impaired immune regulation, including increased activation and total number of peripheral T cells, increased CD4/CD8 ratio, increased number of B cells,and reduced natural killer cell activity.In most cases, the mechanism of POF is unknown.In the United States, it is estimated that 15% of individuals aged 65 to 84 yearshave keratoconjunctivitis sicca, defined as at least one symptom of dry eye often or all of the time. There are 2 major categories of keratoconjunctivitis sicca: aqueous tear deficiency and evaporative tear deficiency.Aqueous tear deficiency is characterized by the decreased volume of tear production by the lacrimal glands, chronic ocular surface inflammation, fluctuating visual disturbance, decreased ability to perform activities of daily living, such as reading and using a computer, and ocular discomfort.Evaporative tear deficiency can result from qualitative disturbance in the tear film with resultant instability, leading to increased evaporation and dryness of the ocular surface. It is most often caused by meibomian gland disease. Although dry eye can occur in men or women of any racial group at any age, many studies have found a higher risk of dry eye in women. Dry eye can be associated with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, or Sjögren syndrome.The role of sex hormones in dry eye has been investigated in several studies.Most recently, Schaumberg et alfound an increased prevalence of dry eye in women who had received hormone therapy (9.1% in those treated with estrogen alone and 6.7% in those treated with estrogen plus progesterone/progestin); the prevalence was lowest in women who had never used hormone therapy (5.9%). It remains unclear, however, what role estrogen excess, androgen deficiency, and/or estrogen-androgen imbalance play in association with dry eye. Androgen deficiency, as seen in congenital androgen insensitivity syndrome and antiandrogen therapy, has been associated with dry eye.Androgen deficiency is also seen in Sjögren syndrome, and it has been proposed to lead to evaporative tear deficiency in affected women.Since women with POF also suffer from androgen deficiency, we hypothesized that they would exhibit signs or symptoms of dry eye more frequently than age-matched controls with normal ovarian status.METHODSSixty-five consecutive women with POF and 36 age-matched normal control women were evaluated for subjective evidence of dry eye symptoms and objective signs of ocular surface disease. Premature ovarian failure was diagnosed as follows: amenorrhea for at least 4 months and 2 consecutive instances of elevated FSH concentrations (≥40 IU/dL) obtained at least 1 month apart. Women were excluded from the control group if they had any of the following: abnormal menstruation, eye disease (except refractive error), contact lens use, or use of prescription medications, including oral contraceptives. The protocol was approved by the institutional review board for the National Institutes of Child Health and Human Development (Bethesda, Md), and all participants signed an informed consent.No controls had ever received hormone therapy at the time of the screening examination. Patients with POF who were currently using hormone therapy were asked to discontinue it for at least 2 weeks prior to the visit. Control women were seen at any time during the menstrual cycle. All participants underwent ETDRS (Early Treatment Diabetic Retinopathy Study) visual acuity assessment, masked slitlamp biomicroscopy, including a standardized grading of eyelid margin thickness and hyperemia, conjunctival erythema, chemosis, tear film debris and mucus, and extent of meibomian gland plugging. Grading of external eyelid disease was accomplished as follows. For meibomian gland disease, 5 meibomian glands were selected in the central lower eyelid, and the number of glands from which meibum could be readily expressed was graded as none (0), mild (+1) if 1 to 2 glands were plugged, moderate (+2) if 3 to 4 glands were plugged, or severe (+3) if all 5 glands were plugged. Eyelid margin erythema was graded as none (0) if there was no erythema, mild (+1) if redness was localized to a small region of the eyelid(s) margin, moderate (+2) if redness affected most or all of the eyelid(s) margin, severe (+3) if redness affected most or all of the eyelid(s) margin and skin, or very severe (+4) if there was marked diffuse redness of the eyelid(s) margin and the skin. Eyelid margin swelling was graded as none (0), mild (+1) if localized to a small region of the eyelid(s), moderate (+2) if it affected most or all of the eyelid(s) but was not prominent, severe (+3) if most or all of the eyelid(s) was affected and prominent, or very severe (+4) if the swelling was prominent, with eversion of the eyelid(s).In addition, we performed tests of tear production (Schirmer test 1 [without anesthesia] and 2 [with anesthesia]) and an assessment of ocular surface damage using vital dye staining with 5 µL of 2% sodium fluorescein or 10 µL of 0.5% lissamine green instilled using capillary tubes. The van Bijsterveld grading method assessed lissamine green staining of the cornea and the temporal and nasal bulbar conjunctiva. The cornea and conjunctiva were graded separately (0-3 for each zone) and then combined for the total van Bijsterveld score.The Oxford method assessed sodium fluorescein staining of the cornea and lissamine green staining of the nasal and temporal bulbar conjunctiva, graded separately (0-5 for each zone) and then combined for the total Oxford score.Determination of tear film stability was assessed by fluorescein tear breakup time. If the tear breakup time was less than 10 seconds, the test was repeated for a total of 3 values, and the average was determined. The tests were performed according to standard operating procedures and in the following order: Schirmer 1, slitlamp examination, vital dye staining, tear breakup time, and Schirmer 2.For statistical analysis, the maximum (worse) score for the 2 eyes of each individual was used for Oxford, lissamine green, and van Bijsterveld, and the minimum (worse) score for the 2 eyes was used for Schirmer 1, Schirmer 2, and tear breakup time. Tear breakup time values greater than or equal to 10 secondswere coded as 10 (normal), and those less than 10 seconds were defined as abnormal. A score of 5 mm or less on Schirmer 1 or a van Bijsterveld score greater than or equal to 4 were used as objective evidence of dry eye, following the past and current European Community Study Group on Classification Criteria for the diagnosis of dry eye for Sjögren Syndrome.Grading of the extent of external disease was performed using a standardized scheme.The Ocular Surface Disease Index (OSDI)(Allergan Inc, Irvine, Calif) was used to quantify the effect of dry eye on quality of life, including gritty or painful eyes, limitation in performance of common activities, such as reading and working on a computer, and the effect of environmental triggers, such as wind, on dry eye symptoms during a 1-week recall period. The effect of dry eye on activities of daily living and visual functioning was determined using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25).Responses to the questionnaires were scored using the methods described by the authors of these instruments.For the NEI-VFQ, subscale scores for general vision, ocular pain, near vision, distance vision, social functioning, mental functioning, role functioning, dependency, driving, color vision, and peripheral vision, as well as an overall score, were computed. The NEI-VFQ scores can range from 0 to 100, with lower scores indicating more problems or symptoms. For the OSDI, 3 subscales for ocular discomfort, visual functioning, and environmental triggers were computed, as well as an overall score. The OSDI scores can range from 0 to 100, with higher scores indicating more problems or symptoms.Preliminary analyses were performed, adjusting for age and race. Because of a racial imbalance between the controls and the other 2 groups, we retained race (grouped as black/Hispanic/other vs white) as a potential confounder in all subsequent analyses. Logistic regression models (SAS version 8.02; SAS Institute, Cary, NC) were used to perform comparisons between controls and patients. χ2or Fisher exact tests were used to compare proportions in 2 × κ contingency tables. Spearman correlation coefficients were computed to assess the strength of the linear relationship between pairs of variables. All participants answered that they had "no difficulty at all" with the single color vision item on the NEI-VFQ, so this subscale was not included in the analyses.RESULTSThe basic demographic and visual acuity characteristics of participants in the 2 groups are presented in Table 1. As expected, the age distributions did not differ between the 2 groups. However, the controls had markedly more black (39%) and other (22%) participants compared with the POF group. Ninety-one percent of women with POF had a visual acuity of 20/20 or better in the better eye compared with 94% of controls. Visual acuity in the worse eye was somewhat worse in patients than in controls: 22% had a visual acuity worse than 20/20 vs 14% of controls (P= .41).Table 1. Characteristics of Participants*Controls (n = 36)POF Patients (n = 65)Age, mean (range), y33 (21-41)34 (17-43)RaceBlack14 (39)11 (17)White14 (39)49 (75)Other8 (22)5 (8)Visual acuityWorse eye20/20+31 (86)41 (78)20/25 and worse5 (14)14 (22)Better eye20/20+34 (94)59 (91)20/25 and worse2 (6)6 (9)Abbreviation: POF, premature ovarian failure.*Data are given as number (percentage) of patients unless otherwise indicated.PHYSICAL EVIDENCE OF DRY EYEMean values for ocular surface and tear film parameters are presented in Table 2. Women with POF had worse mean scores than controls on all measures of ocular surface damage: total Oxford score (P= .001), conjunctival lissamine green (P= .02), corneal fluorescein staining (P<.001), and total van Bijsterveld score (P= .02). The percentages of patients with abnormal ocular surface and tear parameters are presented in Table 3. Thirteen (20%) of 65 women with POF had a van Bijsterveld score greater than or equal to 4 compared with 1 (3%) of 36 controls (P= .02). Furthermore, significantly more POF patients (38%) showed abnormal corneal fluorescein staining (score >1) than did controls (8%) (P<.001 after adjustment for race and age). In addition, significantly more women with POF (30/45 [67%]) demonstrated eyelid margin erythema than controls (11 [31%] of 36; P= .03). The proportion of women with any meibomian gland plugging was similar in each group (controls: 36%, POF: 40%). The mean tear breakup time, Schirmer 1, and Schirmer 2 did not differ between women with POF and controls. Although women with POF were roughly twice as likely to have a Schirmer 1 score less than or equal to 5 mm (23% vs 11%), this difference was not statistically significant. The proportion of women with POF that met the past and current European Community Study Group on Classification Criteria for Sjögren syndrome dry eye(van Bijsterveld ≥4 and/or Schirmer 1 score ≤5 mm) was greater than that of controls (37% vs 22%), although this difference was not statistically significant (P= .19). No significant differences in the percentage with tear film debris were observed.Table 2. Ocular Surface and Tear Film CharacteristicsOutcome MeasureControls (n = 36), Mean (Range)POF Patients (n = 65), Mean (Range)Control vs POF Patients, OR* (95% CI)PValue†Oxford‡ scoreTotal1.7 (0-6)3.2 (0-8)0.62 (0.46-0.83).001Conjunctiva1.3 (0-5)2.1 (0-6)0.70 (0.52-0.95).02Cornea0.42 (0-2)1.17 (0-4)0.37 (0.21-0.65)<.001Total van Bijsterveld‡1.3 (0-4)2.1 (0-7)0.67 (0.48-0.95).02Schirmer 1, mm§13.2 (0-35)16.0 (0-35)0.99 (0.95-1.03).6Schirmer 2, mm§9.6 (1-28)10.4 (0-35)1.00 (0.95-1.06).99TBUT§, s7.0 (2.3-10)6.3 (2.0-10)1.13 (0.96-1.33).14Abbreviations: CI, confidence interval; OR, odds ratio; POF, premature ovarian failure; TBUT, tear breakup time.*The OR of 0.62 indicates that every 1-step increase on the Oxford scale reduces the odds of being normal by 38%; ie, that POF patients tend to have higher Oxford scores. A 95% CI that includes 1.0 indicates that the OR does not differ significantly from 1.0; ie, that scores do not differ between the comparison groups.†Logistic regression model adjusted for age and race.‡Maximum (worse) score for the 2 eyes of an individual.§Minimum (worse) score for the 2 eyes of an individual.Table 3. Participants With Abnormal Ocular Surface and Tear Film Parameters*ControlsPOF PatientsPValueTear breakup time <5 s11/36 (31)22/62 (35).78Tear breakup time <10 s24/36 (67)49/62 (79).26Schirmer 1 ≤5 mm7/36 (19)15/65 (23).86van Bijsterveld score ≥41/36 (3)13/65 (20).02†Meets Sjögren syndrome dry eye criteria8/36 (22)24/65 (37).19Oxford score ≥52/36 (6)19/65 (29).01Meibomian gland plugging >013/36 (36)26/65 (40).86Eyelid margin erythema >011/36 (31)36/65 (55).03Tear film debris >05/36 (14)19/64 (30).12Conjunctival erythema >027/36 (75)42/62 (68).60Conjunctival chemosis >05/36 (14)9/62 (15).83*Values are given as number (percentage) of participants.†Fisher exact test, 2-tailed.SELF-REPORTED SYMPTOMSComparisons of the OSDI and NEI-VFQ subscales were done for patients vs controls (Table 4). After adjusting for age and race, OSDI scores for all 3 subscales and the overall scale were significantly higher (worse) for patients than for controls. These significant differences in OSDI scores did not change when adjustment was made for any of the ocular surface or tear parameters (Oxford, lissamine green, corneal fluorescein staining, van Bijsterveld, Schirmer 1 or 2, and tear breakup time) (data not shown). For the NEI-VFQ overall scale and subscales, general vision, ocular pain, near vision, distance vision, mental functioning, and driving, POF patients had significantly lower (worse) scores than did controls. Scores on the NEI-VFQ subscales remained significantly worse for patients than for controls after adjustment for the ocular surface and tear parameters that differed significantly between patients and controls (total Oxford, conjunctival lissamine green, corneal fluorescein staining, and total van Bijsterveld scores) (data not shown). Compared with controls, patients (n = 22) had significantly worse mean responses to both of the visual analog questions, "how dry do your eyes feel most of the time?" (29 vs 3; P= .004), with responses ranging from 0 = not dry at all to 100 = very dry, and "how often do you experience burning, stinging, or grittiness of your eyes?" (18 vs 2; P= .003), with responses ranging from from 100 = most of the time to 0 = never, even after adjustment for age and race.Table 4. OSDI and NEI-VFQ ScoresControls (n = 36), Mean (Range)POF Patients (n = 65), Mean (Range)Control vs POF Patients, OR* (95% CI)PValue†OSDIOcular discomfort2.1 (0-33.3)15.4 (0-62)0.87 (0.81-0.94)<.001Visual function1.4 (0-20.8)10.0 (0-83)0.85 (0.76-0.95).006Environmental triggers3.5 (0-41.7)15.3 (0-88)0.94 (0.89-0.99).013Overall2.1 (0-14.6)12.5 (0-67)0.82 (0.73-0.92)<.001NEI-VFQGeneral vision95 (80-100)89 (40-100)1.07 (1.02-1.13).01Ocular pain96 (62-100)85 (50-100)1.10 (1.04-1.17).001Near vision99 (92-100)96 (67-100)1.21 (1.03-1.42).02Distance vision98 (83-100)92 (50-100)1.12 (1.03-1.22).01Social function100 (all 100)99 (62-100)1.38 (<.001-∞).99Mental function98 (88-100)91 (19-100)1.15 (1.04-1.28).009Role function98 (75-100)94 (50-100)1.06 (0.98-1.14).13Dependency100 (all 100)98 (50-100)3.78 (<.001-∞).95Driving97 (88-100)92 (62-100)1.15 (1.05-1.25).002Peripheral vision98 (50-100)97 (50-100)1.02 (0.96-1.08).6Overall98 (93-100)94 (60-100)1.47 (1.17-1.84).001Abbreviations: CI, confidence interval; NEI-VFQ, National Eye Institute Visual Function Questionnaire; OR, odds ratio; OSDI, Ocular Surface Disease Index.*Logistic regression model adjusted for age and race.CONDITIONS ASSOCIATED WITH DRY EYEOf those patients who ever used contact lenses, the proportion who discontinued use did not statistically significantly differ between the groups (control: 3/7 [43%]; POF: 12/31 [39%]). In addition, the proportion who discontinued contact lens use because of dryness did not differ between the groups (1 [33%] of 3 controls vs 5 [42%] of 12 patients). Use of tear substitutes or lubricating ointments was, however, statistically significantly more common among patients (21/65 [32%]) than among controls (1/36 [3%]; P= .001). This association did not change after adjustment for age and race (P= .007). The women with evidence of ocular surface damage (van Bijsterveld ≥4) compared with those without were significantly more likely to demonstrate positive antinuclear (6/13 vs 9/51; P= .04) and antiadrenal (2/13 vs 0/50; P= .04) autoantibodies but not thyroid peroxidase or parietal autoantibodies. The frequency of clinically apparent autoimmune disease was low and did not differ between the 2 groups.SELF-REPORTED SYMPTOMS AND CLINICAL SIGNSWe examined the associations between the objectively measured ocular surface and tear parameters and the subjective OSDI and NEI-VFQ scores using various analytic methods, including Spearman correlation coefficients for the continuous variables and Kruskal-Wallis tests for differences in the median OSDI (or NEI-VFQ) score among groups defined according to severity of ocular surface disease (eg, none, mild, severe). Within the POF group, the following showed significant association: worse near vision with lower (more abnormal) tear breakup time (r= 0.33; P= .01) and worse peripheral vision with lower Schirmer 1 score (r= 0.31; P= .02). Within the control group, there were no associations between any of the objective parameters (Oxford, Lissamine green, corneal fluorescein staining, van Bijsterveld, Schirmer 1 or 2, or tear breakup time) and OSDI scores (nearly all rvalues were <0.2). Although there was a consistently significant association of lower (more normal) Oxford score with better driving scores among the controls, it should be noted that only 2 controls had abnormal Oxford scores.COMMENTThe women with POF showed significantly more severe ocular surface damage than controls on all grading scales and scored significantly worse on all of the dry eye symptom assessments and the visual function questionnaire. Further, a larger proportion of POF patients met a diagnostic criterion for dry eye by the severity of ocular surface vital dye staining (van Bijsterveld score ≥4) than did controls; however, aqueous tear production, as measured by the Schirmer test, was not significantly different between the groups.Sex hormone messenger RNAs, proteins, and receptors have been found in ocular tissues, including the cornea, conjunctiva, meibomian glands, lacrimal gland acinar cells, and retinal pigment epithelium.Estrogens in general are immune response stimulators, and androgens act as immunosuppressors.Sullivan et alhave proposed that androgen insufficiency contributes to meibomian gland dysfunction, tear film instability, and evaporative dry eye in menopause, aging, Sjögren syndrome, complete androgen insensitivity syndrome, and antiandrogen use. Hykin and Bronhave documented increased meibomian gland disease and evaporative tear deficiency in postmenopause and with aging. In addition, androgens and estrogens can have profound effects on both the cellular and humoral immune systems. For example, androgens can enhance T-cell suppressor activity and decrease autoreactive antibody formation.This may be one of the reasons that autoimmune diseases are more common in women than in men.The exact pathologic mechanisms of POF remain unclear; however, there is evidence that autoimmunity may play a role in some cases. For example, POF can be seen in autoimmune polyglandular syndrome type I, a disorder characterized by the destruction of endocrine glands, impaired cellular immunity, and ectodermal dystrophy.In contrast, a mutation in FOXL2, a forkhead transcription factor gene that causes blepharophimosis-ptosis-epicanthus-inversus syndrome may be associated with POF.None of the patients in our study demonstrated any eyelid abnormalities. Local ocular disruption of sex hormone homeostasis or androgen deficiency alone may be responsible for the ocular surface disease that we found in women with POF. A common genetic factor could be responsible for both the ovarian and ocular disease; perhaps a shared structural protein or other factor is required to maintain both developing ovarian follicles and a stable tear film and healthy ocular surface. It is possible that the dry eye phenotype may signal a particular cause of POF since not all patients had dry eye.Our study had several limitations. There were more white women in the POF group than in the control group; however, to date, there is no evidence for a racial difference in the prevalence of dry eye. Furthermore, adjustment for race did not modify any of the differences we found between the groups. The average tear breakup time in 129 normal women aged 20 to 24 years has been reported as 18.9 seconds.While the mean tear breakup time of 6.3 seconds in our POF group is less than these previously published values, this difference may have been due to our method of coding values greater than or equal to 10 seconds as 10. There are few publications that document sex- and age-specific data for normal tear production, and most studies have shown that Schirmer test results are highly variable. Normal scores on the Schirmer test with anesthesia have been reported to range from 23.71 mm (range, 14-30 mm) in normal men and womento 33.3 mm in a sample of 48 normal Indian women.Feldman and Woodfound wide variability in scores on the Schirmer test with anesthesia in 10 healthy women (age range, 19-38 years) tested daily for 30 days; mean values ranged from 8.5 to 21 mm, and SDs ranged from 2.7 to 7.6. The mean tear production in our controls (Schirmer 1 = 13.2 mm, Schirmer 2 = 9.6 mm) was lower than we expected for healthy young women with no history of ocular disease. These findings may indicate that the published normal values for these measures are not applicable to women in the 18- to 40-year-old age group, or that our controls or procedures were different from those in published studies. However, this difference would tend to make the controls appear more like dry eye cases, thus tending to diminish any associations observed (ie, any bias would be in a conservative direction).The women with POF and dry eye in this study had somewhat better scores on the overall NEI-VFQ and OSDI than those published for dry eye cases. In a previous study of 75 patients with dry eye evaluated with the NEI-VFQ,the mean ± SD overall score was 87.9 ± 8.4, and the mean ocular pain score was 69.5 ± 18.7. In our study, the women with POF who met the more stringent diagnostic criteria for Sjögren syndrome–related dry eye (Schirmer 1 ≤5 mm and/or van Bijsterveld ≥4) had a somewhat higher (better) mean NEI-VFQ overall score of 93 ± 7. However, their mean ± SD ocular pain subscale score was 82 ± 15, lower (worse) than reported scores for patients with cataract (86 ± 19)and low vision (97.3 ± 8.3).For women with POF meeting the same criteria, the overall mean ± SD OSDI score was 12.2 ± 13.3, lower (better) than the published overall OSDI scores for 83 patients with mild to moderate dry eye (18.1 ± 17.1).We found an increased prevalence and severity of both signs and symptoms of ocular surface disease in patients with karyotypically normal spontaneous POF compared with age-matched normal women. The dysregulation of sex hormones or immunologic dysfunction seen in POF may play a role in the pathogenesis of the ocular surface disease. Epithelial dysfunction or lacrimal gland disease may play a role. An abnormality in tear composition likewise could result in the corneal and conjunctival damage seen. The key role of sex hormones in ocular surface homeostasis is further supported by these findings; however, the specific pathophysiologic mechanisms involved in dry eye in POF remain to be determined. 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production.Cornea.1997;16:645-648.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9395874&dopt=AbstractSSMaudgilAKKhuranaMSinghIPParmarBKAhluwaliaTear film flow and stability in normal Indian subjects.Indian J Ophthalmol.1989;37:182-183.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2638306&dopt=AbstractFFeldmanMMWoodEvaluation of the Schirmer tear test.Can J Ophthalmol.1979;14:257-259.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=550920&dopt=AbstractKKNicholsGLMitchellKZadnikPerformance and repeatability of the NEI-VFQ-25 in patients with dry eye.Cornea.2002;21:578-583.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12131034&dopt=AbstractCMMangionePPLeeJPittsPsychometric properties of the NEI-VFQ Field Test Investigators.Arch Ophthalmol.1998;116:1496-1504.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9823352&dopt=AbstractIUScottWESmiddyJSchiffmanQuality of life of low-vision patients and the impact of low-vision services.Am J Ophthalmol.1999;128:54-62.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10482094&dopt=AbstractCorresponding author and reprints: Janine A. Smith, MD, National Eye Institute, National Institutes of Health, 10 Center Dr, MSC 1863, Bethesda, MD 20892-1863 (e-mail: [email protected]).Submitted for publication March 5, 2003; final revision received July 22, 2003; accepted August 15, 2003.Results from this study were presented at the Association for Research in Vision and Ophthalmology annual meeting; May 9, 2002; Fort Lauderdale, Fla.We are grateful for the support of the POF support group in the referral of women to the National Institutes of Health Clinical Center, Bethesda, for participating in these studies.

Sónego-Krone, Sergio; López-Moreno, Gerson; Beaujon-Balbi, Oscar V.; Arce, Carlos G.; Schor, Paulo; Campos, Mauro

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.159pmid: 14769590

ObjectiveTo measure the corneal power after myopic laser in situ keratomileusis (LASIK).MethodsSix central areas in 6 corneal power maps were studied using the Orbscan II statistical analysis device in 26 eyes that underwent myopic LASIK. Refractive and corneal power changes were compared. Factors related to wrong corneal power measurement were evaluated.Main Outcome MeasuresCycloplegic refraction, refractive change at the corneal plane, and Orbscan II corneal power maps.ResultsPreoperatively, only posterior-mean power (P<<.001) and anterior-posterior power ratio (P<<.001) varied according to the size of the analyzed area. Postoperatively, total-optical (P= .03), keratometric-mean (P= .04), total-mean (P<.001), anterior-mean (P= .03), and posterior-mean (P<<.001) powers; and anterior-posterior power ratio (P<<.001) varied according to the area. Postoperatively, the difference between keratometric-mean and total-mean powers became larger (P<.001), and the anterior-posterior power ratio was reduced (P<<.001). A posterior-mean power change occurred (P= .04). Refractive change after myopic LASIK was best estimated by 2-mm total-mean power (mean ± SD difference, 0.07 ± 0.62 diopters [D]; P= .55) and 4-mm total-optical power (mean ± SD difference, −0.08 ± 0.53 D; P= .37).ConclusionsTotal corneal power is more positive and refractive change is underestimated when deduced from the anterior surface radius and keratometric refractive index. The anterior-posterior power ratio is not a fixed value. The best area to estimate the refractive change depends on the method used to obtain the power in diopters. Refractive change tended to be underestimated in larger areas and higher preoperative myopia. Orbscan II total-mean and total-optical power maps accurately assess the corneal power after myopic LASIK independent of preoperative data or correcting factors, and should improve intraocular lens calculation.As patients who undergo refractive surgery become older, their probabilities of development of cataract are increased. It has been observed that residual refractive errors can occur after cataract surgery in these cases. Thus, a residual hyperopia was found in patients undergoing previous myopic laser in situ keratomileusis (LASIK) or photorefractive keratectomy, and the reason for this error is not clear. It has been suggested that formulas for intraocular lens (IOL) power calculation may not be accurate,and/or that the corneal power may be incorrectly measured.Myopic LASIK produces deliberate modifications in the anterior surface of the cornea and its thickness to correct a refractive defect. The normal prolate (convexity steeper in the center) anterior surface is converted to an oblate (convexity flatter in the center) surface. Therefore, it may not be correct to apply conventional variables assumed for normal corneas to surgically modified corneas.Most IOL calculation formulasassume that the cornea is spherical and commonly use a corneal power determined by means of manual or computerized keratometry or by means of corneal videokeratography (CVK) using Placido disks. These methods deduce the total power of the cornea by measuring the radius of the corneal anterior surface curvature from a central area with a diameter of approximately 3 mm. Conversion of millimeters of radius to diopters (D) is performed using a theoretical effective (keratometric) refractive index of 1.3375.To improve accuracy, attempts to correct this index have been made,resulting in other adapted theoretical indexes that have been applied in automatic keratometers or IOL formulas.On the other hand, combined slit-scanning and Placido-disk CVK (Orbscan II; Bausch & Lomb–Orbtek Inc, Salt Lake City, Utah) is a relatively new technology able to localize 9000 points of the cornea and anterior chamber and transform them to topographic maps. This equipment calculates the power of the cornea by diverse mathematical methods, using the keratometric refractive index (keratometric power maps) or the physiologic refractive indexes (anterior, posterior, or total power maps). Ray tracing (optical power maps), spherical equivalent (mean power maps), astigmatism (astigmatic power maps), differential with best-fit sphere (elevation maps), and thickness (power and pachymetry maps) may be represented.In addition, this system may statistically analyze areas as small as a central point with a 40-µm diameter,and as large as the peripheral limit of data achievement around a 9-mm diameter. The definition and explanation of Orbscan II principles and maps may be obtained elsewhere.Manufacturer nomenclature has been criticized.In scientific reports, the terms totaland mean,used to designate the type of some Orbscan II power maps, may be confused with terms representing values achieved from data analysis. Thus, unless otherwise indicated, this article hyphenates compound words that identify Orbscan II maps.Using this equipment, our group recently reported that the power of normal corneas deduced from the measurement of only the anterior surface using the keratometric refractive index is approximately 1.5 D more positive than the power calculated from all of its optical components and using the physiologic refractive indexes. It has been shown that the size of an analyzed area of less than a 5-mm diameter has no effect in the total power of normal corneas or in the power of their anterior surface. It also has been shown that the power of their posterior surface becomes less negative and that their thickness increases when larger areas are analyzed. Furthermore, the 10:1 ratio traditionally accepted for anterior and posterior corneal powers was not confirmed.This study evaluates the variability of corneal power measurements obtained by means of the Orbscan II topography system before and after myopic LASIK. Changes in the spherical equivalent (calculated using the keratometric or the physiologic refractive indexes) and ray tracing (calculated using the physiologic refractive indexes) corneal powers are compared with the refractive change at the corneal plane. Among factors that have been related to wrong corneal power measurement after refractive surgery,this study analyzes the influence of keratometric and physiologic refractive indexes, the anterior-posterior corneal power ratio, the corneal power change according to the size of the analyzed area, and the contribution of thickness and posterior surface on total power change, with the goal to determine the best variables that should be applied for an accurate and direct assessment of corneal power after myopic LASIK.METHODSThis study was designed as an observational case series. A retrospective review of preoperative and postoperative combined slit-scanning and Placido-disk CVK with the Orbscan II corneal topography system was made in 26 eyes of 18 patients at the Department of Ophthalmology, Paulista School of Medicine, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil. Postoperative examination was made at least 1 month after eyes underwent myopic LASIK using the Ladar Vision excimer laser system (Alcon-Summit Autonomous, Orlando, Fla). Written informed consent and cycloplegic refraction were used routinely. Patients had no other abnormality except myopia (mean ± SD sphere, −3.39 ± 1.83 D) or myopic astigmatism (mean ± SD cylinder, −1.41 ± 1.17 D), and no postoperative complication other than some residual ametropia (mean ± SD spherical equivalent, −0.50 ± 0.56 D). Cases were consecutively selected from the Orbscan II hard disk (Table 1). Average values of all points of total-optical (representing the ray tracing of anterior and posterior surfaces using physiologic refractive indexes), keratometric-mean (representing the spherical equivalent of anterior surface using the keratometric refractive index), total-mean (representing the spherical equivalent of both corneal surfaces plus thickness-mean power using physiologic refractive indexes), anterior-mean and posterior-mean (representing the spherical equivalent of each corneal surface using physiologic refractive indexes), and thickness-mean (representing the contribution of thickness to the total power of the cornea) power maps were assessed using the Orbscan II statistical analysis device (software version 3.00D) for 6 central areas with 0.04-, 1.0-, 2.0-, 3.0-, 4.0-, and 5.0-mm diameters (±0.02 mm) as described elsewhere.Spherical-cylindrical spectacle refraction was converted to a spherical equivalent corneal plane value using a vertex distance of 12 mm. The refractive change (spherical equivalent at the corneal plane) induced by LASIK was calculated by subtracting the postoperative residual refractive defect from the preoperative ametropia, and it was compared with the corneal power change determined by each Orbscan II power map in every analyzed area. The influence of keratometric and physiologic refractive indexes on total corneal power calculation was studied by determining the difference between keratometric-mean and total-mean powers for each eye and then the average for each area. The anterior-posterior corneal power ratio was studied by analyzing the relationship between anterior-mean and posterior-mean powers. A posterior surface change was studied by comparison of the posterior-mean power before and after surgery.Table 1. General Data*CharacteristicFindingEye, No. right/left11/15Sex, No. F/M14/4Age, y34.65 ± 8.29 (25 to 56)Preoperative spherical equivalent, D†−4.09 ± 1.59 (−8.01 to −1.34)Preoperative sphere, D†−3.39 ± 1.83 (−6.88 to −0.25)Preoperative cylinder, D†−1.41 ± 1.17 (−4.22 to 0.00)Postoperative spherical equivalent, D†−0.50 ± 0.56 (−1.47 to +0.89)Refractive change, D†−3.59 ± 1.46 (−6.86 to −0.97)Refractive change, D‡−3.77 ± 1.70 (−7.50 to −1.00)Programmed ablation, µm52.11 ± 16.66 (30.50 to 96.70)Diameter of the treatment area, mm5.60 ± 0.25 (5.5 to 6.5)Postoperative follow-up, mo2.54 ± 1.66 (1 to 6)Abbreviation: D, diopter.*Laser in situ keratomileusis performed in 26 eyes with the Ladar Vision excimer laser system (Alcon-Summit Autonomous, Orlando, Fla). Microkeratomes used included the following: Moria M2 and Moria CB (Moria, Antony, France); Hansatome (Bausch & Lomb Surgical, Miami, Fla); and Automated Corneal Sharper (Chiron Vision Inc, Irvine, Calif). Unless otherwise indicated, data are expressed as mean ± SD (range).†Indicates corneal plane.‡Indicates spectacle plane.The 2-tailed paired ttest, analysis of variance with 1 factor, and linear correlation (R2) were calculated using Excel 2000 7.0 (Microsoft Corporation, Redmond, Wash). Nonparametric Wilcoxon signed rank test and Pearson correlation factor (multiple R) were performed using SPSS 7.5.2S (SPSS Inc, Chicago, Ill). An α risk of .05 was established. Unless otherwise indicated, data are expressed as mean ± SD. This study was reviewed and approved by the UNIFESP/EPM Ethics Committee in Research.RESULTSMean preoperative spherical equivalent was −4.09 ± 1.59 D. Mean refractive change at the corneal plane (gold standard) was –3.59 ± 1.46 D. Mean follow-up for postoperative refraction and topography was 2.54 ± 1.66 months. Information about cases and LASIK variables are summarized in Table 1.CENTRAL CORNEAL POWER ACCORDING TO THE SIZE OF THE ANALYZED AREAPreoperative (Table 2) total-optical, keratometric-mean, total-mean, anterior-mean, and thickness-mean powers were not statistically different in all analyzed areas. The average of the posterior-mean power varied from –6.74 D when measured in the smallest central area to –6.39 D when assessed from an area with a 5-mm diameter. The standard deviation of posterior-mean power in all areas was proportionally similar (3%-5% of average values) to the standard deviation found in all other maps, except thickness-mean power maps (around 10%).Table 2. Orbscan II Corneal Powers Before Myopic LASIK*Diameter of Analyzed Area, mmPValue†≤0.0412345Total-optical power42.54 ± 1.7242.51 ± 1.6342.58 ± 1.5842.66 ± 1.5342.86 ± 1.5343.13 ± 1.54.72Keratometric-mean power43.95 ± 1.4943.91 ± 1.5043.89 ± 1.4743.87 ± 1.4843.83 ± 1.4843.71 ± 1.48>.99Total-mean power42.34 ± 1.5542.32 ± 1.5342.33 ± 1.5242.34 ± 1.4642.42 ± 1.4742.41 ± 1.44>.99Thickness-mean power0.137 ± 0.0140.137 ± 0.0130.138 ± 0.0140.138 ± 0.0140.138 ± 0.0140.138 ± 0.014>.99Anterior-mean power48.96 ± 1.6548.93 ± 1.6548.87 ± 1.6548.88 ± 1.6448.82 ± 1.6548.70 ± 1.65>.99Posterior-mean power−6.74 ± 0.26−6.75 ± 0.25−6.68 ± 0.33−6.64 ± 0.23−6.52 ± 0.24−6.39 ± 0.26<<.001Pearson‡−0.51−0.58−0.52−0.87−0.91−0.84Anterior-posterior power ratio7.27 ± 0.267.26 ± 0.247.33 ± 0.367.36 ± 0.137.49 ± 0.117.63 ± 0.17<<.001Abbreviation: LASIK, laser in situ keratomileusis.*Orbscan II indicates combined slit-scanning and Placido-disk corneal videokeratography (Bausch & Lomb–Orbtek Inc, Salt Lake City, Utah). Unless otherwise indicated, data are expressed as mean ± SD in diopters (n = 26).†Calculated by analysis of variance between diameters.‡Indicates 2-tailed Pearson correlation between anterior-mean and posterior-mean powers with P≤.008.Postoperative (Table 3) total-optical, keratometric-mean, total-mean, and anterior-mean powers became larger (more positive), and posterior-mean power became smaller (less negative) when larger areas were analyzed. Thickness-mean power was not statistically different in all analyzed areas.Table 3. Orbscan II Corneal Powers After Myopic LASIK*Diameter of Analyzed Area, mmPValue†≤0.0412345Total-optical power38.28 ± 2.2038.32 ± 2.1338.47 ± 2.0838.80 ± 2.0339.35 ± 2.0439.92 ± 1.88.03Keratometric-mean power40.75 ± 1.9940.81 ± 1.9540.99 ± 1.8941.26 ± 1.8041.64 ± 1.6042.15 ± 1.56.04Total-mean power38.24 ± 2.0838.35 ± 2.0438.66 ± 1.9439.15 ± 1.8739.72 ± 1.9140.55 ± 1.57<.001Thickness-mean power0.123 ± 0.0130.123 ± 0.0130.124 ± 0.0130.125 ± 0.0130.127 ± 0.0130.128 ± 0.013.70Anterior-mean power45.32 ± 2.2145.46 ± 2.1845.67 ± 2.1045.97 ± 2.0046.44 ± 1.8446.96 ± 1.74.03Posterior-mean power−7.27 ± 0.39−7.22 ± 0.36−7.06 ± 0.36−6.91 ± 0.27−6.67 ± 0.24−6.45 ± 0.24<<.001Pearson‡−0.51−0.46−0.56−0.61−0.69−0.76Anterior-posterior power ratio6.25 ± 0.326.30 ± 0.336.48 ± 0.306.65 ± 0.256.97 ± 0.217.28 ± 0.19<<.001Abbreviation: LASIK, laser in situ keratomileusis.*Orbscan II indicates combined slit-scanning and Placido-disk corneal videokeratography (Bausch & Lomb–Orbtek Inc, Salt Lake City, Utah). Unless otherwise indicated, data are expressed as mean ± SD in diopters (n = 26).†Calculated by analysis of variance between diameters.‡Indicates 2-tailed Pearson correlation between anterior-mean and posterior-mean powers with P≤.017.ANTERIOR-POSTERIOR CORNEAL POWER RELATIONSHIPPreoperative (Table 2) and postoperative (Table 3) better Pearson correlations between anterior-mean and posterior-mean powers were found when larger analyzed areas were measured. Before LASIK, the average of the anterior-posterior corneal power ratio varied from 7.27 in the smallest analyzed area to 7.63 in the 5-mm-diameter area. After the myopic LASIK, this ratio was smaller (2-tailed paired ttest, P<<.001) and varied from 6.25 to 7.28, respectively. Preoperatively and postoperatively, this variability was extremely significant, meaning that the anterior-posterior power ratio was not a fixed value.INFLUENCE OF KERATOMETRIC AND PHYSIOLOGIC REFRACTIVE INDEXESPreoperative keratometric-mean power was more positive than total-mean power by 1.61 D in the smaller analyzed area, and by 1.31 D in the 5-mm-diameter area (Table 4). Postoperatively, this difference was larger and ranged from 2.50 to 1.61 D, respectively.Table 4. Difference Between Keratometric-Mean and Total-Mean Power Maps*Diameter of Analyzed Area, mm≤0.0412345Preoperative†+1.61 ± 0.24+1.59 ± 0.24+1.56 ± 0.18+1.53 ± 0.12+1.41 ± 0.16+1.31 ± 0.11Postoperative‡§+2.50 ± 0.37+2.46 ± 0.34+2.32 ± 0.37+2.11 ± 0.24+1.92 ± 0.48+1.61 ± 0.16*Unless otherwise indicated, data are expressed as mean ± SD in diopters (n = 26).†Preoperative keratometric-mean power was more positive than total-mean power in all 6 analyzed areas (2-tailed paired ttest; P<<.001).‡Postoperative keratometric-mean power was more positive than total-mean power in all 6 analyzed areas (2-tailed paired ttest; P<<.001).§Postoperative difference was larger than preoperative in all 6 analyzed areas (2-tailed paired ttest; P<.001).TOTAL CORNEAL POWER CHANGES AFTER MYOPIC LASIKChanges in keratometric-mean and total-mean powers after myopic LASIK were smaller when assessed in larger areas (Table 5). Changes in total-optical power had this tendency, but they were not statistically different in all 6 analyzed areas. The refractive change at the corneal plane had very good Pearson correlation (P<<.001) with the total-optical (R≥0.80), total-mean (R≥0.87), and keratometric-mean (R≥0.89) power changes. Linear correlation showed that measurement of power on larger areas with total-optical (Figure 1) and total-mean (Figure 2) power maps tended to underestimate the LASIK outcome, especially for higher ametropias.Table 5. Total Corneal Power Changes After Myopic LASIK*Diameter of Analyzed Area, mmPValue†≤0.0412345Total-optical powerPostoperative power Δ−4.26 ± 1.65−4.20 ± 1.67−4.11 ± 1.52−3.86 ± 1.37−3.51 ± 1.34−3.21 ± 1.17.09Difference with refractive Δ0.66 ± 1.000.60 ± 0.900.52 ± 0.760.26 ± 0.66−0.08 ± 0.53−0.39 ± 0.62No. of cases with difference greater than ± 1.0 D997426No. of cases with power Δ >refractive Δ20201917115Pvalue‡.002.002.002.05.43.004Keratometric-mean powerPostoperative power Δ−3.21 ± 1.39−3.10 ± 1.31−2.91 ± 1.17−2.61 ± 1.05−2.18 ± 0.84−1.56 ± 0.67<<.001Difference with refractive Δ−0.39 ± 0.63−0.49 ± 0.58−0.69 ± 0.54−0.98 ± 0.59−1.41 ± 0.77−2.04 ± 0.92No. of cases with difference greater than ± 1.0 D449122024No. of cases with power Δ >refractive Δ773210Pvalue‡.004<.001<<.001<<.001<<.001<<.001Total-mean powerPostoperative power Δ−4.10 ± 1.55−3.97 ± 1.45−3.67 ± 1.30−3.20 ± 1.17−2.70 ± 1.06−1.86 ± 0.74<<.001Difference with refractive Δ0.50 ± 0.770.38 ± 0.700.07 ± 0.62−0.40 ± 0.59−0.90 ± 0.73−1.74 ± 0.86No. of cases with difference greater than ± 1.0 D87161123No. of cases with power Δ >refractive Δ191813532Pvalue‡.003.01.55.002<<.001<<.001Abbreviations: Δ, corneal or refractive change after LASIK; D, diopter; LASIK, laser in situ keratomileusis.*Refractive Δ at the corneal plane (gold standard) was −3.59 ± 1.46. Unless otherwise indicated, data are expressed as mean ± SD in diopters (n = 26).†Calculated by analysis of variance between diameters.‡Calculated by the 2-tailed paired ttest between refractive Δ and respective corneal power Δ.Figure 1.Linear correlation (in diopters [D]) between refractive change at the corneal plane (x-axis) and total-optical power changes (y-axis) assessed in 6 central areas. Ø indicates diameter.Figure 2.Linear correlation (in diopters [D]) between refractive change at the corneal plane (x-axis) and total-mean power changes (y-axis) assessed in 6 central areas. Ø indicates diameter.Total-optical power changes in a 3-mm-(Wilcoxon, P= .07) and a 4-mm-(Wilcoxon, P= .37) diameter area were not different from the refractive change. Total-optical power changes measured in other area sizes were different. Keratometric-mean power changes were best assessed in the smallest analyzed area (Wilcoxon, P= .009), but they were different from the refractive change in all 6 areas. Total-mean power changes were best assessed in a 2-mm-diameter area (Wilcoxon, P= .60). Total-mean power changes in other area sizes were different from the refractive change.Symmetry of values above and below confirmed the more representative areas. A difference of larger than 1 D was found in only 2 eyes (1.15 and −1.02 D) with the 4-mm total-optical power, and in 1 case (1.40 D) with the 2-mm total-mean power.CONTRIBUTION OF ANTERIOR SURFACE, POSTERIOR SURFACE, AND THICKNESS-DERIVED POWERS ON TOTAL CORNEAL POWER CHANGEChanges in anterior-mean power after myopic LASIK were smaller when assessed in larger areas (Table 6). The refractive change at the corneal plane correlated (R≥0.89; P<<.001) with the anterior-mean power change in all 6 analyzed areas. Anterior-mean power changes in the central smallest area (Wilcoxon, P= .85) and in the 1-mm-diameter area (Wilcoxon, P= .27) were not different from the refractive change. Anterior-mean power changes in other area sizes were different from the refractive change.Table 6. Anterior Surface, Posterior Surface, and Thickness-Derived Corneal Power Changes After Myopic LASIK*Diameter of Analyzed Area, mmPValue†≤0.0412345Anterior-mean powerPostoperative power Δ−3.64 ± 1.50−3.47 ± 1.46−3.20 ± 1.26−2.91 ± 1.16−2.38 ± 0.94−1.74 ± 0.74<<.001Pvalue‡.75.30.003<<.001<<.001<<.001Posterior-mean powerPostoperative power Δ−0.52 ± 0.36−0.48 ± 0.33−0.38 ± 0.41−0.27 ± 0.18−0.15 ± 0.11−0.06 ± 0.14<<.001Pvalue§<<.001<<.001<<.001<<.001<<.001.04Thickness-mean powerPostoperative power Δ−0.01 ± 0.01−0.01 ± 0.01−0.01 ± 0.01−0.01 ± 0.01−0.01 ± 0.01−0.01 ± 0.01.22Abbreviations: Δ, corneal or refractive change after LASIK; D, diopter, LASIK, laser in situ keratomileusis.*Refractive Δ at the corneal plane (gold standard) was −3.59 ± 1.46. Unless otherwise indicated, data are expressed as mean ± SD in diopters (n = 26).†Calculated by analysis of variance between diameters.‡Calculated by the 2-tailed paired ttest between refractive Δ and anterior-mean power Δ.§Calculated by the 2-tailed paired ttest between preoperative and postoperative posterior-mean power.The posterior-mean power increased (steepening) almost −0.50 D in the central point and the 1-mm-diameter area (12%-13% of total-mean power change), and some more than −0.25 D in the 2-mm- and 3-mm-diameter areas (8%-10%). The larger the analyzed area, the smaller its contribution to the total-mean power change. Although it had statistical significance, posterior-mean power change was without clinical importance and hardly noticeable when a 5-mm-diameter area was analyzed. The refractive change had no correlation with the change found in the posterior-mean power (R≤−0.28; P≥.17).Preoperative thickness-mean power ranged from 0.11 to 0.17 D (mean, 0.14 D [Table 2]). Changes of thickness-mean power were too small (mean, −0.01 D; never larger than –0.03 D) to have clinical importance, so we waived statistical tests for them.COMMENTThe cornea is an optic system composed of anterior and posterior surfaces, a distance between them (thickness), and basically 3 optical media (air, corneal tissue, and aqueous humor), each one with its own refractive index. Presently, it is known that all these components must be considered when calculating the real power of the cornea.Traditional methods (eg, keratometry, simulated keratometry [sim-K]) assume the total power of the cornea from the measurement of the radius of curvature of its anterior surface. Only recently, when slit-scanning CVK (Orbscan I) measurement of the posterior surface power of the cornea became available, such an assumption began to be challenged. Accuracy questioningand verificationof this technology have been reported. Although its reliability may be controversial, it seems improved after it was combined with Placido-disk–based CVK (Orbscan II).A great variability on corneal power may be achieved with the Orbscan II by measuring different area sizes using different mathematical processes.Essentially, the basis of calculation of all maps is the measurement of the distance between each point localized by the system and the sphere that best fits these points. This distance is called elevationand may be negative (down to the best-fit sphere and represented by cold colors) or positive (up to the best-fit sphere and represented by warm colors).Optical, mean, keratometric, total, and other power maps may be obtained.However, a few values automatically shown are a potential source of confusion if applied in IOL calculation. The power of the posterior best-fit sphere shown on top of default quad maps, for example, is calculated using the keratometric refractive index of the cornea (1.3375), despite the fact that components of this optical interface are the cornea (refractive index of 1.376) and the aqueous humor (refractive index of 1.336). On the other hand, diopters automatically repeated at right of several individual maps, for standard or default statistical zones, also seem to be obtained using the keratometric refractive index, are not the same values found by the Orbscan II statistical analysis device,and should be interpreted only as keratometric data. The Orbscan II statistical analysis device is able to give the average measurement of all identified points in a selected area of any of multiple available maps, its lowest and highest value, and its standard deviation. It is a simple (using the control-a keyboard shortcut) but time-consuming process, and it seems to be the best way to obtain information from this equipment. A suggestion has been made to the manufacturer to simplify the achievement of data with it.Variability of this method is on the third decimal in power maps.Several methods were suggested to measure the power of corneas subjected to refractive surgery. Keratometry has been replaced by Placido-disk–based CVK, by sim-K,or by mean central corneal power.However, these methods evaluate areas of approximately 3 mm in diameter that might not be appropriate to calculate the power of corneas that have undergone refractive surgery when the keratometric refractive index is used. The tendency these keratometric powers have to indicate a more positive total corneal power and to underestimate the refractive change after myopic LASIKor photorefractive keratectomyseems to be compatible with the undercorrection usually found after cataract surgery in patients with myopic refractive surgery.Presently, the criterion standard and the more accurate method for corneal power estimation after refractive surgery is the clinical history method, also called refraction-derived keratometry. The refractive change is subtracted from the power of the cornea before the refractive surgery to determine the final corneal power to be applied in IOL calculation.Since this information is not always available, it was suggested that an overrefraction with a rigid contact lens with a known base curve should be made,a higher fictitious refractive index for the cornea should be adopted,regression formulas to adjust the smallest ring on CVK should be applied,corneal radius correcting factors should be calculated,or computer programs should be used.Although these empirical methods may be effective, they assume an expected value and do not assess a realistic corneal power. A more pragmatic approach would be to understand why traditional methods result in errors and then, instead of adapting these errors, look for how to avoid them. The capability of the Orbscan II corneal topography system to evaluate the central portion of the cornea seems to give us such an opportunity.The keratometric refractive index of 1.3375 assumes that the power of the anterior surface of the cornea is almost 10 times the power of the posterior surface. However, our results show a smaller anterior-posterior corneal power ratio, confirming our earlier report.This seems to be because the Gullstrand model eye from which the keratometric refractive index is deduced assumes a lower theoretical posterior surface power than what was actually assessed by the Orbscan Iand II.Furthermore, this ratio is not fixed in all of the extension of both corneal surfaces, but it changes according to the size of the measured area. That correlation between powers of both surfaces improves when larger areas are assessed. This study also confirms that the total corneal power is more positive when deduced from the anterior surface radius using such a keratometric refractive index. As a consequence of changes on corneal surfaces, these findings are more remarkable after myopic LASIK, suggesting that traditional methods to calculate the corneal power may be inappropriate in these cases.Preoperatively, the total power of the normal cornea and the power of its anterior surface do not vary and are independent of the size of the analyzed area if it has a diameter of less than 5 mm. Nevertheless, the power of the posterior surface becomes less negative when measured in larger areas.Myopic LASIK iatrogenically modifies the normal geometry of the cornea by promoting higher power changes in the central portion of the cornea. The expected flattening (less positive power) of the anterior surface, reflected by the change in anterior-mean power maps, tended to diminish progressively when larger areas were analyzed and, consequently, the total power of the cornea became more positive. The changes on the anterior surface were responsible for most but not all of the myopic correction induced by the LASIK. As this study shows, a change in the power of the posterior surface of the cornea contributes around 10% of the total power change inside a central area 3 mm in diameter.Theoretically, the refractive change (gold standard) induced by the LASIK should be the same as the power change found in the cornea. However, this was not observed in all the Orbscan II maps or in all of the analyzed areas. The refractive change at the spectacle plane might be used, but we decided to compare this change at the corneal plane because the Orbscan II assesses corneal power changes and not spectacle power changes. Although changes in anterior and total power maps in all 6 analyzed areas had good correlation, correlation tests did not confirm which map or which area reflected better the refractive change after myopic LASIK. Thus, refractive and Orbscan II corneal power changes were also compared using the paired tand Wilcoxon tests. Both tests had equivalent results. To simplify, the Pvalues shown in Table 5correspond to paired ttest results. Areas larger than 4 mm in diameter in most maps tended to underestimate the refractive change, particularly for eyes with higher preoperative myopia. The larger underestimation occurred with the keratometric-mean power (Table 5), suggesting that traditional keratometric methods used to obtain the corneal power may be more sensitive to the oblate shape of the anterior surface secondary to the higher energy applied to the central point. Although the effective optical zone of treatment is related to the amount of treatment,we do not yet know whether the size of the effective optical zone may also influence the selection of the best representative central area to compute the refractive change. From this study, we know that the size of this area modifies the result according to the method used to obtain the value in diopters. The best total-optical power map to reflect the refractive change was found using a 4-mm-diameter area (Table 5and Figure 1, bottom and center). Keratometric-mean power maps had their best measurement in the smallest, most central point, but always underestimated the refractive change. The best total-mean power map was found using a 2-mm-diameter area (Table 5and Figure 2, top and right). Anterior-mean power maps also accurately resemble the refractive change when assessed in areas smaller than 1 mm in diameter; however, they do not represent the total corneal power (Table 6). Despite some apparent differences in our methods to obtain the data and the upgraded equipment we used, our more accurate results are in agreement with those of an earlier report, suggesting the use of the 4-mm total-optical power map.We were unable to find any other previous report of this in the literature.Although we studied a limited number of patients, from our results we find it reasonable to recommend the use of the 2-mm total-mean power and/or the 4-mm total-optical power, assessed by the Orbscan II statistical analysis device, as accurate values to be applied for IOL calculation in patients who underwent myopic LASIK. Until more information is collected, it might be prudent to use the smaller of both values when it is known that the corrected refractive defect was higher than −5 D. Caution must be taken to extrapolate our results to other refractive errors. 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2000.BSeitzFTorresALangenbucherABehrensKSuárezPosterior corneal curvature changes after myopic laser in situ keratomileusis.Ophthalmology.2001;108:666-673.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11297480&dopt=AbstractJTHolladayJAJanesTopographic changes in corneal asphericity and effective optical zone after laser in situ keratomileusis.J Cataract Refract Surg.2002;28:942-947.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12036634&dopt=AbstractSSrivannaboonDZReinsteinHFSuttonSPHollandAccuracy of Orbscan total optical power maps in detecting refractive change after myopic laser in situ keratomileusis.J Cataract Refract Surg.1999;25:1596-1599.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10609202&dopt=AbstractCorresponding author and reprints: Carlos G. Arce, MD, Ocular Bioengineer Laboratory, Institute of Vision, Department of Ophthalmology, UNIFESP/EPM, Rua Borges Lagoa 368, São Paulo, SP 04038-000, Brazil (e-mail: [email protected]).Submitted for publication February 19, 2003; final revision received September 1, 2003; accepted October 6, 2003.This study was presented at the XXVII Annual Symposium of the Paraná Association of Ophthalmology; June 13, 2003; Curitiba, Brazil; at the XXXII Brazilian Congress of Ophthalmology; September 11, 2003; Salvador, Brazil; and at the 23rd Biennial Cornea Research Conference, the Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary; Harvard Medical School, October 4, 2003; Boston, Mass.This study is the winner of the Paraná Association of Ophthalmology 2003 Prize and of the 23rd Biennial Cornea Conference Research Award.We thank Peter J. Polack, MD, for editorial assistance.

Shields, Carol L.; Fasiudden, Airey; Mashayekhi, Arman; Shields, Jerry A.

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.167pmid: 14769591

ObjectivesTo describe the clinical features of a conjunctival nevus and to evaluate the lesion for changes in color and size over time.DesignRetrospective, observational, noncomparative case series.ParticipantsFour hundred ten consecutive patients with conjunctival nevi.Main Outcome MeasuresThe 2 main outcome measures were changes in tumor color and size.ResultsOf the 410 patients, 365 (about 89%) were white, 23 (about 6%) were African American, 8 (2%) were Asian, 8 (2%) were Indian, and 6 (1%) were Hispanic. The iris color was brown in 55% (229/418), blue in 20% (85/418), green in 20% (83/418), and not indicated in 5% (21/418). The nevus was brown in 65%, tan in 19%, and completely nonpigmented in 16%. The anatomical location of the nevus was the bulbar conjunctiva (302 eyes, 72%), caruncle (61 eyes, 15%), plica semilunaris (44 eyes, 11%), fornix (6 eyes, 1%), tarsus (3 eyes, 1%), and cornea (2 eyes, <1%). The bulbar conjunctival lesions most commonly abutted the corneoscleral limbus. The nevus quadrant was temporal (190 eyes, 46%), nasal (184 eyes, 44%), superior (23 eyes, 6%), and inferior (21 eyes, 5%). Additional features included intralesional cysts (65%), feeder vessels (33%), and visible intrinsic vessels (38%). Cysts were clinically detected in 70% of histopathologically confirmed compound nevi, 58% of the subepithelial nevi, 40% of the junctional nevi, and 0% of the blue nevi. Of the 149 patients who returned for periodic observation for a mean of 11 years, the lesion color gradually became darker in 5% (7 patients), lighter in 8% (12 patients), and was stable in 87% (130 patients). The lesion size was larger in 7% (10 patients), appeared smaller in 1% (1 patient), and was stable in 92% (137 patients). There were 3 patients who developed malignant melanoma from a preexisting compound nevus (2 cases) or blue nevus (1 case) over a mean interval of 7 years.ConclusionsConjunctival nevus is a benign tumor most often located at the nasal or temporal limbus and rarely in the fornix, tarsus, or cornea. Over time, a change in tumor color was detected in 13% (20/149) and a change in tumor size was detected in 8% (12/149).The conjunctival nevus is a common benign ocular tumor. It can manifest with a spectrum of clinical features.Recent articles about the conjunctival nevus have primarily focused on the histopathologic features of this entity.Over the past 2 decades, there have been only 2 relevant studies on the long-term natural history of conjunctival nevi.Both studies focused on the pathologic correlation of excised lesions with little information on the varied clinical features. In this article, to our knowledge, we provide for the first time in the recent literature a detailed account of the clinical variations of conjunctival nevi in 410 consecutive patients. We provide information regarding the frequency of change in pigmentation and size of these benign tumors. A comparison of the clinical appearance of conjunctival nevi with conjunctival melanoma is also made.METHODSThe clinical records of all patients with a conjunctival nevus, examined and treated on the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pa, between July 1, 1974, and May 30, 2002, were reviewed. Clinical data were gathered retrospectively regarding features of the patient and the conjunctival nevus. The clinical data were then analyzed with regard to 2 main outcome measures—color change within the nevus and size change of the nevus.These data included patient features at the initial examination such as age, race (African American, Hispanic, Asian, or white), and sex (female or male). Data were recorded regarding cutaneous lesions (nevus, dysplastic nevus syndrome, or malignant melanoma), other conjunctival lesions (primary acquired melanosis, pinguecula, pterygium, or squamous cell neoplasia), and choroidal lesions (nevus or melanoma). Data were recorded on iris color (blue, green, brown, or hazel). A history regarding the conjunctival nevus included previous documented growth of the lesion (present or absent), previous treatment of the lesion (none or excisional biopsy), symptoms (spot, inflammation, pain, or none), and the duration of these symptoms.The ocular data included best-corrected Snellen visual acuity, designation of the eye involved (right or left), and the intraocular pressure. The tumor data included the anatomical location (bulbar conjunctiva, fornix, tarsal conjunctiva, plica semilunaris, caruncle, or cornea), quadrant location of the tumor epicenter (superior, temporal, inferior, or nasal), proximity to the limbus (expressed in millimeters), anterior tumor margin (cornea, limbus, bulbar conjunctiva, or fornix), posterior tumor margin (cornea, limbus, bulbar conjunctiva, or fornix), largest basal dimension (expressed in millimeters), largest thickness (expressed in millimeters), elevation status (flat or elevated), color (amelanotic, tan, or brown), intralesional cysts status (present or absent), and the number of cysts per nevus, feeder vessels (present or absent), and intrinsic vessels (present or absent).Follow-up examinations were generally made at 6- to 12-month intervals. In this study we included only patients with photographic follow-up for comparison of clinical data. The follow-up data included the type of color change within the nevus (darker, lighter, or no change) and the type of nevus size change (larger, smaller, or no change).RESULTSThe general information about patient demographics is listed in Table 1. The visual acuity on the initial examination was 20/20 to 20/50 in 403 patients (97%), 20/60 to 20/100 in 5 patients (1%), and 20/200 or worse in 8 patients (2%). Data regarding general ocular findings are listed in Table 2. Data regarding tumor findings are listed in Table 3and in Figure 1, Figure 2, Figure 3, and Figure 4. There were 180 patients (43%) who reported that the lesion appeared to have enlarged over time before the date of the initial examination. The tumor was most commonly located on the bulbar conjunctiva (72%). Of all 418 lesions, the quadrant location of the tumor was temporal in 46% and nasal in 44%; the anterior margin was immediately at the limbus in 48% and behind the limbus in 25%. The median size was 3.5 mm in basal diameter and 0.5 mm in thickness. The lesion was most commonly pigmented (84%) and had intralesional cysts (65%). Feeder vessels (33%) and intrinsic vessels (38%) were found less often. Tumor treatment is listed in Table 4and included observation (62%) or excisional biopsy alone or with cryotherapy (38%). The most common reasons for excisional biopsy included our concern for malignant change based on clinical features (16%), recent growth (8%), color change (<1%), or recurrence of previously excised lesion (2%). The clinical features suggestive of possible melanoma include older patient age at recognition of nevus; corneal, forniceal, or palpebral involvement; prominent feeder vessels; lack of intrinsic cysts; and personal or family history of cutaneous melanoma or dysplastic nevus syndrome. Other reasons for excision included patient's concern for melanoma (7%) or cosmetic appearance (4%).Table 1. Conjunctival Nevus in 410 Consecutive Patients: Patient Findings at the Initial ExaminationDemographics and Clinical FindingsNo. (%) of PatientsAge, mean (median) [range], y32 (30) [2-93]RaceWhite365 (89)African American23 (6)Asian8 (2)Indian8 (2)Hispanic6 (1)SexFemale209 (51)Male201 (49)Skin historyNone322 (79)Nevus*77 (19)Basal cell carcinoma5 (1)Dysplastic nevus syndrome†4 (1)Malignant melanoma†4 (1)*Includes all patients with cutaneous nevi that were diagnosed clinically or histopathologically.†Two patients had a history of having both dysplastic nevus syndrome and malignant melanoma.Table 2. Ocular Findings at the Initial Examination of 418 Conjunctival Nevi in 410 Consecutive PatientsOcular FindingsNo. (%) of EyesEye (n = 410 patients)Right209 (51)Left195 (48)Both6 (1)Iris color (n = 418 eyes)Brown229 (55)Blue85 (20)Green83 (20)Not indicated21 (5)Choroidal findings (n = 418 eyes)None382 (91)Nevus28 (7)Malignant melanoma8 (2)Conjunctival findings (n = 418 eyes)None373 (90)Primary acquired melanosis*†28 (7)Pinguecula†11 (3)Pterygium4 (1)Malignant melanoma*1 (<1)Squamous cell carcinoma1 (<1)Prior ocular trauma (n = 418 eyes)Yes18 (4)No400 (96)*One patient was initially seen with a conjunctival melanoma arising from primary acquired melanosis with atypia.†One patient had both primary acquired melanosis and pinguecula.Table 3. Tumor Findings of 418 Conjunctival Nevi in 410 Consecutive PatientsOcular FindingsNo. (%) of NeviHistory of tumor enlargementPresent180 (43)Absent238 (57)SymptomsSpot366 (88)Inflammation11 (3)Pain1 (<1)None40 (10)Duration of symptoms, mean (median) [range], y10 (3) [0-78]Anatomical locationBulbar conjunctiva302 (72)Caruncle61 (15)Plica semilunaris44 (11)Fornix6 (1)Tarsal conjunctiva3 (1)Cornea2 (<1)Quadrant location (n = 418)Temporal190 (46)Nasal184 (44)Superior23 (6)Inferior21 (5)Anterior margin*Limbus202 (48)Bulbar conjunctiva106 (25)Cornea (overhang)2 (<1)Not applicable†108 (26)Posterior margin*Bulbar conjunctiva303 (73)Limbus4 (1)Fornix3 (1)Not applicable†108 (26)Distance of anterior margin from limbus, mean (median) [range], mm*1 (0) [0-10]Largest basal diameter, mean (median) [range], mm4.1 (3.5) [0.2-30.0]Thickness statusFlat103 (25)Elevated315 (75)Thickness, mean (median) [range], mm0.8 (0.5) [0-6.0]ColorBrown271 (65)Tan80 (19)Amelanotic67 (16)Cyst statusPresent271 (65)Absent147 (35)No. of cysts, mean (median) [range]2 (0) [0-100]Feeder vessel statusPresent137 (33)Absent281 (67)Intrinsic vessel statusYes160 (38)No258 (62)*Includes nevi of the bulbar and forniceal conjunctiva.†Includes nevi of the caruncle, plica semilunaris, tarsus, and fornix.Figure 1.Variations in pigmentation of conjunctival nevi. A, Heavily pigmented conjunctival nevus. B, Lightly pigmented conjunctival nevus.Figure 2.Variations in size of conjunctival nevi. A, Small, pigmented conjunctival nevus measuring approximately 1 mm in basal diameter. B, Giant conjunctival nevus measuring 18 mm in basal diameter.Figure 3.Variations in location of conjunctival nevi. A, The most common location of the conjunctival nevus is on the bulbar conjunctiva at the limbus. B, The second most common location of the conjunctival nevus is in the caruncle. C, The least common location of the conjunctival nevus is in the plica semilunaris.Figure 4.Variations in associated clinical features of conjunctival nevi. A, Pigmented nevus with prominent clear intralesional cysts. B, Lightly pigmented nevus with pigment-lined intralesional cysts. C, Nonpigmented nevus with clear intralesional cysts and dilated feeder vessel. D, Lightly pigmented nevus with prominent vascularity.Table 4. Treatment of 418 Conjunctival Nevi in 410 Consecutive PatientsVariableNo. (%) of NeviTreatmentObservation258 (62)Excisional biopsy with cryotherapy107 (26)Excisional biopsy alone53 (13)Reason for excisional biopsyRule out malignant melanoma95 (23)Rule out other tumor or lesion5 (1)Growth of nevus32 (8)Color change in nevus2 (<1)Cosmetic concern16 (4)Recurrence of excised lesion10 (2)Not applicable*258 (62)Histologic typeCompound nevus103 (25)Subepithelial nevus36 (9)Junctional nevus5 (1)Blue nevus4 (1)CombinedCompound and blue nevi4 (1)Subepithelial and blue nevi2 (<1)Not available†12 (3)Not applicable*258 (62)Recurrence after excisionYes‡10 (2)No150 (36)Not applicable*258 (62)*The nevus was observed and not excised.†In 12 patients the histopathologic record was unavailable for review.‡A second biopsy specimen showed a nevus in 8 patients and a malignant melanoma in 2 patients.The histopathologic diagnoses in the 148 excised lesions are listed in Table 5and included compound nevus (70%), subepithelial nevus (4%), junctional nevus (3%), and blue nevus (3%) (Figure 5). Of these 148 nevi, tumor pigmentation was found in 82% of those classified as compound, 86% of those classified as subepithelial nevi, 100% of those classified as junctional nevi, and 100% of those classified as blue nevi. Cysts were noted in 70% of the compound nevi, 58% of the subepithelial nevi, 40% of the junctional nevi, and 0% of the blue nevi.Table 5. Clinical Features of 148 Histopathologically Confirmed Conjunctival Nevi*Clinical FindingsType of NeviCompound (n = 103)Subepithelial (Stromal) (n = 36)Junctional (n = 5)Blue (n = 4)Patient age, mean (median) [range], y26 (23) [5-74]46 (49) [12-87]33 (18) [15-73]51 (43) [40-71]Anatomical locationBulbar75 (73)17 (47)5 (100)2 (50)Caruncle14 (14)12 (33)00Plica13 (13)6 (17)00Fornix01 (3)01 (25)Tarsal0001 (25)Cornea1 (1)000ColorBrown70 (68)27 (75)5 (100)4 (100)Tan14 (14)4 (11)00Amelanotic19 (18)5 (14)00Cyst statusPresent72 (70)21 (58)2 (40)0Absent31 (30)15 (42)3 (60)4 (100)Feeder vessel statusPresent41 (40)7 (19)3 (60)0Absent62 (60)29 (81)2 (40)4 (100)Intrinsic vessel statusPresent49 (48)15 (42)1 (20)1 (25)Absent54 (52)21 (58)4 (80)3 (75)*Data are given as the number (percentage) of nevi unless otherwise indicated. In 12 patients the histopathologic record was unavailable for review.Figure 5.Variations in the clinical appearance of the 4 histopathologic subtypes of conjunctival nevi. A, Compound nevus of the conjunctiva. B, Subepithelial nevus of the conjunctiva. C, Blue nevus of the conjunctiva.Of the 149 conjunctival nevi followed up for a mean of 11 years without being excised, the tumor showed a color change in 13% and a size change in 8% (Table 6and Figure 6). The clinical features of the 3 patients with nevi that evolved to malignant melanoma (over a mean of 7 years) are listed in Table 7. No patients developed melanoma metastasis.Table 6. Natural Course in 149 Conjunctival Nevi That Were Treated by Observation Only*Main Outcome MeasureNo. (%) of NeviTumor color changeNone129 (87)Lighter12 (8)Darker8 (5)Tumor size changeNo137 (92)Larger10 (7)Smaller2 (1)*In 121 patients the lesion was excised at the first visit so natural course was unavailable; in 148 patients there was no follow-up examination.Figure 6.Change in nevus appearance over time. A, May 1988. Pigmented conjunctival nevus at the limbus in a 26-year-old woman. B, July 1990. Several years later the conjunctival nevus of the same woman was less pigmented and barely visible.Table 7. Initial Clinical Features of the Conjunctival Nevus in 3 Patients Who Eventually Developed Malignant MelanomaClinical FeatureConjunctival Nevus Evolved to Melanoma, No. (%)Patient age at melanoma diagnosis, mean (median) [range], y31 (32) [19-41]White race3 (100)SexFemale2 (67)Male1 (33)Skin historyNevus1 (33)Basal cell carcinoma0Dysplastic nevus syndrome1 (33)Malignant melanoma*0Iris colorBrown2 (67)Blue1 (33)Green0History of tumor enlargementPresent3 (100)Absent0Duration of symptoms, mean (median) [range], y7 (1) [0.3-20.0]Anatomical locationBulbar2 (67)Caruncle0Plica semilunaris0Fornix1 (33)Tarsal conjunctiva0Cornea0Quadrant locationTemporal1 (33)Nasal1 (33)Superior0Inferior1 (33)Distance of anterior margin from limbus, mean (median) [range], mm†0.7 (0) [0-2.0]ColorBrown3 (100)Tan0Amelanotic0Cyst statusPresent1 (33)Absent2 (67)Feeder vessel statusPresent2 (67)Absent1 (33)Intrinsic vessel statusYes1 (33)No2 (67)Nevus histologic typeCompound nevus2 (67)Subepithelial nevus0Junctional nevus0Blue nevus1 (33)*One patient had a family history of cutaneous melanoma. †Pathological findings revealed a conjunctival nevus.COMMENTEpibulbar melanocytic lesions include conditions of the conjunctival epithelium, stroma, and sclera. Some of these conditions include conjunctival racial melanosis, primary acquired melanosis, secondary melanosis, nevus, and melanoma, as well as ocular melanocytosis and extraocular extension of uveal melanoma.The clinical features of these pigmented conditions occasionally overlap and cause diagnostic confusion. Moreover, an amelanotic conjunctival nevus can resemble other nonpigmented conditions including inflamed pingueculum, episcleritis, conjunctival cyst, allergic conjunctivitis, foreign body granuloma, lymphangioma, and squamous epithelial neoplasia. The differentiation of these various conditions is important as it implies diverse ocular and systemic prognoses. The diagnosis is usually made based on the clinical features and occasionally confirmed with histopathologic findings. With regard to the conjunctival nevus, the diagnosis is typically made by recognition of the classic clinical features using slitlamp biomicroscopy. In this article, we describe a comprehensive overview of the various presentations of the conjunctival nevi in 410 consecutive patients.Few articles have focused on the subject of the clinical features of conjunctival nevi. Most previous articles have described the pathological findings with generalizations, but little description of the clinical findings.In 1965, Jayreported the pathological features of benign nevi of the conjunctiva. He gathered basic clinical information only on patient age at diagnosis and noted that the patients most commonly seen by an ophthalmologist were between the ages 10 to 29 years and typically claimed that the lesion was first detected when the patient was younger than 9 years. Other clinical features of the excised tumors were unavailable. Henkind,in 1978, provided a comprehensive summary of conjunctival melanocytic lesions with minor generalizations on the clinical findings of conjunctival nevi. Since then, other articles on this condition have concentrated on related histogenesis, light microscopic findings, and ultrastructural features of common and rare subtypes of nevi.In 1996, a Danish study by Gerner et alprovided a clinicopathologic study on 343 conjunctival nevi. They described the following tumor locations: the bulbar conjunctiva in 33%, caruncle in 29%, limbal conjunctiva in 27%, and at the eyelid margin in 1%. The patients were seen most commonly between the ages of 10 and 19 years. All but 3 patients were white and only 1 nevus evolved into a malignant melanoma. Further specific clinical information was not reported.To our knowledge, our report is the first to delineate the specific clinical features of conjunctival nevi. We found the mean patient age at the initial manifestation was 32 years and most commonly, this tumor was found in white subjects (89%) (Table 1). Many patients had cutaneous nevi (19%) and 1% of patients each reported a history of basal cell carcinoma, dysplastic cutaneous nevi,and previous cutaneous malignant melanoma. Unlike choroidal melanoma or iris melanoma, which is usually found in patients with blue irides,conjunctival nevi were most commonly found in patients with brown irides (55%) (Table 2). Additional choroidal nevi were noted in 7% of the white patients, consistent with the expected number in the white population.With regard to the symptoms and clinical appearance of the tumor, most patients reported noticing a spot on the eye (88%), 3% noted inflammation, less than 1% experienced related pain, and 10% of patients were unaware of the lesion. The symptoms were present for a mean of 10 years. Enlargement or color change in the lesion over the years prior to our examination was reported by 43% of patients, but such enlargement was rarely supported by photographs. The tumor was most commonly found in the bulbar conjunctiva (72%), caruncle(15%), or plica semilunaris (11%) (Table 3). Rarely was the tumor found in the fornix (1%), tarsal conjunctiva (1%), or within the cornea (<1%). We, therefore, suggest that any pigmented lesion in the fornix, tarsus, or cornea might be considered to be a condition other than a nevus.This is especially important if the pigmented lesion is circumscribed and extends into the stroma, in which case malignant melanoma might be considered.In comparison, of 150 consecutive patients with conjunctival melanoma reported by Shields et al,the tumor location was the bulbar conjunctiva (92%), caruncle (1%), plica semilunaris (1%), fornix (3%), and tarsal conjunctiva (4%).Those tumors on the bulbar conjunctiva were a mean of 1 mm (median, 0 mm) from the limbus. In only 2 patients was there corneal involvement and both were unusual cases with small corneal stromal nevi.Corneal involvement from a pigmented conjunctival lesion should suggest primary acquired melanosis or racial melanosis if the conjunctival pigmentation is within the epithelium, but, importantly, should raise consideration for conjunctival melanoma if the conjunctival pigmentation has thickness and extends into the stroma.Conjunctival nevi generally stop abruptly at the limbus and typically do not involve the corneal epithelium or stroma. Overhang of the cornea from a large conjunctival nevus is possible, but invasion of the cornea by a nevus would be distinctly unusual. On the other hand, conjunctival melanoma often grows beyond the limbus into the cornea.The tumor involved the temporal (46%) or nasal (44%) quadrants of the conjunctiva more than the superior (6%) or inferior (5%) quadrants. This distribution along the temporal and nasal quadrants is more common with conjunctival nevus compared with conjunctival melanoma, as conjunctival melanoma has been found in the superior (16%), nasal (17%), and inferior (22%) quadrants less commonly than in the temporal (63%) quadrant.The conjunctival nevi ranged in basal dimension from 0.2 to 30 mm, with a mean of 4.1 mm. The mean thickness was estimated to be less than 1 mm. In comparison, conjunctival melanoma has been detected at a mean size of 8 mm in basal dimension and 2 mm in thickness.All of the patients with large nevi over 10 mm in basal dimension had prominent intralesional cysts to suggest the diagnosis and most had excisional biopsy for histopathologic confirmation. The largest lesions were diffusely multicystic and poorly circumscribed, often resembling a cystic conjunctival lymphangioma or lymphangiectasia.The biomicroscopic appearance of the nevus was critical to its diagnosis. The tumor was most commonly brown (65%) and less often tan (19%) or completely nonpigmented (16%) appearing as a gelatinous translucent mass. Cysts were recognized in 65% of the nevi, feeder vessels in 33%, and intrinsic vessels in 38%. Interestingly, cysts were most common in compound nevus (70%), decreasingly common in subepithelial nevus (58%) and junctional nevus (40%), and absent in blue nevus (0%). Conjunctival melanoma has been recorded as brown in 68%, tan in 19%, and completely nonpigmented but with prominent intrinsic vessels casting a pink rather than gelatinous color in 11% of these lesions.In contrast, however, conjunctival melanoma rarely, if ever, displays intralesional cysts. Feeder vessels are prominent with conjunctival melanoma. Thus, the importance of recognition of tumor cysts is a key point in differentiating conjunctival nevus from malignant melanoma as many other features overlap.Excision of conjunctival nevi was performed in 38% of the cases, mostly for reasons to rule out melanoma or other tumor, recent growth in the lesion, or cosmetic concern (Table 4). Of the 148 lesions for which histopathologic results were available, the findings revealed the following in descending order: compound nevus (70%), subepithelial nevus (24%), combined nevi (4%) (ie, compound and blue nevi or subepithelial and blue nevi), junctional nevus (3%), and blue nevus (3%) (Table 4). Gerner et al,in a clinicopathologic review of 343 conjunctival nevi, found similar distribution of nevi with compound nevi (78%), supepithelial (intrastromal) nevus (15%), junctional nevus (6%), and blue nevus (<1%). Of 57 nevi excised from children and teenagers, McDonnell et alidentified compound nevi (72%), subepithelial nevus (4%), junctional nevus (21%), blue nevus (2%), and Spitz nevus (2%).These results suggest greater junctional activity in children with conjunctival nevi.In our series, a correlation of the clinical features with the specific histopathologic diagnosis was provided (Table 5). Compound and junctional nevi were found in younger aged groups, whereas subepithelial and blue nevi were in slightly older aged groups. Bulbar conjunctival location was found with all 4 groups, but caruncular or plical tumor locations were seen only with compound or subepithelial nevi. Both compound and subepithelial nevi showed a variation in color types, but junctional and blue nevi were always brown. Cysts and feeder vessels were absent in all 4 patients with a blue nevus, but present in the other types.The natural history of the 149 observed conjunctival nevi in our series revealed photographically documented change in tumor color in 13% and in size in 8%. Both were gradual and visible only on careful comparison of photographs over years. The change in apparent tumor size could be related to neoplastic growth, but we suspect more commonly it is related to enlargement of the intrinsic cysts, increased pigmentation in previously amelanotic regions of the nevus, or, importantly, inflammation within the nevus. Zamir et alfound that 75% of the excised conjunctival nevi in children showed some degree of inflammatory infiltrate, some of which showed alarming clinical growth without malignant melanoma formation histopathologically. In our group, 3 patients developed malignant melanoma; all were white; 2 had cutaneous abnormalities including dysplastic nevus syndrome in one patient and a family history of cutaneous malignant melanoma in the other patient. The tumors were dark brown in all cases and lacked cysts in 2 patients. Following excision, evidence for melanoma was confirmed, along with underlying compound nevi in 2 patients and blue nevus in 1 patient. From a reverse perspective, conjunctival melanoma has been found to originate from preexistent nevus in 4% of the patients, primary acquired melanosis in 57%, de novo in 39%, that and not specified in 6%.Nooregaard et alfound melanomas originate from a nevus in 16% of the patients, primary acquired melanosis in 36%, and de novo in 47%.There are limitations in this study that should be realized. First, the cohort of patients was derived from a tertiary care ocular oncology center and, thus, may represent a biased group with more suggestive features. Thus, the 3 patients who developed conjunctival malignant melanoma likely represent a higher rate than expected in the general population of patients with conjunctival nevi. Second, there was incomplete photographic follow-up on some of the patients in this cohort. This could inflate the worst-case scenario as the stable patient might choose no further follow-up, whereas those with prominent lesions or tumor growth might choose close follow-up. Third, data collection were retrospective and although the collection was extensive, some data were incomplete. Fourth, not all patients had histopathologic confirmation of the nevus because many were followed up conservatively without surgery.CONCLUSIONSConjunctival nevi display a spectrum of clinical features from heavy pigmentation to a complete lack of pigmentation, from diffuse confluence of cysts to a complete lack of cysts, and from a tiny dotlike size lesion to extensive tumors occupying 1 or 2 quadrants of the ocular surface. The natural history of conjunctival nevi is benign with minor gradual changes of pigmentation in 13% of the patients and gradual change in size in 8% of patients.JAShieldsCLShieldsTumors and pseudotumors of the conjunctiva.Atlas of Eyelid and Conjunctival Tumors.Philadelphia, Pa: Lippincott Williams & Wilkins Co; 1999:199-334.HEGrossniklausWRGreenMLuckenbachCCChanConjunctival lesions in adults: a clinical and histopathologic review.Cornea.1987;6:78-116.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3301209&dopt=AbstractRFolbergFAJakobiecVBBernardinoTIwamotoBenign conjunctival melanotic lesions: clinicopathologic features.Ophthalmology.1989;96:436-461.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2657539&dopt=AbstractJMMcDonnellJDCarpenterPJacobsWLWanJEGilmoreConjunctival melanocytic lesions in children.Ophthalmology.1989;96:986-993.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2771364&dopt=AbstractJABlickerJRootmanVAWhiteCellular blue nevus of the conjunctiva.Ophthalmology.1992;99:1714-1717.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1454347&dopt=AbstractNGernerJCNorregaardOAJensenJUPrauseConjunctival naevi in Denmark, 1960-1980: a 21-year follow-up study.Acta Ophthalmol Scand.1996;74:334-337.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8883545&dopt=AbstractJBCrawfordELHowes JrDHCharCombined nevi of the conjunctiva.Arch Ophthalmol.1999;117:1121-1127.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10496382&dopt=AbstractHDemirciCLShieldsJAShieldsRCEagle JrMalignant melanoma arising from unusual conjunctival blue nevus.Arch Ophthalmol.2000;118:1581-1584.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11074819&dopt=AbstractBJayNaevi and melanomata of the conjunctiva.Br J Ophthalmol.1965;49:169-204.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14289056&dopt=AbstractPHenkindConjunctival melanocytic lesions: natural history.In: Jakobiec FA, ed. 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In: Jakobiec FA, ed. Ocular and Adnexal Tumors.Birmingham, Ala: Aesculapius Publishers Inc; 1978:600-630.CLShieldsJAShieldsKGunduzConjunctival melanoma: risk factors for recurrence, exenteration, metastasis and death in 150 consecutive patients.Arch Ophthalmol.2000;118:1497-1507.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11074806&dopt=AbstractJCNooregaardNGernerOAJensenJUPrauseMalignant melanoma of the conjunctiva: occurrence and survival following surgery and radiotherapy in a Danish population.Graefes Arch Clin Exp Ophthalmol.1996;234:569-572.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8880155&dopt=AbstractJAShieldsCLShieldsRCEagle JrAParkerCompound nevus of the cornea simulating a foreign body.Am J Ophthalmol.2000;130:235-236.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11004302&dopt=AbstractEZamirHMechoulamAMiceraFLevi-SchafferJPe'erInflamed juvenile conjunctival nevus: clinicopathological characterization.Br J Ophthalmol.2002;86:28-30.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11801498&dopt=AbstractCorresponding author and reprints: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, 840 Walnut St, Philadelphia, PA 19107.Submitted for publication May 20, 2003; final revision received September 7, 2003; accepted October 1, 2003.This study was supported by the Eye Tumor Research Foundation, Philadelphia, Pa (Dr C. L. Shields); the Macula Foundation, New York, NY (Dr C. L. Shields); the Center for Eye Research, Tehran, Iran (Dr Mashaykhi); the Rosenthal Award of the Macula Society, Cleveland, Ohio (Dr C. L. Shields); and the Paul Kayser International Award of Merit in Retina Research, Houston Tex (Dr J. A. Shields).

Rowsey, J. James; Macias-Rodriguez, Yolanda; Cukrowski, Chris

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.179pmid: 14769592

ObjectivesTo describe a method to measure the progression of ocular cicatricial pemphigoid and to compare its facility with traditional methods used to measure the progression of the disease.MethodsThe proposed method consists of measuring (in millimeters) the total relative inferior conjunctival surface available in 3 gaze positions. This method was used to monitor 7 eyes of 4 patients with ocular cicatricial pemphigoid over 2 years. The changes in the conjunctival measurements from baseline were compared with the changes documented by traditional methods.ResultsDuring the study, 2 eyes remained stable (changes, <3 mm), 2 had a decrease of 10 mm or more, and 3 had a change in measurements between 4 and 9 mm. With the proposed method, we demonstrated the detection of more subtle changes in the conjunctiva of all patients. Patients who had changes between 4 and 9 mm easily underwent staging by the traditional systems when the new technique was used as a reference.ConclusionThe proposed method offers an objective variable that can be used in consecutive visits to detect subtle progression or disease control in patients with ocular cicatricial pemphigoid.Ocular cicatricial pemphigoid (OCP) is an acquired autoimmune mucous membrane pemphigoid, type II hypersensitivity reaction, in which the antigen-antibody-complement interaction occurs at the level of the conjunctival epithelial basement membrane zone.Bullous pemphigoid 180, laminin 5, and β4integrin are the purported antigens located in the transmembrane hemidesmosomal area in the lamina lucida.Clinically, OCP is a bilateral disease that is characterized by acute inflammation of the conjunctiva, with redness, blisters, and ulceration of the conjunctiva. Chronic inflammation is associated with subepithelial scarring that leads to fornix shortening.More recently, the combined influences of connective tissue growth factor and transforming growth factor β1in the cascade of scarring have been demonstrated.This scarring induces eyelid distortion, keratinization of the ocular surface, and eventual ocular fixation causing blindness.The progression of pemphigoid may be subtle and variable, despite aggressive immunosuppressive therapy. Minimal changes in the conjunctiva, especially conjunctival shrinkage, fornix shortening, and progressive symblepharon, may elude documentation. Algorithms may not categorize the progressive loss of the conjunctival surface and may miss valuable intervention time.The proved methods for monitoring changes in patients with OCP are the staging systems described by Tauber and coworkers,Foster,and Mondino and Brown.These methods are invaluable for staging the disease, but do not provide sufficient discriminate information for detecting subtle changes in the conjunctival fornix. The disease can progress undocumented within the same stage in either system. We have developed a method to document nuances of progression that has been helpful for providing earlier intervention whenever the disease becomes more active. This article describes this method and compares its facility with traditional methods used to measure the progression of the disease.METHODSA clinical method to measure the amount of conjunctival shrinkage was designed to detect progressive cicatricial changes in the conjunctiva of patients with OCP. It was used in the regular appointments of 4 patients for 2 years. Each patient was informed of the measurement technique being used and the purpose of the measurement. No observer was masked. This method was compared with 2 of the standard methods of staging the disease, described by Tauber et aland Mondino and Brown.The comparison was made to see which methods could document minute changes in the conjunctiva of the patients with OCP between appointments.PATIENTSWe made the comparison in 4 patients with confirmed OCP (7 eyes). The 4 patients were women, ranging in age from 69 to 77 years. Table 1shows the clinical summaries of the patients.Table 1. Clinical Summaries of the Patients*Patient No.Age, yTime of Disease Diagnosis, y†Systemic DiseasesImmunosuppressive TherapyPreviousFor Treatment‡1740High blood pressure, arthritis, and claustrophobiaNoMethotrexate, 15 mg/wk2770Poliomyositis and bullous emphysemaNoMethotrexate, 7.5 mg/wk36930ThyroidMethotrexate, 25 mg/wkMethotrexate4726High blood pressure, thyroid, arthritis, and claustrophobiaNo; allergy to azathioprine (Imuran)Methotrexate, 10 mg/wk; and prednisone, 20 mg/d*All patients were women.†Time before the first appointment.‡At the last appointment.Measurements and staging were performed at each appointment of these 4 patients, and the changes between each appointment were documented.NEW METHOD TO MEASURE THE CONJUNCTIVAThe new method consists of measuring (in millimeters) the distance between the lower limbus and the posterior edge of the retracted lower eyelid margin in 3 different gaze positions: looking up, looking up to the right, and looking up to the left. These gaze positions place the examined conjunctiva on stretch at the 5-, 6-, and 7-o'clock positions. Measurements are taken in millimeters of the stretched conjunctiva. The subconjunctival cicatrix allows eyelid traction to pull the eye inferiorly. As the patient looks up, the eyelid is pulled down until the globe first moves due to the traction on the eyelid. A measurement is taken along each direction of gaze (Figure 1, A-D).A, Conjunctival stretching measurements in a patient with cicatricial pemphigoid. The measures (in millimeters) are taken in 3 different gaze positions. The 5-o'clock position is demonstrated. B-D, Method to measure the conjunctiva. The measures (in millimeters) are taken from the lower limbus to the posterior edge of the retracted lower eyelid in 3 different gaze positions: 5-o'clock position (B), 6-o'clock position (C), and 7-o'clock position (D). The sum of the 3 measurements (B, 13 mm; C, 10 mm; and D, 13 mm) represents the final value (36 mm). E, Schematic diagram used in the medical records to describe the measurements in 3 gaze positions. This diagram summarizes the measurements in parts B through D.The result of the sum of the 3 measurements is noted in the medical record at each appointment beside a simple line diagram (Figure 1, E). The normal conjunctiva measurement is approximately 15 mm in each area of the inspection (sum, 45 mm). This is the total "available" conjunctiva.We compared the apparent conjunctival shrinkage in millimeters with the staging system of Mondino and Brown.THE STAGING SYSTEM OF MONDINO AND BROWNThis method is based on the percentage of conjunctival shrinkage. Stage I of cicatricial pemphigoid shows 25% or less shrinkage of the conjunctival fornices. Stage II of cicatricial pemphigoid shows 25% to 50% conjunctival shrinkage. Stage III of cicatricial pemphigoid shows conjunctival shrinkage of about 75%. The inferior fornix is nearly obliterated; the shallow superior fornix is still present. Stage IV or the end stage of cicatricial pemphigoid shows obliteration of the conjunctival fornices.THE STAGING SYSTEM OF TAUBER ET ALThis method describes conjunctival destruction and the presence of symblepharon: stage I, chronic conjunctivitis and subepithelial fibrosis; stage II, fornix foreshortening by any degree; stage III, symblepharon by any degree; and stage IV, ankyloblepharon and a frozen globe.To describe degrees within stages II and III, a indicates 0% to 25%; b, 25% to 50%; c, 50% to 75%; and d, 75% to 100%.For stage II, a through d describe percentage loss of inferior fornix depth. For stage III, a through d describe percentage of horizontal involvement by symblephara, and describe the number of symblephara counted in each patient.RESULTSThe results of these 4 patients are congruent with the extant staging systems of Mondino and Brownand Tauber et al.These methods were compared at each appointment. We compared date of service, conjunctival measurement, stages of Tauber et aland Mondino and Brown,time between visits, changes from baseline, and interventions.We calculated the stage of Tauber et aland Mondino and Brown,based on the difference in millimeters measured at the slitlamp examination. If 100% of the available conjunctiva measures 45 mm in a healthy eye, then 32 mm represents 25% of conjunctival loss; 22 mm, 50% loss; and 11 mm, 75% loss.In patient 1, minimal shortening was noted at the first visit in each eye. After surgical procedures on the eyelid in both eyes, the right eye showed a shortening of 12 mm in 6 months, and the left eye fornix was reduced after the surgery from 42 to 30 mm (loss of 12 mm). These changes represent progression from stage IIaIIIa(1) to IIbIIIa(1) by Tauber et alor from stage I to II by Mondino and Brownfor the right eye, and from stage IIa to IIb by Tauber et al or from stage I to II by Mondino and Brown for the left eye. The treatment with methotrexate was increased to 20 mg/wk, and then reduced to 15 mg/wk (Table 2).Table 2. Measurements and Changes During the Study in Patient 1DatePresent Study Conjunctiva, mmStaging SystemTime, moChanges From BaselineSystemic Immunosuppressants and InterventionsTauber et alMondino and BrownPresent StudyTauber et alMondino and BrownRight Eye10/19/0115 + 14 + 15 = 44IIaIIIa(1)INANANANAEntropion repair6/6/0211 + 10 + 11 = 32IIbIIIa(1)II3½4 + 4 + 4 = 12IIa-IIbI-IIMethotrexate, 10 mg/wk8/29/0212 + 10 + 11 = 33IIaIIIa(1)I103 + 4 + 4 = 1100Methotrexate, 15 mg/wk10/3/0213 + 9 + 8 = 30IIbIIIa(1)II112 + 5 + 7 = 14IIa-IIbI-IIMethotrexate, 15 mg/wk; and 0.2% topical cyclosporine10/25/0212 + 10 + 11 = 33IIaIIIa(1)I123 + 4 + 4 = 1100Methotrexate, 20 mg/wk11/21/0212 + 10 + 11 = 33IIaIIIa(1)I133 + 4 + 4 = 1100Methotrexate, 15 mg/wkLeft Eye10/19/0113 + 15 + 14 = 42IIaINANANANANA6/6/0214 + 13 + 13 = 40IIaI8−1 + 2 + 1 = 200Methotrexate, 10 mg/wk; and entropion repair8/29/0211 + 9 + 11 = 31IIbII102 + 6 + 3 = 11IIa-IIbI-IIMethotrexate, 15 mg/wk10/3/029 + 9 + 11 = 29IIbII114 + 6 + 3 = 13IIa-IIbI-IIMethotrexate, 15 mg/wk; and 0.2% topical cyclosporine10/25/0210 + 8 + 12 = 30IIbII123 + 7 + 2 = 12IIa-IIbI-IIMethotrexate, 20 mg/wk11/21/0210 + 9 + 11 = 30IIbII133 + 6 + 3 = 12IIa-IIbI-IIMethotrexate, 15 mg/wkAbbreviation: NA, data not applicable.In patient 2, the right eye demonstrated no progression in 9 months, but the left eye demonstrated a minute progression of 2 mm. This 2 mm is within the variation of the measurement technique. By measuring the staging change, the left eye demonstrated progression from stage IIa to IIb (Tauber et al) and from stage I to II (Mondino and Brown). The eye remained stable throughout the follow-up (Table 3).Table 3. Measurements and Changes During the Study in Patients 2 Through 4Patient No.EyeDatePresent Study Conjunctiva, mmStaging SystemTime, moChanges From BaselineSystemic Immunosuppressants and InterventionsTauber et alMondino and BrownPresent StudyTauber et alMondino and Brown2Right4/19/028 + 7 + 7 = 22IIcIIIa(1)IIINANANANAPrednisone, 15 mg/d1/15/038 + 7 + 7 = 22IIcIIIa(1)III90 + 1 + 0 = 100Methotrexate, 7.5 mg/wkLeft4/19/0211 + 10 + 13 = 34IIaIIIa(1)INANANANAPrednisone, 15 mg/d1/15/0310 + 10 + 12 = 32IIbIIIa(1)II91 + 0 + 1 = 2IIa-IIbI-IIMethotrexate, 7.5 mg/wk3Right8/15/0115 + 11 + 10 = 36IIaIIIb(1)INANANANAMethotrexate, 25 mg/wk2/11/0212 + 9 + 9 = 30IIbIIIb(1)II63 + 2 + 1 = 6IIa-IIbI-IIMethotrexate, 25 mg/wk; and cyclosporine, 100 mg/d1/13/0313 + 10 + 9 = 32IIaIIIb(1)I172 + 1 + 1 = 400Methotrexate, 25 mg/wk; and cyclosporine, 100 mg/dLeft8/15/0110 + 10 + 14 = 34IIaIIIb(1)INANANANAMethotrexate, 25 mg/wk2/11/0210 + 9 + 12 = 31IIbIIIb(1)II60 + 1 + 2 = 3IIa-IIbI-IIMethotrexate, 25 mg/wk; and cyclosporine, 100 mg/d1/13/039 + 8 + 13 = 30IIbIIIb(1)II172 + 1 + 1 = 4IIa-IIbI-IIMethotrexate, 25 mg/wk; and cyclosporine, 100 mg/d4Left5/17/0210 + 9 + 11 = 30IIbIIIa(1)IINANANANAMethotrexate, 10 mg/wk11/14/0212 + 10 + 14 = 36IIaIIIa(1)I6−2 + −1 + −3 = −6IIb-IIaII-IPrednisone, 30-40 mg/d; and methotrexate, 10 mg/wk1/20/0313 + 11 + 13 = 37IIaIIIa(1)I8−3 + −2 + −2 = −7IIb-IIaII-IMethotrexate, 10 mg/wk; and prednisone, 20 mg/dAbbreviation: NA, data not applicable.In patient 3, the right eye progressed from 36 to 32 mm. When the patient was treated with methotrexate, 25 mg/wk, only 4 mm of conjunctival surface was subsequently lost in the follow-up period. This corresponds to a change from stage IIaIIIb(1) to IIbIIIb(1) (Tauber et al) and from stage I to II (Mondino and Brown) (Table 3).The left eye progressed from 34 to 30 mm in 17 months, or a decrease from stage IIaIIIb(1) to IIbIIIb(1) (Tauber et al) and from stage I to II (Mondino and Brown). Immunosuppressive initial treatment was methotrexate, 25 mg/wk; then, cyclosporine, 100 mg/d, was added (Table 3).Patient 4 demonstrated 30 mm of conjunctiva at the first visit, and after 6 months of treatment with prednisone, in doses from 30 to 40 mg/d, and methotrexate, 10 mg/wk, had an expansion of the conjunctiva to 36 mm. This relaxation of the conjunctiva with treatment is consistent with a regression of scarring from stage IIbIIIa(1) to IIaIIIa(1) by Tauber et aland from stage II to I by Mondino and Brown(Table 3).COMMENTTwo major therapeutic frustrations confront the clinician treating OCP: the early diagnosis and the determination of progression when the diagnosis is established.This potentially blinding disease may be missed in the early stages because of nonspecific patient complaints of redness and irritation and the subtle conjunctival changes of subepithelial fibrosis.These patient complaints may be treated as different common conjunctival entities for years before the true nature of the problem surfaces with the earliest signs of conjunctival shrinkage.The most common mimics of pemphigoid are old acute or current chronic conjunctivitis, chemical injuries, drug toxicities, Sjögren syndrome, and sarcoid.A history of severe prior conjunctivitis, corneal scars of old adenovirus, cultures of the conjunctiva, a history of fluids splashed in the eye, and prior drug use, especially for glaucoma, may all help in delineating the cause of conjunctival scarring.Treatment modalities, such as oral dapsone,topical or systemic corticosteroids,elimination of toxic drugs, immunosuppressive agents,or conjunctival reconstruction,all hinge on the perspicacity of the clinician in determining progression.Acute disease activity may lead to rapid progression, whereas slow progression may be associated with minimal conjunctival erythema.Mondino and Brownnoted that 9 (50%) of 18 patients with stage I disease demonstrated progression during a 22-month follow-up period. Unfortunately, the more severe the disease, the greater the tendency to progression. Patients with stage II disease demonstrated a 75% progression rate, and those with stage III disease, a 78% progression rate. This study suggests that the later stages of the disease may progress without careful monitoring and intervention. The advanced staging system of Tauber et aldefines more readily the presence of symblephara in addition to fornix depth loss.We propose a method of measurement that one of us (J.J.R.) has used for the past 6 years to determine if disease progression or stability can be ascertained in the face of a reasonable therapeutic intervention. We have noted that the normal measurement of the inferior conjunctiva is approximately 15 mm in each observed area, for a cumulative total of 45 mm. Patients are first diagnosed as having the disease, however, after conjunctival shrinkage has already occurred. No patient demonstrated a full 45 mm of residual conjunctiva when diagnosed as having pemphigoid.The proposed technique is useful for comparing the same patient data against previous examination results. A cumulative measurement decrease of more than 3 mm is reasonably consistent with disease progression. The instruction to retract the lower eyelid while the patient is in an upward gaze provides comparable results between observers. Intraobserver and interobserver variations have not been addressed in this analysis. Measurement errors between examinations may occur if a different retraction pressure is applied to the lower eyelid. The end point of first globe movement on eyelid retraction is the best standardized technique for providing consistent measurements. It is reasonably easy to stage the disease by the published methods, once the progression (in millimeters) is documented. The millimeter measurement is more readily compared than even a serial photographic comparison. It is easy to document a linear 45-mm cicatrization to 33 mm, all in stage IIa of the disease (0%-25% loss). Similarly, cumulative loss of the conjunctival total from 32 to 22 mm is more readily appreciated than determining if any progression has occurred within stage IIb (25%-50% loss). We have documented the independent addition of symblephara at each visit on the medical record, but have noted that this progressive shortening is normally documented as an extension of the subepithelial fibrosis already being measured. Horizontal shortening of the eyelid seems to be reflected in the simultaneous vertical conjunctival fibrosis being measured. We were intrigued that some disease regression appeared with heavy treatment, as in patient 4. Previous observers have not suggested disease regression with expansion of the conjunctival surface with aggressive intervention. We are unable to determine if this is truly relaxation and expansion of the conjunctiva or decreased orbicularis spasm with eyelid retraction when the disease remits. By using this technique, we were able to classify our patients more readily than by the system of either Tauber et alor Mondino and Brown,and were able to ascertain subtle progression between stages. Validation of the technique with a larger series of patients with OCP is warranted. We submit this proposed simplified technique for others to consider in these difficult therapeutic decisions.In conclusion, a new method of measuring conjunctival progressive fibrosis in patients with OCP is proposed. Four patients demonstrated changes in conjunctival cicatrization during a 2-year period. Use of this method demonstrates subtle progression of pemphigoid.SGiuriOcular cicatricial pemphigoid [in Romanian].Oftalmologia.1999;47:13-21.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10641097&dopt=AbstractDZillikensAcquired skin disease of hemidesmosomes.J Dermatol Sci.1999;20:134-154.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10379705&dopt=AbstractLSChanHuman skin basement membrane in health and in autoimmune diseases.Front Biosci.1997;2:D343-D352.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9232815&dopt=AbstractSKumariKCBholRKSimmonsIdentification of ocular cicatricial pemphigoid antibody binding site(s) in human β4 integrin.Invest Ophthalmol Vis Sci.2001;42:379-385.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11157870&dopt=AbstractCAEganKBYanceyThe clinical and immunopathological manifestations of anti-epiligrin cicatricial pemphigoid, a recently defined subepithelial autoimmune blistering disease.Eur J Dermatol.2000;10:585-589.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11125317&dopt=AbstractMLeverkusESchmidtZLazarovaEBBrockerKBYanceyDZillikensAntiepiligrin cicatricial pemphigoid: an underdiagnosed entity within the spectrum of scarring autoimmune subepidermal bullous diseases?Arch Dermatol.1999;135:1091-1098.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10490114&dopt=AbstractDZillikensBP180 as the common autoantigen in blistering diseases with different clinical phenotypes.Keio J Med.2002;51:21-28.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11951375&dopt=AbstractAKrommingaCSitaruJMeyerCicatricial pemphigoid differs from bullous pemphigoid and pemphigoid gestationis regarding the fine specificity of autoantibodies to the BP180 NC16A domain.J Dermatol Sci.2002;28:68-75.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11916132&dopt=AbstractGKirtschigAutoantigens of cicatricial pemphigoid and their pathogenetic significance [in German].Hautarzt.1998;49:818-825.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9879480&dopt=AbstractZLazarovaRHsuCYeeKBYanceyAntiepiligrin cicatricial pemphigoid represents an autoimmune response to subunits present in laminin 5 (α3β3γ2).Br J Dermatol.1998;139:791-797.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9892943&dopt=AbstractWFujimotoYToiFOkazakiZLazarovaKBYanceyJArataAnti-epiligrin cicatricial pemphigoid with IgG autoantibodies to the beta and gamma subunits of laminin 5.J Am Acad Dermatol.1999;40:637-639.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10188690&dopt=AbstractBJMondinoRMantheyDermatological diseases and the peripheral cornea.Int Ophthalmol Clin.1986;26:121-136.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2948933&dopt=AbstractBJMondinoJBartlyJHovanesianUPleyerBullous diseases of the skin and mucous membranes.In: Duane, eds. Clinical Ophthalmology[book on CD-ROM]. Vol 4. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:chap 12.BJMondinoCicatricial pemphigoid and erythema multiforme.Ophthalmology.1990;97:939-952.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2199891&dopt=AbstractMSRazzaqueCSFosterARAhmedRole of connective tissue growth factor in the pathogenesis of conjunctival scarring in ocular cicatricial pemphigoid.Invest Ophthalmol Vis Sci.2003;44:1998-2003.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12714635&dopt=AbstractBJMondinoSIBrownSLempertMSJenkinsThe acute manifestations of ocular cicatricial pemphigoid: diagnosis and treatment.Ophthalmology.1979;86:543-555.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=537759&dopt=AbstractJTauberNJabburCSFosterImproved detection of disease progression in ocular cicatricial pemphigoid.Cornea.1992;11:446-451.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1424674&dopt=AbstractCSFosterCicatricial pemphigoid.Trans Am Ophthalmol Soc.1986;84:527-663.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3296406&dopt=AbstractBJMondinoSIBrownOcular cicatricial pemphigoid.Ophthalmology.1981;88:95-100.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7015218&dopt=AbstractDSHolsclawOcular cicatricial pemphigoid.Int Ophthalmol Clin.1998;38:89-106.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10200078&dopt=AbstractEMMessmerCRHintschichKPartschtGMesserAKampikOcular cicatricial pemphigoid: retrospective analysis of risk factors and complications [in German].Ophthalmologe.2000;97:113-120.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10734737&dopt=AbstractMJElderWBernauerJLeonardJKDartProgression of disease in ocular cicatricial pemphigoid.Br J Ophthalmol.1996;80:292-296.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8703876&dopt=AbstractGBaierDZillikensCicatricial pemphigoid—an important differential diagnosis in inflammatory mucous membrane changes [in German].Laryngorhinootologie.1999;78:632-637.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10615658&dopt=AbstractAFlachSymblepharon in sarcoidosis.Am J Ophthalmol.1978;85:210-214.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=623192&dopt=AbstractSDarougarMPQuinlanJAGibsonBRJonesEpidemic keratoconjunctivitis and chronic papillary conjunctivitis in London due to adenovirus type 19.Br J Ophthalmol.1977;61:76-85.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=191054&dopt=AbstractABialy-GolanSBrennerPenicillamine-induced bullous dermatoses.J Am Acad Dermatol.1996;35(pt 1):732-742.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8912569&dopt=AbstractJHLassRAThoftCHDohlmanIdoxuridine-induced conjunctival cicatrization.Arch Ophthalmol.1983;101:747-750.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6342581&dopt=AbstractJTPattenHDCavanaghMRAllansmithInduced ocular pseudopemphigoid.Am J Ophthalmol.1976;82:272-276.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=782253&dopt=AbstractMKuboTSakurabaYAraiMNakazawaA case of suspected drug-induced ocular pemphigoid [in Japanese].Nippon Ganka Gakkai Zasshi.2001;105:189-192.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11280879&dopt=AbstractYPouliquenAPateyCSFosterLGoichotMSavoldelliDrug-induced cicatricial pemphigoid affecting the conjunctiva: light and electron microscopic features.Ophthalmology.1986;93:775-783.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3526226&dopt=AbstractPMFioreIHJacobsDBGoldbergDrug-induced pemphigoid: a spectrum of diseases.Arch Ophthalmol.1987;105:1660-1663.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3318771&dopt=AbstractRSRogers 3rdJRSeehaferHOPerryTreatment of cicatricial (benign mucous membrane) pemphigoid with dapsone.J Am Acad Dermatol.1982;6:215-223.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7037880&dopt=AbstractBJMondinoSIBrownImmunosuppressive therapy in ocular cicatricial pemphigoid.Am J Ophthalmol.1983;96:453-459.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6353928&dopt=AbstractJTauberMSainz de la MazaCSFosterSystemic chemotherapy for ocular cicatricial pemphigoid.Cornea.1991;10:185-195.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2055022&dopt=AbstractMJElderSLightmanJKDartRole of cyclophosphamide and high dose steroid in ocular cicatricial pemphigoid.Br J Ophthalmol.1995;79:264-266.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7703207&dopt=AbstractJBohnSJonssonRHolstSuccessful treatment of recalcitrant cicatricial pemphigoid with a combination of plasma exchange and cyclophosphamide.Br J Dermatol.1999;141:536-540.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10583063&dopt=AbstractATriguiBKammounMGhodhbaneMFouratiMMseddiMChaabouniPenetrating keratoplasty in ocular cicatricial pemphigoid [in French].J Fr Ophtalmol.2002;25:48-51.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11965118&dopt=AbstractCorresponding author and reprints: J. James Rowsey, MD, Department of Cornea and External Diseases, St Luke's Cataract and Laser Institute, 43309 US Hwy 19 N, PO Box 5000, Tarpon Springs, FL 34688-5000 (e-mail: [email protected]).Submitted for publication March 21, 2003; final revision received October 8, 2003; accepted October 14, 2003.We thank Mark Erickson, Department of Photography, St Luke's Cataract and Laser Institute (www.jirehdesign.com), for providing the illustrations.

2004 Archives of Ophthalmology

doi: 10.1001/archopht.122.2.184

At the beginning of last year, the report by an outstanding expert ofthe judicial court of St Petersburg that they had identified a murderer inSsaratow by means of an Optogram, which they had succeeded in obtaining fromthe eye of the slain, created a great commotion in the Russian press. In my article, "About Optography and its Medicolegal Aspects," printedin the "Journal of Hygiene, Medicolegal and Practical Medicine" of January,published by the Ministry of the Interior, I refuted not only the fact ofthe discovery of the murderer—which had turned out to be untrue—butalso the possibility that such Optograms could preserve themsleves on theretina of slain person and then be photographed. I concluded my article byattaching the following letter of Profesor W. Kuehne, which he had sent megraciously from Heidelberg: Esteemed Doctor! Since the visual purple is bleached by lightto a visible degree, and therefore should be unsuitable for still photography,since furthermore the eye has the tendency not to remain fixed for any time,or—if it were to remain fixed—in most instances the objects beforeit would be moving and not rest, therefore, like in the case which you havecited, one should not count on finding a picture in the post mortem eye. Sincethe very first paper about Optography were published, no additional ones haveappeared about this subject. Heidelberg, Insitute of Physiology, 29./X 1891 Respectfully, ProfessorW. Kuehne Klin Monatsbl F. Augenheilk. 1892;30:356-361.

Sihota, Ramanjit; Saxena, Rohit; Agarwal, H. C.; Gulati, Vikas

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.185pmid: 14769594

ObjectiveTo compare latanoprost and timolol maleate as primary therapy in 60 eyes with chronic primary angle-closure glaucoma after a laser iridotomy.MethodsWe performed a prospective, randomized, crossover study of 60 eyes of 30 patients with chronic primary angle-closure glaucoma after laser iridotomy. Patients were randomized to 2 groups: those taking latanoprost once daily or those taking timolol twice daily. Three months after treatment with the first drug, the second drug was substituted. The circadian rhythm of intraocular pressure (IOP) was recorded before the start of therapy, at 3 months, and at 7 months. The fourth month was the washout period for the first drug.ResultsThe mean baseline IOP was 23.5 ± 2.1 mm Hg, which decreased by 8.2 ± 2.0 mm Hg with latanoprost (P<.001) and by 6.1 ± 1.7 mm Hg with timolol (P= .01). The decrease in IOP was greater for patients taking latanoprost (P<.001). Latanoprost was significantly more effective in eyes having morning and afternoon peaks of IOP. A total of 43 eyes (72%) of patients taking latanoprost and 26 (43%) on timolol achieved a reduction of more than 30% from baseline IOP.ConclusionThere were greater mean and peak IOP reductions achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily.Latanoprost, a phenyl-substituted prostaglandin analogue, has been studied extensively for its intraocular pressure (IOP)-lowering efficacy and adverse effects in cases of primary open-angle glaucoma.Numerous studieshave also compared its effect with that of timolol maleate in cases of primary open-angle glaucoma. Chronic primary angle-closure glaucoma constitutes a significant proportion of all glaucomas, especially in Asia. β-Blockers and pilocarpine nitrate have been routinely used for the medical therapy of chronic primary angle-closure glaucoma after an iridotomy; however, the role of newer antiglaucoma medications like latanoprost needs evaluation. The formation of peripheral anterior synechiae in chronic primary angle-closure glaucoma could diminish access to the uveoscleral outflow, the major mechanism of action of latanoprost. To our knowledge, no long-term, crossover study has evaluated latanoprost and timolol with respect to their efficacy in cases of chronic primary angle-closure glaucoma. The aim of the present study was to compare the effect of latanoprost administered once at night with timolol administered twice daily in a masked, crossover study in chronic primary angle-closure glaucoma eyes.METHODSThe study was designed as a prospective, randomized, crossover trial comparing the efficacy and adverse effects of timolol and latanoprost as monotherapy in freshly diagnosed cases of eyes having chronic primary angle-closure glaucoma after an Nd:YAG laser iridotomy. Consecutive adult patients with bilateral, untreated, chronic primary angle-closure glaucoma were included in the study after providing informed consent. Human investigation guidelines were adhered to. All patients had an occludable angle, with peripheral anterior synechiae involving more than 180°, a baseline IOP of more than 21 mm Hg without any antiglaucoma medication on more than 2 occasions, and optic nerve head and visual field changes commensurate with the diagnosis of glaucoma. All patients had a patent peripheral iridotomy.Exclusion criteria included prior medical or surgical intervention for the control of IOP, any previous ocular surgery, any other intraocular disorder, or any condition preventing reliable applanation tonometry. Patients using systemic β-blockers were excluded. Known hypersensitivity to any component of the drugs to be used, patients who were unable to adhere to the follow-up protocol, or those with systemic or ocular problems that contraindicated the use of either of the 2 study drugs were also excluded. Patients with a baseline IOP of more than 35 mm Hg or cases with advanced glaucoma (defined as cupping ratio of 0.9 and/or perimetric evidence of visual field loss within 10° of fixation in one or more quadrants) were also excluded from the study.At the time of enrollment in the study, a complete medical and ocular history was taken, and any concurrent medical therapies were recorded. A systemic examination was performed to evaluate the cardiovascular and respiratory status. A comprehensive ocular examination was performed, including best-corrected visual acuity, slitlamp examination, biomicroscopic fundus evaluation, 3-hourly applanation tonometry from 7 AMto 10 PM on a single day using a Goldmann applanation tonometer, and full threshold automated perimetry on the 30-2 program of Humphrey field analyzer.The patients were then randomized into 2 parallel study groups: one group received 0.005% latanoprost at 10 PM once daily, and the other group received 0.5% timolol maleate at 8 AMand 8 PM. Follow-up examination was performed at 3 weeks, 6 weeks, and 3 months after the start of therapy. Best-corrected visual acuity, IOP recording, and fundus evaluation were performed at each follow-up visit. After 3 months, the second medication was substituted (ie, patients in the latanoprost group started taking timolol and vice versa). The first month of treatment with the second drug (ie, the fourth month of the trial) was deemed the washout period for the first drug used during the first 3 months of therapy. Additional follow-up was performed at 3 weeks, 6 weeks, and 3 months after the washout period.A circadian recording of IOP and full threshold automated perimetry were repeated at 3 and 7 months after enrollment in the study (ie, 3 months following the use of each drug). The timings of the diurnal recording of IOP were 7 AM, 10 AM, 1 PM, 4 PM, 7 PM, and 10 PM; on all occasions the IOP recorded was performed by applanation tonometry in the sitting position by a single masked observer. Patients were recalled on an outpatient basis every 3 hours on 1 day.At each of the follow-up visits, the patient's eye was examined with slitlamp biomicroscopy to rule out any uveitis, iris color changes, or any eyelash changes. The patients were also asked in detail about any adverse ocular and systemic events that occurred during the treatment. A subsequent systemic examination with heart rate and blood pressure measurement was performed at each follow-up visit.The efficacy of the 2 drugs was evaluated with respect to the dampening of the range of diurnal variation in IOP, its effect on the different types of circadian cycles, and drug efficacy regarding baseline peak IOP. The effectiveness of the 2 drugs was also evaluated with respect to age, sex, and the presence or absence of diabetes and hypertension.Peak pressure was defined as the highest pressure recorded in each individual circadian rhythm. Trough pressure was defined as the lowest pressure recorded in each individual circadian rhythm. A change in the timing of the peak pressures recorded at baseline and on diurnal measurements of IOP at 3 and 7 months was recorded in each individual. It was considered negative if the peak IOP in the circadian rhythm on treatment was previously earlier compared with the timing of the baseline peak and positive if it occurred later.Each baseline circadian rhythm was classified as morning type, noon type, and evening type, depending on the timing of the peak pressures recorded in that diurnal curve. Morning type was defined as peak pressures at 7 AM or 10 AM. Noon type was defined as peak pressures at 1 PM or 4 PM. Evening type was defined as peak pressures at 7 PM or 10 PM.Statistical analysis was performed with STATA Intercooled statistical software, version 6.0 (Stata Corp, College Station, Tex) using the unpaired ttest and 2-way analysis of variance. Data are presented as mean ± SD.RESULTSSixty eyes of 30 patients were enrolled in the study during an enrollment period of 3 months. The mean age of the patients was 57.7 ± 7.4 years (age range, 46-76 years). There were 18 men and 12 women. The prevalence of diabetes mellitus was 30%, and the prevalence of hypertension was 13%. Both the diseases were controlled with oral medication. None of the patients were taking oral β-blockers for control of elevated blood pressures. The mean cup-disc ratio was 0.6 ± 0.8. Peripheral anterior synechiae extended from 180° to 270° in all the eyes studied.The mean of the baseline IOP was 23.5 ± 2.1 mm Hg and was decreased to 15.3 ± 1.8 mm Hg (34.9%) with latanoprost (P<.01) and to 17.4 ± 1.7 mm Hg (26.0%) with timolol (P<.01). The baseline circadian rhythm of IOP and the IOP with latanoprost and timolol are detailed in Table 1and Figure 1. Both the drugs significantly reduced IOP compared with baseline at all points on the diurnal curve. Latanoprost was significantly more effective in lowering IOP than timolol at 7 AM, 10 AM, 1 PM, 4 PM, and 7 PM. At 10 PMpatients taking latanoprost recorded lower IOPs compared with those taking timolol, but the difference between the 2 drugs was not statistically significant (P= .25).Table 1. Diurnal Variation of Intraocular Pressure (IOP) at Baseline and After 3 Months of Therapy With Latanoprost and Timolol in 60 EyesTime of IOP RecordingMean ± SD Baseline IOP, mm HgLatanoprostTimolol MaleatePValueMean ± SD IOP, mm HgDecrease in IOPMean ± SD IOP, mm HgDecrease in IOPMean ± SD, mm Hg%Mean ± SD, mm Hg%7 AM23.5 ± 3.114.0 ± 2.29.5 ± 3.340.418.3 ± 3.25.2 ± 3.622.1<.0110 AM24.6 ± 3.914.6 ± 2.810.0 ± 4.340.617.9 ± 3.66.7 ± 3.527.2<.011 PM23.6 ± 2.716.2 ± 2.77.4 ± 3.431.417.1 ± 3.26.5 ± 3.827.5.044 PM23.2 ± 2.715.7 ± 3.47.5 ± 3.332.317.7 ± 3.95.6 ± 3.724.1<.017 PM22.4 ± 3.115.6 ± 3.16.8 ± 3.430.416.9 ± 3.85.6 ± 3.925.0.0110 PM23.3 ± 2.915.6 ± 3.07.6 ± 3.932.616.3 ± 3.46.9 ± 3.629.6.25Mean23.4 ± 2.115.3 ± 1.88.2 ± 2.034.917.4 ± 1.76.1 ± 1.726.0<.01Baseline intraocular pressure (IOP) and IOP after 3 months of therapy with latanoprost and timolol maleate at different times during the day. Error bars indicate 95% confidence intervals.The average of the peak pressures recorded in the 60 individual baseline IOP curves was 27.5 ± 2.7 mm Hg. The average of the highest IOP recorded in each of the subsequent individual circadian rhythms was 18.1 ± 2.4 mm Hg after treatment with latanoprost for 3 months and 20.4 ± 2.5 mm Hg after treatment with timolol for 3 months; both the drugs showed a significant reduction compared with baseline peak pressures (P<.01). The peak IOP reduction was greater for latanoprost compared with timolol (P<.01).The average of the trough IOP recorded in each of the individual baseline IOP curves was 20.2 ± 2.1 mm Hg. The average of the trough IOP that was recorded at any point of time on each of the diurnal curves was 12.5 ± 2.1 mm Hg with latanoprost (P<.01) and 14.4 ± 2.9 mm Hg with timolol (P<.01). The IOP reduction was greater for patients taking latanoprost compared with those taking timolol (P<.01).In each of the individual diurnal curves, the alteration in timing of IOP peaks on therapy with both the drugs was compared with the time of the peak IOP on the baseline diurnal curve of the same patient. The average of this shift in the time of the peak pressures was recorded for both the drugs used (Table 2). The results showed that with timolol there was no significant time shift of the peak IOP compared with baseline in all the 3 types of circadian rhythms, and overall the peak IOP was recorded 0.15 ± 0.4 hours later than that recorded in the baseline curve. Latanoprost caused the peak IOP to occur 3.3 ± 1.79 hours later in the day, especially for those with a morning or afternoon peak.Table 2. Time Shift of Baseline Peak Intraocular Pressure After Treatment in 60 Eyes*Circadian RhythmChange in Time of Peak Pressure, Mean ± SD, hLatanoprostTimolol MaleateMorning peak (30 eyes)+4.8 ± 2.1+1.6 ± 1.3Afternoon peak (20 eyes)+3.3 ± 2.0−0.5 ± 4.5Evening peak (10 eyes)−1.2 ± 1.4+1.1 ± 1.4Total (60 eyes)+3.3 ± 1.9+0.82 ± 0.3*Plus sign indicates that peak occurs later; minus sign, peak occurs earlier.The circadian rhythm recorded on baseline evaluation was divided into 3 categories: those with peaks in the morning (30 eyes, 50%), noon (20 eyes, 33.3%), or evening (10 eyes, 16.7%). Evaluating measurements of IOP at the time of the baseline peak, the decrease in the IOP after the use of latanoprost or timolol was analyzed in each of the 3 types of circadian patterns (Table 3). Timolol caused a similar decrease in IOP in all the 3 types of circadian rhythms, whereas latanoprost caused a mean percentage decrease in IOP of 40.9% ± 5.5% in those with a morning peak, 34.8% ± 6.3% for afternoon peaks, and 31.9% ± 6.5% in eyes having a peak at night. This difference in the efficacy of latanoprost in patients with a night peak (31.9%) compared with patients with a morning peak (40.9%) was statistically significant (P<.01).Table 3. Change in Mean Intraocular Pressure (IOP) on Therapy in 60 Eyes With Different Circadian Rhythms*Circadian RhythmDecrease in IOP, mm HgPercent Change in IOPLatanoprostTimolol MaleatePValueLatanoprostTimololPValueMorning peak, 7 AMand 10 AM(30 eyes)10.2 ± 1.56.9 ± 1.3<.0140.9 ± 5.527.8 ± 5.9<.01Afternoon peak, 1 PMand 4 PM(20 eyes)8.1 ± 1.66.1 ± 1.9<.0134.8 ± 6.324.6 ± 10.1<.01Evening peak, 7 PMand 10 PM(10 eyes)7.4 ± 1.65.7 ± 2.4<.0131.9 ± 6.526.6 ± 8.1<.01Total (60 eyes)8.2 ± 1.26.1 ± 1.8<.0134.926.0<.01*Data are given as mean ± SD change compared with baseline IOP.Different age groups, the sex of the patient, the presence or absence of hypertension or diabetes, and the height of the baseline peak, trough, and mean IOP did not affect the pressure reduction achieved with either drug. The effect of the 2 drugs was similar whether used first or second in the study.The numbers of patients who did not achieve a mean IOP of 21 mm Hg or less with treatment were 6 (10%) in the timolol group and 1 in the latanoprost group. A peak IOP of more than 21 mm Hg was seen in 15 cases (25%) in the timolol group and 4 cases (7%) in the latanoprost group. An IOP reduction of less than 20% was noted in 5 cases (8%) after latanoprost treatment and in 13 (22%) after timolol treatment. A pressure reduction of 30% or more from baseline was observed in 43 eyes (72%) of patients taking latanoprost compared with 26 (43%) of those taking timolol (P<.001) (Table 4). The patient whose condition was uncontrolled with latanoprost showed a mild elevation of IOP to 25 mm Hg, which was confirmed on stopping use of and rechallenging with latanoprost.Table 4. Percentage Reduction in Mean Intraocular Pressure (IOP) After 3 Months of Therapy With Latanoprost and Timolol in 60 EyesReduction in IOP From Baseline, %Latanoprost, No. (%)Timolol Maleate, No. (%)≥4012 (20)2 (3)35-<4016 (27)1 (2)30-<3515 (25)23 (38)25-<305 (8)13 (22)20-<257 (12)8 (13)15-<203 (5)3 (5)<152 (3)10 (17)Total60 (100)60 (100)No significant adverse effects were observed during the study period. Four patients taking latanoprost complained of discomfort during the study period, 2 patients taking latanoprost complained of conjunctival hyperemia, and 2 patients reported foreign body sensation after instilling timolol drops. None of the adverse effects were significant enough to result in discontinuation of therapy. There was no significant change in the pulse rate and blood pressure of patients taking any of the medications used in our study compared with the baseline.COMMENTIn chronic primary angle-closure glaucoma, a peripheral iridotomy helps to relieve the pupillary block and further attacks of angle closure; however, medication is required to control the chronically elevated IOP caused by obstruction of aqueous outflow secondary to synechial angle closure and trabecular meshwork damage.Previous studieshave noted that patients with chronic angle-closure glaucoma in whom disc and field changes had occurred were not likely to have their condition controlled with an iridectomy but required a trabeculectomy to control their IOP. Pilocarpine and β-blockers have been the mainstay of therapy for chronic angle-closure glaucomaand were seen to control the IOP in 30% of chronic primary angle-closure glaucoma eyes.There are many new antiglaucoma drugs now available, the most efficacious being prostaglandin analogues, which act by increasing the uveoscleral outflow. Access to the uveoscleral pathway is through the ciliary muscle bundles into the supraciliary and suprachoroidal spaces from which it is drained through sclera. The presence of peripheral anterior synechiae could possibly hamper the flow of aqueous into this pathway and perhaps decrease the efficacy of drugs such as prostaglandin analogues.The efficacy of latanoprost has been compared with timolol in multiple studies, but to the best of our knowledge, there has been no previous long-term, crossover study regarding their effect on peak IOPs in cases of primary angle-closure glaucoma. The current study was undertaken to evaluate and compare the efficacy of latanoprost with timolol in eyes with chronic primary angle-closure glaucoma. The 2 medications have a different viscosity and different administration regimens that made masking difficult. Because the same patients were tested with both drugs, confounding factors were minimized.We noted the mean reduction of IOP to be 8.2 ± 0.4 mm Hg with latanoprost and 6.1 ± 0.2 mm Hg with timolol. A similar reduction was reported by Aung et alin a small number of eyes studied for 2 weeks; latanoprost reduced the IOP by 8.8 ± 1.1 mm Hg compared with 5.7 ± 0.7 mm Hg by timolol. Hedman and Almreported a mean decrease of 7.7 ± 0.1 mm Hg in a meta-analysis of primary open-angle glaucoma eyes compared with a mean decrease of 8.7 ± 2.2 mm Hg in our study, starting from similar baseline IOPs.A previous studyhas shown that patients with IOP consistently below 15 mm Hg had a higher chance of remaining stable. However, because different patients have different baseline pressures and different target pressures, it may be reasonable to lower the IOP by at least 30% of baseline pressures to prevent progression of field loss.The effect of latanoprost on mean IOP was clinically more significant than timolol in our study in causing a reduction of more than 30% from baseline. This decrease of more than 30% from baseline was seen in 72% of primary angle-closure glaucoma eyes of patients taking latanoprost and 43% of primary angle-closure glaucoma eyes of patients taking timolol.We evaluated the circadian rhythm in eyes with chronic primary angle-closure glaucoma before and after therapy with latanoprost and timolol. Our study noted a significantly higher reduction of peak and trough IOP with latanoprost compared with timolol. There was thus a greater dampening of the circadian rhythm of IOP with latanoprost in chronic primary angle-closure glaucoma eyes. The evening efficacy of latanoprost and timolol was similar. Orzalesi et aland Racz et alhave also noted that latanoprost leads to a more uniform circadian rhythm in primary open-angle glaucoma eyes. Hedman and Almfound latanoprost to be more effective than timolol in primary open-angle glaucoma eyes when morning, noon, and afternoon IOPs were averaged to determine the diurnal IOP. In our study, latanoprost used at night was less effective in the control of baseline IOP peaks that occurred in the evening (7-10 PM). Timolol was equally effective in all types of circadian rhythms and appeared to work around the clock, albeit to a lesser extent.It is important to schedule the follow-up of glaucoma patients around the time that the highest IOP is expected. We studied the temporal change of the highest recorded IOP in eyes after the use of latanoprost and timolol. The time shift of peak IOPs in eyes of patients taking timolol was insignificant in all types of circadian rhythms. Of patients taking latanoprost, the peak IOP in eyes with morning and afternoon baseline peaks were shifted 3 to 7 hours later in the day. This could be due to its efficacy waning with time. The time difference noted by us could be kept in mind when scheduling follow-up visits. In conclusion, latanoprost was clinically more effective than timolol because it lowered the IOP to a greater extent and dampened the circadian rhythm of IOP.CBCamrasAAlmPWatsonJStjernschantzLatanoprost Study GroupsLatanoprost, a prostaglandin analogue, for glaucoma treatment: efficacy and safety after 1 year of treatment in 198 patients.Ophthalmology.1996;103:1916-1924.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8942890&dopt=AbstractPGWatsonLatanoprost Study GroupsLatanoprost: two years experience of its use in the United Kingdom.Ophthalmology.1998;105:82-87.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9442782&dopt=AbstractMSuzukiHKMishimaKMasudaMAraicYKitazawaIAzumaEfficacy and safety of latanoprost eye drops for glaucoma treatment: a 1-year study in Japan.Jpn J Ophthalmol.2000;44:33-38.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10698023&dopt=AbstractCBCamrasUnited States Latanoprost Study GroupsComparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six month, masked, multicentric trial in the United States.Ophthalmology.1996;103:138-147.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8628544&dopt=AbstractPWatsonJStjernschantzStudy GroupLatanoprostA six month randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension.Ophthalmology.1996;103:126-137.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8628543&dopt=AbstractRSihotaNCLakshmaiahKBWaliaSSharmaJPailoorHCAgarwalThe trabecular meshwork in acute and chronic angle-closure glaucoma.Indian J Ophthalmol.2001;49:255-260.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12930118&dopt=AbstractECGelberDRAndersonSurgical decisions in chronic angle-closure glaucoma.Arch Ophthalmol.1976;94:1481-1484.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=962659&dopt=AbstractTJPlayfairPGWatsonManagement of chronic or intermittent primary angle-closure glaucoma: a long-term follow-up of the results of peripheral iridectomy used as an initial procedure.Br J Ophthalmol.1979;63:23-28.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=760772&dopt=AbstractPDSteinbachDGGruiaLong-term study of chronic glaucoma treated with beta blockers (timolol).Klin Monatsbl Augenheilkd.1987;190:534-538.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3114544&dopt=AbstractRSihotaHCAgarwalProfile of the subtypes of angle-closure glaucoma in a tertiary hospital in India.Indian J Ophthalmol.1998;46:25-29.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9707844&dopt=AbstractTAungHTWongCCYipJYLeongYHChanPTChewComparison of the intraocular pressure lowering effect of latanoprost and timolol in patients with chronic angle-closure glaucoma: a preliminary study.Ophthalmology.2000;107:1178-1183.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10857840&dopt=AbstractKHedmanAAlmA pooled data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol.Eur J Ophthalmol.2000;10:95-104.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10887918&dopt=AbstractGHovdingHAasvedPrognostic factors in development of manifest open-angle glaucoma: a long term follow up study of hypertensive and normotensive eyes.Acta Ophthalmol (Copenh).1986;64:601-608.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3811873&dopt=AbstractSAsraniRZeimerJWilinskyDGieserSVitaleKLindenmuthLarge diurnal fluctuations in intraocular pressure are an independent risk factor in patients of glaucoma.J Glaucoma.2000;9:134-142.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10782622&dopt=AbstractNOrzalesiLRossettiTInvernizziABottoliAAuteitanoEffect of timolol, latanoprost and dorzolamide on circadian intraocular pressure in glaucoma or ocular hypertension.Invest Ophthalmol Vis Sci.2000;41:2566-2572.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10937568&dopt=AbstractPRaczMRRuzsonyiZTNagyAround-the-clock (circadian) intraocular pressure reduction with once-daily application of 0.005% latanoprost by itself or in combination with timolol.Arch Ophthalmol.1996;114:268-273.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8600885&dopt=AbstractCorresponding author: Ramanjit Sihota, MD, FRCS, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India (e-mail: [email protected]).Submitted for publication June 6, 2003; final revision received August 17, 2003; accepted September 15, 2003.The principal author takes full responsibility for the integrity of the data and the reliability of the data analysis.

Tsukamoto, Hidetoshi; Larsson, Lill-Inger

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.190pmid: 14769595

ObjectivesTo measure the effectiveness of topical 0.2% brimonidine tartrate as a suppressor of aqueous humor flow in the human eye compared with the effectiveness of 2% dorzolamide hydrochloride, and to measure the additivity of the effects of the 2 drugs.DesignA randomized, double-masked, placebo-controlled study was performed in 20 healthy human subjects. The topical drugs were instilled twice daily the day before and again in the morning on the day of the measurements. The rate of aqueous humor flow was measured from 8 AMto 4 PMby clearance of topically applied fluorescein using a fluorophotometer, after administration of doses of each drug singly and both drugs together. Intraocular pressure (IOP) was measured with applanation tonometry.ResultsCompared with placebo, brimonidine reduced the aqueous humor flow by a mean ± SD of 28.2% ± 18.0% (P<.001), dorzolamide by 19.3% ± 22.0% (P= .007), and the combination of brimonidine and dorzolamide by 37.2% ± 20.6% (P<.001). The combination of both drugs statistically significantly suppressed aqueous humor flow compared with dorzolamide alone (P<.001) and brimonidine alone (P= .04). The IOP was reduced by a mean ± SD of 11.6% ± 10.1% (P<.001) by brimonidine, 8.5% ± 14.1% (P= .02) by dorzolamide, and 17.9% ± 16.5% (P<.001) by the combination. The combination of drugs reduced IOP better than dorzolamide (P<.001), but not more than brimonidine (P= .06).ConclusionsThe combination of brimonidine and dorzolamide caused a further reduction of aqueous humor flow compared with each drug applied alone. The IOP was further reduced by the combination compared with dorzolamide alone, but not compared with brimonidine alone.The adrenergic α2-receptor agonist brimonidine tartrateis a topically applied ocular hypotensive agent. Studies of brimonidine have demonstrated that the ocular hypotensive effect primarily is caused by reduction of aqueous humor production,but increased uveoscleral outflow has also been reported in rabbitsand in humans.Dorzolamide hydrochloride is a carbonic anhydrase inhibitor that is used for treatment of glaucoma. This topically applied drug lowers the intraocular pressure (IOP) by suppressing the aqueous humor production.Compared with a systemically administered drug of the same class, it has fewer systemic adverse effects, but its ability to reduce the aqueous humor formation is weaker.Monotherapy is not always sufficient for an adequate control of the IOP in patients with glaucoma, and additional treatment may be prescribed. Because there are many ocular hypotensive drugs commercially available, different therapeutic regimens exist. Brimonidine added to treatment with β-adrenergic antagonists has been shown to lead to a significant additive lowering of the IOP and of the aqueous humor production.Brimonidine and dorzolamide are used in clinical practice not only as monotherapies but also in different combination treatments.The purpose of the present study was to measure aqueous humor flow and IOP after topical administration of brimonidine, alone and in combination with dorzolamide, to determine whether the effects of the 2 drugs are additive on aqueous flow and IOP.METHODSThe study was carried out at the Department of Ophthalmology, Uppsala University Hospital. Twenty healthy volunteers were enrolled into the study. There were 10 women and 10 men (mean age, 29.2 years; range, 24-49 years). All subjects underwent an eligibility examination consisting of a medical and ophthalmic history, visual acuity measurement, slitlamp examination, applanation tonometry, and ophthalmoscopy. Exclusion criteria were ocular disease, systemic disease requiring long-term medical treatment, pregnancy or lactation, inability to comply with tonometry or fluorophotometry, an IOP difference between the 2 eyes greater than 3 mm Hg, and known drug hypersensitivity. The research protocol followed the tenets of the Declaration of Helsinki and was approved by the Ethical Committee of Uppsala University. An informed consent was obtained from all participants. The study consisted of 2 parts. At least 4 weeks elapsed between the parts to ensure complete elimination of the drugs. In part 1, the effect of 0.2% brimonidine–treated eyes vs placebo-treated eyes was studied. In part 2, topical application of 2% dorzolamide was added to both eyes. Four treatment regimens were thus compared, with 20 eyes in each treatment group: (1) placebo-treated eyes, (2) brimonidine-treated eyes, (3) dorzolamide-treated eyes, and (4) brimonidine and dorzolamide–treated eyes.The study was randomized, double-masked, and placebo-controlled. The brimonidine, dorzolamide, and placebo eyedrops were given by random assignment and were administered from identical-appearing dropper bottles labeled by subject number, sequence, and right and left eyes. These sterile eyedropper bottles contained 0.2% brimonidine tartrate (Alphagan; Allergan, Inc, Irvine, Calif), 2% dorzolamide hydrochloride (Trusopt; Merck Sharp and Dohme/Isotopes, St Louis, Mo), or placebo (Isopto-Plain; Alcon Laboratories, Fort Worth, Tex).Each part of the study was performed on 2 sequential days, day 1 and day 2. On day 1, the subjects reported to the research area at 8 AM, and they were given 1 drop of 0.2% brimonidine in one eye and 1 drop of placebo in the other eye. The procedure was repeated at 5 PM. On day 2, when flow was measured, eyedrops were again instilled at 8 AM. As a precaution to prevent cross-contamination between the eyes, subjects were given separate tissues for each eye and were asked to blot only one eye with each tissue. In part 2, brimonidine and placebo eyedrops were administered according to the same schedule as in part 1, but at every time point for eyedrop instillation, 1 drop of 2% dorzolamide was also administered to both eyes 5 minutes after the other eyedrops (ie, dorzolamide was administered twice daily). The research personnel administered all eyedrops, except fluorescein, because of the risk of error with eyedrop self-administration.The subjects were instructed to awaken at 2 AMon day 2 and instill 1 drop of 2% fluorescein into each eye 3 to 5 times, according to age, at 5-minute intervals, and then they returned to sleep. The subjects reported to the test area at 8 AMand underwent measurements of the fluorescence of the cornea and the anterior chamber with a fluorophotometer (Fluorotron Master; Coherent Radiation, Palo Alto, Calif). The procedure was repeated every other hour until 4 PM. Immediately after each measurement of fluorescence, the IOP was measured with a Goldmann tonometer. Tonometry was started in the right eye, alternating between the eyes for a total of 3 readings per eye. The IOP was then recorded as the mean of the 3 measurements. Dilute milk rather than fluorescein was used as the disclosing agent to avoid the introduction of more fluorescein to the cornea and mismeasurement of aqueous humor flow.Aqueous humor flow was calculated from the clearance of fluorescein at each 2-hour interval by using the following equation: clearance = ΔM/(CaΔt), where ΔM is the loss of mass of fluorescein in the combined cornea and anterior chamber during Δt interval, and Cais the mean concentration in the anterior chamber during the interval, estimated from the initial and final fluorescence and assuming a single exponential decay. Aqueous humor flow was calculated from the rate of clearance of fluorescein after subtracting the presumed rate of diffusional clearance (0.25 µL/min).After completion of the study and tabulation of the data, the code was broken and the data stratified by drug. The statistical analysis was carried out using a 2-sided ttest for paired samples. P<.05 was considered statistically significant. The coefficient of variation of measurements of aqueous humor flow under conditions similar to those in this experiment is approximately 23%.The mean ± SD aqueous humor flow in daytime is 2.75 ± 0.63 µL/min.A sample size of 20 in each group provided a power of 95% for detecting a true difference of 20% between the eyes.RESULTSThe effects of the different drugs on aqueous humor flow are presented in Table 1. Brimonidine reduced aqueous humor flow by a mean ± SD of 28.2% ± 18.0% (P<.001) and dorzolamide by 19.3% ± 22.0% (P= .007) compared with placebo, while there was no statistically significant difference between brimonidine and dorzolamide (P= .09). Brimonidine and dorzolamide applied in combination suppressed the flow by a mean ± SD of 37.2% ± 20.6% compared with placebo (P<.001). The aqueous humor flow was statistically significantly reduced by the combination of both drugs compared with dorzolamide alone (P<.001) and brimonidine alone (P= .04).Table 1. Aqueous Humor Flow From 8 AMto 4 PM*Drug AppliedNo. of EyesAqueous Humor Flow, µL/min% Difference (PValue)vs Placebovs Dorzolamide Hydrochloridevs Brimonidine TartratePlacebo203.04 ± 0.86. . .. . .. . .Dorzolamide202.45 ± 0.5619.3 ± 22.0 (.007). . .. . .Brimonidine202.18 ± 0.5428.2 ± 18.0 (<.001)11.0 ± 20.5 (<.09). . .Brimonidine and dorzolamide201.91 ± 0.5037.2 ± 20.6 (<.001)22.1 ± 18.7 (<.001)12.5 ± 22.1 (.04)*Data are given as mean ± SD.The IOP (Table 2) was statistically significantly reduced by a mean ± SD of 11.6% ± 10.1% by brimonidine alone (P<.001) and 8.5% ± 14.1% by dorzolamide alone (P= .02) compared with placebo, but there was no difference between the effects of the 2 drugs in reducing IOP (P= .35). The combination of both drugs statistically significantly reduced IOP compared with dorzolamide (P<.001), but not compared with brimonidine (P= .06).Table 2. Intraocular Pressure at 4 PM*Drug AppliedNo. of EyesIntraocular Pressure, mm Hg% Difference (PValue)vs Placebovs Dorzolamide Hydrochloridevs Brimonidine TartratePlacebo2011.5 ± 2.5. . .. . .. . .Dorzolamide2010.6 ± 2.68.5 ± 14.1 (.02). . .. . .Brimonidine2010.2 ± 2.311.6 ± 10.1 (<.001)3.4 ± 17.0 (.35). . .Brimonidine and dorzolamide209.5 ± 2.517.9 ± 16.5 (<.001)10.3 ± 11.0 (<.001)7.2 ± 15.5 (.06)*Data are given as mean ± SD.COMMENTThe results of this study confirm previous results that 0.2% brimonidine tartrate and 2% dorzolamide hydrochloride suppress the aqueous humor formation. There was no statistically significant difference in the flow reduction when brimonidine or dorzolamide was given separately. When they were applied in combination, a further reduction of flow was seen.Table 3lists the aqueous humor flow rates in this study along with those in other studies involving brimonidine and dorzolamide. The studies used the fluorophotometric technique for determining flow, and there is good consistency between the studies in the effects of the different drugs.Table 3. Previous Studies of Aqueous Humor FlowDrug and SourceInhibition of Aqueous Flow, %Brimonidine tartrateToris et al,199520Maus et al,199922Larsson,200133Present study28Dorzolamide hydrochlorideMaus et al,199717Wayman et al,199718Larsson and Alm,199817Vanlandingham and Brubaker,199813Vanlandingham et al,199813Ingram and Brubaker,199914Present study19Brimonidine and timololLarsson,200159Dorzolamide and timololWayman et al,199755Brubaker et al,200051Brimonidine and dorzolamidePresent study37The effect on aqueous humor flow of short-term administration of apraclonidine hydrochloride and brimonidine in healthy volunteers was measured by Schadlu and coworkers.The reduction of aqueous humor flow by each drug could explain the reduction of IOP. In addition, a consensual effect on aqueous humor flow in the fellow eye was noted: 16% for apraclonidine and 17% for brimonidine. The total effect of brimonidine on reducing the aqueous humor flow was 44% to 48% in their study. Considering the consensual effect, the reduction of 28% by brimonidine alone that was found in the present study corresponds well with their findings. The consensual effect of brimonidine could also have affected the second part of the present study, when the combination of brimonidine and dorzolamide was administered to one eye and dorzolamide was instilled in the other eye. The flow measured in the dorzolamide-treated eye could thus reflect a crossover effect of brimonidine.In the present study, the IOP was further reduced by the combination of brimonidine and dorzolamide compared with dorzolamide alone, but not with brimonidine. This finding was inconsistent with the results from the flow measurements. Only healthy volunteers were included in the study, and the mean ± SD baseline IOP of 11.5 ± 2.5 mm Hg was low. A deviation of 1 to 2 mm Hg from the true IOP is inherent in the technique, and the discrepancy between the results from the IOP measurements and the flow measurements could be explained by this.Traditionally, the medical treatment of glaucoma has consisted of empirical trials of single drugs or combinations of drugs in individual patients, a process that is efficient when few effective choices are available. With the increasing number of effective ocular hypotensive drugs for glaucoma treatment, the number of potential trial sequences or combinations rapidly increases. Clinicians need a management strategy based on pharmacological mechanisms and relative efficacy. Previous investigations suggest that the efficacy of combining different aqueous flow suppressants would be less than the combined effect of each given as monotherapy,and the present study supports this. 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Ophthalmol.1999;128:292-296.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10511022&dopt=AbstractLILarssonAqueous humor flow in normal human eyes treated with brimonidine and timolol, alone and in combination.Arch Ophthalmol.2001;119:492-495.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11296014&dopt=AbstractJEBoyleKGhoshDKGieserIAAdamsonsDorzolamide-Timolol Study GroupA randomized trial comparing the dorzolamide-timolol combination given twice daily to monotherapy with timolol and dorzolamide.Ophthalmology.1998;105:1945-1951.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9787368&dopt=AbstractCMClineschmidtRDWilliamsESnyderIAAdamsonsDorzolamide-Timolol Combination Study GroupA randomized trial in patients inadequately controlled with timolol alone comparing the dorzolamide-timolol combination to monotherapy with timolol or dorzolamide.Ophthalmology.1998;105:1952-1959.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9787369&dopt=AbstractIAAdamsonsAPolisCSOstrovJEBoyleDorzolamide Safety Study GroupTwo-year safety study of dorzolamide as monotherapy and with timolol and pilocarpine.J Glaucoma.1998;7:395-401.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9871861&dopt=AbstractHHLeMRChangQChengDALeeDHartenbaumThe effectiveness and safety of dorzolamide 2% in addition to multiple topical antiglaucoma medications.J Ocul Pharmacol Ther.1999;15:305-312.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10463869&dopt=AbstractKHEmmerichComparison of latanoprost monotherapy to dorzolamide combined with timolol in patients with glaucoma and ocular hypertension: a 3-month randomised study.Graefes Arch Clin Exp Ophthalmol.2000;238:19-23.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10664047&dopt=AbstractRFBrubakerMeasurement of aqueous flow by fluorophotometry.In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas. Vol 1. St Louis, Mo: CV Mosby Co; 1989:337-344.RFBrubakerFlow of aqueous humor in humans: the Friedenwald Lecture.Invest Ophthalmol Vis Sci.1991;32:3145-3166.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1748546&dopt=AbstractWJDixonJFMassey JrIntroduction to Statistical Analysis.New York, NY: McGraw-Hill Book Co; 1969:516.TLMausCNauRFBrubakerComparison of the early effects of brimonidine and apraclonidine as topical ocular hypotensive agents.Arch Ophthalmol.1999;117:586-591.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10326954&dopt=AbstractRFBrubakerCJIngramEOSchoffCBNauComparison of the efficacy of betaxolol-brinzolamide and timolol-dorzolamide as suppressors of aqueous humor flow in human subjects.Ophthalmology.2000;107:283-287.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10690826&dopt=AbstractCorresponding author and reprints: Lill-Inger Larsson, MD, PhD, Department of Ophthalmology, Uppsala University Hospital, S-751 85 Uppsala, Sweden (e-mail: [email protected]).Submitted for publication June 21, 2002; final revision received August 17, 2003; accepted September 10, 2003.This study was supported in part by grants from the Glaucoma Research Foundation, Uppsala University, and from Kronprinsessans Arbetsnämnd för de Synskadade, Stockholm, Sweden.

Plange, Niklas; Kaup, Marion; Weber, Anke; Remky, Andreas; Arend, Oliver

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.195pmid: 14769596

ObjectivesTo evaluate absolute filling defects of the optic nerve head in normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG) and to compare the filling defects with topographic analysis of the optic disc.MethodsTwenty-five patients with NTG, 25 patients with POAG, and 25 age-matched controls were included. Fluorescein angiograms were performed by means of a scanning laser ophthalmoscope. The extent of absolute filling defects of the optic nerve head was assessed using digital image analysis of early-phase angiograms. Topographic measurements of the optic disc were acquired using the Heidelberg Retina Tomograph II.ResultsAbsolute filling defects were significantly larger (P= .001) and were seen more often (P<.001) in patients with NTG (n = 18) and POAG (n = 19) compared with controls (n = 3). Rim area (P= .006), rim volume (P= .007), cup-disc area ratio (P= .008), linear cup-disc ratio (P= .005), maximum cup depth (P= .002), cup shape measure (P= .03), and nerve fiber layer thickness (P= .008) and cross-sectional area (P= .006) were significantly different between patients with glaucoma and controls. Absolute filling defects were significantly correlated with cup area (r= 0.31; P= .007), rim area (r= −0.38; P<.001), rim volume (r= −0.35; P= .002), cup-disc area ratio (r= 0.49; P<.001), linear cup-disc ratio (r= 0.48; P<.001), cup shape measure (r= 0.27; P= .02), and nerve fiber layer thickness (r= −0.33; P= .004) and cross-sectional area (r= −0.30; P= .009).ConclusionsFluorescein filling defects of the optic disc are present in NTG and POAG. The extent of these filling defects is correlated with the morphologic disc damage.The pathogenetic concepts of glaucoma, defined as a progressive optic neuropathy characterized by optic nerve head excavation and glaucomatous visual field loss, include mechanical and vasogenic mechanisms.A vascular failure leading to perfusion deficits of the optic nerve head, retina, choroid, or retrobulbar vessels, by means of vasosclerosis, small vessel disease, vasospasms, or autoregulatory dysfunction, may contribute to the nerve fiber loss in glaucomatous optic neuropathy.The mechanical damage is regarded as intraocular pressure (IOP)–dependent axonal dysfunction and loss. The lamina cribrosa and changes in extracellular matrix seem to have a substantial effect on the mechanical damage.Fluorescein angiographic studies may describe perfusion alterations of the optic nerve head, retina, and choroid. In different studies,morphologic and dynamic perfusion variables demonstrated impaired ocular blood flow in glaucoma.Fluorescein filling defects of the optic nerve head are areas of hypoperfusion, and they have been described in glaucomatous optic neuropathy since the 1970s.Absolute filling defects are persistent hypofluorescent areas, and they seem to correspond to capillary dropout in the surface nerve fiber layer of the optic disc.In contrast, relative defects are areas of delayed fluorescence, and they show a slower filling pattern with fluorescein.The filling defects are interpreted as areas of hypovascularity, as they are reproducible, with no consistent correlation with IOP and systemic blood pressure.The number, extent, and topography of fluorescein filling defects correspond to visual field loss, nerve fiber layer defects, and cupping in glaucoma.Absolute filling defects are larger and of greater number in patients with glaucoma compared with those with ocular hypertension or controls.Several investigatorshave reported high specificity of filling defects for glaucoma and anterior ischemic optic neuropathy. Furthermore, the regions of pallor of the disc in optic atrophy seem to result from alterations in the tissue reflectance after axonal loss and from alterations in extracellular matrix and glial tissue rather than from a decrease in microvascular structures.In contrast, O'Day et alalso reported decreased fluorescence in different types of optic atrophy. In glaucoma, fluorescein filling defects of the optic disc are preferentially located at the margin of the optic disc excavation, mainly inferotemporally and superotemporally, and are more often found at the wall than at the floor of the cup.Several researchersemphasize the relevance of fluorescein filling defects in glaucomatous optic neuropathy and postulate that filling defects may be the initial damage in glaucoma.The Heidelberg Retina Tomograph II (HRT II) (Heidelberg Engineering, Heidelberg, Germany) is a confocal scanning laser ophthalmoscope for quantitative stereometric analysis of the optic nerve head.The scanning laser technique allows for 3-dimensional assessment of the optic disc based on a digital image of its surface. Differentiation of the neuroretinal rim and the optic nerve head cup requires an operator-dependent contour line–based standard reference plane.Most stereometric variables depend on this reference plane.The HRT II aims to detect glaucomatous optic disc appearances and structural changes in the retinal nerve fiber layer in glaucoma. Morphologic assessment of the optic disc in detecting early glaucoma may improve diagnostic reliability if structural damage precedes functional damage, as measured by conventional white-on-white perimetry.The purpose of this study is to investigate the correlation between hypofluorescent areas of the optic disc and morphologic damage in glaucomatous optic neuropathy. Absolute fluorescein filling defects of the optic disc are compared with stereometric variables of the optic nerve head, as measured by confocal scanning laser tomography (HRT II). The filling defects of the optic disc and its stereometric variables are evaluated in patients with normal tension glaucoma (NTG), patients with primary open-angle glaucoma (POAG), and controls. The filling defects and morphologic variables of the optic nerve head are compared among groups and correlated with each other.METHODSPATIENTSTwenty-five patients with NTG, 25 patients with POAG, and 25 age-matched controls are included in this prospective clinical study. For statistical analysis, 1 eye of each participant was randomly chosen. All individuals, including control subjects, provided informed consent. Adherence to the Declaration of Helsinki for research involving human subjects is confirmed.Patients with NTG and POAG had glaucomatous optic nerve head cupping and glaucomatous visual field defects as defined by the European Glaucoma Society in the absence of retinal or neurologic disease affecting the visual field. The diagnostic criteria for glaucomatous visual field loss are as follows. Field loss was considered significant when (1) glaucoma hemifield test results were abnormal, (2) 3 points were confirmed with P<.05 probability of being normal (one of which should have P<.01), not contiguous with the blind spot, or (3) the corrected pattern SD was abnormal with P<.05.All variables were confirmed on 2 consecutive visual field examinations performed using the Humphrey visual field analyzer (model 750; Humphrey-Zeiss, San Leandro, Calif) (full-threshold program 24-2).All patients with glaucomatous visual field loss underwent diurnal curves of IOP measurements (Goldmann applanation tonometry) at 8 AM, noon, 4 PM, 8 PM, and midnight without any topical or systemic IOP-lowering medication. In patients with NTG, IOP never measured greater than 21 mm Hg.Visual acuity was 20/40 or better, and no previous laser or surgical treatment had been performed. Patients with refractive aberrations of more than ±4 diopters, diabetes mellitus, and hypersensitivity to sodium fluorescein were excluded from this study.Control subjects had no history of ophthalmologic disease. Automatic static white-on-white and short-wavelength automated perimetry did not reveal substantial visual field loss. Nerve fiber layer imaging using a scanning laser ophthalmoscope (SLO; Rodenstock, Ottobrunn, Germany) with blue light (argon-blue 488 nm) indicated a regular nerve fiber layer structure without any nerve fiber bundle defects.No statistically significant differences between patients with NTG and POAG were found for age, refraction, systolic and diastolic blood pressure, and heart rate. Patients with POAG had a significantly higher IOP compared with patients with NTG (P= .02). Seventeen patients with POAG, 16 patients with NTG, and 16 controls had a history of systemic cardiovascular disease, including arterial hypertension, treated with systemic medications. The mean number of local IOP-lowering medications was 1.48 for POAG, 0.64 for NTG, and 0.24 for controls. Six controls were initially treated as patients with NTG but were later reevaluated as controls with physiologic excavation of the optic nerve head. The clinical and demographic characteristics of all individuals included in the study are given in Table 1.Table 1. Clinical and Demographic Characteristics of the Patient Groups*POAG Group (n = 25)NTG Group (n = 25)Controls (n = 25)PValue†Age, y62 ± 962 ± 858 ± 9.22Intraocular pressure, mm Hg17.2 ± 3.015.2 ± 3.016.0 ± 3.0.07Mean deviation, dB−8.1 ± 7.5−7.7 ± 7.4−0.7 ± 1.4<.001Pattern standard deviation, dB6.7 ± 4.46.6 ± 3.81.8 ± 0.3<.001Spherical equivalent, diopters−0.9 ± 4.2−0.3 ± 2.50.2 ± 1.7.49Systolic blood pressure, mm Hg143 ± 16137 ± 18140 ± 21.58Diastolic blood pressure, mm Hg81 ± 979 ± 1077 ± 9.50Abbreviations: NTG, normal tension glaucoma; POAG, primary open-angle glaucoma.*Data are given as mean ± SD.†By analysis of variance.PROCEDURESPatients with POAG, patients with NTG, and control subjects underwent a detailed ophthalmologic examination, videofluorescein angiography using the SLO, and a scanning laser tomographic examination using the HRT II.Fluorescein angiography of the optic nerve head was performed using the SLO. The confocal video scanning laser ophthalmoscope, with a resolution of 512 × 512 pixels, detects temporal high-resolution images with high frequencies (25 Hz). To visualize the capillary network of the optic nerve head, the 20° field of observation of the SLO was used. Videofluorescein angiograms permit the selection of images with the best possible visualization of the superficial capillaries.To start the angiography, 10% sodium fluorescein dye (2.5 mL) was injected into an antecubital vein. The videofluorescein angiograms were performed with the optic nerve head centered. Images of the early phase (<3 minutes) were digitized visualizing the superficial capillaries of the optic nerve head. The angiograms were analyzed offline using digital image analysis (Matrox Inspector; Matrox Electronic Systems Ltd, Dorval, Quebec). The extent of absolute fluorescein filling defects was measured in relation to the area of the optic nerve head (percentage of the optic disc). Absolute filling defects of the optic nerve head are defined as areas of persistent hypofluorescence during the whole angiogram. During the angiogram, the focus was changed from the neuroretinal rim to the bottom of the cup to avoid artefacts. For evaluation of the hypofluorescent areas of the optic nerve head, the digitized single images were analyzed in a masked manner. Three observers (N.P., A.R., and O.A.) measured the extent of the absolute filling defects in agreement. As a reference for the disc area, digitized red-free images (argon laser 488-nm SLO) of the optic nerve head were used.Systolic and diastolic blood pressure and heart rate were measured after a 5-minute rest in the sitting position before fluorescein angiography. Nerve fiber layer imaging with a blue laser (argon laser 488 nm) was performed. Nerve fiber layer defects confirmed the diagnosis of POAG or NTG.Visual field examinations were performed using the Humphrey visual field analyzer and the white-on-white 24-2 full-threshold program. The standard visual field variables of mean deviation, pattern standard deviation, short-term fluctuation, and corrected pattern standard deviation were used for diagnosis and statistical analysis.All patients and control subjects underwent confocal scanning laser tomography of the optic nerve head using the HRT II (software 2.01). The HRT software analyzes the mean topography of 3 consecutively performed confocal scanning laser images of the optic disc. The variability of the scanning images is expressed by the standard deviation of the topography. The border of the optic nerve head at the level of the Elschnig scleral ring was outlined manually by an experienced examiner (N.P.). Depending on this operator-based contour line, the HRT II software 2.01 calculates a reference plane delineating the neuroretinal layer from the optic cup. Most of the stereometric variables describing the optic nerve head depend on this reference plane. The contour line–based reference plane is located perpendicular to the z-axis, 50 µm below the contour line at 354° to 360° of the optic nerve head circumference. Magnification error was corrected using keratometry values for each individual. For statistical analysis, the following variables were determined: disc area, cup area, rim area, cup volume, rim volume (area above and volume below the reference plane), cup-disc area ratio, linear cup-disc ratio, mean cup depth, maximum cup depth, cup shape measure (the third moment of the frequency distribution of depth values relative to the contour line), height variation contour (maximum minus minimum of the relative height values of the contour line), nerve fiber layer thickness, and nerve fiber layer cross-sectional area (the calculated distance and area between the reference plane and the contour line). Disc area, mean and maximum cup depth, height variation contour, and cup shape measure are independent of the selection of the reference plane.The fluorescein filling defects and the stereometric variables of the optic disc were compared among groups using analysis of variance. Correlations were tested using the Fisher rto ztest. In all analyses, P<.05 was regarded as statistically significant.RESULTSPatients with POAG and NTG more often had absolute filling defects of the optic nerve head compared with controls. Absolute filling defects were present in 18 of the 25 patients with NTG, 19 of the 25 patients with POAG, and only 3 of the 25 controls (P<.001). The diagnostic validity to differentiate patients with glaucoma from controls was expressed as a specificity of 88% and a sensitivity of 74%. The absolute filling defects of the optic nerve head were significantly larger in patients with NTG and POAG compared with controls (P<.01). The extent of the filling defects was not significantly different in POAG and NTG (P= .91) (Table 2).Table 2. Fluorescein Filling Defects of the Optic Nerve Head and Stereometric Variables of the Confocal Scanning Laser Image Analysis*POAG Group (n = 25)NTG Group (n = 25)Controls (n = 25)PValue†Fluorescein filling defects, % of the disc area12.6 ± 14.813.0 ± 16.50.7 ± 2.4.001‡Disc area, mm22.29 ± 0.72.27 ± 0.42.39 ± 0.6.74Cup area, mm21.20 ± 0.51.23 ± 0.51.06 ± 0.6.46Rim area, mm1.09 ± 0.51.01 ± 0.351.34 ± 0.3.006‡Cup volume, mm30.36 ± 0.20.33 ± 0.20.38 ± 0.3.79Rim volume, mm30.22 ± 0.10.22 ± 0.10.30 ± 0.1.007‡Cup-disc area ratio0.52 ± 0.10.54 ± 0.10.42 ± 0.1.008‡Linear cup-disc ratio0.72 ± 0.10.73 ± 0.10.64 ± 0.1.005‡Mean cup depth, mm0.30 ± 0.10.32 ± 0.10.35 ± 0.1.20Maximum cup depth, mm0.67 ± 0.20.69 ± 0.20.81 ± 0.21.02‡Cup shape measure−0.065 ± 0.07−0.054 ± 0.07−0.15 ± 0.22.03‡Height variation contour, mm0.33 ± 0.10.41 ± 0.20.38 ± 0.10.11Nerve fiber layer thickness, mm0.16 ± 0.10.18 ± 0.10.23 ± 0.10.008‡Nerve fiber layer cross-sectional area, mm20.88 ± 0.40.97 ± 0.51.25 ± 0.40.006‡Standard deviation of topography21 ± 2319 ± 1316 ± 8.60Abbreviations: NTG, normal tension glaucoma; POAG, primary open-angle glaucoma.*Data are given as mean ± SD.†By analysis of variance.‡Statistically significant difference, NTG and POAG vs controls.The following stereometric variables of the optic nerve head measured by confocal scanning laser ophthalmoscopy (HRT II) differed significantly between patients with glaucoma (POAG and NTG) and controls. Patients with glaucoma had smaller neuroretinal rim areas and rim volumes and larger cup-disc area ratios and linear cup-disc ratios. The maximum cup depth was smaller in patients with glaucoma. The cup shape measure showed significantly less negative values in the glaucoma groups, and the nerve fiber layer thickness and cross-sectional area were smaller. No significant difference between patients with glaucoma and controls was found for disc area, cup area, cup volume, mean cup depth, and the standard deviation of the calculated mean topography of the optic disc. The only variable found to differ significantly between patients with POAG and NTG was the height variation contour (P<.05). The results are given in Table 2.Further analysis was performed to investigate correlations between fluorescein filling defects and stereometric variables of the optic disc. For all participants included in this study, the absolute filling defects were significantly correlated with cup area (r= 0.31), rim area (r= −0.38), rim volume (r= −0.35), cup-disc area ratio (r= 0.49), linear cup-disc ratio (r= 0.48), cup shape measure (r= 0.27), and retinal nerve fiber layer thickness (r= −0.33) and cross-sectional area (r= −0.30) (P<.05 for all) (Table 3). No correlations were found for disc area, cup volume, mean and maximum excavation depth, and height variation contour. For patients with POAG, the filling defects were significantly correlated with cup-disc area ratio (r= 0.43) and linear cup-disc ratio (r= 0.43) (Table 4). In NTG, the filling defects were significantly correlated with rim area (r= −0.51), rim volume (r= −0.51), cup-disc area ratio (r= 0.55), linear cup-disc ratio (r= 0.55), maximum cup depth (r= −0.40), and nerve fiber layer thickness (r= −0.49) and cross-sectional area (r= −0.48) (Table 4). Controls exhibited a significant correlation of the filling defects with the maximum excavation depth only (r= 0.58; P<.01). None of the other stereometric variables of the controls were statistically significantly correlated with the extent of the filling defects.Table 3. Correlations for the Absolute Fluorescein Filling Defects With Stereometric Variables of the Optic Nerve Head for All 75 ParticipantsAbsolute Filling Defects (% of the Optic Disc) andPValueCoefficient of Correlation r*Disc area.770.03Cup area.0070.31Rim area<.001−0.38Cup volume.710.04Rim volume.002−0.35Cup-disc area ratio<.0010.49Linear cup-disc ratio<.0010.48Mean cup depth.57−0.07Maximum cup depth.07−0.21Cup shape measure.020.27Height variation contour.63−0.06Nerve fiber layer thickness.004−0.33Nerve fiber layer cross-sectional area.009−0.30*Correlations were tested using the Fisher rto ztest.Table 4. Correlations for the Absolute Fluorescein Filling Defects With Stereometric Variables of the Optic Nerve Head for Patients With POAG and NTGAbsolute Filling Defects (% of the Optic Disc) andPOAG Group (n = 25)NTG Group (n = 25)PValueCoefficient of Correlation r*PValueCoefficient of Correlation r*Disc area.43−0.16.980.003Cup area.060.38.080.36Rim area.52−0.14.002−0.51Cup volume.780.06.580.12Rim volume.83−0.05.009−0.51Cup-disc area ratio.030.43.0040.55Linear cup-disc ratio.030.43.0030.55Mean cup depth.400.18.39−0.18Maximum cup depth.700.08.04−0.40Cup shape measure.060.38.060.39Height variation contour.600.11.48−0.15Nerve fiber layer thickness.620.10.01−0.49Nerve fiber layer cross-sectional area.390.18.01−0.48Abbreviations: NTG, normal tension glaucoma; POAG, primary open-angle glaucoma.*Correlations were tested using the Fisher rto ztest.COMMENTAbsolute fluorescein filling defects of the optic nerve head were statistically significantly larger and were seen more often in patients with POAG and NTG compared with controls. These results confirm findings of various previous studies.In the present study, filling defects of the optic disc as a tool of differentiation between patients with glaucoma and controls had a specificity of 88% and a sensitivity of 74%. The filling defects observed on fluorescein angiograms reflect an area of hypoperfusion of the superficial nerve fiber layer of the optic nerve head in glaucomatous optic neuropathy and seem to correspond to capillary dropout.Several histologic studies examined changes in the vascular structure of the optic nerve head in glaucoma to study interference of capillary loss and morphologic change of the optic disc. In experimental nonglaucomatous optic atrophy, the number of capillaries remained stable and was expressed as a ratio to the optic nerve tissue. The size and relative volume of the capillaries diminished, whereas fluorescein angiography did not alter.The studies of experimental optic disc pallor showed a rearrangement of astrocytes beside ganglion nerve fiber loss. Quigley and Andersonand Radius and Maumeneeinterpreted these findings as causative for optic disc pallor rather than the vascular alterations because in complete ganglion cell loss, capillaries are still present in a pale optic disc, and fluorescein angiography of the optic disc was not altered. Furthermore, optic atrophy of various causes, including ischemia, is rarely combined with an increasing cup-disc ratio, as in glaucomatous optic nerve degeneration.Sebag et alfound reduced blood volume (approximately 50%) and oxygen delivery (approximately 40%) using vessel oxymetry, laser Doppler technique, and disc reflectometry in experimental optic atrophy. The Doppler measurements were substantiated by histologic studies of microsphere distribution (decrease of 80% in flow in anterior optic atrophy). Again, no abnormalities were detected by fluorescein angiography.In contrast to glaucomatous optic atrophy, optic pallor in optic atrophy seems to result from ganglion cell loss, astrocyte rearrangement, or reduced blood volume or oxygen content, alterations not seen with fluorescein angiography.In glaucomatous optic neuropathy, Elschnig,Cristini,and François and Neetensfound a reduced capillary network in the optic nerve head and choriocapillaries. These qualitative studiesemphasized capillary rarefaction in glaucomatous optic neuropathy. Kornzweig et aland Alterman and Henkinddescribed selective atrophy in radial peripapillary capillaries in postmortem eyes with chronic glaucoma and in experimental glaucoma. Quigley et al,however, stated that in their quantitative histologic studies of experimental glaucoma, capillary atrophy paralleled the nerve fiber loss. They found a stable capillary-tissue ratio in glaucomatous optic neuropathy and could not detect early damage angiographically. Consequently, these alterations in the capillary network of the optic nerve head were assumed to be secondary to nerve fiber tissue loss.In contrast, clinical studiesdealing with fluorescein angiographic filling defects of the optic nerve head stated that the filling defects, at least in some cases, precede morphologic damage, and vertical studiesrevealed a strong interrelationship to functional defects. The few longitudinal follow-up studies available concluded that filling defects emphasized progressive optic nerve damage,and new field defects were related to new filling defects in glaucomatous optic neuropathy.In the present study, the filling defects were correlated with the stereometric variables of the optic nerve head measured by scanning laser ophthalmoscopy. The statistically significant correlation with cup-disc area ratio and linear cup-disc ratio confirmed previous findings, even more so since in controls no such correlation was found. The filling defects were positively correlated with cup area and cup shape measure and negatively correlated with rim volume and nerve fiber layer thickness and cross-sectional area. In NTG, we found a statistically significant correlation with various variables, although in POAG the filling defects were only statistically significantly correlated with cup-disc area ratio and linear cup-disc ratio. As patients with POAG and NTG did not differ in the extent of the filling defects and all stereometric variables except height variation contour, this may reflect a stronger relation of vascular and morphologic damage of the optic nerve head in NTG. The question of whether NTG refers to a single disease entity or to a subgroup of open-angle glaucoma with lower tolerance to IOP must be mentioned again. The extent and incidence of fluorescein filling defects of the optic nerve head did not differ in POAG and NTG in the presented study. Therefore, the concept of ischemic damage of the optic nerve head (ie, capillary dropout) in glaucomatous optic neuropathy seems to be applicable to both types of glaucoma. Whether capillary dropout of the optic nerve head precedes or follows neuronal loss needs to be clarified in longitudinal follow-up studies.Few studies investigated blood flow variables compared with stereometric variables of the optic nerve head or functional data. Ciancaglini et alfound a significant correlation between blood flow variables measured using laser Doppler flowmetry and nerve fiber layer variables of scanning laser ophthalmoscopy. Kuba et alcould not find such correlation comparing laser Doppler flowmetry and scanning laser polarimetry. However, these studies have methodological limitations, as the dependence of blood flow measurement by scanning laser Doppler flowmetry on nerve fiber layer structures and the tissue volume included in the analysis remains unclear. Arend et alinvestigated fluorescein angiograms of patients with NTG and asymmetrical visual field loss. The altitudinal visual field defects were associated with prolonged arteriovenous passage time.The fluorescein filling defects were highly correlated with the visual field testing in various studies.In a blue field entoptic phenomenon approach, Sponsel et almeasured higher leukocyte velocities in eyes with better visual function, as expressed by the global index mean deviation. In a study by Fontana et al,pulsatile ocular blood flow was lower in NTG eyes with field loss compared with the contralateral normal visual fields. Ciancaglini et alfound a correlation between laser Doppler flowmetry variables of the lamina cribrosa region and visual field defects, although no correlation was found for the neuroretinal rim. In an indocyanine green fluorescence angiography study by Sato et al,the watershed zones including the optic nerve head were associated with larger field defects in NTG.In summary, this study implies a relationship between morphologic damage and superficial capillary loss observed in fluorescein angiography of the optic nerve head in glaucoma. 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The Hague, the Netherlands: Dr W Junk Publishers; 1983:67-73.KNanbaBSchwartzNerve fiber layer and optic disc fluorescein defects in glaucoma and ocular hypertension.Ophthalmology.1988;95:1227-1233.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3211501&dopt=AbstractETalusanBSchwartzSpecificity of fluorescein angiographic defects of the optic disc in glaucoma.Arch Ophthalmol.1977;95:2166-2175.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=588109&dopt=AbstractSSHayrehColour and fluorescence of the optic disc.Ophthalmologica.1972;165:100-108.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4629760&dopt=AbstractRLRadiusDRAndersonThe mechanism of disc pallor in experimental optic atrophy: a fluorescein angiographic study.Arch Ophthalmol.1979;97:532-535.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=105695&dopt=AbstractHAQuigleyRMHohmannEMAddicksQuantitative study of optic nerve head capillaries in experimental optic disc pallor.Am J Ophthalmol.1982;93:689-699.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7046447&dopt=AbstractHAQuigleyDRAndersonThe histological basis of optic disc pallor in experimental optic atrophy.Am J Ophthalmol.1977;83:709-717.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=405870&dopt=AbstractGAdamBSchwartzIncreased fluorescein filling defects in the wall of the optic disc cup in glaucoma.Arch Ophthalmol.1980;98:1590-1592.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7425920&dopt=AbstractEDTalusanBSchwartzLMWilcox JrFluorescein angiography of the optic disc: a longitudinal follow-up study.Arch Ophthalmol.1980;98:1579-1587.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7425919&dopt=AbstractATuulonenPNaginBSchwartzDWuIncrease of pallor and fluorescein-filling defects of the optic disc in the follow-up of ocular hypertensives measured by computerized image analysis.Ophthalmology.1987;94:558-563.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3601372&dopt=AbstractAmerican Academy of OphthalmologyOptic nerve head and retinal nerve fiber layer analysis.Ophthalmology.1999;106:1414-1424.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10406631&dopt=AbstractROWBurkKVihanninjokiTBartkeDevelopment of the standard reference plane for the Heidelberg retina tomograph.Graefes Arch Clin Exp Ophthalmol.2000;238:375-384.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10901468&dopt=AbstractCYMardinAGMJünemannThe diagnostic value of optic nerve imaging in early glaucoma.Curr Opin Ophthalmol.2001;12:100-104.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11224715&dopt=AbstractJBJonasWMBuddeDiagnosis and pathogenesis of glaucomatous optic neuropathy: morphological aspects.Prog Retin Eye Res.2000;19:1-40.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10614679&dopt=AbstractJCaprioliDiscrimination between normal and glaucomatous eyes.Invest Ophthalmol Vis Sci.1992;33:153-159.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1730536&dopt=AbstractKVihanninjokiPTeesaluROWBurkELääräATuulonenPJAiraksinenSearch for an optimal combination of structural and functional parameters for the diagnosis of glaucoma.Graefes Arch Clin Exp Ophthalmol.2000;238:477-481.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10943670&dopt=AbstractEuropean Glaucoma SocietyTerminology and Guidelines for Glaucoma.Savona, Italy: European Glaucoma Society; 1998.RLRadiusAEMaumeneeOptic atrophy and glaucomatous cupping.Am J Ophthalmol.1978;85:145-153.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=623182&dopt=AbstractJSebagGTFekeFCDeloriJJWeiterAnterior optic nerve blood flow in experimental optic atrophy.Invest Ophthalmol Vis Sci.1985;26:1415-1422.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4044169&dopt=AbstractJSebagFCDeloriGTFekeJJWeiterEffects of optic atrophy on retinal blood flow and oxygen saturation in humans.Arch Ophthalmol.1989;107:222-226.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2916975&dopt=AbstractJSebagFCDeloriGTFekeAnterior optic nerve blood flow decrease in clinical neurogenic optic atrophy.Ophthalmology.1986;93:858-865.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3526230&dopt=AbstractAElschnigÜber glaukom.Albrecht Von Graefes Arch Ophthalmol.1928;120:94-116.GCristiniCommon pathological basis of the nervous ocular symptoms in chronic glaucoma.Br J Ophthalmol.1951;35:11-20.JFrançoisANeetensVascularity of the eye and the optic nerve in glaucoma.Arch Ophthalmol.1964;71:219-225.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14089395&dopt=AbstractALKornzweigIEliasophMFeldsteinSelective atrophy of the radial peripapillary capillaries in chronic glaucoma.Arch Ophthalmol.1968;80:696-702.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4177355&dopt=AbstractMAltermanPHenkindRadial peripapillary capillaries of the retina, II: possible role in Bjerrum scotoma.Br J Ophthalmol.1968;52:26-31.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=5635900&dopt=AbstractHAQuigleyRMHohmanEMAddicksWRGreenBlood vessels of the glaucomatous optic disc in experimetal primate and human eyes.Invest Ophthalmol Vis Sci.1984;25:918-931.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6746235&dopt=AbstractMCiancagliniPCarpinetoGFalconioBlood circulation and morphology of optic nerve head in primary open-angle glauoma.Acta Ophthalmol Scand Suppl.2000;232:40.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11235528&dopt=AbstractGBKubaLEPillunatAGBöhmMKlemmRetinale Nervenfaserschichtdicke und peripapillärer Blutfluss bei Glaukompatienten und Gesunden.Ophthalmologe.2001;98:41-46.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11220270&dopt=AbstractWESponselKLDePaulPLKaufmanCorrelation of visual function and retinal leukocyte velocity in glaucoma.Am J Ophthalmol.1990;109:49-54.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2297032&dopt=AbstractLFontanaDPionoosawmyCVBunceCO'BrienRAHitchingsPulsatile ocular blood flow investigation in asymmetric normal tension glaucoma and normal subjects.Br J Ophthalmol.1998;82:731-736.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9924361&dopt=AbstractMCiancagliniPCarpinetoCCostagliolaLMatropasquaPerfusion of the optic nerve head and visual field damage in glaucomatous patients.Graefes Arch Clin Exp Ophthalmol.2001;239:549-555.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11585309&dopt=AbstractYSatoGTomitaEOndaYGotoAOguriYKitazawaAssociation between watershed zones and visual field defect in normal tension glaucoma.Jpn J Ophthalmol.2000;44:39-45.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10698024&dopt=AbstractCorresponding author and reprints: Niklas Plange, MD, Augenklinik des Universitätsklinikum Aachen, Pauwelsstr. 30, 52057 Aachen, Germany (e-mail: [email protected]).Submitted for publication April 10, 2003; final revision received August 27, 2003; accepted September 10, 2003.This study was presented in part at the Deutsche Ophthalmologische Gesellschaft Congress 2002; September 27, 2002; Berlin, Germany.

2004 Archives of Ophthalmology

doi: 10.1001/archopht.122.2.201

Congratulations to the winner of our October quiz, James A. Kimble,MD, University of Alabama at Birmingham. The correct answer to our Octoberchallenge was acquired parafoveal telangiectasis. For a complete discussionof this case, see the Photo Essay section in the November ARCHIVES (MartinezJA. Intravitreal triamcinolone acetonide for bilateral acquired parafovealtelangiectasis. 2003;121:1658-1659). View LargeDownload Be sure to visit the Archives of Ophthalmology Website (http://www.archophthalmol.com) and try your hand at our ClinicalChallenge Interactive Quiz. We invite visitors to make a diagnosis based onselected information from a case report or other feature scheduled to be publishedin the following month's print edition of the ARCHIVES. The first visitorto e-mail our Web editors with the correct answer will be recognized in theprint journal and on our Web site and will also be able to choose one of thefollowing books published by AMA Press: Clinical Eye Atlas,Clinical Retina, or Users' Guides to the MedicalLiterature.

Brodsky, Michael C.; Tusa, Ronald J.

2004 JAMA Ophthalmology

doi: 10.1001/archopht.122.2.202pmid: 14769597

BackgroundLatent nystagmus is a horizontal binocular oscillation that is evoked by unequal visual input to the 2 eyes. It develops primarily in humans with congenital esotropia.ObjectiveTo investigate the interrelationship between latent and peripheral vestibular nystagmus and their corollary neuroanatomical pathways.MethodsExamination of subcortical neuroanatomical pathways producing latent nystagmus and review of the neurophysiological mechanisms by which they become activated in congenital esotropia.ResultsThe vestibular nucleus presides over motion input from the eyes and labyrinths. Latent nystagmus corresponds to the optokinetic component of ocular rotation that is driven monocularly by nasal optic flow during a turning movement of the body in lateral-eyed animals. Congenital esotropia alters visual pathway development from the visual cortex to subcortical centers that project to the vestibular nucleus, allowing this primitive subcortical motion detection system to generate latent nystagmus under conditions of monocular fixation.ConclusionsLatent nystagmus is the ocular counterpart of peripheral vestibular nystagmus. Its clinical expression in humans proclaims the evolutionary function of the eyes as sensory balance organs.Vestibular disease holds little interest for the ophthalmologist. Although patients with vestibular disease can develop nystagmus, diplopia, and oscillopsia, these symptoms can be treated empirically. Peripheral vestibular disease is caused by injury to the labyrinth rather than to the eye, whereas central vestibular disease is caused by brainstem or cerebellar disorders involving the central vestibular pathways along their course to the ocular motor nuclei.But the ophthalmologist encounters a unique form of vestibular nystagmus that is caused by unbalanced input from the two eyes rather than from the two labyrinths. This visuo-vestibular nystagmus is known as "latent nystagmus."Congenital esotropia is associated with a clinical triad of latent nystagmus, inferior oblique muscle overaction, and dissociated vertical divergence.These unique eye movements conform to primitive vision-dependent tonus mechanisms that are reactivated by congenital strabismus or early abnormal visual experience.Evolutionary analogues of primary oblique muscle overaction and dissociated vertical divergence have been identified in lower vertebrates.In fish, these are physiologic extraocular movements that use weighted binocular visual input to modulate extraocular muscle tonus and to maintain visual orientation during body movements.The stimulus for bilateral inferior oblique muscle overaction corresponds to a visuo-vestibular imbalance in the sagittal (pitch) plane, while dissociated vertical divergence corresponds to a similar imbalance in the coronal (roll) plane.We propose that latent nystagmus results from a similar visuo-vestibular tonus imbalance in the horizontal turning (yaw) plane.WHAT IS LATENT NYSTAGMUS?Latent nystagmus is a binocular horizontal oscillation that becomes apparent when 1 eye is covered. First described by Faucon in 1872,latent nystagmus develops when congenital esotropia precludes frontal binocular vision early in infancy.In this setting, a conjugate horizontal jerk nystagmus can be induced by covering 1 eye, blurring 1 eye, or reducing image brightness in 1 eye.In latent nystagmus, the slow-phase rotation of the fixating eye is directed toward the nose and the fast-phase rotation of the fixating eye is directed toward the ear.As such, fixation with the right eye generates a right-beating nystagmus, while fixation with the left eye produces a left-beating nystagmus.In children with congenital esotropia and alternating fixation, the direction of nystagmus will spontaneously reverse when fixation is switched from one eye to the other.Even after the eyes have been surgically realigned, occlusion of either eye will continue to induce latent nystagmus. The intensity of latent nystagmus is maximal in abduction and minimal in adduction, causing some patients to maintain a head turn to place the fixating eye in an adducted position. The intensity of latent nystagmus decreases when visual attention declines and increases during attempted fixation.In fact, some patients can reverse the direction of their latent nystagmus by looking at an imagined target and mentally switching fixation from one eye to the other.In children with latent nystagmus, the development of amblyopia or the recurrence of ocular misalignment can disrupt binocular vision and make a latent nystagmus become manifest.The magnitude of the resulting manifest latent nystagmus is proportional to the degree of the interocular visual disparity.Most patients with clinical latent nystagmus actually have a small spontaneous jerk nystagmus that can be measured with both eyes open using eye movement recording.However, successful treatment of amblyopia or strabismus can convert a manifest latent nystagmus to a clinical latent nystagmus.Manifest latent nystagmus has also been reported in children with unilaterally reduced vision and sensory esotropia resulting from congenital disorders such as cataract or optic nerve hypoplasia.In this setting, a child will often maintain a head turn to position the fixating eye in adduction.Various theories have been advanced to explain latent nystagmus.These include a primitive tonus imbalance,an egocentric disorder,a disorder of the subcortical optokinetic system,a subcortical maldevelopment of retinal slip control,abnormal cortical motion processing,a disorder of proprioception,and an evolutionary preponderance of the nasal half of the retina.These disparate theories can be reconciled by considering the critical evolutionary function of the eyes as sensory balance organs.NASOTEMPORAL ASYMMETRY AND LATENT NYSTAGMUSLatent nystagmus is associated with nasotemporal asymmetry of the horizontal optokinetic response during monocular viewing.However, not all patients with nasotemporal asymmetry have latent nystagmus.In patients with nasotemporal asymmetry, the monocular optokinetic responses to nasally moving targets are brisk, while those to temporally moving targets are poor in each eye. This "nasalward" movement bias under monocular viewing conditions corresponds both in direction and in waveform to the nasalward slow-phase drift of the fixating eye in latent nystagmus.To our knowledge, Roelofsfirst observed horizontal optokinetic asymmetry in patients with latent nystagmus in 1928. Fifty years later, experiments by van Hof–van Duinand Wood et alsuggested that reduced binocularity in strabismus can lead to nasotemporal asymmetry. In 1977, Kommerellsuggested that latent nystagmus could be regarded as the consequence of horizontal optokinetic asymmetry. In 1982, Hoffmandeveloped a model to explain nasotemporal asymmetry based on combined cortical and subcortical input to the nucleus of the optic tract in the cat. In 1983, Schorproposed that latent nystagmus and nasotemporal optokinetic asymmetry are mediated by the nucleus of the optic tract.Human nasotemporal asymmetry has received considerable attention because it persists throughout life in humans with congenital strabismus.Even after surgical realignment, nasotemporal asymmetry remains as a "footprint in the snow" of abnormal visual development.Nasotemporal asymmetry is seen in rabbits, kittens, monkey infants, and human infants within the first 6 months of life.The evolutionary retention of this primitive nasotemporal asymmetry in human infancy shows how ontogeny recapitulates phylogeny during human visual development.In ordinary life, large parts of the visual field move together during self-motion.Optic flow occurs during translation (which is signaled by the otoliths and linear optic flow) and rotation (which is signaled by the semicircular canals and rotational optic flow).The low sensitivity to nasal to temporal optic flow in afoveate, lateral-eyed animals is commonly assigned the function of preventing the locomoting animal from responding to the image motion of stationary contours during forward motion, while permitting full compensation for rotational input during turning movements.The absence of nasotemporal optokinetic responses in lateral-eyed animals assures that during forward movements, ineffective temporalward eye movements do not destabilize images of objects that are directly ahead of the animal.The optokinetic responses of both eyes are controlled by whichever eye is stimulated by temporal-to-nasal movement of the visual world.Latent nystagmus recapitulates this monocularly driven horizontal optokinetic movement.IS LATENT NYSTAGMUS A VESTIBULAR NYSTAGMUS?Vestibular eye movements are reflex contraversive rotations of the eyes that occur during involuntary head movements, acting to stabilize the position of the eyes in space and thereby maintain visual orientation.According to Walls, " . . . vestibularly-controlled reflex eye movements are historically the oldest of all, with all other kinds of eye-muscle controls and operations accreted to them above the primitive fish level of evolution."(p71)During head movements, input to the semicircular canals within the 2 labyrinths provides the afferent stimulus for the vestibulo-ocular reflex.The semicircular canals respond to angular acceleration and produce dynamic vestibulo-ocular eye movements. Damage to a horizontal semicircular canal pathway produces a nystagmus in the plane of the injured canal.In lateral- and frontal-eyed animals, the geometry of the semicircular canals conforms closely with the orientation of the extraocular muscles.When the head is rotated in a particular plane, a semicircular canal within the labyrinth detects acceleration and sends excitatory innervation to the corresponding extraocular muscles. Within the brainstem and cerebellum, peripheral vestibular input is summated to produce innervation to the appropriate extraocular muscle subnuclei and to maintain the position of the eyes in space. Each horizontal semicircular canal provides excitatory input to the ipsilateral medial rectus muscle and the contralateral lateral rectus muscle.Visual stabilization mechanisms act in concert with labyrinthine reflexes.In normal life, optokinetic responses are elicited mainly by head movements, which also stimulate the vestibular system.Because vestibular neurons receive such prominent visual and vestibular inputs, disrupting either input reduces the tonic activation of these neurons, with the effect of disturbing the responses to the other sensory modality.Thus, labyrinthectomy eliminates optokinetic nystagmus in rabbits,whereas blocking optic nerve activity with tetrodotoxin reduces the gain of the vestibulo-ocular reflex.According to Miles, each sensory modality "has played such a major role in the evolution of the other that it is impossible to understand the operation of either one in isolation."(p393)A confluence of neuroanatomical, clinical, evolutionary, and experimental evidence has led us to conclude that latent nystagmus is a vestibular nystagmus that is brought about by unequal visual input from the 2 eyes rather than from the 2 ears (ie, a visuo-vestibular nystagmus). The evidence that latent nystagmus arises when the 2 eyes revert to their primitive function as balance organs can be summarized as follows.Neuroanatomy of Latent NystagmusStudies in subhuman primates have shown that latent nystagmus arises as a result of incomplete development of visual input from occipitotemporal cortex to subcortical vestibular pathways.In monkeys with latent nystagmus, there is a loss of binocularity in the nucleus of the optic tract (NOT), the subcortical structure that feeds into the vestibular system, with most cells driven by the contralateral eye.The areas that normally provide binocular input to the NOT are the middle temporal (MT) visual area and the medial superior temporal (MST) visual area in occipitotemporal cortex. When strabismus is surgically induced in infant monkeys during the first 2 weeks of life, these monkeys also develop latent nystagmus and visual area MT/MST loses binocularity. If either eye is covered during infancy, visual area MT/MST and NOT develop normal binocularity, but the striate cortex still shows loss of binocularity and these monkeys do not develop latent nystagmus.This finding suggests that the initial cause of latent nystagmus is loss of binocularity in visual area MT/MST from the misaligned eye during the first few weeks of life.Neuroanatomical experiments have confirmed the Schor hypothesisthat the NOT is the generator of latent nystagmus.A latent nystagmus occurs in monkeys following artificial induction of esotropia within the first 2 weeks of life.Unilateral electrical stimulation of the NOT in binocularly deprived monkeys induces a conjugate nystagmus with the slow phases directed toward the side of stimulation.Latent nystagmus can be abolished by direct injection of muscimol, a potent γ-aminobutyric acid A agonist into the NOT in monkeys.Simultaneous bilateral blockage of the NOT virtually abolishes latent nystagmus for the duration of the blockade.Subcortical optokinetic responses are also mediated by the pretectal NOT.The monocular pathways subserving nasotemporal asymmetry and its neutralization by binocularly driven pathways from the visual cortex were first elucidated by Hoffman in the cat.The cat NOT is a diffuse cell aggregation in the pretectum that is optimally located to integrate direct retinal and diffuse cortical projections.These nuclei have high levels of spontaneous activity and operate in a push-pull fashion such that the sum of their opponent innervation determines the optokinetic response.The NOT contains neurons that are sensitive to visual motion.Many units in the primate NOT have large receptive fields that are appropriate for encoding full-field visual motion to support optokinetic eye movements.Stimulation of the right and left NOT results in optokinetic nystagmus with slow phases to the right and left, respectively.Output from the NOT is maximal for horizontal movements but 0 for vertical movements.This phylogenetically ancient subcortical system is depicted in Figure 1. Crossed connections from each eye to the contralateral NOT transmit horizontal visual motion information to the vestibular nucleus before impinging on the ocular motor nuclei.Pretectal neurons in the left NOT receive only crossed input from the right eye and respond only to leftward motion, while those in the right NOT receive only crossed input from the left eye and respond only to rightward motion.In the first 6 months of infancy, this subcortical system predominates in humans, so that temporally directed monocular optokinetic responses are poor in early infancy compared with nasally directed optokinetic responses.By 6 months of age, cortical binocular pathways, which are responsive to temporally directed motion, provide a route whereby the NOT, with its specialized directional responses, can be accessed from either eye.In animals with well-developed foveae and frontal, stereoscopic vision, the visual inputs feeding directly to the pretectum are supplemented by inputs routed through the visual cortex that selectively respond to moving images with no positional disparity in the 2 eyes.This coupling between optokinetic nystagmus and stereopsis allows frontal-eyed animals to selectively stabilize the moving images of those parts of the scene within a selected depth plane, while disregarding induced image motion of the visual world at other distances.In humans with congenital strabismus, binocularly driven cortico-pretectal pathways never become established, allowing the primitive monocular nasotemporal asymmetry to predominate.Figure 1.Schematic diagram depicting cortical and optokinetic pathways. Cortical input to temporally directed movement, which is present only in frontal-eyed animals, requires the establishment of normal binocular cortical connections. This input is absent in humans with congenital strabismus. Direct crossed pathways from the eye to the nucleus of the optic tract provide nasalward subcortical optokinetic responses even when binocular cortical connections are absent (R and L represent monocular cortical cells corresponding to the right and left eyes, respectively). Note that the nucleus of the optic tract (NOT) relays horizontal visuo-vestibular information to the vestibular nucleus (VN), where it is integrated with horizontal vestibular input from the labyrinths to establish horizontal extraocular muscle tonus. LGN indicates lateral geniculate nucleus; CC, corpus callosum; V1, abducens nucleus; III, oculomotor nucleus; LR, lateral rectus muscle; MR, medial rectus muscle; AC, anterior canal; PC, posterior canal; and HC, horizontal canal.Clinical Signs of Vestibular OriginBilateral positioning of the eyes and ears promotes survival by enabling the organism to crosslink input from different sense organs to impart balance. Each eye and its ipsilateral semicircular canals share the same directional bias to movement. For example, the right horizontal semicircular canal is activated by head rotation to the right (which induces a rotation of the visual world to the left) and inhibited by head rotation to the left (which induces a rotation of the visual world to the right).The monaural and monocular directional biases summate, so that activation of the right horizontal semicircular canal during rightward head rotation is reinforced by the physiologic activation of the right eye by the induced nasal rotation of the visual world. The close geometrical relationship between the semicircular canals and the extraocular muscles presumably facilitates the integration of head motion and visual movement and their orderly summation to produce transformation to an appropriate ocular motor response.Latent nystagmus usually conforms to Alexander's law, which states that the intensity of a peripheral vestibular nystagmus increases when the eyes are moved in the direction of the fast phase and decreases when the eyes are moved in the direction of the slow phase.Latent nystagmus damps when the fixating eye is turned toward the nose (which is also the direction of the slow phase) and increases in intensity when the fixating eye is turned toward the ipsilateral ear (which is in the direction of the fast phase).A similar damping of horizontal nystagmus is seen in peripheral horizontal vestibular nystagmus after disease or injury to 1 horizontal semicircular canal. By contrast, Alexander's law does not apply to congenital nystagmus, which reverses direction in different positions of gaze. The contraversive head turn in latent nystagmus (ie, a head turn opposite in direction to the deviation of the fixating eye) also characterizes vestibular eye movements.Additional evidence for the duality of optic and vestibular innervation can be elicited by occluding 1 eye in the patient with latent nystagmus, spinning the patient, suddenly stopping the spin, then immediately observing the effect of the postrotational nystagmus on the latent nystagmus when either eye is occluded. A horizontal nystagmus induced by body spinning nullifies or accentuates latent nystagmus depending on the direction of spin relative to the fixating eye (Figure 2). For example, spinning the patient to the right excites the right horizontal canal and inhibits the left horizontal semicircular canal to induce a nystagmus with a slow-phase rotation to the left and a fast-phase rotation to the right. If the spin is suddenly stopped (after approximately 10 rotations), a shift in endolymph deflects the cupula in the opposite direction, causing transient excitation of the left horizontal semicircular canal and transient inhibition of the right horizontal semicircular canal and inducing a left-beating nystagmus (termed "postrotational nystagmus"). If the left eye is occluded to induce latent nystagmus prior to this maneuver, the latent nystagmus will diminish or disappear immediately following cessation of the spin. If the occluder is quickly moved to cover the right eye, the intensity of the latent nystagmus with the left eye viewing will be correspondingly increased relative to that observed with the left eye fixating before the spin. In this way, the clinician can observe how visual input is summated with vestibular input to establish central vestibular tone in the horizontal plane.Figure 2.Visual and vestibular interaction in latent nystagmus. Latent nystagmus decreases with spinning toward the fixating eye and increases with spinning toward the occluded eye. O represents direction of ocular (visuo-vestibular) tonus; V, direction of horizontal vestibular tonus. Both O and V correspond to the slow phase of the induced nystagmus. ++ Indicates stimulated horizontal semicircular canal; −−, inhibited horizontal semicircular canal; A, Occlusion of the left eye increases visuo-vestibular tonus to the left. B, The patient with latent nystagmus is spun to the right to stimulate the right horizontal semicircular canal, which increases leftward horizontal vestibular tonus and causes a slow conjugate drift of both eyes to the left. At this point, the latent nystagmus would be enhanced by vestibular input (if the examiner could observe it). C, When the spinning is suddenly stopped, the opposite vestibular stimulus is exerted, causing the left semicircular canal to drive the eyes to the right. This rightward vestibular tonus imbalance nullifies the leftward visual tonus imbalance induced by monocular fixation with the right eye, thereby reducing the intensity of the latent nystagmus. D, When the occluder is quickly switched to the right eye, the visual tonus imbalance is augmented by an ipsidirectional visual tonus imbalance, increasing the intensity of the latent nystagmus.The more visual input is dominated by 1 eye in latent nystagmus, the higher the velocity of the slow-phase rotations in the direction toward the opposite eye.Simonsz and Kommerellperformed eye movement recordings before and after occlusion therapy for amblyopia in patients with latent nystagmus. After prolonged occlusion, the slow-phase velocity of the nystagmus in the amblyopic eye decreased to the same extent that the slow-phase velocity of the nystagmus in the preferred eye increased. The sum of the 2 slow-phase velocities remained the same in straight-ahead gaze, demonstrating that visual input to the 2 eyes (just like rotational input to the 2 horizontal canals) maintains a push-pull relationship.This observation lends further support to a vestibular underpinning for latent nystagmus. The clinical similarities between latent nystagmus and peripheral vestibular nystagmus are summarized in Table 1.Table 1. Peripheral Vestibular Nystagmus vs Latent NystagmusPeripheral Vestibular NystagmusLatent NystagmusInduced by unequal bilateral labyrinthine inputInduced by unequal binocular visual inputStimulation of right horizontal semicircular canal evokes a conjugate right-beating nystagmusStimulation of right eye evokes a conjugate right-beating nystagmusNystagmus intensity proportional to the degree of horizontal canal imbalanceNystagmus intensity proportional to the degree of binocular visual imbalanceDamps during gaze away from the side of the normal canalDamps during gaze away from the side of the fixating eyeConforms to Alexander's lawConforms to Alexander's lawModulated by subcortical neural pathwaysModulated by cortical and subcortical neural pathwaysEvolutionary Underpinnings of Latent NystagmusThe notion of latent nystagmus as a horizontal visuo-vestibular tonus imbalance provides conceptual unification with its associated inferior oblique overaction and dissociated vertical divergence in patients with congenital esotropia. The evolutionary progenitors of all of these visuo-vestibular movements use binocular input to establish physical orientation in space. These primitive reflexes rely on a dissociated form of binocular vision between the 2 laterally placed eyes, which has been superseded by normal cortical binocular vision in humans.In congenital esotropia, however, these primitive subcortical reflexes are not erased by binocular cortical input. Eye movement recordings have demonstrated that dissociated vertical divergence incorporates a vertical latent nystagmus, suggesting a shared common origin for these movements.Given that visual and labyrinthine input are pooled together within the central vestibular system of lower animals,a visual counterpart to peripheral vestibular nystagmus would seem necessary on evolutionary grounds. Many authors have attributed latent nystagmus as a tonus imbalance of the horizontal extraocular muscles.Latent nystagmus corresponds to a tropotactic vision-induced tonus imbalance (ie, one that functions to reestablish binocular equilibrium rather than to directionally orient an eye toward incoming light).Ohm recognized the physiologic coaptation of visual and vestibular innervation and its role in the generation of latent nystagmus long before others did (as was also the case with dissociated vertical divergence and primary oblique muscle overaction).In a monograph written near the end of his life, he stated, "The impulses that originate from both eyes keep both vestibular nuclei in equilibrium. The equilibrium becomes unbalanced when one eye is being occluded. Then, a nystagmus beating towards the side of the open eye appears."Kestenbaumemphasized that latent nystagmus could not be attributed to luminance per se, since shining a bright light in the right eye worked like occlusion of the right eye and caused a left-beating nystagmus. He noted that the presence of a sharper visual image on the retina of one eye than the other appeared to be the decisive stimulus for inducing latent nystagmus.Predominance of a primitive visuo-vestibular imbalance provides an evolutionary basis for the shift in egocenter that has been invoked to explain latent nystagmus.According to this hypothesis, the egocenter is localized to the median body plane under normal binocular conditions, but shifts to the side of the fixating eye under monocular conditions. Dell'Osso et alhypothesized that humans with latent nystagmus retain an abnormal egocenter in the median plane even under monocular conditions, causing the fixating eye to drift toward midline. In the lateral-eyed animal, fixation with the right eye would instantaneously shift the egocenter to the left of the object of regard, necessitating a body turn to frontalize the object and a contraversive eye rotation to maintain fixation.As neatly summarized by Dichgans and Brandt:. . . the results of visual and vestibular stimulation on egocentric localization indicate the close similarity in the perceptual consequences of stimulation of the two organs. The assumption of a unitary central representation of egocentric space, based on visual and vestibular (as well as acoustic and somatosensory) afferents is perceptually obvious.(pp763-764)It remains to be determined whether a higher order egocentric shift could cause the visuo-vestibular imbalance which generates the linear slow phase of latent nystagmus.Experimental Evidence That Latent Nystagmus Is Vestibular in OriginOptokinetic responses are fundamentally intertwined with vestibular responses, and a major site of this commingling is the vestibular complex.Waespe and Hennand Henn et alperformed single-cell recordings from the medial vestibular nucleus in monkeys and found that single neurons can be activated either by body rotation or optokinetic stimulation. Units that were excited by head acceleration to the left were also exited by motion of optokinetic stripes to the right. Most cells responded to both the whole-field visual motion, as well as to the vestibular indications of head rotation, and the responses of vestibular neurons followed approximately the same time course as the delayed component of optokinetic nystagmus.As summarized by Dichgans and Brandt:All of the recent studies performed in awake animals show a tonic modulation of resting discharge of vestibular units in response to exclusive constant velocity motion of the visual surround. The modulation, although to a variable degree, seems to occur in the great majority of horizontal semicircular canal-dependent units of all vertebrate species tested. A unit which is excited by a head acceleration, say, to the left is also excited by motion of the surround to the right, which represents the optokinetic stimulus that in man would cause the sensation of turning to the left.(pp781,783)This underlying vestibular response to both visual motion and body rotational stimuli may explain the overlapping nystagmus response that characterizes latent, optokinetic, and peripheral vestibular nystagmus.This overlap may reflect the fact that all 3 movements subserve a similar physiologic function (ie, detection of rotation of the body and visual environment).Latent nystagmus, optokinetic nystagmus, and the vestibuloocular reflex also show velocity storage, a phenomenon in which constant vestibular input or visual flow in the same direction is stored for up to 20 seconds in the brainstem, even when the stimulus is terminated (Table 2).The presence of velocity storage serves to enhance the slow-tracking eye movements to vestibular stimulation and optic flow response at low frequencies of rotation.Although latent nystagmus has variously been attributed to anomalous cortical motion processing,or a cortical pursuit asymmetry,the absence of velocity storage mechanism within the pursuit system implicates the vestibular system as the generator of latent nystagmus.Table 2. Experimental Evidence That Latent Nystagmus Is Vestibular in OriginNucleus of the Optic Tract (NOT) in MonkeysLatent Nystagmus in MonkeysLatent Nystagmus in HumansElectrical stimulation of NOT on one side causes conjugate nystagmus in both eyes with slow phases directed to the same side as the stimulated NOT.Covering one eye causes conjugate nystagmus in both eyes with slow phases directed to the same side as the activated NOT (contralateral to the viewing eye).SameThe velocity of the slow phases of nystagmus from electrical stimulation of NOT slowly increases. When stimulation is stopped, the slow-phase functioning eye velocity slowly decays. This slow increase and slow decay in eye velocity is due to the charging and discharge of the vestibular velocity storage system.When one eye is covered, the velocity of the slow phases of nystagmus slowly increases. When the eye is uncovered, the slow-phase eye velocity slowly decays.Slow rise and slow decay is usually not seen because the eye velocity in humans is much slower (1-5 dynes [d/s]) than that found in monkeys (20-90 d/s). In some humans, latent nystagmus eye velocity can be 20 d/s and in those cases a slow rise and slow decay is found (R.J.T., unpublished data).NOT projects to the vestibular velocity storage system and NOT is responsible for eliciting optokinetic after nystagmus (OKAN), which is the portion of optokinetic nystagmus that is mediated by the velocity storage system.Chemical suppression of NOT blocks OKAN and suppresses latent nystagmus.UnknownCONCLUSIONSLatent nystagmus is a unique form of vestibular nystagmus that is evoked by unbalanced visual input from the 2 eyes rather than unequal rotational input from the 2 labyrinths. The neurophysiological substrate for latent nystagmus is operative in lateral-eyed animals and in human infants with undeveloped binocular corticopretectal pathways. When congenital esotropia disrupts the establishment of these binocular visual connections, visual input from the fixating eye to the contralateral NOT evokes a visuo-vestibular counterrotation of the eyes that corresponds to a turning or twisting movement of the body toward the object of regard ("vestibular nystagmus with a twist"). In this setting, unbalanced binocular visual input can induce a motion bias in the vestibular nucleus to generate the visual counterpart of horizontal labyrinthine nystagmus, namely, latent nystagmus. As the eyes rotate frontally during evolution, this visuo-vestibular function is sacrificed, but the central nervous system retains these latent subcortical visual pathways. 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humans.Ann N Y Acad Sci.1981;374:421-433.LTychsenRRHurtigWEScottPursuit is impaired but the vestibulo-ocular reflex is normal in infantile strabismus.Arch Ophthalmol.1985;103:536-559.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3872654&dopt=AbstractCorresponding author and reprints: Michael C. Brodsky, MD, Departments of Ophthalmology and Pediatrics, Arkansas Children's Hospital, 800 Marshall St, Little Rock, AR 72202.Submitted for publication October 8, 2002; final revision received September 15, 2003; accepted October 14, 2003.This study was supported in part by a grant from Research to Prevent Blindness Inc, New York, NY.We thank Guntram Kommerell, MD, for his valuable suggestions during the preparation of the manuscript.