1 Department of Ophthalmology, University Hospitals Leicester, Infirmary Square, Leicester LE1 5WW, UK
2 Department of Health Sciences, University of Leicester, 22-28 Princess Road West, Leicester LE1 6TP, UK
3 Department of Ophthalmology, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, UK
Professor Irene Gottlob
Department of Ophthalmology, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, UK; firstname.lastname@example.org
Accepted for publication 25 May 2005
Aim: To investigate the influence of nystagmus on visual and social function and determine if parents are able to assess visual and social function in children with nystagmus.
Method: A postal questionnaire comprising 14 questions related to visual function (VF-14) and questions pertaining to social function were sent to all 1013 members of the Nystagmus Network—a UK based organisation for nystagmus sufferers and their families. Visual and social function scores were compared by regression analysis.
Results: 180 adult, 233 parent, and 124 child questionnaires were returned. Idiopathic nystagmus was the most common cause. In adults the mean VF-14 score indicated very low visual function, in the same range as patients assessed in low vision services. Children’s visual function scored better than adults, between scores of patients with age related macular disease and corneal grafts. There was a strong correlation between perceived visual and social function for adults (p<0.001) and parental assessment of their children (p<0.001), but not between child self assessment of visual and social function. There was strong correlation between parental and child assessment of visual and social function (p<0.001, p<0.001)
Conclusion: Questionnaires indicated that nystagmus is associated with very low visual function. There is a strong correlation between visual and social impairment. The authors have shown for the first time in an ophthalmic disease that parents are able to estimate the impact of nystagmus on their child both in terms of visual and social functioning, although they underestimate the impact of nystagmus on emotional aspects of wellbeing.
Abbreviations: NN, Nystagmus Network; SF, social function; VF, visual function
Keywords: nystagmus; quality of life; epidemiology; visual function
Nystagmus often occurs in early childhood and can be idiopathic, associated with albinism, ocular, or neurological diseases. The prevalence of infantile nystagmus is one in 1000–6000.1,2 The impact of nystagmus on visual function (VF; ability to perform activities of daily life) and social function (SF; self perception of wellbeing, interaction with and contribution to society) is unknown.
Functional impairment in ocular disease can be explored with questionnaires. The VF-14 is a valid, reliable tool for measuring visual impairment. It was designed for patients with cataract3 and has been used for other visual diseases.4–8 VF is variably affected depending on the eye disease. Experienced difficulties have found to be contrast and near tasks in cataract,3 sport in myopia,4 and fine details and driving in macular degeneration.5
Disease specific tools3,9–13 have been developed. These questionnaires contain items of little relevance for patients with nystagmus who have, in addition to visual impairment from unusual eye movements, abnormal head movements and/or oscillopsia. Factors associated with quality of life in visual impairment include worry, independence, concerns about the future, social relationships, and career.9,12,13 Because of altered cosmesis, teasing and self confidence was found to be changed in myopia,4 while abnormal head posture and ocular deviation affected interpersonal communication and employment in strabismus.12
Poor VF is associated with poor SF8,9,11–13; however, the psychosocial implications of the effect of nystagmus has not, to our knowledge, been investigated. Our aim was to quantify and compare VF and SF in nystagmus including a comparison of parental and child perception.
Questionnaires were sent anonymously to all (1013) members of the Nystagmus Network UK (NN), a charity for patients and families with nystagmus. Envelopes contained three questionnaires—one for affected adults, one for parents of affected children, and one for affected children. Upon request, additional questionnaires (for example, more than one child affected) and questionnaires on disc and tape were supplied. A reminder was placed in the NN newsletter after 2 months. Questionnaires returned after 6 months were included.
The original VF-14 was used to assess VF3 (see appendix). The question pertaining to driving was omitted for children. A SF questionnaire was derived from vision and social function related questionnaires9,14,15 for adults and children with nystagmus. Parents were asked to respond about their child and consider if their child could independently complete an additional questionnaire. Returned parent and child responses were directly compared using VF-14 and SF questions appearing in the same form on both questionnaires (see appendix). There were variations between parental and child questionnaires, to incorporate preschool child assessment (see appendix). Additional questions addressed sex, age, and nystagmus type.
Following a pilot questionnaire sent to NN committee members, the number of questions for children was reduced (questions 15–17 removed), wording was altered to aid comprehension (question 11; "Do you feel lonely" to "Do you feel isolated"), and several social score questions were changed to a positive turn (adult A, B, C, L: parent 15–17).
SF questions were given scores between 1 and 4 (1 = great deal of difficulty, 2 = moderate difficulty, 3 = a little bit of difficulty, 4 = no difficulty).3 Questions 1, 2, and 12 had scores reversed to account for their positive turn. Scores were divided by number of questions answered, then multiplied by 25 to give total scores in the range 0-100: the higher the score, the better the function. Results were compared using regression analysis on SPSS.
In all, 398 (39%) of the 1013 envelopes were returned, containing 180 adult and 233 parent/child questionnaires; 22 with more than one affected family member.
The mean age of adult responders was 41 years (range 18–75, SD 15.6; 52% females and 48% males). The most common nystagmus cause was idiopathic/no reason (table 1).
Table 1 Aetiologies, mean VF-14 score, and social score for adult, parental assessment of child and child self assessment
Figure 1A shows the correlation between VF-14 and SF scores for adults (R2 = 0.35, p<0.001). There was a trend for higher VF-14 scores in idiopathic nystagmus than for other aetiologies. Neither SF nor VF was associated with age or sex.
Figure 1 (A) Adult VF-14 score versus social function score. (B) Parent assessment of child VF-14 versus social function score. (C) Parent versus child self assessment of social function score. (D) Parent versus child self assessment of VF-14.
Parent and child data
Of the 233 datasets, 124 contained a non-affected parent together with an affected child response. The average age of affected children was 7.5 years (range 0–18, SD 4.3). The male:female ratio was 60:40. The most common nystagmus cause was idiopathic/no reason (table 1). A trend was found for higher parental than child self assessment of VF and higher VF-14 scores in both parental and child self assessment for idiopathic nystagmus than other aetiologies. In contrast with adults, nystagmus associated with squint had a high VF. A weak positive association was found between VF and age (p<0.044). No association was found between sex and VF-14 score.
There was strong positive correlation between parental assessment of child VF and SF (R2 = 0.39, p<0.001) (fig 1B). Figure 1C and D show correlations between SF scores (R2 = 0.72, p <0.001) and VF-14 scores (R2 = 0.74, p<0.001) assessed by children and parents. A positive association was found with age for SF scores for parental and child assessment, but not for sex or type of nystagmus.
Although parents’ and children’s assessment of social score correlated highly, there was disagreement on two questions: 11% of parents thought their child was bullied "a great deal" because of nystagmus, whereas 26% children with nystagmus responded this way; 3% of parents thought their child worried a great deal about eyesight but 32% children responded likewise.
VF-14 was higher in children than adults. Adults thought they had a great deal of difficulty recognising people (11%); this was a problem for only a few children (2%) or their parents (4%). Twenty seven per cent of adults reported inability to participate in sports, in contrast with 3% of children.
We found a strong correlation between VF and SF for adults and parental assessment of children with nystagmus and between parental and child self assessment of VF and SF.
Children had lower SF scores than adults. Most children scored low in areas concerned with appearance and confidence, whereas few adults thought that career and education had been affected by nystagmus. This may reflect difficulty in accepting those who are "different" by children. Children’s lifestyles affect their current wellbeing, development, and adult health.12,13,16 Studies on quality of life with strabismus and amblyopia show interference with schooling, influence in job choice, and social activity.12,13 Research on childhood strabismus concluded that psychological development and self esteem suffered because of other children’s attitudes.12
An association was found with age for parental assessment of child VF and SF. Decreasing nystagmus amplitude with age17 might contribute to better VF and SF scores in older children. However, measuring VF and SF is challenging in children because of difficulties in interpreting social interaction, varying parental experience, and rapid change in skills.18
The visual impairment caused by nystagmus is shown in table 2.4–8 For adults it is equivalent to patients requiring low vision aids. In children it is above VF in patients with age related macular degeneration.
Table 2 Comparison of VF 14 scores from this study with other chronic ocular diseases
A lower mean VF score was found for albinism than for idiopathic nystagmus. Patients with idiopathic nystagmus have better visual acuity than in secondary nystagmus.1 In future studies it would be interesting to correlate visual acuity with VF and SF.
It is possible nystagmus sufferers who are members of NN are biased towards worse VF. A response rate of 39% may reflect those with worse vision. However, VF ranged widely (0–100 adults: 6.25–100 children), enabling us to correlate a wide range of VF with SF.
In our study parents and children showed agreement between SF and VF. To our knowledge no previous studies compared parental assessment and child self assessment of VF. Current research regarding chronic childhood disease19–21 shows parents overestimate the illness impact on physical ability, but underestimate emotional, cognitive, and social implications. This is confirmed here, where parents overestimated difficulty with participating in sports and underestimated the impact of appearance and the likelihood of being bullied because of nystagmus. Children indicating fewer problems with sports than adults could reflect on good school integration, the competitive nature of organised sport for adults, or other neurological impairment in adults with acquired nystagmus.
It is possible that children completing self assessment questionnaires were influenced by parents. However, consistent differences in results (for example, bullying and appearance) support independent completion of questionnaires.
The majority of ocular quality of life questionnaires concentrate on tasks and symptoms rather than wellbeing and SF. It is important to develop quality of life instruments, which correlate visual acuity with functional ability and integration in society, to judge the impact of visual disability and appropriately direct services.
Poor VF is associated with poor SF in nystagmus. This is the first study to show VF scores in nystagmus are low compared with other causes of chronic visual loss. We show for the first time in an ophthalmic disease that parents are able to estimate the impact of nystagmus on visual and social functioning, and are well placed to assess their child’s needs. Children with nystagmus perceive social exclusion, which should be addressed by a multidisciplinary team.
Do you have any difficulty, even with glasses.....
1 Reading small print—eg, food label, phone book
2 Reading a book or newspaper
3 Reading a large print book or recognising numbers on TV
4 Recognising people when they are close to you
5 Seeing steps, stairs, or curbs
6 Reading traffic signs, street signs, or shop signs
7 Doing fine handwork—eg, sewing, knitting, crafts
8 Filling in forms
9 Playing games—eg, cards, dominoes, board games
10 Taking part in sport
12 Watching television
13 Driving during the day—omitted from child questionnaire
14 Driving at night—omitted from child questionnaire
ADULT SOCIAL SCORE (*SCORES REVERSED)
Because of nystagmus
A Do you enjoy making friends?*
B Do you go out socially?*
C Do you consider yourself independent?*
E Were decisions about further education affected?
F Were decisions about career choice affected?
G Has career progression been affected?
H Do you feel you have been prevented from working?
I Do you worry about losing your job?
J Do you dislike leaving home on your own?
K Do you have problems getting along with people?
L Do you have difficulty caring for family members?
M Are you happy with life?*
N Do you need help from other people?
O Do you feel less inclined to meet new people?
P Do you feel less inclined to meet family?
Q Do you feel isolated from those around you?
R Do you feel frustrated with life?
S Have you been bullied or teased?
T Do you worry about your eyesight?
U Are you concerned about your appearance?
CHILD SOCIAL SCORE —SELF ASSESSMENT
(Underlined questions used for direct comparison)
1 Are you shy, withdrawn, or nervous?
2 Do you spend time worrying about your vision?
3 Do you feel frustrated?
4 Have you been bullied or teased?
5 Are you concerned about your appearance?
6 Do you have difficulty making friends?
7 Do you need help at school?
8 Do you consider yourself disabled or handicapped?
9 Do you feel less inclined to go out and meet friends?
10 Do you feel less inclined to meet family?
11 Do you feel lonely?
CHILD SOCIAL SCORE —PARENTAL ASSESSMENT
Because of nystagmus....
1 Is he/she shy withdrawn or nervous?
2 Does he/she spend time worrying about their vision?
3 Is he/she frustrated?
4 Has he/she been bullied or teased?
5 Is he/she concerned about his/her appearance?
6 Does he/she have difficulty making friends?
7 Does he/she need help at school?
8 Do you consider your child disabled or handicapped?
9 Do you feel less inclined to meet new friends?
10 Do you feel less inclined to meet family?
11 Do you feel isolated from other parents?
12 Do you feel downhearted?
13 Do you worry about future children having nystagmus?
14 Are you concerned about your child’s appearance?
15 Is your child happy?*
16 Does your child get on well at school?*
17 Does your child interact well with other children?*
We thank the members of the Nystagmus Network for help designing and piloting the questionnaires and members of the Nystagmus Network who participated. This study was supported by the Ulverscroft Foundation.
Abadi RV, Bjerre A. Motor and sensory characteristics of infantile nystagmus. Br J Ophthalmol 2002;86:1152–60.
Hemmes GD. Hereditary nystagmus. Am J Ophthalmol 1924;10:149–50.
Steinberg EP, Tielsen JM, Schien OD, et al. The VF14—an index of functional impairment in patients with cataract. Arch Ophthalmol 1994;112:630–638.
Ross K, Harper R, Tromans C, et al. Quality of life in myopia. Br J Ophthalmol 2000;84:1031–4.
Riusala A, Sarna S, Immonen I. Visual function 14 in long duration age related macular degeneration Am J Ophthalmol 2003;135:206–12.
Boisjoly H, Grosset J, Fontaine N, et al. The VF14 index of functional visual improvement in candidates for corneal graft. Am J Ophthalmol 1999;128:38–44.
Linder M, Chang TS, Scott IU, et al. Validity of VF14 in patients with retinal disease. Arch Ophthalmol 1999;117:1611–16.
Scott IU, Smeddy WE, Schiffman J, et al. Quality of life of low vision patients and the impact of low vision services. Am J Ophthalmol 1999;128:54–6231.
Mangione CM, Berry S, Spritzer MS, et al. Identifying content area for the 51 item NEI-VFQ. Arch Ophthalmol 1998;116:227–33.
Mangione CM, Phillips RS, Seddon JM, et al. Development of the ‘Activities of Daily Vision Scale’. Med Care 1992;30:1111–26.
Terwee CB, Gerding MN, Dekeer FW, et al. Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL. Br J Ophthalmol 1998;82:773–9.
Sutterfield D, Keitner JL, Morrison TL. Psychosocial aspects of strabismus study. Arch Ophthalmol 1993;111:1100–5.
Packwood EA, Cruz O, Rychwalski PJ, et al. The psychosocial effects of amblyopia study. J AAPOS 1999;3:15–17.
Jette AM, Davies AR, Cleary PD, et al. The functional status questionnaire: reliability and validity when used in primary care. J Gen Int Med 1986;1:143–9.
Eiser C, Morse R. Can parents rate their child’s health-related quality of life? Results of a systematic review. Qual Life Res 2001;10:347–57.
Antwerp CA. The lifestyle questionnaire for school aged children: a tool for primary care. J Paediatr Health Care 1995;9:251–5.
Reinecke RD, Guo S, Goldstein HP. Waveform evolution in infantile nystagmus: an electro-oculo-graphic study of 35 cases. Binoc Vis 1988;3:191–202.
Felius J, Stager DR, Berry PM, et al. Development of an instrument to assess vision-related quality of life in young children. Am J Ophthalmol 2004;138:362–72.
Erickson SR, Munzenberger PJ, Plante MJ, et al. Influence of sociodemographics on the health-related quality of life of pediatric patients with asthma and their caregivers. J Asthma 2002;39:107–17.
Ennett ST, DeVellis BM, Earp JA, et al. Disease experience and psychosocial adjustment in children with juvenile rheumatoid arthritis: children’s versus mothers’ reports. J Paediatr Psychol 1991;16:557–68.
Theunissen NC, Vogels TG, Koopman HM, et al. The proxy problem: child report versus parent report in health-related quality of life research. Qual Life Res 1998;7:387–97.
Glaucoma Service, Ophthalmology Department, University of S?o Paulo, Brazil
Dr R M Vessani
Rua Itambé 422, apt 52, S?o Paulo, S?o Paulo, Brazil; email@example.com
Accepted for publication 1 April 2005
Aim: To compare the results of the water drinking test between glaucomatous eyes with and without visual field progression.
Methods: Retrospective analysis of 76 eyes of 76 open angle glaucoma patients followed for a mean period of 26.0 (SD 13.8) months. Patients were submitted to the water drinking test at the beginning of the follow up period. Reliable achromatic automated perimetry tests performed during the studied period were used to characterise visual field progression. All subjects were under clinical therapy and had an intraocular pressure (IOP) lower than 17 mm Hg monitored by isolated measurements during the follow up period. The results of the water drinking test were compared between glaucomatous eyes with and without visual field progression.
Results: Twenty eight eyes reached definite visual field progression. There were no significant differences in the mean age, sex, race, basal IOP, number of antiglaucomatous drugs, initial mean deviation (MD), and corrected pattern standard deviation (CPSD) between eyes that showed visual field progression and the ones who did not progress. A significant difference of 1.9 (SD 0.6) mm Hg (p = 0.001, analysis of covariance; 95% CI 0.8 to 3.0) was observed between glaucomatous eyes that showed visual field deterioration and glaucomatous eyes that did not progress. A significant difference of 16.8% (SD 4.6%) in the mean percentage of IOP variation was also observed between the two groups (p<0.001, analysis of covariance; 95% CI 7.7 to 26.0).
Conclusions: Mean IOP peak and percentage of IOP variation during water drinking test were significantly higher in patients with visual field progression compared with patients who did not progress.
Abbreviations: CPSD, corrected pattern standard deviation; IOP, intraocular pressure
Keywords: intraocular pressure; diurnal tension curve; glaucoma; visual field progression; water drinking test
Increased intraocular pressure (IOP) is the main risk factor for the development of glaucoma and its progression.1 Lowering IOP is believed to be beneficial in slowing down glaucomatous changes of the optic nerves and visual field.2–4 However, reduction of IOP to a preselected level does not always prevent deterioration.5–7 Factors independent of IOP may be responsible, in part, for the sustained progression of glaucoma8 but it has been suggested that in some cases the progressive damage could be caused by peaks of IOP or diurnal IOP variability not detected by tonometry during office hours.9–12
A diurnal IOP curve gives a better estimate of an individual’s IOP level and fluctuations than a single measurement during the office visit, but demands hospital admission where IOP is measured over 24 hours.10 Some authors have demonstrated "home tonometry" as another form to obtain 24 hour IOP data;11–13 however, this kind of monitoring is demanding and may be susceptible to bias.
Many studies have been aimed at finding some way of predicting the peak diurnal IOP. The water drinking test was considered to have an inadequate diagnostic value in the past14,15 but it has been proposed as a practical method to predict the IOP peak of the diurnal tension curve. Previous studies observed a correlation between the IOP peak in the diurnal tension curve and in the water drinking test.16,17 This test may be used to access the efficacy of different forms of IOP reduction (clinical or surgical).17,18
To study the risk associated with diurnal IOP variations in patients with open angle glaucoma, we evaluated the water drinking test performance in open angle glaucoma eyes before a longitudinal follow up with periodic visual field examinations.
One hundred and eighty patients with diagnosis of open angle glaucoma who were submitted to the water drinking test between January 1998 and December 2003 had their charts reviewed. Patients were selected based on inclusion and exclusion criteria. One eye of each patient was included in this study. If both eyes of the same patient were eligible, one was randomly selected.
All included eyes had a corrected visual acuity of 20/40 or better during the entire period of the study, spherical refraction within plus or minus 5.00 dioptres, and cylinder correction within plus or minus 3.00 dioptres. Eyes with closed or narrow angles at gonioscopy exam were excluded. Patients submitted to any surgical procedure or laser intervention during the evaluation period and patients with retinal disease, non-glaucomatous optic neuropathy, or any other disease that could interfere with visual field testing were also excluded.
Eyes with open angle glaucoma had to present an open angle at gonioscopy and a glaucomatous optic disk associated with reproducible glaucomatous visual field defect based on Anderson’s criteria.19 Visual field defect was defined by the presence of a cluster of three or more non-edge points that have sensitivities with p<5% and one of the points has a sensitivity with p<1% or corrected pattern standard deviation (CPSD) value with p<5% or glaucoma hemifield test (GHT) outside normal limits.
All subjects were under clinical therapy and had IOP lower than 17 mm Hg monitored by isolated measurements during the follow up period.
Patients were submitted to the water drinking test at the beginning of the follow up period. The water drinking test was performed after obtaining a baseline IOP measurement. Patients had to drink one litre of tap water in 5 minutes. IOP was measured three times at 15 minutes intervals. Water drinking tests were performed between 4:00pm and 5:00pm. The maximum value of the three measurements was considered as the maximum IOP during the water drinking test.
IOP measurements were obtained with Goldmann applanation tonometry. Achromatic perimetry was performed with the Humphrey Visual Field Analyser (Humphrey Instruments, San Leandro, CA, USA) standard full threshold 24-2). All patients had previous experience with visual field tests and only eyes with reliable exams (less than 20% of fixation losses, and/or less than 33% of false positive and false negative rates) were included. The last reliable visual field exam performed before the evaluated period was considered as the baseline exam. The method adopted to evaluate visual field progression was based on Anderson’s progression criteria20 and was characterised by the rise of a new defect or worsening of a previous defect. A new defect was defined by the presence of a new cluster of three or more non-edge points that have sensitivities with p<5% with one of the points having a sensitivity with p<1%. Worsening of a previously defective region was characterised by the deterioration of three or more points in that region by 10 db.
The end point for the eyes with visual field progression was considered the day of confirmation of the visual field deterioration. For the patients without visual field progression the last visual field exam performed during the evaluated period was considered the end point.
The number of eyes that developed visual field progression was determined. The performance of the water drinking test was compared between the eyes that developed visual field deterioration and those that did not.
Statistical analysis was performed with commercial software (SPSS 10.0, SPSS Inc, Chicago, IL, USA). Analysis of variance and 2 test were used to compare, respectively, continuous and categorical demographic data between groups. The data included mean age, sex, ethnical group, basal IOP, number of antiglaucomatous drugs, initial mean deviation (MD) and correct pattern standard deviation (CPSD), period of follow up, and numbers of visual fields exams. Intraocular pressure peak and percentage of IOP fluctuation (intraocular pressure peak–baseline IOP/baseline IOP) during the water drinking test were evaluated in all eyes by analysis of covariance with initial IOP as a covariate.
Seventy six eyes of 76 patients were included in this study. Demographic data are presented in table 1. The mean age of all participants was 67.1 (SD 11.8) years. Thirty five (46.1%) patients were women. The majority of subjects were White (88.2%). The mean follow up period of all subjects was 26.0 (SD 13.8) months (5–67 months).
Table 1 Demographic data of open angle glaucoma eyes with and without visual field deterioration
Twenty eight (36.8%) eyes reached definite visual field progression based on the study criteria. No significant differences were found in the mean follow up time and the number of visual field exams performed between eyes with and without visual field deterioration (table 1). Similarly, no significant difference in the mean age, sex, race, basal IOP, initial MD, and CPSD was observed between groups (table 1).
From a overall baseline of 12.7 mm Hg, a mean (standard error of the mean) difference of 1.9 (SEM 0.6) mm Hg in the mean IOP peak was observed between glaucomatous eyes that showed visual field progression and the ones that did not. This difference was significant (p = 0.001, ANCOVA; 95% CI 0.8 to 3.0) (see table 2).
Table 2 Water drinking test results: IOP peaks and percentage of IOP fluctuations
In the same way, a difference of 16.8% (SEM 4.6%) in the mean percentage of IOP variation was observed between glaucomatous eyes which showed visual field deterioration and the ones that did not progress. This difference was also considered significant (p<0.001, ANCOVA; 95% CI 7.7 to 26.0).
The mean (standard deviation) number of antiglaucomatous drugs used in the eyes that demonstrated visual field progression was 2.4 (SD 1.4) compared with 2.1 (SD 1.3) in the non-progressive group (p = 0.42). Prostaglandins were part of the clinical treatment in 15 (53.6%) of the 28 eyes that showed visual field progression and in 32 (66.7%) of the 48 eyes that remained stable (p = 0.26). No significant difference was observed in the number of eyes using beta blockers, carbonic anhydrase inhibitors, and alpha agonists between the two groups (table 3). The number of eyes submitted to glaucoma surgery (trabeculectomy) before the studied period was seven (25%) in the progressive group and 12 (25%) in the non-progressive group (p = 0.84).
Table 3 Percentage of eyes under each major kind of topical antiglaucoma drugs
Among eyes that reached definite visual field progression, 25% (7/28) showed IOP >21 mm Hg during the water drinking test compared with 4.2% (2/48) observed in the group that remained stable (p = 0.007). In this group, four of 48 (8.3%) eyes had an IOP variation 6 mm Hg in the water drinking test compared with 35.7% (10/28) of eyes that demonstrated visual field progression (p = 0.003).
The water drinking test is a provocative test that was widely used a few decades ago to help in the diagnosis of open angle glaucoma,15,16 but was found to be inadequate due to many false positive and false negative results in 10 year prospective studies.15 However, after some years, the emphasis on the value of this test has changed. As a result of the correlation with the diurnal tensional curve,16 the water drinking test has been proposed as an alternative method to check IOP control.
In this study we performed the water drinking test in glaucomatous eyes with an IOP lower than 17 mm Hg under clinical and/or surgical therapy. Our findings revealed a significant difference in the results of the water drinking test between eyes that showed glaucoma progression compared with eyes that remained stable.
Previous studies had already suggested the importance of the water drinking test to determine a risk factor for the development of glaucomatous visual field defect. In the 1980s, based on a large prospective study (Collaborative Glaucoma Study), Armaly and coworkers21,22 reported the pressure change after drinking water as one of five potential risk factors significantly related to the development of glaucomatous visual field defects in patients with ocular hypertension.
Another study performed by Yoshikawa et al23 in normal tension glaucoma patients showed that the maximum IOP levels after the water drinking test in patients with progressive visual field loss was significantly greater than the levels observed for the non-progressive group. Unlike their study, we also included open angle glaucoma patients with an IOP higher than 21 mm Hg at the time of diagnosis. In agreement with their results, we observed a difference of almost 2 mm Hg in the IOP peak during the water drinking test between eyes that progressed and the ones that did not. In addition, more eyes with IOP peaks higher than 21 mm Hg during the water drinking test were observed in the progressive group.
The importance of IOP peaks in the development of glaucoma progression has been already reported by Zeimer et al11 and also by Martinez-Belló et al.24 In our study, we did not observe a difference in the mean basal IOP obtained during isolated office visits between the two groups, but our results revealed that the percentage of IOP variation during the water drinking test in eyes with visual field progression was almost twice the value observed in the other group.
Despite the results obtained by our study and previous reports, the mechanisms involved in the water drinking test are not completely understood. After drinking water or any hypotonic fluid, there is absorption of water into blood and body tissues including the eye. This is associated with a consequent rise in IOP. The ability of the eye to recover from this transient IOP rise depends on the outflow facility. The rapid inflow of aqueous humour and the low facility of outflow in the glaucomatous eye may lead, at least in part, to larger IOP fluctuation.
Recently, Brubaker25 proposed that the water drinking test could be used as an indirect measurement of outflow facility to compare the IOP responses of glaucoma eyes to different drugs. Drugs such as prostaglandins improve the outflow facility and are expected to show less IOP variation secondary to water challenge. Although eyes were under different hypotensive medication regimen in this study, no significant difference in the frequency of prostaglandins as part of the clinical treatment was observed between the two groups. The presence or not of any filtration surgery should also be considered when comparing water drinking test results between eyes. Earlier studies already showed a relatively small range of diurnal IOP variation in trabeculectomised eyes.17,26 In our study no significant difference in the number of eyes submitted to glaucoma surgery (trabeculectomy) before the studied period was found between the progressive group and the non-progressive group, reducing possible bias.
This study may be vulnerable to some other biases related to a retrospective analysis. Although no significant difference was found in the number of visual fields performed between eyes that progressed and the ones that remained stable, visual field examination was not performed at the same intervals in all patients. Despite this, no significant difference between groups was found in other baseline variables that could possibly influence the outcome parameters of the water drinking test.
In this study we did not try identify which value of IOP peak or IOP variation would suggest a higher risk of progression. Cutoffs may not be useful when evaluating water drinking test results to assess the risk of progression for all individuals. Each result of the water drinking test may provide important information when evaluating treatment efficacy for a specific patient once the clinician has established the target pressure.
In summary, the water drinking test is a low cost and feasible test and may reflect one of the important and common disturbances to steady state IOP during a common activity of daily living: drinking water.25 Our findings suggest that the emphasis on the value of the water drinking test should be changed. It may be useful as a complementary exam to check IOP control in the clinical practice. The peak and percentage of IOP variation of this test should be considered when analysing risk factors for glaucoma progression. Future randomised controlled longitudinal studies may give a better evaluation of this possibility.
Liu JH. Diurnal measurement of intraocular pressure. J Glaucoma 2001;10:S39–41.
The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Ophthalmol 2000;130:429–40.
The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 1998;126:498–505.
Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003;121:48–56.
Kass MA, Kolker AE, Becker B. Prognostic factors in glaucomatous visual field loss. Arch Ophthalmol 1976;94:1274–6.
Werner EB, Drance SM. Progression of glaucomatous field defects despite successful filtration. Can J Ophthalmol 1977;12:275–80.
Chauhan BC, Drance SM. The relationship between intraocular pressure and visual field progression in glaucoma. Graefes Arch Clin Exp Ophthalmol 1992;230:521–6.
Brubaker RF. Delayed functional loss in glaucoma. LII Edward Jackson Memorial Lecture. Am J Ophthalmol 1996;121:473–83.
Zeimer R. Circadian variations in intraocular pressure. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas. St Louis: CV Mosby Co, 1996.
Hughes E, Spry P, Diamond J. 24-hour monitoring of intraocular pressure in glaucoma management: a retrospective review. J Glaucoma 2003;12:232–6.
Zeimer RC, Wilensky JT, Gieser DK, et al. Association between intraocular pressure peaks and progression of visual field loss. Ophthalmology 1991;98:64–9.
Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma 2000;9:134–42.
Zeimer RC, Wilensky JT, Gieser DK, et al. Application of a self-tonometer to home tonometry. Arch Ophthalmol 1986;104:49–53.
Rasmussen KE, Jorgensen HA. Diagnostic value of the water drinking test in early detection of simple glaucoma. Acta Ophthalmol (Copenh) 1976;54:160–6.
Roth JA. Inadequate diagnostic value of the water-drinking test. Br J Ophthalmol 1974;58:55–61.
Miller D. The relationship between diurnal tension variation and the water-drinking test. Am J Ophthalmol 1964;58:243–6.
Medeiros FA, Pinheiro A, Moura FC, et al. Intraocular pressure fluctuations in medical versus surgically treated glaucomatous patients. J Ocul Pharmacol Ther 2002;18:489–98.
Frankelson EN. The role of the water test in evaluation of glaucoma control. Can J Ophthalmol 1974;9:408–10.
Anderson DR. Automated Static Perimetry. St Louis: Mosby-Year Book, 1992.
Anderson DR. Automated Static Perimetry. Second Edition. St Louis: Mosby-Year Book, 1999.
Armaly MF. Lessons to be learned from the Collaborative Glaucoma Study. Surv Ophthalmol 1980;25:139–44.
Armaly MF, Krueger DE, Maunder L, et al. Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual-field defects. Arch Ophthalmol 1980;98:2163–71.
Yoshikawa K, Inoue T, Inoue Y. Normal tension glaucoma: the value of predictive tests. Acta Ophthalmol (Copenh) 1993;71:463–70.
Martinez-Bello C, Chauhan BC, Nicolela MT, et al. Intraocular pressure and progression of glaucomatous visual field loss. Am J Ophthalmol 2000;129:302–8.
Brubaker RF. Importance of outflow facility. IGR 2001;3:1.
Saiz A, Alcuaz A, Maquet JA, et al. Pressure-curve variations after trabeculectomy for chronic primary open-angle glaucoma. Ophthalmic Surg 1990;21:799–801.
The National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
Dr Sarah Cooper
The National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; firstname.lastname@example.org
Accepted for publication 15 July 2005
Background: The Heidenhain variant of sporadic Creutzfeldt-Jakob disease (sCJD) is commonly understood to represent cases with early, prominent visual complaints. The term is clarified to represent those who present with isolated visual symptoms. This group may pose diagnostic difficulties and often present to ophthalmologists where they may undergo needless invasive procedures.
Method: A retrospective review of 594 pathologically proved sCJD cases referred to the UK National CJD Surveillance Unit over a 15 year period to identify Heidenhain cases.
Results: 22 cases had isolated visual symptoms at onset with a mean illness duration of 4 months. The mean age at disease onset was 67 years. Most displayed myoclonus, pyramidal signs, and a delay in the onset of dementia for some weeks. 17 (77%) were referred initially to ophthalmology. Two underwent cataract extraction before diagnosis. All tested cases were homozygous for methionine at codon 129 of the prion protein gene.
Conclusions: This rare, but clinically distinct, group of patients with sCJD may cause diagnostic difficulties. Because ocular intervention carries with it the risk of onward transmission awareness of this condition among ophthalmologists is important.
Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging; NCJDSU, National CJD Surveillance Unit; sCJD, sporadic Creutzfeldt-Jakob disease
Keywords: Creutzfeldt-Jakob disease; visual loss; Heidenhain variant
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare and uniformly fatal prion disease classically presenting as a rapidly progressive dementia resulting in death usually within 6 months.1,2
A subgroup of cases of sCJD present with isolated visual symptoms. These can persist in the absence of cognitive decline for some weeks.3 Historically, these are termed the "Heidenhain variant" of sCJD after work by Heidenhain in 1929.4 He described three cases of spongiform encephalopathy, two of which had prominent, early visual symptoms. The third presented with sensory complaints and athetosis. Meyer et al described, in 1954, the case of a 38 year old man who "became forgetful, experienced difficulty in concentrating...suffered from headaches and his vision began to fail." A right homonymous hemianopia was detected and death occurred 6 months after the onset of symptoms.5
Subsequently, the term has been used rather imprecisely in all cases where visual symptoms occur along with otherwise characteristic early features. Visual symptoms are common in sCJD and, in the early stages of the disease, have been described in 20%.6 This study seeks to clarify Heidenhain cases as a clinically distinct group where visual symptoms occur initially in isolation. These cases may cause diagnostic difficulty and raise particular public health concerns. They are likely to present to ophthalmologists and may be subject to needless ocular intervention, with risks of onward transmission.
MATERIALS AND METHODS
A retrospective case file review was performed on all pathologically proved cases of sCJD referred to the UK National CJD Surveillance Unit (NCJDSU) between January 1990 and March 2005 inclusive. Case files comprised clinical and epidemiological information collected by NCJDSU staff and copies of hospital and general practitioner records. A clinical assessment and interview with patients’ relatives was conducted by a surveillance neurologist whenever possible and usually while the patient was alive. Electroencephalogram (EEG) recordings and magnetic resonance brain imaging (MRI) were reviewed at the NCJDSU.
Cases were identified whose first symptom was visual and who exhibited no other cognitive, behavioural, or physical symptoms for at least 2 weeks. The presence or absence of cognitive decline was assessed by a review of case files, including a detailed discussion with relatives and a questionnaire completed by the NCJDSU neurologist. Patients were excluded if there were any memory difficulties, behavioural changes, episodes of confusion or disorientation, speech problems, or other neurological symptoms or signs within 2 weeks of the first symptom. Cases were identified on a clinical basis without awareness of PRNP codon 129 genotype data. Genetic analysis was performed with informed consent of the patient or the next of kin.
Twenty two patients out of 594 (3.7%) with pathologically proved sCJD had clearly documented purely visual symptoms for at least the first 2 weeks of the illness. The nature of these initial symptoms is summarised in table 1.
Table 1 Visual symptoms at onset (n = 22)
Fourteen (64%) cases were women. Mean age at onset was 67 years (median 66 years, range 50–88 years). Mean duration of illness was 4 months (median 3 months, range 1–17 months). Seventeen patients (77%) lived for 3 months or less.
Throughout the illness myoclonus was observed in 21 (95%), pyramidal signs in 19 (86%), cerebellar signs in 12 (55%), psychiatric symptoms in seven (32%), other involuntary movements in six (27%), sensory symptoms in four (18%), and extrapyramidal signs in one (5%). None had documented seizures. A rapidly progressive dementia was observed in all after the initial period of cognitive preservation which lasted from 2–6 weeks.
A 73 year old man complained of difficulty reading, with blank spaces appearing in words. He also complained of colours appearing abnormally enhanced. He was assessed by an ophthalmologist when there was normal visual acuity but dense scotomata lying to the right of fixation bilaterally. A provisional diagnosis of an occipital infarct was made. Six weeks after onset he developed myoclonus, followed by ataxia and ultimately dementia. His vision deteriorated with oculomotor apraxia and cortical blindness. He died 3 months after disease onset.
A 62 year old woman presented with deteriorating visual acuity. She felt that her vision was "fogging up" and complained of tunnel vision. She attended an optician but no abnormality was identified. A week later she complained that everything appeared green. An MRI brain scan was ordered following referral to the ophthalmology department but no diagnosis made. Over the next month her gait became unsteady and she was increasingly forgetful. By the time she developed myoclonus she could only perceive light. She died in an akinetic and mute state 4 months after onset.
Twenty patients had at least one EEG. These were considered typical for sCJD1 after review at the NCJDSU in seven cases (35%). CSF 14-3-3 was analysed in five patients (positive in all). Cerebral MRI was available for review in only six cases, showing high signal in the basal ganglia in two (33%) and being normal in four. Sixteen cases (73%) had PRNP gene codon 129 genotype data. All of these were homozygous for methionine. In nine the glycotype was known and was type 1 in all.1
Seventeen patients (77%) were initially referred to the ophthalmology department. Two underwent cataract extraction after the onset of symptoms and before a diagnosis of sCJD. Thirteen (59%) were referred to the NCJDSU within 2 months of onset. Three cases were referred after death, one of these after a necropsy revealed sCJD.
Although visual symptoms in sCJD are not uncommon they often occur in the context of symptoms indicative of a more widespread cortical involvement. These cases are distinct because of the isolated visual symptoms at onset and the striking early preservation of cognitive function. Aside from the onset the cases are remarkably "typical" for sCJD. The majority display an extremely rapid decline with associated myoclonus once dementia has supervened. Nearly 60% of these patients were referred to the NCJDSU within 2 months of onset and only one case was referred as a result of diagnosis at necropsy (compared to 19% of total cases of sCJD referred in this way7). Two cases underwent cataract extraction before the diagnosis of sCJD was considered. Previous work has highlighted the incidence of ocular surgery in sCJD cases with visual symptoms8. Although there have not been any reports of CJD transmission following cataract surgery, it has been reported after corneal grafting. Abnormal prion protein has been isolated from ocular tissue.9 It is important that ophthalmologists are aware of the condition despite its rarity as onward transmission through ocular surgical intervention remains a concern.
All tested cases were homozygous for methionine at codon 129 of the PRNP gene. This genotype is associated with a clinically typical disease course10 rather than isolated visual symptoms themselves. The methodology in this study differs from that previously employed as unselected, consecutive cases from surveillance in one country were obtained by applying a careful definition of a "Heidenhain" case. We have shown that 22 cases have been identified over 15 years out of a population of approximately 58 million in the United Kingdom. The more defined inclusion criteria for visual onset cases used here compared to those employed in the past6 may have identified a distinct subgroup of cases as reflected in the genotype findings.
Defining a group of cases with isolated visual symptoms at onset may aid future recognition of similar cases. By clarifying the definition of Heidenhain cases we have identified a group who generally exhibit short illness duration, myoclonus, and a PRNP codon 129 MM genotype. As well as aiding diagnosis these findings may contribute to the understanding of the how abnormal prion protein causes disease within the central nervous system.
We would like to thank the referring clinicians and the patients and relatives of patients with CJD for their assistance with the surveillance work.
Knight R, Collins S. Human prion diseases: cause, clinical and diagnostic aspects. In: Rabenau HF, Cinatl J, Doerr HW, eds. Prions. a challenge for science, medicine and public health systems. Basle: Karger, 2001;68–92,.
Brown P, Cathala F, Sadowsky D, et al. Creutzfeldt-Jakob disease in France: II. Clinical characteristics of 124 consecutive verified cases during the decade 1968–1977. Ann Neurol 1979;6:430–7.
Vargas ME, Kupersmith MJ, Savino PJ, et al. Homonymous field defect as the first manifestation of Creutzfeldt-Jakob disease. Am J Ophthalmol 1995;119:497–504.
Heidenhain A. Klinische und anatomische Untersuchungen über eine eigenartige organische Erkrankung des Zentralnervensystems im Praesenium. Zeitschrift für die gesamte Neurologie und Psychiatrie 1928;118:49–114.
Meyer A, Leigh D, Bagg CE. A rare presenile dementia associated with cortical blindness (Heidenhain’s syndrome). J Neurol Neurosurg Psychiatry 1954;17:129–33.
Kropp S, Schulz-Schaeffer WJ, Finkenstaedt M, et al. The Heidenhain variant of Creutzfeldt-Jakob disease. Arch Neurol 1999;56:55–61.
National UK Creutzfeldt-Jakob Disease Surveillance Unit. 2005. Unpublished work.
S-Juan P, Ward HJT, De Silva R, et al. Ophthalmic surgery and Creutzfeldt-Jakob disease. Br J Ophthalmol 2004;88:446–9.
Head MW, Northcott V, Rennison KA, et al. Prion protein accumulation in eyes of patients with sporadic and variant Creutzfeldt Jakob disease. Invest Ophthalmol Vis Sci 2003;44:342–6.
Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224–33.
1 The Eye Institute at Alexandra Hospital, National Healthcare Group, Singapore, The Eye Institute at Tan Tock Seng Hospital, National Healthcare Group, Singapore, Department of Ophthalmology, National Univeristy of Singapore, Singapore, Singapore Eye Research Institute, Singapore
2 The Eye Institute at Tan Tock Seng Hospital, National Healthcare Group, Singapore
3 Aravind Eye Hospitals, Pondicherry, India
4 Lions Aravind Institute of Community Ophthalmology, Modurai, India
5 Hauser-Ross Eye Institute, Sycamore, IL, USA
6 Academic Department of Anaesthesia, The James Cook University Hospital, UK
Dr Kah-Guan Au Eong
Alexandra Hospital 378 Alexandra Road Singapore, Singapore 159964; email@example.com
Accepted for publication 13 May 2005
Keywords: cataract; intraoperative visual experiences
We read with interest Zia et al’s article, which highlights a professional artist’s and a poet’s respective renditions of their visual experiences during phacoemulsification and intraocular lens implantation under local anaesthesia.1 While it is unclear from the report whether the artist’s elaborate drawing resembling a "colourful monkey" was associated with a pleasant or frightening visual experience, it appears from the poem that the poet’s visual experience was most probably pleasant and delightful.
We have previously reported that the visual experience during cataract surgery under local anaesthesia can be frightening in up to 16.2% of patients.2–8 The anxiety that may result from the intraoperative visual experience is clinically significant because it may cause patients to become uncooperative during the procedure and trigger a sympathetic stress response. This may result in hypertension, tachycardia, ischaemic strain on the heart, hyperventilation, and acute panic attacks. These stress responses are particularly undesirable in cataract patients who are often elderly, with systemic co-morbidities such as hypertension and ischaemic heart disease.2,9 The frightening experience may also lower patients’ satisfaction with the surgery.10,11
The poet’s experience reported by Zia et al reminds us that the intraoperative visual experience during cataract surgery can be pleasant for some patients.1 In fact, our experience has shown that the majority of patients find their visual experiences pleasant and, in some cases, the visual experience actually increases their satisfaction with the surgery. In a recently reported randomised controlled trial conducted in India involving 304 patients who underwent phacoemulsification under either topical anaesthesia (TA) or retrobulbar anaesthesia (RA), the visual experience was reported by 106 out of 154 (68.8%) TA and 102 out of 150 (68%) RA patients to be pleasant and by 47 (30.5%) TA and 46 (30.7%) RA patients to be unpleasant.12 In a separate unpublished study conducted in Singapore, eight of 98 patients (8.2%) who had phacoemulsification under TA reported that their satisfaction with the surgery increased because of their visual experiences, whereas only two patients (2.0%) experienced a decrease in satisfaction. The remaining 88 patients (89.8%) reported that their visual experience did not affect their satisfaction with the surgery. Some of the patients who found their visual experiences pleasant commented on the "fantastic colours" that they experienced. In another similar study on patients who had cataract surgery under RA, nine of 152 patients (5.9%) experienced an increase in satisfaction, whereas five patients (3.3%) thought that their satisfaction had decreased as a result of the visual experiences and the remaining 138 patients (90.8%) experienced no change in their satisfaction.
An additional observation is from videotaped interviews conducted by one of us (CMK) with several leading ophthalmic anaesthesia providers in the United States who had cataract surgery under local anaesthesia themselves. The video recordings were made during the annual scientific meeting of the Ophthalmic Anaesthesia Society held in Chicago in October 2004. The videos clearly showed they reported seeing pleasant and beautiful images during their surgery.
In summary, patients may experience pleasant or unpleasant visual sensations during cataract surgery under local anaesthesia. Further investigation is warranted to help ascertain how we can reduce the possibility of the experience being unpleasant or frightening.
Zia R, Schlichtenbrede FC, Greaves B, et al. "Only rarely seen in dreams"—visual experiences during cataract surgery. Br J Ophthalmol 2005;89:247–8.
Au Eong KG. 6th Yahya Cohen lecture: visual experience during cataract surgery. Ann Acad Med Singapore 2002;31:666–74.
Prasad N, Kumar CM, Patil BB, et al. Subjective visual experience during phacoemulsification cataract surgery under sub-Tenon’s block. Eye 2003;17:407–9.
Au Eong KG. The Royal College of Ophthalmologists cataract surgery guidelines: what can patients see with their operated eye during cataract surgery? Eye 2002;16:109–10.
Au Eong KG, Lim TH, Lee HM, et al. Subjective visual experience during phacoemulsification and intraocular lens implantation using retrobulbar anaesthesia. J Cataract Refract Surg 2000;26:842–6.
Au Eong KG, Low CH, Heng WJ, et al. Subjective visual experience during phacoemulsification and intraocular lens implantation under topical anaesthesia. Ophthalmology 2000;107:248–50.
Au Eong KG, Lee HM, Lim ATH, et al. Subjective visual experience during extracapsular cataract extraction and intraocular lens implantation under retrobulbar anaesthesia. Eye 1999;13:325–8.
Tranos PG, Wickremasinghe SS, Sinclair N, et al. Visual perception during phacoemulsification surgery under topical and regional anaesthesia. Acta Ophthalmol Scand 2003;81:118–22.
Tan CSH, Rengaraj V, Au Eong KG. Visual experiences of cataract surgery. J Cataract Refract Surg 2003;29:1453–4.
Leo SW, Au Eong KG. Comments on anaesthesia for cataract surgery. J Cataract Refract Surg 2003;29:633–5.
Leo SW, Au Eong KG, Rengaraj V, et al. The Misericordia Health Centre cataract comfort study. Can J Ophthalmol 2003;38:23–4.
Rengaraj V, Radhakrishnan M, Au Eong KG, et al. Visual experience during phacoemulsification under topical versus retrobulbar anaesthesia: results of a prospective, randomised, controlled, trial. Am J Ophthalmol 2004;138:641–8.
1 Division of Ophthalmology, University of Bristol, Bristol, UK
2 Department of Ophthalmology, Torbay General Hospital, Torquay, UK
Professor Andrew Dick
Department of Clinical Sciences, University of Bristol, Bristol Eye Hospital, Lower Maudlin Street, Bristol BS1 2LX, UK; firstname.lastname@example.org
Accepted for publication 1 March 2005
Aims: To assess visual function, vision related quality of life (VR-QOL), and general health related quality of life (HR-QOL) in intermediate uveitis (IU).
Methods: VR-QOL and HR-QOL were evaluated in 42 patients with IU using the VCM1 and SF-36 questionnaires, respectively. LogMAR visual acuity (VA), Pelli-Robson contrast sensitivity (CS), Farnsworth-Munsell 100 hue colour vision (CV), and Estermann visual field (VF) were recorded monocularly and binocularly.
Results: Median (interquartile range) visual acuity (VA) and CS of 72 affected eyes were 0.1 (0.015–0.3) and 1.55 (1.35–1.65), respectively. 9.5% of patients had a VCM1 score of more than 2.0, indicating "more than a little" concern over vision. Worse eye VA (p = 0.045) and CS (p = 0.042) were predictive of a VCM1 score of more than 2.0 independently of age, sex, uveitis duration, laterality and activity, systemic uveitis therapy, and medical co-morbidity. The physical and mental component summary scores of the SF-36 were significantly worse in those who reported significant impairment of vision on the VCM1 than those who did not.
Conclusions: The majority of patients with IU maintain good visual function and quality of life. VR-QOL impairment in IU correlates with vision in the worse eye and is associated with impaired HR-QOL.
Abbreviations: BIO score, binocular indirect ophthalmoscopy score; CS, contrast sensitivity; CV, colour vision; HR-QOL, health related quality of life; IU, intermediate uveitis; MCS, mental component summary score; PCS, physical component summary score; SF-36 questionnaire, short form 36 questionnaire; VA, visual acuity; VF, visual field; VR-QOL, vision related quality of life
Keywords: intermediate uveitis; visual function; quality of life; VCM1; SF-36
Intermediate uveitis is a type of chronic relapsing uveitis characterised by vitritis, peripheral retinal vasculitis, cystoid macular oedema, and the absence of significant chorioretinal inflammation. Its impact on visual function and quality of life is not accurately known.
Visual acuity is usually the only measure of visual function routinely tested in uveitis clinics.1 However, considered alone it inadequately describes visual performance, which can be affected by other measures of visual function including colour vision, contrast sensitivity, and visual field. It is becoming increasingly recognised that vision related quality of life (VR-QOL) questionnaires, which measure the global impact of visual impairment on physical, psychological, and social functioning in day to day life, provide an additional and effective means of measuring visual functioning, as has been demonstrated for patients with cataract, glaucoma, macular disease and, more recently, uveitis.2–6 In addition to using VR-QOL instruments to measure the effect of visual impairment on quality of life, generic instruments can be used to measure overall health related quality of life (HR-QOL), such as the short form 36 (SF-36) questionnaire.7
In this study we performed a comprehensive evaluation of the impact of intermediate uveitis on visual functioning by measuring visual acuity, contrast sensitivity, colour vision, and visual field. We explored patients’ perceptions of their vision and health related quality of life and attempted to identify what clinical and demographic factors contributed to their impaired health status. We elected to study intermediate uveitis in this context because it is a clearly defined clinical entity, has a relatively small number of causes, and is more common than most sight threatening uveitis entities.
PATIENTS AND METHODS
In all, 42 consecutive patients with intermediate uveitis attending a specialist uveitis clinic were enrolled in this study between August and December 2002. Two patients who were asked to participate during the study period declined involvement. The diagnosis of intermediate uveitis was based on the presence of vitreous inflammation, inferior vitreous "snowballs" and peripheral retinal vasculitis with or without anterior chamber inflammation, and cystoid macular oedema. Significant chorioretinal inflammation was absent in all cases. After agreeing to participate, patients underwent a detailed interview, quality of life assessment, visual function evaluation and finally clinical examination, in that order. This study was approved by the hospital ethics committee and informed consent was obtained from all patients.
Quality of life assessment
HR-QOL was evaluated using the UK standard version of the SF-36, which consists of 36 items grouped into eight scales to measure health, including physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy/vitality, bodily pain, and general health perception.8 The SF-36 subscale scores range from 0% to 100%, with higher scores indicating better health. General population data for the UK version of the SF-36, which were used for comparison with the intermediate uveitis patients, were derived from the Oxford Healthy Life Survey in which HR-QOL was evaluated in 13 042 randomly selected subjects of working age.9 VR-QOL was measured using the VCM1, a 10 item questionnaire that provides a subjective measure of concern regarding vision with scores ranging from 0.0 (best score) to 5.0 (worst score) with 50 intervals.10 The questionnaires were self administered in approximately 10 minutes. The validity and reliability of the VCM1 and the SF-36 as tools for measuring VR-QOL and HR-QOL in a variety of diseases have been well established.7,11,12
Visual function assessment
Visual acuity (VA), contrast sensitivity (CS), colour vision (CV), and visual field (VF) were assessed wearing usual distance spectacle correction, if any, first monocularly then binocularly. Best corrected logMAR VA scored for individual letters was measured at 4 metres with the ETDRS chart mounted on the Lighthouse Chart Illumination Unit (USA). Pelli-Robson CS was measured as recommended by the manufacturer and under controlled illumination; the screen luminance was 85–120 cd/m2.13 CS was scored letter by letter as this method gives greatest reliability.14 The Esterman test was used to record monocular and binocular VF on the Humphrey field analyser II perimeter.15 The VF was scored using the Esterman efficiency score, which is the percentage of test points correctly seen by the patient. CV was measured using the Farnsworth-Munsell 100 hue test under standard controlled lighting conditions, as described by the manufacturers. Published normal ranges for VA, CS, and CV were used for comparison with the intermediate uveitis patients to qualify the extent of their visual impairment.14,16,17 An Esterman efficiency score of less than 100 was considered abnormal.
In each case, the ocular examination was performed by the same observer (EHH), who was masked to the outcome of the quality of life and visual function assessments and had no knowledge of the patients’ past history. The international uveitis scoring system was used to grade uveitis activity.1 To facilitate comparisons, uveitis was graded as "inactive" if the anterior chamber was 1+ or less and the binocular indirect ophthalmoscopy score (BIO) score was 0, or "active" if more significant inflammation was present. Lens opacities were graded using the LOCS III method.18
To facilitate comparison with age and sex matched general population norms, the SF-36 subscale scores are presented as T scores, which were calculated using means and standard deviations derived from the age and sex matched UK normative data set.8 For T scores, the normative data set has a mean of 50 and a standard deviation of 10 so that patient scores greater than 50 represent better than average quality of life and those below 50 represent worse than average quality of life. The eight domains of the SF-36 were also summarised into the physical component summary score (PCS, derived from the physical functioning, role physical, bodily pain, and general health perception subscales) and the mental component summary score (MCS, derived from the energy/vitality, social functioning, role emotional, and mental health subscales) to reduce the number of SF-36 variables for statistical analysis.19
Statistical analyses were performed using Prism version 3.02 (GraphPad, San Diego, CA, USA) and SPSS version 10.0 for Windows. All tests were two tailed and statistical significance attributed when p<0.05. Patient and normative data were compared using independent t tests. The associations between visual function tests and quality of life scores were examined using Spearman correlation analysis. Logistic regression analysis was used to determine whether the following clinical and demographic variables were predictive of a VCM1 score of more than 2.0: VA, CS, CV, VF, age, sex, medical co-morbidities, and uveitis duration, activity, laterality, and treatment (systemic immunosuppression or not). Systemic co-morbidities were recorded as present or absent, giving equal weight to all systemic conditions. Stepwise multiple linear regression analysis was used to determine the variance of the physical and mental component summary scores resulting from these same clinical and demographic variables.
Clinical and demographic characteristics
The clinical and demographic characteristics of the group are described in table 1. An unusually high percentage of patients had unilateral disease (28.6%). At the time of evaluation 27 (64.3%) patients were taking systemic corticosteroids and/or immunosuppressive agents and, in the past, 33 (78.6%) had required systemic therapy at some time to control their intraocular inflammation. Uveitis was inactive (anterior chamber cells +1 or less and BIO score zero in the absence of other signs of posterior segment activity) in 29 (69%) patients. Clinical signs of activity that were present were cystoid macular oedema in 11 (15.3%) eyes and BIO score of 2 or more in 12 (16.7%) eyes. Table 2 indicates the frequency of sight threatening clinical features and the probable causes of visual impairment. Two patients had snow banking suggesting pars planitis. None of the patients had any ocular pathology unrelated to uveitis.
Table 1 Clinical and demographic characteristics
Table 2 Frequency of sight threatening clinical features
Effect of intermediate uveitis on visual function
Table 3 describes the VA, CS, CV, and VF of this intermediate uveitis cohort. VA was 0.3 logMAR (equivalent to 20/40) or better in 77.8% of affected eyes. Three (7.1%) patients had unilateral legal blindness, as defined in the United States as a VA of less than 1.0 logMAR (equivalent to 20/200) in the worse eye.20 Nine (21.4%) patients had unilateral visual impairment, defined as a logMAR equal to or less than 0.5 (equivalent to 20/63) in their worse eye.21 VA, CS, CV, and VF were worse than published normal standards for this age group in 33 (45.8%), 33 (45.8%), 23 (31.9%), and 54 (75.0%) affected eyes (n = 72), respectively.14,16,17 As shown in table 4, significant correlations were found between all of the visual function tests. The closest association was found for VA and CS (R = –0.69, p<0.0001). Longer duration of disease was associated with worse VA (Spearman r = 0.512, p<0.0001) but not worse VR-QOL.
Table 3 Outcome of the visual function tests
Table 4 Visual function test correlation matrix (n = 72 eyes)
Vision related quality of life
The median (interquartile range) VCM1 score was 0.8 (0.5–1.4). As shown in figure 1, 9.5% of patients had a VCM1 score of more than 2.0, which represents "more than a little" concern about vision.11 The VCM1 correlated with worse eye VA, worse eye VF, and binocular VF but did not correlate with any of the better eye visual function tests, as shown in table 3. In the logistic regression analysis, worse eye VA (p = 0.045) and worse eye CS (p = 0.042) were predictive of a VCM1 score of more than 2.0 independently of age, sex, uveitis duration, laterality and activity, systemic uveitis therapy, and medical co-morbidity. The other visual function tests, including the better eye and binocular results, were not associated with the VCM1 score in the regression analysis.
Figure 1 Distribution of VCM1 scores.
Health related quality of life
The SF-36 subscales social functioning, general health perception, and pain were significantly worse for the intermediate uveitis patients than the general population in the United Kingdom when matched for age and sex, as shown in table 5 (p = 0.0002, p<0.0001 and p = 0.01, respectively).9 The other SF-36 subscales were similar to the general population. In the multivariate regression analysis, the PCS and MCS were not associated with age, sex, uveitis duration, treatment, laterality or activity, the presence of systemic co-morbidity, or any of the measures of visual function. However, the VCM1 was predictive of the MCS score after adjusting for the above variables (R2 = 0.26, p = 0.001). The VCM1 did not have significant predictive value with regard to the PCS score.
Table 5 SF-36 subscale T scores for the intermediate uveitis patients and the age and sex matched general population in the United Kingdom
Table 6 indicates the correlations between the SF-36 subscales and the visual function tests and VCM1. Significant correlations were found between the VCM1 and all of the SF-36 scales (r = –0.39 to –0.68, p<0.05 for all). Correlations between the visual function tests and the SF-36 subscales were mostly not significant and as with the VCM1, better eye visual function had no correlation with the SF-36 subscale scores. Notably, however, worse binocular VF was associated with worse SF-36 scores across all subscales except role emotional, general health perception, and the physical component summary score. Patients who expressed "more than a little" concern over their vision (VCM1 score >2.0) had significantly worse PCS and MCS scores than patients who had expressed little or no concern over their vision (VCM1<2.1), as shown in figure 2.
Table 6 Correlation between the VCM1 visual function tests, and SF-36 subscale measures
Figure 2 PCS scores (A) and MCS scores (B) for patients with (VCM1 >2.0) and without (VCM1 2.0) "more than a little" concern over their vision.
This study explored the impact of intermediate uveitis on visual performance and self reported vision and health related quality of life. Despite the severe disease in this cohort, reflected by the need for systemic immunotherapy in the past in almost 80% of the patients, over half of the eyes maintained visual acuity and contrast sensitivity of 0.1 logMAR (equivalent to 20/25) and 1.55 log units or better, the lower limits of normal.14,16 Furthermore, only two (4.7%) patients had a VA of worse than 0.3 logMAR (equivalent to 20/40) in their better eye, the minimum required for driving in the United Kingdom, and none of the patients was legally blind. These results compare with those of Rothova et al, who described the prevalence and severity of visual impairment in a cohort of 78 patients with intermediate uveitis as part of a large retrospective analysis of visual loss in uveitis.21
This is the first study to our knowledge to describe colour vision and visual field performance in intermediate uveitis. Colour vision was the least affected of the four measures of visual function; it was recorded as normal in over two thirds of uveitic eyes and correlated poorly with the patients’ perceptions of their visual performance as measured with the VCM1. Visual field loss was recorded in three quarters of uveitic eyes by the monocular Esterman visual field test. As previously reported, the most common cause of visual impairment was macular involvement, usually manifested as cystoid macular oedema or as an epiretinal membrane.21
Only 9.5% of the patients reported "more than a little" concern over their vision, suggesting that vision is well preserved in the vast majority of patients with intermediate uveitis. Schiffman et al described vision and health related quality of life in 76 patients with various types of uveitis and concluded that uveitis has a "more pervasive impact on VR-QOL than does age related macular degeneration."4 Only 22% of their cohort had intermediate uveitis and it is likely that the greater visual impairment recorded in their series compared with the present study resulted from the greater proportion of patients with posterior and panuveitis.
Worse eye VA and CS were predictive of the VCM1 score after adjusting for other clinical and demographic variables and significant correlations were found between the VCM1 and the worse eye VA and VF but not the better eye results. This contrasts with the usual finding that VR-QOL is more closely associated with the better eye VA, as reported for cataract, age related macular degeneration, and patients awaiting a corneal graft.22–24 Gardiner et al used the VCM1 to evaluate visual performance in a group of 132 patients with various types of uveitis and found that worse eye, better eye and binocular high contrast VA correlated with VR-QOL.5
Although the mean HR-QOL scores of the intermediate uveitis cohort were worse than the age and sex matched population average for all eight domains of the SF-36, this difference only reached significance for the subscales social functioning, general health perception, and pain. In the regression analysis, none of the variance of the physical and mental component summary scores could be attributed to any of the patients’ clinical or demographic characteristics recorded or the clinical measures of visual function. The impact of subjective visual functioning on HR-QOL in intermediate uveitis was confirmed by the significantly worse PCS and MCS scores in patients with a VCM1 score greater than 2.0. Strong correlations between the SF-36 subscales and the VCM1 suggest that vision is the key factor that influences global quality of life in intermediate uveitis.
In conclusion, this study demonstrates that visual function and general health are well maintained in the majority of patients with intermediate uveitis and highlights the impact of impaired vision related quality of life on general health related quality of life in this form of uveitis.
Benezra D , Forrester JV, Nussenblatt RB, et al. Uveitis scoring system. Berlin: Springer-Verlag, 1991:8.
Legro MW. Quality of life and cataracts: a review of patient-centered studies of cataract surgery outcomes. Ophthalmic Surg 1991;22:431–43.
Parrish RK, Gedde SJ, Scott IU, et al. Visual function and quality of life among patients with glaucoma. Arch Ophthalmol 1997;115:1447–55.
Schiffman RM, Jacobson G, Whitcup SM. Visual functioning and general health status in patients with uveitis. Arch Ophthalmol 2001;119:841–9.
Gardiner AM, Armstrong RA, Dunne MC, et al. Correlation between visual function and visual ability in patients with uveitis. Br J Ophthalmol 2002;86:993–6.
Mackenzie PJ, Chang TS, Scott IU, et al. Assessment of vision-related function in patients with age-related macular degeneration Ophthalmology 2002;109:720–9.
Ware JE Jr. SF-36 health survey update. Spine 2000;25:3130–9.
Jenkinson C , Layte R, Wright L, et al. The UK-36: an analysis and interpretation manual. Oxford: Joshua Horgan print partnership, 1996.
Jenkinson C , Coulter A, Wright L. Short form 36 (SF-36) health survey questionnaire: normative data for adults of working age. BMJ 1993;306:1437–40.
Frost NA, Sparrow JM, Durant JS, et al. Development of a questionnaire for measurement of vision-related quality of life. Ophthalmic Epidemiol 1998;5:185–210.
Frost A , Eachus J, Sparrow J, et al. Vision-related quality of life impairment in an elderly UK population: associations with age, sex, social class and material deprivation. Eye 2001;15:739–44.
Frost NA, Sparrow JM, Hopper CD, et al. Reliability of the VCM1 questionnaire when administered by post and by telephone. Ophthalmic Epidemiol 2001;8:1–11.
Pelli DG, Robson JG, Wilkins AJ. The design of a new letter chart for measuring contrast sensitivity. Clin Vis Sci 1988;2:187–99.
Elliott DB, Bullimore MA, Bailey IA. Improving the reiliability of the Pelli-Robson contrast sensitivity test. Clin Vis Sci 1991;6:471–5.
Esterman B . Functional scoring of the binocular field. Ophthalmology 1982;89:1226–34.
Elliott DB, Hurst MA. Simple clinical techniques to evaluate visual function in patients with early cataract Optom Vis Sci 1990;67:822–5.
Verriest G , Van Laethem J, Uvijls A. A new assessment of the normal ranges of the Farnsworth-Munsell 100-hue test scores. Am J Ophthalmol 1982;93:635–42.
Chylack LT Jr. Wolfe JK, Singer DM, et al. The Lens Opacities Classification System III. The Longitudinal Study of Cataract Study Group. Arch Ophthalmol 1993;111:831–6.
Jenkinson C . The SF-36 physical and mental health summary measures: an example of how to interpret scores. J Health Serv Res Policy 1998;3:92–6.
Kraut KA, McCabe CP. The problem of low vision. Definition and common problems. In, Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology Philadelphia, WB Saunders 1994:3664–6.
Rothova A , Suttorp-van Schulten MS, Frits Treffers W, et al. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol 1996;80:332–6.
Steinberg EP, Tielsch JM, Schein O, et al. An index of functional impairment in patients with cataract. Arch Ophthalmol 1994;112:630–8.
Miskala PH, Bressler NM, Meinert CL. Relative contributions of reduced vision and general health to NEI-VFQ scores in patients with neovascular age-related macular degeneration. Arch Ophthalmol 2004;122:758–66.
Boisjoly H , Gresset J, Fontaine N, et al. The VF-14 index of functional visual impairment in candidates for a corneal graft. Am J Ophthalmol 1999;128:38–44.
1 Neuroophthalmology Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
2 Visual Physiology Department, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
MD, Neuro-ophthalmology Service, Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA 19107, USA; email@example.com
Accepted for publication 1 February 2005
Aim: To determine the anatomical site and extent of electrophysiological dysfunction in patients with ethambutol associated visual loss.
Methods: A comparative case series. Four patients with ethambutol associated visual loss underwent multifocal electroretinography (mERG). Two patients had advanced visual loss while two had early signs of toxicity. The N1-P1, N1, P1 amplitudes, N1, and P1 latencies were compared to 10 age and sex matched controls.
Results: mERG abnormalities were detected in the ethambutol treated patients. The N1 amplitude was significantly lower in the ethambutol treated patients than in the control group.
Conclusion: Ethambutol is possibly toxic to the retina, and not only the optic nerve. The multifocal ERG may be of value to diagnose and monitor patients taking ethambutol.
Abbreviations: CT, computed tomography; ERG, electroretinography; MAC, Mycobacteriumavium complex; mERG, multifocal electroretinography; MRI, magnetic resonance imaging; RAPD, relative afferent pupillary defect
Keywords: ethambutol; visual loss; electroretinography
Ethambutol is commonly used for the treatment of tuberculosis and Mycobacteriumavium complex (MAC) infections. It has been associated with optic neuropathy,1,2 colour vision abnormalities, and visual field defects.3–5 Ocular toxicity is dose and duration dependent with the incidence as high as 6% in patients receiving more than 15–25 mg/kg/day.6,7
We used multifocal electroretinography (mERG) to test four patients diagnosed with ethambutol ocular toxicity and compared them to normal age and sex matched control subjects. Our aim was to is investigate whether there is electrophysiological dysfunction at the level of photoreceptors and outer plexiform layer (outer retina). Ethambutol toxicity has so far been associated mainly with optic nerve damage (inner retina).1,2,8
PATIENTS AND METHODS
Multiple retinal areas were stimulated to record local retinal responses with the mERG technique using the Veris 4.8 software (Veris; Electro-Diagnostic Imaging, San Mateo, CA, USA). Fixation was carefully monitored throughout the test procedure. The fixation target was enlarged for subjects who had poor vision. Segments with large eye movements, losses of fixation, or blinks were discarded and re-recorded.
A 60 year old woman presented with complaints of "visual blurring" and "intolerance to bright lights" in both eyes a month after beginning ethambutol (13.65 mg/kg per day) for a recurrent pulmonary MAC infection.
Visual acuity was 20/25 in each eye. She had normal colour vision, and her anterior segment examination was unremarkable. Both pupils were sluggish to direct light stimulation with no relative afferent pupillary defect (RAPD). Fundus examination showed normal discs and maculae. Using the Humphrey10-2 program, an early central defect was found in the right eye and a centrocaecal defect in the left eye. The mERG waveforms were decreased in amplitude in both eyes to pattern stimuli (fig 1)
Figure 1 Trace arrays showing subnormal mERG with decreased amplitudes in the both eyes. In (A) the right eye, and (B) the left eye, there are decreased amplitudes in the central area. The three dimensional topography map shows blunted foveal peaks more in the right (C) than the left eye (D).
Ethambutol was discontinued and 6 months later the visual acuity was 20/20 in each eye, her colour vision was full and her visual fields were normal. Repeated mERG showed a persistent decrease in amplitudes in both eyes with delayed latencies to pattern stimuli (fig 2).
Figure 2 Trace arrays of multifocal ERG in (A) right and (B) left eyes. Amplitudes are diminished centrally more in the right eye than the left eye. The three dimensional topography map shows blunted foveal peaks more in the right (C) than the left eye (D).
An 80 year old woman presented with decreased vision in both eyes for 3 weeks. She was being treated with ethambutol (15 mg/kg per day) for 7 months for a pulmonary MAC infection. Visual acuity was counting fingers in each eye. Examination of the anterior segment was normal. The pupillary light reactions were sluggish bilaterally with a left RAPD. Visual field testing by confrontation showed dense central scotomas bilaterally; visual acuity was too poor for formal visual field testing. She had pale optic nerve heads bilaterally. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain and orbits were normal.
Multifocal ERG results showed diffuse reduction in the amplitudes, especially in the central area (fig 3) She was seen 4 months after discontinuation of ethambutol and her vision had improved to 20/100 right eye and 20/40 left eye. Repeat mERG still showed decreased amplitudes, and diminished foveal peaks. There was no appreciable change compared to the first mERG (fig 4).
Figure 3 Trace arrays of (A) the right eye and (B) left eye show diminished amplitudes especially in the central areas. The topographic (three dimensional) density plots show blunted foveal peaks in the right (C) and the left (D) eye.
Figure 4 Trace arrays of (A) the right eye and (B) the left eye decreased amplitudes centrally. The topographic (three dimensional) density plots show flattened foveal peaks in the right eye (C) and reduced peak in the left eye (D).
A 66 year old man who was diagnosed 5 months earlier with MAC pulmonary infection and was started on ethambutol (15 mg/kg per day) presented with a complaint of "objects looking too bright" and "difficulty of adjusting from bright to dim light conditions." Visual acuity was 20/30 in the right and 20/20 in the left eye. Colour vision was normal in both eyes. Slit lamp examination was unremarkable. The pupils were normal with no RAPD. Fundus examination showed normal discs and maculae. Automated static perimetry (Humphrey 24-2) was normal, but a using a Humphrey 10-2 program, there was one area of depression in the right eye. Full field ERG was normal in both eyes. mERG demonstrated decreased amplitudes and reduced foveal peaks in both eyes to pattern stimuli (fig 5).
Figure 5 Trace arrays of the right eye (A) and left eye (B) showing decreased amplitudes more in the central region of both eyes. The three dimensional topography map shows blunted foveal peaks in the right eye (C) and left eye (D).
A 75 year old woman noticed worsening of vision after undergoing cataract surgery in the left eye. She had been on ethambutol, isoniazid and rifampin for a pulmonary MAC infection. Visual acuity was counting fingers at 2 feet in the right and at 6 feet in the left eye. She identified only the test plates of the Ishihara pseudoisochromatic plates in each eye. Slit lamp examination was unremarkable. The pupils were sluggish to light stimulation without an RAPD. Fundus examination showed mild disc pallor with normal maculae.
Automated static perimetry (Humphrey 10-2 program) showed bilateral central scotomas. mERG showed decreased amplitudes to pattern stimuli (fig 6).
Figure 6 Decreased amplitudes in the central region of the right eye (A) and left eye (B). The three dimensional topography map shows blunting of the foveal peaks in both eyes. (C) Right eye, (D) left eye.
Three months after discontinuation of ethambutol, her vision had improved to 20/60 in the right and 20/50 in the left eye. Colour vision improved to five of 11 colour plates in each eye. The mERG was still abnormal (fig 7).
Figure 7 Four months after the first mERG. The amplitudes are still diminished centrally in both (A) right eye and (B) left eye. The three dimensional map still shows blunting of the foveal peaks. (C) Right eye, (D) left eye.
Using Veris 4.8, first order kernel responses were evaluated for latencies (implicit time) for N1 (first negative trough), P1 (first positive peak); amplitudes N1 (from baseline to the trough of the first negative wave), P1 (from baseline to the peak of the first positive way), and N1-P1 (from the first negative trough to the first positive peak). The responses elicited by the central six hexagons were summated and designated as ring 1 (central 7 degrees, foveal and parafoveal); and the responses from another concentric ring of 16 hexagons were also summated and designated ring 2 (central 10–12 degrees, parafoveal). Because we were looking for a retinal dysfunction in the macular region, we limited the analysis to the responses elicited in those two rings (fig 8). The N1, P1 latencies and the N1-P1, N1, and P1 amplitudes of both eyes were averaged. These were then compared in the ethambutol treated patients to 10 control subjects (six women and four men) with a mean age of 61.5 (SD 5.75) years using the non-parametric Wilcoxon rank sum test. There was no statistically significant difference between the mean age of the control group and the ethambutol treated patients (p = 0.14). Each one of the control group subjects had a visual acuity of 20/30 or better in one or both eye, and a normal neuro-ophthalmic assessment. In addition, none of the control group subjects was taking any medications that could adversely affect retinal function
Figure 8 Diagram showing the two rings we tested with Veris 4.8. Ring 1 comprises the six central hexagons in the central 7 degrees, while ring 2 comprises 16 hexagons located 10–12 degrees from the centre.
The mean N1 amplitude in ring 1 was significantly lower in the ethambutol treated patients than the control group (3.20 versus 9.25 nV/degree 2) (p<0.05) (fig 9). The mean N1-P1 amplitudes, P1 amplitudes, and the mean N1 and P1 latencies in ring 1 were not significantly lower in the ethambutol treated patients compared to the control groups (table 1). There was no significant difference in any of the latencies and the amplitudes in ring 2 between the ethambutol treated patients and the control group (table 2).
Figure 9 A box plot diagram showing the difference in the mean N1 amplitude in the ethambutol treated patients and the control group. Mean amplitude in nV/deg2
Table 1 Responses elicited from ring 1
Table 2 Responses elicited from ring 2
We have demonstrated mERG abnormalities in patients with presumed ethambutol optic neuropathy. These changes are characterised by a decrease in amplitude with predilection for the central areas (macula). Previous studies have found abnormalities in the visual evoked potentials,9 full field ERG and EOG in patients with presumed ethambutol optic neuropathy.10–12 In experiments on fish, ethambutol altered synaptic connections between horizontal cells and cones in a dose related fashion, resulting in degeneration of the cone pedicles.13
In our study, the N1 amplitude was found to be significantly lower in the ethambutol treated patients compared to age matched controls. The source of the multifocal ERG signals, as in full field ERG, is thought to be from the outer retina with very little contribution from the inner retina (ganglion cell layer).14,15 Therefore, for a disease to decrease the amplitude of the mERG, the cone photoreceptors or cone driven bipolar cells must be abnormal. Although there was a statistically significant difference only between the N1 amplitude of the patients and control subjects, it is possible that our patient group comprised patients in various stages of ethambutol toxicity. In fact, when we compared the N1-P1, and P1 amplitudes of patients 2 and 4 (advanced toxicity) with the control group, they were significantly lower (p = <0.05). These two patients, however, were also older than patients 1 and 3. It still is possible though that given enough time, N1-P1 and P1 amplitudes would eventually be affected in the other patients.
Because of the small sample size of this study, it is difficult to reach a definite conclusion about our observations. Although an abnormal mERG can be caused by eccentric fixation, either voluntary (functional visual loss) or because of a small central visual field loss caused by optic atrophy, fixation was meticulously monitored during testing in all patients.
With the resurgence of tuberculosis, especially in the immunocompromised group, and the increasing reports of MAC pulmonary infections even in immunocompetent16,17 and elderly women with no predisposing factors,18 prompt diagnosing of ethambutol toxicity can be important in preventing permanent visual loss. We believe our findings merit re-examining the widely accepted notion that ethambutol causes primarily optic neuropathy. Future studies with a larger sample size are needed to determine the early stages and the natural history of retinal toxicity caused by ethambutol.
Carr RE, Henkind P. Ocular manifestations of ethambutol. Arch Ophthalmol 1962;67:566–71.
Barron GJ, Tepper L, Iovine G. Ocular toxicity from ethambutol. Am J Ophthalmol 1974;77:256–60.
Joubert PH, Strobele JG, Ogle CW, et al. Subclinical impairment of colour vision in patients receiving ethambutol. Br J Clin Pharmacol 1986;21:213–6.
Arruga J. Subjective color desaturation test in the diagnosis of the effects of ethambutol on the anterior optic pathway. Bull Soc Ophtalmol Fr 1982;82:189–92.
Choi SY, Hwang JM. Optic neuropathy associated with ethambutol in Koreans. Korean J Ophthalmol 1997;11:106–10.
Kuumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it reversible? J Clin Neuro-ophthalmol 1993;13:15–17.
Alvarez KL, Krop LC. Ethambutol-induced ocular toxicity revisited. Ann Pharmacother 1993;27:102–3.
Lessell S. Toxic and deficiency optic neuropathies. In: Smith JL, Glaser JS, eds. Neuro-ophthalmology symposium of the University of Miami and the Bascom Palmer Eye Institute. Vol 7. St Louis: CV Mosby, 1973:21–37.
Yiannkias C, Walsh JC, McLeod JG. Visual evoked potentials in the detection of subclinical optic toxic effects secondary to ethambutol. Arch Neurol 1983;40:645–8.
Hennekes R. Clinical ERG findings in ethambutol intoxication. Graefes Arch Clin Exp Ophthalmol 1982;218:319–21.
Kakisu Y, Adachi-Usami E, Mizota A. Pattern electroretinogram and visual evoked cortical potential in ethambutol optic neuropathy. Doc Ophthalmol 1987;67:327–34.
Yen MY, Wang AG, Chiang SC, et al. Ethambutol retinal toxicity: an electrophysiologic study. J Formos Med Assoc 2000;99:630–4.
Kohler K, Zrenner E, Weiler R. Ethambutol alters spinule-type synaptic connections and induces morphologic alterations in the cone pedicles of the fish retina. Invest Ophthalmol Vis Sci 1995;36:1046–55.
Marmor MF, Hood DC, Keating D, et al. Guidelines for basic multifocal electroretinography (mffERG). Doc Ophthalmol 2003;106:105–15.
Hood DC, Odel JG, Chen CS, et al. The multifocal electroretinogram. J Neuroophthalmol 2003;23:225–35.
Bux-Gewher I, Hagan HP, Rusch Gerdes S, et al. Fatal pulmonary infection with Mycobacterium celatum in an apparently immnunocompetent patient. J Clin Microbiol 1998;36:586–9.
Tjhie JHT, Van Belle AF, Dessens-Kroons M, et al. Misidentification and diagnostic delay caused by false positive amplified Mycobacterium tuberculosis direct test in an immunocompetent patient with mycobacterium celatum infection. J Clin Microbiol 2001;39:2311–2.
Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989;321:863–8.
University of Birmingham, Birmingham, UK
Professor P I Murray
Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham, Birmingham and Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, City Hospital, Dudley Road, Birmingham B18 7QU, UK; firstname.lastname@example.org
Accepted for publication 3 December 2004
Background/aims: To assess the current level of under-registration of blindness and partial sight among patients attending a large teaching hospital, and to determine any risk factors for under-registration.
Methods: Medical records of all patients attending general ophthalmology outpatient clinics over a 3 month period were included in a retrospective analysis of registration rates; questionnaire survey assessing the level of knowledge of registration practices among 35 ophthalmologists working in the West Midlands.
Results: 146/2161 (7%) patients were eligible for blind or partial sight registration, or were in possession of a completed BD8 form. Of these 146 patients, 65 (45%) were unregistered with 18 fulfilling the criteria for blind and 47 for partially sight. In addition, 32/81 (40%) registered patients appeared to have been inappropriately registered. Partially sighted patients were more likely to be unregistered than blind patients (OR 2.31, 95% CI 1.15 to 4.63, p = 0187), and patients from ethnic minorities were more than three times more likely to be unregistered than white patients (OR 3.23, 95% CI 1.56 to 6.65, p = 0.0015). A patient with a treatable condition was more likely to be unregistered than a patient with an untreatable condition (OR 4.87, 95% CI 2.10 to 11.33, p = 0.0002). The overall level of knowledge of registration practices among doctors was found to be low and there was no indication of increasing knowledge with increasing experience.
Conclusions: There has been little improvement in registration rates of visually impaired patients over the past decade. Ophthalmologists lack the necessary knowledge to cater for visually impaired patients’ needs.
Abbreviations: BMEC, Birmingham and Midland Eye Centre; BST, basic specialist training; DoH, Department of Health; HST, higher specialist training; PS, partially sighted; RNIB, Royal National Institute for the Blind
Keywords: blind; partial sight; registration
The latest estimates from the Royal National Institute for the Blind (RNIB) suggest that there are as many as 260 000 unregistered blind, and 500 000 unregistered partially sighted (PS) people living in the United Kingdom.1 Ophthalmologists have long been aware that a substantial proportion of those eligible for registration remains unregistered,2–5 with approximately 53% of eligible patients not been registered despite consultation with an ophthalmologist.3–5 Studies from the United States have shown that under-registration may be exacerbated by a lack of knowledge among eyecare providers themselves, with registration rates proportional to the experience of the examining doctor.6,7
In response to these findings, we decided to undertake a study with two broad aims:
To update the most recent under-registration statistics collected in 1994, and assess whether there has been any improvement in the UK registration system.
To assess the level of awareness of registration in doctors practising ophthalmology in the United Kingdom.
Research was undertaken at the Birmingham and Midland Eye Centre (BMEC), a large single specialty hospital in west Birmingham. The West Birmingham local research ethics committee granted ethical approval for the study.
Medical records of all patients attending general ophthalmology outpatient clinics at BMEC between October and December 2003 were scrutinised in a retrospective analysis of registration rates. General clinics were selected as analysis of special interest clinics may give a biased impression of the level of blind and PS registration. These months were chosen as plots of the distribution of blind and PS registrations by month between 1999–2003 revealed little between month variability (data not shown).
Patients previously registered as blind or PS, or who met the Department of Health (DoH) eligibility criteria for blind or PS registration as printed on the BD8 certificate on the day of their most recent clinic attendance in the study period were included.
A further group of patients (previously highlighted by Robinson et al3) were included if they met the World Health Organization (WHO) criteria for PS as used in the RNIB needs survey,1 and had a visual acuity of 6/24 Snellen to 6/36 Snellen but no visual field defect, opacities in media, or aphakia. This group of patients is not included in BD8 guidelines for PS registration, and these patients were listed separately as the "6/24–6/36 group."
Ophthalmologists’ awareness study
A questionnaire was constructed for the purpose of a pilot study to assess the level of knowledge of registration practices among doctors practising in the West Midlands, and in particular to investigate the relation between grade and experience with the level of knowledge. The questionnaire was aimed at answering whether these doctors
have a detailed knowledge of who should and should not be registered? (based on the DoH guidelines as printed on the BD8 form, and as further defined by Bunce et al4)
have a detailed knowledge of the benefits of registration to a visually impaired individual, as indicated by the DoH?8
offer any other services to visually impaired patients at the point of registration? (based on the findings of Greenblatt7).
Questionnaires were scored out of a total of 35, and distributed to all grades of ophthalmologist attending the weekly regional postgraduate teaching programme. This gave no opportunity to look up answers, and little chance to confer.
All data were entered into a Microsoft Excel spreadsheet, then analysed on a PC using the logistic regression function of StatsDirect.
A total of 2161 patients attended general ophthalmology clinics at BMEC between October and December 2003; 146 (7%) patients met DoH eligibility criteria for blind or PS registration, or were in possession of a completed BD8 form (table 1).
Table 1 Study sample demographics
Of these 146 patients, 56 (38%) were registered as (38/56), or were eligible (18/56) to be certified blind. Ninety patients (62%) were registered as (43/90), or were eligible (47/90) to be certified PS. Overall, 65/146 (45%) eligible patients were found to be unregistered. Of these 65, 18 fulfilled the criteria for blind and 47 for PS registration (fig 1).
Figure 1 Flow diagram to illustrate the blind/partial sight breakdown of the study sample.
In addition, 32/81 (40%) registered patients appeared inappropriately registered; 13/38 (34%) of those registered as blind and 19/43 (44%) of those registered PS were not certified in accordance with their level of visual impairment (fig 1).
There were 34 patients identified as meeting WHO criteria for PS, but did not meet BD8 guidelines and were therefore unregisterable ("6/24–6/36 group").
Glaucoma was the commonest cause of visual impairment, followed by ARMD, with cataract and retinitis pigmentosa joint third (fig 2).
Figure 2 Primary ophthalmic diagnosis and registration status of visually impaired patients in attendance at general ophthalmology clinics at BMEC for the period October to December 2003.
At least 80% of patients with a primary diagnosis of cataract, corneal pathology or unexplained causes were found to be unregistered. All patients with aphakia, congenital blindness, optic atrophy, and retinitis pigmentosa were registered (fig 2).
Unregistered patients had been, on average, eligible for 1 year (range 0–12 years) and made an average of four visits (range 1–54) to BMEC by the end of the study period (table 2).
Table 2 Number of visits made to BMEC and number of years since unregistered patients in the study sample first became eligible for registration
Table 3 shows PS patients were more likely to be unregistered than blind patients, and patients from ethnic minority groups (Asian, black, mixed, or other) were shown to be more than three times more likely to be unregistered than White patients. A patient who made a total of four or fewer visits to BMEC was more likely to be unregistered than a patient making five or more visits, and a patient with a treatable condition was more likely to be unregistered than a patient with an untreatable condition. There was a statistically significant association between registration status and presence of a reversible diagnosis. Patients aged 65 or over were more likely to be inappropriately registered than those under the age of 65. No association was found between registration status and the grade of the examining doctor (p>0.9; OR not calculated).
Table 3 Logistic regression analysis showing statistically significant variables
The questionnaire study revealed doctors demonstrated an overall low level of knowledge (less than 50% awareness). There was no increase in awareness with increasing years experience or advancing grade (table 4).
Table 4 Questionnaire scores stratified by grade of doctor
Using DH eligibility criteria, we identified 65 patients who were unregistered and therefore receiving an inadequate level of support for their visual impairment. On average, these patients had been excluded from the blind and PS registers at four separate consultations over a 1 year period. Nevertheless, there may be limitations with generalisation of these findings, as the study was undertaken at a single inner city unit.
This study has again highlighted an unregisterable group of patients, the "6/24–6/36 group," who were visually impaired under the WHO classification of PS, but not under DoH guidelines. These patients are undoubtedly visually impaired and deserve the benefits offered by registration, but cannot legally be registered.
A PS person was almost 2.5 times more likely to be unregistered than a blind patient, which is broadly similar to that quoted by Bunce et al,4 and this trend mirrors previous studies.2–5,10 Furthermore, this suggests little has changed since the work of Gibson et al2 in the 1980s. Owing to the retrospective nature of this investigation, we were unable to confirm whether each patient had been offered registration or not. However, apart from one patient in the "6/24–6/36 group" there was no documentation in the medical records to suggest that any other patients had declined the chance of registration if it was offered.
In agreement with Robinson et al.3 another significant risk factor of under-registration identified was patient ethnicity. A patient who is "non-white" is more than three times more likely to be unregistered than a patient from a "white" ethnic group. One possible explanation is that there may be communication difficulties during the consultation between a member of an ethnic minority group and a doctor. It has been suggested that this leads to a reduced awareness of health information resulting in the patient not understanding the need for registration.11 Another explanation may be that patients in ethnic minority groups have more inhibitions to being registered than those from a white background, particularly in the case of elderly patients.12
Our results also suggest that patients with a treatable ophthalmic diagnosis are less likely to be registered than those with an untreatable condition. This confirms the findings of previous researchers,4 and adds further weight to the view expressed by King et al that registration is seen by ophthalmologists to be a last resort in the treatment of a visually impaired patient.5 A similar association was found when comparing patients with potentially reversible diagnoses with those with irreversible diagnoses.
Another finding was that under-registration was not associated with the grade of the examining doctor, suggesting possible inadequacies in the training of ophthalmologists. Further evidence for this came from the questionnaire study revealing the doctors’ poor awareness, with no statistically significant difference between the proportions of correct answers given by any two grades of ophthalmologist. Although only a small number of ophthalmologists took part, it was thought that this group was representative of each training grade. Despite this being a pilot study and the limitations associated with this type of questionnaire, our findings suggest that the current system for training UK ophthalmologists in the area of low vision appears inadequate. There is little or no formal teaching on low vision and is only briefly mentioned in the curricula of basic specialist training (BST)13 and higher specialist training (HST)14 in ophthalmology from the Royal College of Ophthalmologists and the Royal College of Surgeons of Edinburgh.
It can be seen that the current registration system is still failing many, already disadvantaged, patients. Low vision must have a higher profile in the training of UK ophthalmologists if we are to make any inroads into the problem of under-registration of the vision impaired.
Bruce IW, McKennel AC, Walker EC. Blind and partially sighted adults in Britain: the RNIB survey. Vol 1. London: HMSO, 1991.
Gibson JM, Lavery JR, Rosenthal AR. Blindness and partial sight in an elderly population. Br J Ophthalmol 1986;70:700–5.
Robinson R, Deutsch J, Jones HS, et al. Unrecognized and unregistered visual impairment. Br J Ophthalmol 1994;78:736–40.
Bunce C, Evans J, Fraser S, et al. BD8 certification of visually impaired people. Br J Ophthalmol 1998;82:72–6.
King AJW, Reddy A, Thompson JR, et al. The rates of blindness and partial sight registration in glaucoma patients. Eye 2000;14:613–19.
El-Hashimy MM, Aubert RE, Alich K, et al. Strategies to improve the reporting of legal blindness in Massachusetts. Am J Public Health 1997;87:425–8.
Greenblatt SL. Physicians and chronic impairment: a study of ophthalmologists interactions with visually impaired and blind patients. Soc Sci Med 1988;26:393–9.
Royal National Institute of the Blind. Benefits and concessions for registered blind and partially sighted people (April 2003).
National Statistics Online. Ethnicity and religion. www.statistics.gov.uk/about/classifications/ns_ethnic_classification.asp (accessed 24 Oct 2003).
Aclimandos WA, Galloway NR. Blindness in the city of Nottingham (1980–1985). Eye 1988;2:431–4.
Ritch AE, Ehtisham M, Guthrie S, et al. Ethnic influence on health and dependency of inner city residents. J R Coll Physicians Lond 1996;30:215–20.
Pardhan S, Mahomed I. The clinical characteristics of Asian and Caucasian patients on Bradford’s low vision register. Eye 2002;16:572–6.
Curriculum of Basic Specialist Training in Ophthalmology, CB6/99. www.rcophth.ac.uk/edu_train/guides-curricular.html (accessed 9 Oct 2004).
Curriculum of Higher Specialist Training in Ophthalmology, CH03/03. www.rcophth.ac.uk/edu_train/guides-curricular.html (accessed 9 Oct 2004).
Glaucoma Service, Department of Ophthalmology, University of S?o Paulo, Brazil
Roberto M Vessani
MD, Glaucoma Service, Department of Ophthalmology, University of S?o Paulo Medical School, Brazil; email@example.com
Accepted for publication 1 December 2004
Background/aims: Scanning laser polarimetry (SLP) uses a confocal scanning laser ophthalmoscope with an integrated polarimeter to evaluate the thickness of the retinal nerve fibre layer (RNFL). The aim of this study was to verify the ability of the SLP to detect differences in RNFL thickness between normal and glaucomatous eyes and between glaucomatous eyes subdivided in groups by the severity of visual field damage.
Methods: This was a cross sectional retrospective study. The charts of 40 healthy subjects and 68 glaucoma patients who underwent complete ophthalmological examination, optic disc stereophotography, peripapillary, and macular SLP imaging were reviewed. The right eye of subjects eligible for the study was enrolled. Only eyes with SLP examinations indicating a minimised effect of anterior segment birefringence based on macular image were included. The ability of retardation parameters to discriminate between healthy and glaucomatous eyes was evaluated. Based on visual field loss, glaucoma patients were subdivided in three subgroups (early, moderate, and severe). RNFL thickness between healthy control group and glaucoma subgroups was compared. RNFL thickness and visual field loss correlation was evaluated.
Results: There was a significant difference in superior and inferior maximum RNFL thickness between normal and glaucomatous eyes (p<0.001). With these two parameters, the area under receiver operator characteristic curve was 0.75 and 0.74, respectively. Superior and inferior RNFL thickness was significantly different between healthy control group and all glaucoma subgroups (p<0.001) and between glaucoma subgroups (p<0.05), except for early and moderate glaucoma subgroups (p>0.05). Linear regression showed a weak correlation between RNFL thickness and visual field loss.
Conclusion: These results suggest that once visual field loss is established, smaller reductions in the RNFL thickness detected by SLP are necessary for a given reduction of mean defect value.
Abbreviations: CPSD, corrected pattern standard deviation; GHT, glaucoma hemifield test; IOP. intraocular pressure, ; MD, mean defect; RNFL, retinal nerve fibre layer; ROC, receiver operator characteristic; SLP, scanning laser polarimetry
Keywords: retinal nerve fibre layer; glaucoma; visual field loss
Glaucoma is characterised by a progressive degeneration of retinal ganglion cells and their axonal fibres. Retinal nerve fibre layer (RNFL) loss, optic disc cupping and visual field loss can be detected and used to diagnose and monitor this disease. Scanning laser polarimetry (SLP) uses a confocal scanning laser ophthalmoscope with an integrated polarimeter to quantitatively evaluate the thickness of the RNFL.1 This measurement is based on birefringent properties of the retinal ganglion cell axons that can change the state of polarisation of an illuminating laser beam. The change in polarisation, referred to as retardation, is proportional to the thickness of the birefringent medium and measured to give an index of RNFL thickness. The technology incorporates an anterior segment compensator to neutralise the polarisation effects of the cornea and crystalline lens.2
Previous studies found that quantitative measures of the retinal nerve fibre layer with SLP correlate with the visual field loss in patients with glaucoma,3,4 but the amount of variation explained by the models was relatively modest. One possible explanation may be related to the anterior segment birefringence.
Recent studies have demonstrated that the narrow band corneal compensator used by the GDx scanning laser polarimeter is inappropriately compensating for corneal birefringence in many healthy and glaucomatous eyes.5,6 Nevertheless, a good number of eyes have anterior segment birefringence well compensated by the instrument.
The purpose of our investigation was to verify, in these eyes, the ability of the SLP (GDx) to detect differences in RNFL thickness between normal and glaucomatous eyes. To study the correlation between RNFL structural damage and visual function, patients with glaucoma were divided in subgroups based on visual field loss and their RNFL thicknesses were compared.
PATIENTS AND METHODS
The charts of 160 glaucoma patients and 100 healthy volunteers examined between January and March 1998 were reviewed. The right eyes from subjects meeting entry criteria were enrolled in this retrospective study. All subjects were between 19 and 84 years old. All eyes included had best corrected visual acuity of 20/20, spherical refraction within plus or minus 5.0 dioptres, and cylinder correction within plus or minus 2.5 dioptres. Eyes with coexisting retinal disease, uveitis, amblyopia, non-glaucomatous optic neuropathy, or other ocular disease that could affect visual field performance were excluded from this investigation.
All participants underwent a complete ophthalmological examination including stereoscopic photographs of the optic nerve and achromatic automated perimetry performed with the Humphrey field analyser (Humphrey Systems, Inc, Dublin, CA, USA), full threshold, program 24-2.
Healthy subjects had no history of ocular disease, surgery, or elevated intraocular pressure (IOP). Their examination revealed IOP less 21 mm Hg (Goldmann applanation tonometry) on more than one occasion, normal optic disc appearance, and normal findings on visual field test. Absence of glaucomatous optic neuropathy was defined as vertical cup/disc asymmetry less than 0.2, cup/disc ratio less than 0.6, and an intact neuroretinal rim without peripapillary haemorrhages, notches, localised pallor, or an RNFL defect. Normal visual field indices were defined as a mean defect (MD) and corrected pattern standard deviation (CPSD) within 95% confidence limits and a glaucoma hemifield test (GHT) result within normal limits. Fixation loss and false positives and false negatives less than 20% characterised a reliable visual field examination.
Glaucomatous optic neuropathy was defined as cup/disc asymmetry between fellow eyes of greater than 0.2, rim thinning, notching, excavation, or RNFL defect.
Patients with glaucoma presented glaucomatous optic nerve damage and associated visual field loss confirmed by a second examination. Visual field defect on the Humphrey field analyser, was defined as GHT result outside the 99% normal limits and/or corrected pattern standard deviation outside the 95% normal limits. Examinations with a "borderline" or a "generalised depression of sensitivity" result in the GHT test were excluded.
All eyes underwent undilated RNFL measurements obtained with a scanning laser polarimeter (GDx nerve fibre analyser; Laser Diagnostic Technologies Inc, San Diego, CA, USA) by an experienced operator. The technology has been described in detail previously.1,7 The same operator performed image acquisition in a standardised fashion. The optic disc margin was approximated by a circle or ellipse placed by the operator around the inner margin of the peripapillary scleral ring. A measuring circle or ellipse was then generated by the instrument at 1.75 disc diameters concentric with the margin of the optic disc.
A baseline image was obtained from the mean of three scans accepted by GDx, that yielded a mean pixel standard deviation less than or equal to 8.0 μm.
Recent studies suggest that the narrow band corneal compensator used by the GDx scanning laser polarimeter is inappropriately compensating for anterior segment birefringence in many eyes. Assessment of macular images may indicate which eyes the original fixed corneal compensator would appropriately compensate. In this case, the macular image should be uniform and dark around the fovea and yield a flat macular retardation profile.8 In this study, one macular polarimetry image was obtained from each subject and evaluated by two experienced examiners. Only eyes that presented a macular image with those characteristics (indicating a minimised effect of anterior segment birefringence) were included.
The original software of GDx provides many variables for analysis. In this particular study, the following parameters were chosen to assess the RNFL thickness: superior maximum (the average of the 1500 thickest pixels in the superior quadrant), inferior maximum (the average of the 1500 thickest pixels in the superior quadrant), temporal median (average of the 1500 median pixels in the temporal quadrant), and nasal median (average of the 1500 median pixels in the nasal quadrant).
Achromatic automated perimetry was performed within 3 months of clinical examination and RNFL thickness determination.
To evaluate differences in RNFL thickness between different stages of glaucoma neuropathy, patients were classified in three subgroups based on MD index of visual field: early, moderate, and severe glaucoma. Early glaucoma was defined by a visual field loss with an MD no worse than –5 dB. Moderate glaucoma was defined by a visual field with an MD value between –5 dB and –10 dB. An MD worse than –10 dB characterised patients with severe visual field loss.
Statistical analysis was performed using commercially available software (JMP; SAS Institute, Cary, NC, and SPSS 10.0; SPSS Inc, Chicago, IL, USA). Student’s t test was used to evaluate differences in RNFL thickness between normal and glaucomatous eyes. Logistic regression and area under the receiver operator characteristic (ROC) curve were used to assess the ability of SLP variables to differentiate between healthy and glaucomatous eyes. Analysis of variance with the Student-Newman-Keuls test for multiple comparisons was used to test differences in SLP variables within groups. Linear and polynomial regression analysis was performed to evaluate the relation between MD value and SLP RNFL thickness measurements of all subjects.
One hundred and eight eyes (40 normal, 68 glaucomatous) of 108 subjects (65 (60%) female, 43 (40%) male) were enrolled in this investigation. Demographic characteristics of the study population are described in table 1. Patients with glaucoma were significantly older than normal subjects (p<0.001). There were statistically significant differences between healthy subjects and glaucomatous groups for superior and inferior maximum thickness (p<0.0001), but not for temporal and nasal median thickness (table 2). Using logistic regression analysis, superior maximum and inferior maximum thickness showed a good ability to discriminate between healthy and glaucomatous eyes. Their area under ROC was 0.75 and 0.74, respectively (fig 1). With an arbitrarily selected cut off of lower than 80 μm as glaucoma, sensitivity and specificity of superior maximum were 79% and 75%, respectively. For an arbitrary cut off of 84 μm, sensitivity and specificity of inferior maximum were 63% and 78%.
Table 1 Clinical characteristics of the study population
Table 2 Superior and inferior maximum retardation parameters and global visual field indexes of normal control group and glaucoma subgroups
Figure 1 Receiver operating characteristic curve for superior maximum thickness (μm) (solid line) and inferior maximum thickness (μm) (broken line).
There was no significant difference in age and sex between glaucoma subgroups (p<0.05). Mean superior and inferior maximum thickness of control group and all glaucoma subgroups are presented in table 2.
There was a significant difference in these retardation parameters between patients with early glaucoma and healthy subjects (p<0.0001). In the early glaucoma subgroup, superior and inferior maximum mean value were respectively 22.7 μm (21.6%) and 19.1 μm (19.6%) thinner than healthy control group.
Superior and inferior maximum thickness measured in the subgroup of moderate glaucoma were, respectively, 5.5 μm (6.6%) and 1.8 μm (2.3%) thinner than initial glaucoma subgroup. This difference was not significant.
The same retardation parameters measured in severe glaucoma subgroup were, respectively, 12.1 μm (15.2%) and 15.6 μm (20.3%) thinner than moderate glaucoma subgroup (p = 0.04).
There was a difference of 20.9 μm in mean RNFL thickness (mean of superior and inferior maximum) between healthy subjects and patients with early glaucoma. This was associated with a difference of 1.61 dB in the mean MD value between these groups. Mean RNFL thickness in severe glaucoma patients was 18.0 μm thinner than patients with early glaucoma. The same groups presented a difference of 10.32 dB in the mean MD value.
Linear regression showed a modest correlation between MD value and mean RNFL thickness (mean of superior and inferior maximum thickness) (r2 = 0.24, p<0.001). The same was observed for CPSD value (r2 = 0.25; p<0.001). This correlation was slightly, but not significantly, better with a polynomial regression of degree 2 (figs 2 and 3). A parabola fit shows small variations in MD value for higher RNFL thickness measurements and larger differences in MD values for lower RNFL thickness measurements.
Figure 2 Fitted curve between visual field indexes (MD and CPSD) and mean RNFL thickness (mean of superior and inferior maximum) of all subjects based on a polynomial regression of degree2. MD = –17 52862+0 1580892 RNFL –0 001195 (RNFL –84 5458)2. CPSD = 11 64816–0 0927809 RNFL +0 0004628 (RNFL –84 5458)2. Scatter plot shows small variability of MD and CPSD values for higher RNFL thickness measurements and larger changes in those visual field indexes for lower RNFL thickness measurements (r2 = 0.26; p<0.001 for both indexes).
Figure 3 Fitted curve between visual field indexes (MD and CPSD) and mean RNFL thickness (mean of superior and inferior maximum) of all subjects based on a polynomial regression of degree2. MD = –17 52862+0 1580892 RNFL –0 001195 (RNFL –84 5458)2. CPSD = 11 64816–0 0927809 RNFL +0 0004628 (RNFL –84 5458)2. Scatter plot shows small variability of MD and CPSD values for higher RNFL thickness measurements and larger changes in those visual field indexes for lower RNFL thickness measurements (r2 = 0.26; p<0.001 for both indexes).
In this study, we evaluated a particular group of patients who present a better compensation for anterior segment birefringence when using the SLP with fixed corneal compensation. Our results showed an overlap between healthy and glaucomatous eyes in the range of values for all retardation parameters studied. This finding is in agreement with previous studies.3,9 However, our study showed a good ability to differentiate between healthy and glaucomatous eyes using superior and inferior maximum parameters, differently from other reports.9,10 The selection of eyes with better anterior segment compensation by the instrument may account for these findings. A recent publication by Greenfield and colleagues11 observed that correction for corneal polarisation axis improves the ability to discriminate between normal and glaucomatous eyes for five retardation parameters quantifying RNFL thickness. Superior and inferior maximum thicknesses were not reported in their study. Although these are not parameters that have been found to have the best correlation with visual function in other studies1,9 they were evaluated without considering the corneal compensation issue. In this study we decided to use these two parameters because they may be more directly related to RNFL thickness measurement than other coefficients based on various algorithms (such as "the number") which would be of better interest when analysing the relation between structure and function.
The difference in age between normal healthy subjects and patients with glaucoma may be considered a source of bias in the discriminating power of SLP parameters for detection of glaucomatous eyes in this study. However, the amount of influence would be probably small considering the suggested RNFL decay rate between 0.2 μm and 0.38 μm/year.12
To study the correlation between RNFL structural damage and visual field loss, we compared differences in RNFL thickness with differences in visual field MD index between groups. We detected a significant difference in RNFL thickness between eyes of healthy subjects and eyes of patients with early glaucoma, but not between early and moderate glaucomatous eyes. By the same time, similar reductions in RNFL thickness were correlated with different reductions in MD value when we observed the comparisons between healthy subjects and patients with early glaucoma and between patients with early and severe glaucoma. These findings suggest that once the visual field loss is established, smaller amounts of RNFL thickness are necessary for a given reduction of MD value.
These observations also help explain the weak linear correlation between mean RNFL thickness and visual field global indexes of all subjects in our study. Because of that we tried an alternative model that does not provide a significant better fit for our scatter plot, but may highlight the variability of the relation between structure and function. The scatter plot shows small differences in MD value for higher RNFL thickness measurements and larger variations for thinner measurements, suggesting an important change in the relation between these two variables with increasing visual field defect and RNFL thickness reduction. CPSD index shows the same correlation. Similar findings were observed by Kwon and co-workers.4 The authors suggested a bilinear correlation with great variability between SLP RNFL measurements and visual field parameters.
Our results are also in agreement with histological studies. Quigley and co-workers13 showed that up to 40% to 50% of nerve fibres could be lost in the absence of a field defect. A later study with a larger number of eyes showed that a reduction of at least 25% to 35% in retinal ganglion cell population is associated with statistical abnormalities in automated perimetry.14 This same study also provided a modest linear correlation between the MD value and the total axon number estimate in each eye. The same was observed for CPSD index. One experimental glaucoma study in monkeys observed a non-linear relation between the proportional losses of ganglion cells and visual sensitivity, measured with either white or coloured stimuli.15
There are inherent limitations of a cross sectional study to examine the relation between structure and function.3 The variability of the number of nerve fibres in the normal optic nerve contributes for a difficult correlation between visual field loss and RNFL thickness damage when studying different patients. In addition, it is possible that different glaucoma patients would need to lose different amounts of retinal nerve fibres to produce similar visual field defects. One might expect, therefore, that the strength of this association could vary depending on the glaucoma patients included in the study and the severity of their disease.3
Our study was able to give an estimative of the relation between visual field performance and RNFL thickness variation measured by SLP among normal subjects and glaucoma patients in different stages of the disease. It seems that once the visual field loss is established, smaller amounts of RNFL thickness are necessary for a given reduction of MD value. Future prospective longitudinal studies evaluating changes in visual field performance and RNFL thickness in the same subjects may confirm our findings and give more details about this relation. Although a new version of GDx is available, the instrument with fixed compensator is still being used by various glaucoma specialists and general ophthalmologists around the world. Properly selected images obtained with this instrument may still reveal important information about the relation between structure and function in glaucoma damage, especially from longitudinal evaluation.
Weinreb RN, Shakiba S, Zangwill L. Scanning laser polarimetry to measure the nerve fiber layer of normal and glaucomatous eyes. Am J Ophthalmol 1995;119:627–36.
Dreher A, Reiter K (inventors). Retinal eye disease diagnostic system. Patent No. 5787890. United States: Laser Diagnostic Technologies, Inc, 1994.
Weinreb RN, Shakiba S, Sample PA, et al. Association between quantitative nerve fiber layer measurement and visual field loss in glaucoma. Am J Ophthalmol 1995;120:732–8.
Kwon YH, Hong S, Honkanen RA, et al. Correlation of automated visual field parameters and peripapillary nerve fiber layer thickness as measured by scanning laser polarimetry. J Glaucoma 2000;9:281–8.
Greenfield DS, Knighton RW. Stability of corneal polarization axis measurements for scanning laser polarimetry. Ophthalmology 2001;108:1065–9.
Weinreb RN, Bowd C, Greenfield DS, et al. Measurement of the magnitude and axis of corneal polarization with scanning laser polarimetry. Arch Ophthalmol 2002;120:901–6.
Zangwill L, Berry CA, Garden VS, et al. Reproducibility of retardation measurements with the nerve fiber analyzer II. J Glaucoma 1997;6:384–9.
Zhou Q, Weinreb RN. Individualized compensation of anterior segment birefringence during scanning laser polarimetry. Invest Ophthalmol Vis Sci 2002;43:2221–8.
Weinreb RN, Zangwill L, Berry CC, et al. Detection of glaucoma with scanning laser polarimetry. Arch Ophthalmol 1998;116:1583–9.
Bowd C, Zangwill LM, Berry CC, et al. Detecting early glaucoma by assessment of retinal nerve fiber layer thickness and visual function. Invest Ophthalmol Vis Sci 2001;42:1993–2003.
Greenfield DS, Knighton RW, Feuer WJ, et al. Correction for corneal polarization axis improves the discriminating power of scanning laser polarimetry. Am J Ophthalmol 2002;134:27–33.
Poinoosawmy D, Fontana L, Wu JX, et al. Variation of nerve fibre layer thickness measurements with age and ethnicity by scanning laser polarimetry. Br J Ophthalmol 1997;81:350–4.
Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol 1982;100:135–46.
Kerrigan-Baumrind LA, Quigley HA, Pease ME, et al. Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci 2000;41:741–8.
Harwerth RS, Carter-Dawson L, Shen F, et al. Ganglion cell losses underlying visual field defects from experimental glaucoma. Invest Ophthalmol Vis Sci 1999;40:2242–50.