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EDITORIALS 663

Central serous chorioretinopathy study. In fact, others have shown an Br J Ophthalmol: first published as 10.1136/bjo.87.6.665 on 1 June 2003. Downloaded from ...... inverse correlation between TABP and psychopathology.12 CSC remains a unique ophthalmic Central serous chorioretinopathy condition in which a definite link be- tween psychological profile and end J M Jumper organ alterations may one day be made...... Our continued attention to this disease is vital. The clinical and psychological find- What is the telling us? ings as well as the neuroendocrine asso- ciations may lead to a better understand- ing not only of CSC but also of other entral serous chorioretinopathy reaction and an avenue for further (CSC) has captured the attention investigation. Based on the inconsistent macular and, possibly, vascular diseases. of physicians for nearly 150 years. results of all psychological testing per- Alternatively, treatments directed at be- C haviour modification or neuroendocrine Psychic stress and behavioural traits formed to date, the authors see no scien- were originally described as potential tific evidence that psychosocial factors alteration in patients with TABP and contributing factors in the development have a dominant role in the pathogenesis cardiovascular disease may translate to of this disorder by Horniker in 1927.1 of CSC. improved treatments for CSC. Since that time, many others have While this or other studies have not Br J Ophthalmol 2003;87:663 attempted to better define this relation. proved the psychogenic induced hypoth- Gelber and Schatz reported results of esis of CSC, an intriguing pattern re- detailed psychiatric interviews (which mains. Repeated studies have shown an ...... included the gold standard structured association with , both endo- Author’s affiliations interview) with CSC patients.2 Of the 33 genous and exogenous.45 Also, CSC has J M Jumper, One Daniel Burnham Court, Suite patients studied, 91% described a dis- been associated with hypertension and 210C, San Francisco, CA 94109, USA; turbing psychological event immediately disease states that result in elevated lev- [email protected] preceding their loss of vision. These els of serum cortisol (Cushing’s disease) or are commonly treated with patients had type A personality scores REFERENCES .467 Jampol and coworkers comparable to patients with myocardial 1 Horniker E. Su di unaforma di retinite infarction. In 1987, Yannuzzi reported a have recently summarised the possible centrale di origine vasoneurotica. Ann higher proportion of type A behaviour genomic and non-genomic pathways Ottalmol 1927;55:830–40. pattern as measured by the Jenkins that may affect in the 2 Gelber GS, Schatz H. Loss of vision due to 8 central serous chorioretinopathy following Activity Survey in patients with CSC chorioretinal complex in CSC. psychological stress. Am J Psychiatr compared to control subjects with other 1987;144:46–50. forms of central vision loss.3 These two CSC remains a unique ophthalmic 3 Yannuzzi LA. Type-A behavior and central serous chorioretinopathy. studies would suggest that the constitu- condition in which a definite link 1987;7:111–31. tion of the patient in combination with between psychological profile and 4 Carvalho-Recchia CA, Yannuzzi LA, Negrao psychic stress have a role in the develop- end organ alterations may one S, et al. Corticosteroids and central serous ment of CSC. chorioretinopathy. http://bjo.bmj.com/ day be made 2002;109:1834–7. Just as fundus biomicroscopy, angio- 5 Garg SP, Dada T, Talwar D, et al. graphy, and optical coherence tomogra- As previously mentioned, an associ- Endogenous cortisol profile in patients with phy have aided our understanding of the central serous chorioretinopathy. Br J ation between the type A behaviour Ophthalmol 1997;81:962–4. pathological response of the retina and pattern (TABP) and CSC has been 6 Bouzas EA, Scott MH, Mastorakos G, et al. in CSC, our understanding of the described.23 The TABP has been exten- Central serous chorioretinopathy in psychosocial aspects of disease have sively studied as it relates to cardiovas- endogenous hypercortisolism. Arch Ophthalmol 1993;111:1229–33. been enhanced by standardised ques- cular disease. Investigators feel that this 7 Tittl MK, Spaide RF, Wong D, et al. Systemic on September 29, 2021 by guest. Protected copyright. tionnaires which have been validated behaviour pattern acts on the adreno- findings associated with central serous and can be compared to large sample medullary sympathetic system to alter chorioretinopathy. Am J Ophthalmol populations of normal subjects. In this 1999;128:63–8. cardiovascular tone, blood rheology, lipid 8 Jampol LM, Weinreb R, Yannuzzi L. 9 issue of the BJO (p 704), Spahn and profiles, and serum hormone levels. Involvement of corticosteroids and coworkers performed psychometric Interestingly, subjects who demonstrate catecholamines in the pathogenesis of central studies (Symptom Checklist, Symptom serous chorioretinopathy: a rationale for new the TABP share many physiological treatment strategies. Ophthalmology List, Sixteen Personality Factor Ques- changes that have been described in 2002;109:1765–6. tionnaire, and Questionnaire on Social CSC, including elevated blood pressure 9 Fredrikson M, Blumenthal JA. Serum lipids, Support) on patients diagnosed with and increased serum stress hormones neuroendocrine and cardiovascular responses 910 to stress in healthy type A men. Biol Psychol CSC up to 6 weeks earlier. Thirty seven such as cortisol and catecholamines. 1992;34:45–58. per cent of these patients had elevated Promising research has demonstrated 10 Manuck SB, Garland FN. Coronary-prone psychic stress within the week before that the TABP is modifiable and that behavior pattern, task incentive, and cardiovascular response. Psychophysiology testing. CSC patients were found to have behavioural changes can, in turn, lower 1979;16:136–42. greater social support and no evidence of the patients’ risk of recurrent myocardial 11 Friedman M, Thoresen CE, Gill JJ, et al. abnormal psychosomatic symptoms infarction.11 Alteration of type A behavior and its effect on compared to normal sample populations. Is the TABP measured by the psycho- cardiac recurrences in post myocardial infarction patients: summary results of the Personality testing revealed increased metric tests performed by Spahn and recurrent coronary prevention project. Am emotional instability and insecurity as coworkers? While a controversial issue, Heart J 1986;112:653–65. well as greater spontaneity and flexibil- the TABP as measured by the Jenkins 12 Wadden TA, Anderton CH, Foster GD, et al. The Jenkins activity survey: does it measure ity, suggesting to the authors that inner Activity Survey appears unrelated to fac- psychopathology? J Psychosom Res turmoil may be a cause of the stress tors assessed by the tests reported in this 1983;27:321–5.

www.bjophthalmol.com 664 EDITORIALS

Stains in retinal surgery solution; it is the hypo-osmolarity of the Br J Ophthalmol: first published as 10.1136/bjo.87.6.665 on 1 June 2003. Downloaded from ...... solvent and the final solution that is sus- pected by the authors of disrupting cellular elements of the neural retinal. In Second generation vital stains in contrast, infracyanine green, which uses 5% glucose solution as its solvent for an retinal surgery iso-osmotic final solution, offers compar- able staining of the ILM while reducing R B Bhisitkul the untoward osmotic effects. In previ- ous in vitro studies by this group, ...... infracyanine green in 5% glucose did not demonstrate cytotoxicity to cultured Further innovations may enable novel surgical strategies RPE cells, while ICG exposure led to sig- nificantly increased cell death.9 Similarly, n an article in this issue of the BJO by ILM specimens have demonstrated dis- in the present study ILM specimens Stalmans and colleagues (p 713) and ruption of retinal elements after ICG excised with infracyanine green were another recently by Li and colleagues,1 application. Muller cell fragments, as not noted to include Muller cell foot- I plates or other evidence of neural retinal the novel vital stains trypan blue (TB) well as astrocytes and cellular debris, and infracyanine green are investigated were observed in ILM specimens peeled disruption when examined by histopath- clinically. These vital stains are promis- with ICG; this was in contrast with those ology and electron microscopy. Compar- ing in vitreoretinal surgery as alterna- peeled using no ICG,57 suggesting an ing ICG and infracyanine green, maybe the grass is actually greener on the other tives to the by now familiar agent alteration of the “cleavage plane” be- side of the fence. indocyanine green (ICG). Firstly, a brief tween the ILM and underlying neural Another central aspect of the paper by history of membrane staining. ICG, a retina. In vitro studies have indicated Stalmans et al and also that of Li et al is fluorescent dye used in choroidal angio- toxicity of ICG and its aqueous solvent to 89 the use of trypan blue for epiretinal graphy, was recognised for its potential cultured RPE cells, a possible correlate membrane surgery. The introduction of in the operating room by sur- to the clinical study of central RPE atro- trypan blue is more than just a change in geons, who first used it to stain the ante- phy after macular hole surgery using ICG 6 colour schemes; its properties as a vital in some patients. Such concerns have rior capsule to facilitate capsulorrhexis stain are quite distinct from those we’re led some surgeons to attempt to mini- in difficult cases. Vitreoretinal surgeons, accustomed to with indocyanine green mise ICG exposure during surgery, with taking notice of their anterior segment (or even infracyanine green). Unlike the reduced concentrations and application colleagues’ success, soon found that ICG green dyes which selectively stain the times of the dye, as well as circumscribed similarly stained the internal limiting acellular ILM but not overlying mem- indications for adjunctive ICG use. membrane (ILM) of the retina. This was branes and vitreous, trypan blue directly important because peeling of the nearly stains epiretinal membranes (ERMs), invisible ILM from the retinal surface making it valuable in cases such as had recently been advocated in macular macular pucker removal. Whereas ICG hole surgery23; this was easier said than

can only indicate the presence of the http://bjo.bmj.com/ done, however, until the arrival of ICG ERM by its lack of green staining within made ILM peeling easier, faster, and less an area of stained ILM (referred to as traumatic. Thus, a trend in posterior seg- “negative staining”), trypan blue has an ment surgery was born, and ICG soon affinity for the cellular material compos- enjoyed widespread attention. A flurry of ing epiretinal membranes (ERMs), pro- articles appeared, with several early viding visualisation and localisation. One clinical series reporting impressive suc- advantage of this is noted by the authors, cess rates in macular hole surgery with who found in some cases that trypan on September 29, 2021 by guest. Protected copyright. 45 ICG assisted ILM peeling. ICG staining blue reveals the extent of the ERM to be has by now entered the mainstream of much larger than suspected clinically. It retinal surgery as a useful tool in macu- is possible that macular pucker surgery lar hole repair and unaided by trypan blue can underesti- removal. mate the size of the membrane, resulting But, more recently, some doubts have Here’s where the work presented by in incomplete ERM removal and residual arisen around ICG, as a critical reassess- Stalmans et al comes in. They performed macular distortion. Trypan blue has ment has followed the initial enthusi- double staining with trypan blue and other potential surgical benefits; Li et al asm. As discussed by the authors of both infracyanine green to enhance visualisa- found that it not only stains ERMs but of these papers, greater clinical experi- tion during macular pucker surgery. One also provides adequate staining of the ence has begun to reveal possible toxic of two important aspects of this paper is ILM, and they forwarded the use of effects of ICG on the RPE and neural the introduction of infracyanine green as trypan blue as yet another alternative to retina. Engelbrecht et al published a an alternative to indocyanine green for ICG in macular hole repair with ILM clinical series that found central RPE vital staining in posterior segment sur- peeling. Finally, in another twist, Stal- atrophy with poor visual outcomes after gery. Under the theory that retinal toxic- mans et al exploit the “complementarity” some cases of ICG assisted macular hole ity may be a consequence of the hypoto- of these dyes in a double staining repair, possibly caused by direct contact nicity of standard indocyanine green in technique for macular pucker removal, of ICG with RPE cells in the area of the its aqueous solvent, the authors have first with trypan blue to peel the ERM, hole.6 Laboratory studies, in a perhaps turned to infracyanine green as an then with infracyanine green to peel the inverted sequence, have followed the ini- iso-osmotic alternative. underlying ILM. It would appear that no tial clinical reports and have raised Indocyanine green is prepared for sur- membrane is safe from vitreoretinal sur- further concerns of overlooked ICG gical use by reconstituting it with pure geons these days. toxicity. Histological and electron micro- water as a solvent, before bringing it to The introduction of trypan blue and scopic examinations of surgically excised its final concentration in balanced infracyanine green by no means lays to

www.bjophthalmol.com EDITORIALS 665 rest the issue of retinal toxicity. Trypan dyes having distinct affinities for specific 2 Park DW, Sipperly JO, Sneed SR, et al. Br J Ophthalmol: first published as 10.1136/bjo.87.6.665 on 1 June 2003. Downloaded from blue stained ILM fragments were found membranes or cell types. Diabetic fibro- Macular hole surgery with internal-limiting membrane peeling and intravitreous air. by Li et al to contain glial elements from vascular membranes, vitreous cortical Ophthalmology 1999;106:1392–8. the neurosensory retina, raising again hyaloid, proliferative vitreoretinopathy 3 Brooks HL, Jr. Macular hole surgery with and without internal limiting membrane peeling. the spectre of retinal disruption which membranes, neurosensory retina, Ophthalmology 2000;107: 1939–48. can affect visual outcomes. As with ICG, choroidal neovascular membranes, ac- 4 Da Mata AP, Burk SE, Riemann CD, et al. with more study and clinical experience tive tumour cells—all might be promis- Indocyanine green-assisted peeling of the retinal internal limiting membrane during the limitations of trypan blue and infra- ing targets for vital stains. Such advances for macular hole repair. cyanine green will be defined while their will probably require that we move Ophthalmology 2001;108: 1187–92. dosages and application times are opti- beyond “off the shelf” agents and 5 Kwok AKH, Li WWY, Pang CP, et al. Indocyanine green staining and removal of mised. Other barriers also remain to be instead turn our attention to the re- the internal limiting membrane in macular hole overcome, not the least of which is that search and development of new vital surgery: histology and outcome. Am J trypan blue and infracyanine green are stains specifically for ophthalmic surgery. Ophthalmol 2001;132:178–83. unavailable for surgical use in many 6 Engelbrecht NE, Freeman J, Sternberg Jr P, Br J Ophthalmol 2003;87:664–665 et al. Retinal pigment epithelial changes after countries including the United States. macular hole surgery with indocyanine But the work presented in these two green-assisted internal limiting membrane ...... peeling. Am J Ophthalmol 2002;133: 89–94. papers marks an important development Author’s affiliations 7 Gandorfer A, Haritoglou C, Gass CA, et al. in this relatively new technology, moving Indocyanine green-assisted peeling of the R B Bhisitkul, UCSF Department of beyond ICG as the sole dye to a second internal limiting membrane may cause retinal Ophthalmology 10 Kirkham Street, K301 San damage. Am J Ophthalmol 2001;132:431–3. generation of vital stains for intraocular Francisco, CA 94143, USA; 8 Sippy BD, Engelbrecht NE, Hubbard GB, et surgery. As more types of vital stains [email protected] al. Indocyanine green effect on cultured with distinct properties are added to our human retinal pigment epithelial cells: implications for macular hole surgery. Am J arsenal, further innovations may enable REFERENCES Ophthalmol 2001;132: 433–5. novel surgical strategies. One can envi- 1 Li K, Wong D, Hiscott P, et al. Trypan blue 9 Stalmans P, Van Aken E, Veckeneer M, et al. sion in the future an array of vital stains, staining of internal limiting membrane and Toxic effects of indocyanine green on retinal epiretinal membrane during vitrectomy: visual pigment related to osmotic effects a sort of surgical palette, with different results and histopathological findings. Br J of the solvent. Am J Ophthalmol 2002;134: intraoperative dyes or even non-invasive Ophthalmol 2003;87:216–19. 282–5.

Dry eye Problems arise, however, when dry eye ...... symptoms become by inference dry eye syndromes. As stated in their abstract the aim of the study was “To determine the Too dry or not too dry prevalence and identify associated risk factors for in a J P Whitcher population in Sumatra, Indonesia.” Dry eye syndromes by definition encompass ...... a constellation of diverse disease proc- http://bjo.bmj.com/ esses that produce objective signs of Is that really the question or do eye symptoms lie? sicca (KCS) with or without a concomitant decrease in tear 2 or those of us who see patients on a dry eye symptoms were assessed using a production. The classic prototype of the dry eye syndrome is Sjögren’s syndrome, regular basis, how many times a day six item questionnaire. The questions but there are many other causes of KCS do we hear the recurring complaint, were, essentially, do your ever feel F including cicatrising conjunctival dis- “Doctor, my eyes feel so dry . . . they itch, dry,do you experience grittiness, burning, on September 29, 2021 by guest. Protected copyright. eases such as and pemphigoid, they burn, they feel constantly irri- or redness, do you have crusting, and are non-cicatrising syndromes causing spe- your eyes ever stuck shut? The frequency tated”? As doctors we must ask, with a cific dry eye findings, and atypical of these symptoms was graded for each sense of wonder, do all of these patients syndromes such as in really have dry eyes? Are we currently in individual as rarely, sometimes, often, or which the eye is symptomatically and the midst of a global epidemic of ocular all the time. One or more of these objectively dry but tear production is dryness that has caught us unawares symptoms occurring often or all the time paradoxically normal.2 The diagnosis of and unprepared? Our patients are telling was felt to be significant, and those dry eye syndrome or KCS implies that us something when they describe their subjects who responded positively to the patient has a specific disease entity symptoms, but in the process are they these questions were placed in the dry eye as an underlying cause and that the con- also unintentionally misleading us? Are symptom group and included in the dition is potentially treatable. their eyes truly dry, and if they are not, is analysis. The presence or absence of it possible for us to tell the difference? in each individual was also The dry eye in most cases is truly a Lee et al in the December issue of the documented. Lee et al then submitted diagnostic dilemma until objective BJO have done a superb job of document- their data to detailed statistical analysis tests are performed ing the prevalence of dry eye symptoms in and arrived at the conclusion that 27.5% a village population in Sumatra, of all the individuals questioned experi- Lee et al have documented the preva- Indonesia.1 Their statistical approach is enced one or more of the six ocular symp- lence of dry eye symptoms in this village impeccable. Using a one stage cluster toms often or all the time, and that the population in Indonesia, but they have sampling procedure, they randomly se- only factors found to be associated with not provided us with objective proof that lected 100 households in each of five rural these symptoms were a history of current any of the subjects in the study actually villages and one provincial town in Riau smoking and the presence of a pterygium. had signs of KCS. The authors remarked Province overa3month period in 2001. Interestingly, the prevalence for dry eye on this shortcoming in their discussion Demographic, life style, and medical data symptoms was 1.4 times greater in men and stated that local sociocultural sensi- were collected from 1058 participants and than in women. tivities precluded an interventional study

www.bjophthalmol.com 666 EDITORIALS that would allow objective dry eye tests. responses—pain, foreign body sensation, those who were symptomatic but were Br J Ophthalmol: first published as 10.1136/bjo.87.6.665 on 1 June 2003. Downloaded from This is unfortunate because we still do not burning, itching, dryness. Any of these not actually dry (p value <0.00001).5 know the true prevalence of KCS in this symptoms can be caused by any number Questions about ocular symptoms of interesting group of patients. With mini- of ocular conditions from infections to dryness are definitely important, but mal intervention this question could have allergic reactions to something as simple only as corroborative evidence to point been answered by performing Schirmer’s as conjunctival concretions. It is impor- the way to objective tests. Is the eye guilty of being dry? It must remain tests without anaesthesia, fluorescein tant to always invoke the innocent until innocent until proved otherwise beyond staining, tear break up time, and rose proved guilty principle when suspecting bengal staining on all the subjects. Using the shadow of a doubt. That is the a dry eye. Until ocular dryness can be dilemma. Is the eye too dry or not too these objective tests the true prevalence of proved by objective tests, mere testimony dry eyes in this population could have dry? The answer to this question only (symptoms) can only be used to raise our serves to guide us as doctors to the been easily determined. suspicion that it may exist. objective tests with which we can ulti- Why is it necessary to perform objec- The dry eye in most cases is truly a mately determine the true diagnosis. tive tests? Don’t the patients’ symptoms diagnostic dilemma until objective tests give us a good indication of whether or Br J Ophthalmol 2003;87:665–666 are performed. For years we asked pa- not they really have dry eyes? Lee et al tients in our dry eye clinic a standard ...... have provided the answer in Table 3 of series of questions. Those patients both Author’s affiliations their article. The relation between symp- with and without an objective diagnosis J P Whitcher, UCSF, Department of toms of dryness and objective findings of of ocular dryness gave positive answers to Ophthalmology, 95 Kirkham Street, San dryness is like comparing apples and Francisco, CA 94143–0944, USA; oranges. Ask the same individuals questions regarding foreign body sensa- [email protected] tion, burning, redness, inability to tear, whether or not their eyes feel dry and REFERENCES then perform objective tests, and you itching, etc. It wasn’t until we retrospec- tively looked at 304 patients with objec- 1 Lee AJ, Lee J, Saw S-M, et al. Prevalence and find as much as a sevenfold difference in risk factors associated with dry eye symptoms: the outcome (14.6% with symptoms, tively proved KCS and compared them a population based study in Indonesia. Br J 3 with 195 patients with ocular complaints Ophthalmol 2002;86:1347–51. 2.0% with staining). In 2 Whitcher JP. Clinical diagnosis of the dry some populations that were questioned but who did not have proved KCS that we eye. Int Ophthalmol Clin 1987;27:7–24. about their dry eye symptoms, the realised it was the specificity of the ques- 3 Schein OD, Munoz B, Tielsch JM, et al. tions that was important, not the sensitiv- Prevalence of dry eye among the elderly. Am J prevalence rate was as high as 28.7% Ophthalmol 1997;124:723–8. (Table 3).4 How can there be such a ity. So what was the most important 4 Coffrey BE, Richter D, Simpson T, et al. The disparity between the symptoms of dry- question to ask a patient who may have a Canadian dry eye epidemiology study. In: Sulllivan DA, et al,eds., tear ness and the objective findings of dry- dry eye? “Can you cry?” Patients who film, and dry eye syndromes 2. New York: ness? The simple answer is that the eye is were unable to produce even under Plenum Press, 1998:805–6. 5 Whitcher JP, Gritz DC, Daniels TE. The dry not very smart. When it is stressed it has stressful conditions were very likely to eye: a diagnostic dilemma. Int Ophthalmol a very limited range of symptomatic have a true dry eye syndrome compared to Clin 1998;33:23–37. http://bjo.bmj.com/ on September 29, 2021 by guest. Protected copyright.

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