Correspondence Address:
C Abraham
[email protected]

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Scientific thinking is necessary to critically evaluate deliberations at scientific meetings, understand and get the most out of research publications, develop one's own research plan, and practice ophthalmology on a sound basis. While ophthalmologists and patients are aware, and at times carried away by the technological marvels of today and the ease with which information can be accessed, advances in scientific thinking that have developed over the past 20 years seem to be less talked about and even take a beating at our conferences. To develop scientific thinking in ophthalmology, we must first look at the evolution and progress of knowledge in general and then at science, medicine, and ophthalmology in particular.

The quest for knowledge began soon after man's physical needs were met and evolved around myth, superstition, gods and goddesses, observation and reasoning, gradually grouping into subjects like philosophy, religion, art, science and medicine. These subjects often overlapped and influenced each other, with some individuals remarkably proficient in more than one field. Centuries ago, Aristotle stated that knowledge was gained by reasoning from self-evident principles that explained 'why' things happened[1] and his theory of the four elements was qualitative, not predictive.[2] In the later centuries, Galileo combined observations with controlled experiments that explained 'how' things happened.[1] For the first time, observations could be repeated with nearly identical results and theories led to predictions. Later, Newton's laws of gravitation and Einstein's theory of relativity predicted, among other things, the orbit of planets.[2] Science progressed further with the application of Occam's razor (the principle that cuts out all features of a theory that cannot be observed) and the development of quantum physics[2] though it passed through a brief period of conflict. This is because the major conflicts arose between Newtonian physics on one hand, and relativity and quantum physics on the other. Relativity, where space and time are relative and not absolute; quantum physics, where one could predict for a group but not for individual electrons; and Heisenberg's 'uncertainty principle' where one cannot accurately measure both the position and velocity of an electron at the same time, shook two pillars of classical science - casuality and determinism[1]; cause and effect. Conflicts between classical Newtonian physics and quantum physics were sorted out when modern scientists acknowledged the introduction of an unavoidable element of unpredictability and randomness into science.[2] Statistics arose out of caution in the face of such uncertainity, with the risk of error being quantified and stated.[3] This led to the acceptance of statistical concepts and theories of probability where one could not predict a single definite outcome but only suggest different possibilities with a likelihood for each.[2]

Medicine evolved along similar lines. Myth and superstition were replaced by observation and reasoning. Different branches of medicine, including ophthalmology, witnessed considerable progress through discoveries, innovations, anecdotal reports and case-series analyses that were retrospective and without controls. The introduction of general anaesthesia; the advent of penicillin and insulin; surgery for cataract and intraocular lens implantation; scleral buckling for retinal detachment and enucleation for retinoblastoma are examples where the results were too obvious and overwhelming that controls were not necessary. A problem, however, arises when results are not all that obvious, natural history data are lacking and there are widely opposed claims. Anecdotal reports and retrospective case-series analyses are prone to bias related to the sample, the observer, definitions, standardisation, choice of treatment, follow-up and so on, with the result that conclusions drawn from such studies are questionable and not reproducible. Moreover, such reports depend entirely on eyewitnesses who may be unreliable.[4] The hits are recorded and the misses are not and human nature unconsciously conspires to produce a biased reporting of the frequency of certain events.[4] It is this bias which may be obvious or hidden and not the clinician's credibility that invalidates results. In any study, one should look for the evidence that supports any claim. Personalities do not count and while extrodinary claims may be true, they require extrodinary evidence.[4] Two centuries ago, Haygarth showed that wood was as effective as metal in Perkin's traction in the relief of body pain.[5] A century later, Sutton noted that placebos were as effective as medicines in rheumatic arthritis and that the tendency to natural cure was high.[5] Nearly 50 years ago, Friedenwald cautioned that diabetic retinopathy could show spontaneous remission and that interventions could give rise to false therapeutic hope.[6]

Scientific thinking was inculcated in clinical ophthalmology with the introduction of Prospective Randomised Controlled Clinical Trials in the 1970s, and the inclusion of medical statistics imposed a semblance of science in academic communications.[7] Randomisation was considered more ethical than giving a new or standard therapy as if one knew which was better, when either could have been more harmful than beneficial.[8]These trials were successful, not because of scientific bodies alone but also because participating clinicians and patients were convinced of their need. Several editorials and articles have periodically outlined the different aspects of clinical trials and provide valuable information to clinicians.[9],[24]

Results from the many Multicentric Clinical Trials and the work of some individual investigators have augmented, clarified or negated popular and sometimes dogmatic views held by clinicians on the natural course, indications, technique and outcome of treatment in several ocular conditions. Natural course data on lattice degeneration and retinal breaks[25][26][27] showed that prophylactic treatment for retinal detachment was routinely over-done. The Diabetic Retinopathy Study showed that panretinal photocoagulation prevented severe visual loss in patients with proliferative diabetic retinopathy and high-risk characteristics.[28],[29] Until then, though most clinicians rightly believed in the efficacy of this treatment, there was no agreement on the indications or technique of treatment, and very little on long-term visual results. The Early Treatment Diabetic Retinopathy Studies (ETDRS)[30][31][32][33][34] established the visual benefits of laser treatment in patients with clinically significant macular oedema. Scatter laser treatment in nonproliferative diabetic retinopathy (NPDR) had no demonstrable effect on macular edema or subsequent neovascularisation, and aspirin did not prevent progression of early retinopathy or increase the tendency to vitreous haemorrhage. Though laser treatment for diabetic macular edema was practised prior to the ETDRS, there was no agreement on definitions, treatment techniques or visual results. Earlier claims on the benefits of scatter laser treatment in NPDR were negated; the use of aspirin in NPDR and its withdrawal in the presence of proliferation or vitreous haemorrhage were clarified.

Controversies over clinical and experimental studies on the effect of diabetic control on retinopathy were addressed by the Diabetes Control and Complications Trial which demonstrated that intensive control of diabetes in insulin- dependent patients delayed the onset of retinopathy and slowed progression of early retinopathy.[35] Earlier observations that retinopathy could worsen were confirmed but additional information that it had no long-term ill effect was gained. The Branch Vein Occlusion Study[36],[37] showed that selected patients with macular edema or neovascularisation benefitted from grid or segmental laser. Till then, many advocated laser treatment of nonperfused retina to decrease the incidence of neovascularisation. That even astute clinicians and academicians could be caught on the wrong foot was evident from Hayreh's observations[38] followed by the Central Vein Occlusion Study results.[39],[40] Strong beliefs that laser treatment prevented neovascularisation of the iris and angle, and that laser could be beneficial in macular edema were negated. Almost all specialists believed in early laser treatment of central serous retinopathy (CSR), as long-standing fluid at the macula was considered detrimental to visual function. Many claimed that CSR resolved even if treatment was not directed towards the leak. Natural course and controlled studies however showed that though laser significantly hastened recovery, visual results in treated and untreated eyes were comparable after one year and that indirect treatment was not effective.[41],[42] The recognised benefits of laser treatment to well-defined extrafoveal choroidal neovascular membranes in age-related macular degeneration were demonstrated in subsequent clinical trials but the drop in treatment benefits after 1 or 2 years due to a high recurrence rate emphasised the limitations of treatment.[43],[44] Many investigators reported disappearance of drusen following laser treatment and some pilot studies showed better visual results in treated eyes. Results recently presented from the Choroidal Neovascularisation Prevention Trial however revealed an outcome that was least expected, that laser hastened choroidal neovascularisation in the unilateral group and that most membranes developed adjacent laser scars. The initial results of teletherapy for age-related subfoveal neovascular membranes[45] have not been fully substantiated by others and it remains to be seen if a clinical trial is warranted. But for such trials, treatment could be denied to those who need it most and offered to many who do not need it.

Components of clinical trials are similar to any scientific experiment and include posing an important question; choosing an appropriate sample and study design; involving statisticians from the start; use of randomisation, masking and controls; standardisation of procedures; collection and verification of data; monitoring; analysis and arriving at reasonable conclusions. Results from such trials are predictive and reproducible. Clinicians must however be cautious in distinguishing results that are statistically or clinically significant and in interpreting cause and effect relationships. The limitations of such trials are that they cannot answer all questions, need elaborate organisation, are expensive and are not always used by clinicians. As with pure science they do not provide absolute answers and do not predict for individual patients. Fuzzy logic, considered by some as probability in disguise[46] and alternative therapeutic approaches[47] tend to emphasise the accepted limitations of conventional science rather than provide answers to the very questions they raise. While ophthalmology will continue to progress through basic research, innovations, technological advances, or through presently unpredictable means, it is the application of scientific thinking to these advances that would enrich our knowledge, ensure adequate patient care and educate future generations. It is time that scientific thinking permeated our clinical studies, conference halls, teaching and consulting rooms.

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