Anders Heijl, Professor and Senior Consultant, Department of Ophthalmology, Skåne University Hospital Malmö, Chair of the Expert Panel on Open-Angle Glaucoma of the Swedish Council on Health Technology Assessment (SBU), and Chair of the Swedish Glaucoma Society. Albert Alm, Professor Emeritus, Department of Ophthalmology, Academic Hospital, Uppsala, member of the SBU Expert Panel on Open-Angle Glaucoma, and member of the Board of the Swedish Glaucoma Society. Boel Bengtsson, Associate Professor, Clinical Sciences Malmö, Department of Ophthalmology, Lund University, member of the SBU Expert Panel on Open-Angle Glaucoma, and member of the Board of the Swedish Glaucoma Society. Anders Bergström, Senior Consultant, Department of Ophthalmology, Skåne University Hospital Malmö-Lund, and member of the Board of the Swedish Glaucoma Society. Berit Calissendorff, Associate Professor, member of the SBU Expert Panel on Open-Angle Glaucoma, and former Senior Consultant and Director of St. Erik Eye Hospital, Stockholm. Bertil Lindblom, Professor and Senior Consultant, Sahlgrenska Academy, University of Gothenburg, and former Chair of the Swedish Glaucoma Society. Christina Lindén, Associate Professor and Senior Consultant, Department of Clinical Sciences, Ophthalmology, Umeå University, member of the SBU Expert Panel on Open-Angle Glaucoma, and Secretary of the Swedish Glaucoma Society. In 1995, the Swedish Glaucoma Society proposed Guidelines for the Management of Open-Angle Glaucoma and Ocular Hypertension, which were subsequently accepted and recommended by the Swedish Ophthalmological Society. In 1997, the Swedish National Board of Health and Welfare published a state-of-the-art report entitled Open-Angle Glaucoma. Requests to update these documents were long expressed, and it seemed rather reasonable that that should be performed considering the important advances that have been made in the field of glaucoma over the past decade, for example, in large randomized studies of this disease. Nonetheless, it was necessary to put such improvement on hold pending the outcome of several years’ work on an extensive systematic evaluation of treatment and diagnostics of glaucoma. The results of that assessment were published by SBU in October 2008 in the report Diagnostics, follow-up, and treatment in open-angle glaucoma: a systematic review of the literature. After the SBU report appeared, it was logical that the next step would be to develop new guidelines. Work on that task was commissioned by the Swedish Ophthalmological Society and was performed by the members of the SBU Expert Panel (Albert Alm, Boel Bengtsson, Berit Calissendorff, Christina Lindén and myself) and two experts from the Board of the Swedish Glaucoma Society (Anders Bergström and Bertil Lindblom). On assignment from the Swedish Ophthalmological Society, the guidelines that were created were reviewed by Björn Friström and Enping Chen and subsequently revised. It is the ambition of the Swedish Ophthalmological Society that these new guidelines be put to widespread use in glaucoma care in Sweden. The authors also hope that these Guidelines will be of interest to an international readership, when they have now been translated into English for publication in Acta Ophthalmologica. Anders Heijl on behalf of the Expert Panel 30 December 2011 Conflicts of Interest Anders Heijl is a paid consultant to Carl Zeiss Meditec, Allergan and Alcon. Boel Bengtsson is a paid consultant to Carl Zeiss Meditec. Anders Bergström briefly served as a paid consultant to Alcon. Christina Linden is a member of the Allergan Nordic Advisory Board. Bertil Lindblom, Berit Calissendorff and Albert Alm have no potential conflicts to declare. List of Contents Glaucoma is defined as a progressive disease that causes characteristic degenerative changes in the optic disc, the retinal nerve fibre layer and the visual field. Increased intraocular pressure (IOP) was initially considered to be a prerequisite for a diagnosis of open-angle glaucoma, whereas such a rise in pressure is no longer included in the definition of this disease. Patients with normal IOP were previously classified as having low-tension glaucoma. However, today a diagnosis of primary open-angle glaucoma is given to patients who have elevated IOP as well as those who have normal pressure, and the disease in the latter group is preferably called normal-tension rather than low-tension glaucoma. In primary open-angle glaucoma, the anterior chamber angle is open and there are no identifiable causes of the disease. Exfoliation glaucoma is regarded as a secondary form of glaucoma in most parts of the world, although not always in the Nordic countries. Exfoliation glaucoma is a synonym for the terms pseudoexfoliation glaucoma and capsular glaucoma, which were used more often in the past. In the Western world, open-angle glaucoma is the second most common cause of blindness after macular degeneration (Resnikoff et al. 2004). About 3–5% of patients with glaucoma are blind (Quigley & Broman 2006), but glaucoma is a progressive disease and thus that proportion increases with advancing age. Consequently, a larger number of people with glaucoma go blind during their lifetimes, with figures in the range 6–15% at the last examination before death (Hattenhauer et al. 1998; Forsman et al. 2007). It is more common to be blind in one eye only. The main risk factor for blindness is having extensive visual impairment at diagnosis (Chen 2004), although younger age at diagnosis obviously increases the risk as well. The average age at diagnosis is approximately 70 years, and hence a 60-year old who is diagnosed with manifest glaucoma must be regarded as a relatively young patient (Rudnicka et al. 2006). The proportion of blind individuals varies with the definition of blindness. The WHO definition (sidebar) is used in Sweden. The United States has introduced disability benefits for glaucoma patients with severe visual impairment defined as a mean deviation (MD) value worse than −22 dB on Humphrey threshold perimetry in the best eye (section 2.03 at http://ssa.gov/disability/professionals/bluebook/2.00-SpecialSensesandSpeech-Adult.htm) Research and interest in quality of life (QoL) have increased steadily in recent years. The influence of QoL is highly important from the perspective of the patient. Information about QoL helps to create a more balanced picture of the consequences of the disease than would be possible if only functional impairments caused by the disease were to be included in the description. The concept of QoL is multidimensional and complex in that it includes physical and psychological functions, and also mental and general health, as well as social and economic aspects. The way a patient experiences QoL depends on the person’s state of mind and possible presence of comorbidities. In addition, many survey instruments are designed to address an issue more from the perspective of the researcher (i.e. considering the expected outcome of the disease) than from the standpoint of the individual patient. Awareness of the significance of the survey tools has led to development and validation of an increasing number of instruments over the last decade. Depending on the topic of interest, various validated instruments are available: General/Global instruments measure general dimensions of QoL and are used to compare different groups of disorders. Vision-specific instruments assess visual function in relation to QoL. Utility estimates patients’ own evaluations of their state of health. Some general or global QoL instruments have been validated for comparing groups or for conducting intraindividual assessment over time. The SF-36 Health Survey questionnaire is used most widely and has been translated into several different languages. EuroQoL (EQ-5D), which is based on British material, is frequently used in Europe, and it is also the instrument employed most often in both clinical and population studies in Sweden. Inasmuch as the type of disease per se affects QoL, in recent years specific strategies have been developed for investigating various disorders. An example of this is the Visual Activities Questionnaire (VAQ), which has been modified to assess certain eye diseases. The vision-related instrument VFQ-25 has also been translated into Swedish and validated. A review article published by Severn et al. (2008) illustrates the difficulties associated with designing instruments that can adequately evaluate QoL in patients with glaucoma. To achieve a better basis for allocation of resources, an instrument that assesses patient ‘benefit’ (utility) has also been developed to allow patients’ own experiences of their diseases to be correlated with cost efficiency. This tool measures how a patient evaluates a given state of health on a scale ranging from perfect health (score 1) to death (score 0). Quality of life is so complex and multidimensional in nature that there are no instruments for comprehensive assessment of this concept. Furthermore, validity problems and the lack of a ‘gold standard’ make it difficult to interpret and compare findings. Indeed, even internationally approved and validated questionnaires can provide disparate results when analysing the same patient material. Most studies of QoL in glaucoma have concerned visual function and have shown that marked loss of vision leads to lower QoL (Gutierrez et al. 1997; Sherwood et al. 1998; Janz et al. 2001; Hyman et al. 2005; Varma et al. 2006). However, there is no consensus regarding what degree and type of impairments reduce QoL. Many eye-specific assessment instruments focus on visual acuity, and few concern any particular visual field defects, which makes it difficult to compare results. Conclusions are also contradictory with respect to whether QoL is affected by the treatment provided or by economic factors. On the other hand, there is agreement that being informed of the diagnosis has a negative impact on the patient. Nonetheless, the initial anxiety decreases over time, as shown in some longitudinal studies (Janz et al. 2007). Two large treatment studies called the Early Manifest Glaucoma Trial (EMGT; Hyman et al. 2005) and the Collaborative Initial Glaucoma Treatment Study (CIGTS; Janz et al. 2001) have compared the effects of different therapeutic strategies on QoL during long-term follow-up. After 5 years in the CIGTS, local eye problems were found to be somewhat more common in the surgically treated patients than in those given only medications, although the two patient groups were essentially comparable in other aspects and showed relatively good QoL. In the EMGT, no difference in QoL was observed between treated and untreated patients at 6-year follow-up. One of the difficulties in assessing QoL in patients with glaucoma, compared to individuals who do not have this disease, is the above-mentioned choice of survey instrument. Other problems are related to finding age-matched controls. Control patients are often younger. Also, some investigators have found no definite difference in QoL between patients with glaucoma and controls (Gutierrez et al. 1997; Parrish et al. 1997; Wandell et al. 1997), whereas others have noted lower QoL in patients with glaucoma (Sherwood et al. 1998; Wilson et al. 1998). In Sweden, Wandell et al. (1997) compared patients with glaucoma with an age-matched group of nonglaucomatous subjects by using the Swedish version of the general Health-Related Quality of Life (HRQoL) questionnaire. These authors found no difference in QoL between the two groups, nor did it appear that QoL was affected by treatment with beta-blockers. Glaucoma is the most widespread age-related eye disease after cataract (Ryskulova et al. 2008), and it is the second most common cause of blindness in the world (Resnikoff et al. 2004; Quigley & Broman 2006). It has been estimated that about 60 million people over the age of 40 would be affected in 2010, and that one-fourth of those would have angle-closure glaucoma and the rest open-angle glaucoma. Calculations have indicated that the prevalence of open-angle glaucoma (i.e. the proportion of the population suffering from the disease) is approximately 2% in populatitons over the age of 40 (Quigley & Broman 2006), although the rate varies depending on the age group and the population under consideration. In the European population, the prevalence of glaucoma has been found to be 2% in people over the age of 40 (Quigley & Broman 2006) or 6% in people over the age of 70 (Rudnicka et al. 2006). Similar results were obtained in the large Swedish screening study entitled the Malmö Eye Survey, which showed a prevalence of more than 5% in 75-year-olds (SBU, 2008) and more than 2% in the age group 57–79 years. Other investigations in Sweden have indicated both lower (Bengtsson 1981) and higher (Ekström 1996; Åström et al. 2007) prevalences. Some of these discrepancies might be explained by the occurrence of exfoliation syndrome. Exfoliation syndrome is common in Sweden, predominantly in women (Ekström 1996; Åström & Lindén 2007), and prevalence increases substantially with greater age (Åström et al. 2007). In the north of Sweden, Åström and colleagues (2007) detected exfoliations in 23% of all 66-year-olds, and, after 21 years of follow-up (subjects aged 87), 61% of the cohort had developed exfoliations in one or both eyes. Ocular hypertension (elevated IOP without signs of glaucoma damage) is another risk factor that increases with age. A number of studies have found prevalence of 5–9% for this condition, which is several times higher than the level noted for open-angle glaucoma. In the Malmö Eye Survey, ocular hypertension was found to be twice as common as glaucoma (SBU, 2008). Since there is no difference in life expectancy between people with and without glaucoma (Grødum et al. 2004), age-specific prevalence data can be used to estimate the incidence of this disease (i.e. the proportion who recently developed glaucoma; Podgor et al. 1983). Since the prevalence increases exponentially with advancing age, most markedly in the white population, it can be concluded that the incidence also rises with age (Rudnicka et al. 2006). Accordingly, older age is associated with a greater risk of developing glaucoma. Only a few studies in the literature have addressed the incidence of glaucoma, and several of them were conducted in Sweden. The incidence found in those investigations varies from 0.24% among 65- to 80-year-olds in Dalby (Bengtsson 1989) to 0.64% in the corresponding age group in Tierp (Ekström 2008) and 0.9% in 66- to 87-year-olds in Skellefteå (Åström et al. 2007). Such high incidence numbers have otherwise only been reported in a black population (Leske et al. 2007b). It has been shown that half (Ekström 1996; Quigley 1996) or more than half (Quigley & Broman 2006) of all cases of glaucoma revealed by population surveys are undiagnosed. It is not known exactly how many people in Sweden have been identified as having glaucoma. Nonetheless, the number has been estimated to be approximately 100 000, although that value is highly uncertain. Considering that 4.6 million people in Sweden are over the age of 40 (SCB. Statistiska Centralbyrån 2008), 100 000 known cases of glaucoma would imply the following: most of the people with glaucoma in this country are identified, which is contradicted by prevalence studies performed thus far; or glaucoma prevalence is higher than 2%, an assumption for which there is some support; or the estimate is incorrect and also includes, for example, patients with ocular hypertension. In a fairly recent meta-analysis that comprised 25 studies including more than 60 000 subjects, 1355 of them with glaucoma, Rudnicka et al. (2006) noted that glaucoma prevalence was more than about 1.4 times greater in men than in women. However, other analyses have provided conflicting results. Patients with glaucoma detected by population screening differ in many ways from patients who are diagnosed at an eye department. Individuals in the latter group are much more likely to exhibit higher IOP, more extensive visual field damage and bilateral disease (Grødum et al. 2002a), as well as exfoliation syndrome. In Malmö and Tierp, exfoliation glaucoma constituted 44% and 60% of clinically diagnosed patients with glaucoma, respectively, but only 16% of the cases detected at screening, in both cities. On the other hand, normal-tension glaucoma was detected more often by screening. In Malmö, half of the cases identified by screening had low-tension glaucoma, one-third in Tierp. Clinically diagnosed patients were considerably fewer, 14% and 0% in Malmö and Tierp, respectively (Ekström 1996; Grødum et al. 2002a). These observations suggest that normal-tension glaucoma is frequently overlooked in clinical examinations. A risk factor is an event, a condition, a behaviour or some other aspect that can have an impact on development of a disease. There is both a causal and a statistical relationship between a risk factor and the illness in question. A simple statistical relationship between the risk and the disease can suffice as a marker or an indicator of risk. In many cases, we do not distinguish between these two concepts and instead, somewhat imprecisely, refer to them as risk factors, which also applies in these guidelines. Many risk factors are confirmed in cross-sectional epidemiological studies, and hence it is important to have a uniform definition of the disease when studying risk factors. Vision 2020 is a global initiative that was established jointly by the WHO and other organizations with the intention of eliminating all avoidable blindness. Vision 2020 defines glaucoma as both structural and functional damages. In some cases, for instance, optic disc changes or abnormal values in a visual field index are interpreted as risk factors for glaucoma. These are signs of disease and thus cannot actually be regarded as risk factors for developing glaucoma. A number of other factors have been reported to increase the risk of both occurrence and progression of glaucoma. However, although these factors are often the same, it seems that they may differ regarding their impact on development and progression of the disease. Older age is strongly related to glaucoma. Both incidence and prevalence increase with age (Gordon et al. 2002; de Voogd et al. 2005; Miglior et al. 2007b; Leske et al. 2008), and older age is also a risk factor for glaucoma progression (Lichter et al. 2001; The advanced glaucoma intervention study (AGIS) 2002; Leske et al. 2007a,b; Chauhan et al. 2008b). Prevalence of glaucoma is higher in people of African descent than in those of European ancestry (Leske et al. 1994). In one study (Tielsch et al. 1991), prevalence in the comparatively young age range of 51–60 years was found to be four times higher in black Americans than in white Americans. Glaucoma in first- or second-degree family members is a risk factor, regardless of IOP (Hulsman et al. 2002; Leske et al. 2008). The risk may be greater if a sibling has glaucoma than if a parent has the disease (Wolfs et al. 1998). Recommendations concerning medical checkups are given in the section headed Glaucoma and positive family history (p. 32). Elevated IOP is the most important risk factor for both development (Kass et al. 2002) and progression (Heijl et al. 2002) of glaucoma. In addition, raised eye pressure is the only treatable risk factor. There is no evidence that fluctuation in IOP is an independent risk factor for development or progression of glaucoma. Several studies have provided contradictory results (Singh & Shrivastava 2009). Several investigations have demonstrated a relationship between low ocular perfusion pressure and both development and progression of glaucoma (Leske 2009). The clinical significance of these observations is not clear. Perfusion pressure is related to how blood pressure can affect circulation in the eye, but this concept is much too imprecise to be used in the management of individual patients. In ‘Terminology and Guidelines for Glaucoma’ published by the European Glaucoma Society (2008, p. 89), ocular perfusion pressure is defined as the difference between arterial blood pressure and IOP. However, perfusion pressure is a concept based on general physiological principles, and it does not take into account the decrease in pressure between the eye and the heart, which is also determined by the position of the body or by the drop in pressure in the small vessels leading to the eye. Measuring blood pressure and IOP in a single patient cannot give a definite picture of the perfusion pressure in the eye that is examined in that particular person. The risk of glaucoma is markedly increased in the presence of exfoliation syndrome accompanied by elevated IOP, although it seems that exfoliation syndrome alone does not raise the risk of glaucoma (Grødum et al. 2005; Ekström & Alm 2008). Exfoliation syndrome is also a strong risk factor for glaucoma progression, and there is evidence that this is independent of IOP (Leske et al. 2003). Exfoliation syndrome is common in the Nordic countries. For more information, see the section of this chapter entitled Epidemiology (p. 7). For recommendations regarding management of patients with exfoliation syndrome, see page 32 in the chapter entitled ‘Management of suspected glaucoma and ocular hypertension’. Myopia is a risk factor for glaucoma in people with normal IOP (Grødum et al. 2001; Oku et al. 2009). It is more difficult to detect glaucoma damage in eyes with small optic discs (Heijl & Mölder 1993). Accordingly, larger discs in myopic eyes might explain the association between myopia and glaucoma, although the results of studies of optic disc size and refraction are contradictory (Miglior et al. 1994; Varma et al. 1994). Myopia is probably not a risk factor for progression (Leske et al. 2007a,b). The Goldmann applanation tonometer gives erroneously low measurements in eyes with a thin cornea and inaccurately high values in those with a thick cornea. Therefore, a thin cornea is a risk factor for developing glaucoma (Kass et al. 2002) but represents a nonimportant risk for progression (Leske et al. 2007a,b). Structural and functional changes included in the definition of glaucoma cannot be regarded as risk factors for developing this disease. Consequently, the impact or the size of such changes can only be evaluated in relation to progression of glaucoma. The disease progresses at a faster rate in eyes that have more visual field loss than in those with less loss (Leske et al. 2007a,b). Optic disc haemorrhages increase the risk of progression (Siegner & Netland 1996; Leske et al. 2007a,b; Bengtsson et al 2009a). There is a positive correlation between blood pressure and IOP, whereas no association exists between blood pressure and development or progression of glaucoma (Tielsch et al. 1995b). An explanation for this might be that high blood pressure improves ocular perfusion pressure and thereby reduces the risk caused by elevated IOP. Reports in the literature on this subject are not unequivocal. Some recently published epidemiological studies found an association between cardiovascular disease and glaucoma (Lee et al. 2006; Wu et al. 2008), which other earlier investigations had not been able to demonstrate (Klein et al. 1995; Borger et al. 2003). In the Early Manifest Glaucoma Trial conducted in Sweden, cardiovascular disease was not a significant risk factor for progression of glaucoma after 6 years of follow-up, whereas it was such a factor after 8 years (Leske et al. 2007a,b). In a longitudinal study performed in Canada (Chauhan et al. 2008b), an association was observed after 5 years of follow-up. Diabetes has long been considered a risk factor for glaucoma, which may be explained by bias: patients with diabetes undergo regular eye examinations, which other groups do not, and hence there is a greater probability of detecting glaucoma in diabetics. Notwithstanding, the Blue Mountains Eye Study did find a relationship between diabetes and glaucoma (Mitchell et al. 1997), whereas several other contemporary studies obtained no indication that diabetes was a risk factor for glaucoma in the subjects that were examined, even though IOP was higher in those with diabetes (Tielsch et al. 1995a; de Voogd 2006). Also, in the Ocular Hypertension Treatment Study (Gordon et al. 2002), diabetes was observed to protect against glaucoma. Thus, it seems that there is no evidence that diabetes is a risk factor for glaucoma. It has been suggested that vasospasm, which occurs in both migraine and Raynaud’s syndrome, entails a risk for normal-tension glaucoma (Gasser et al. 1990). However, it is not clear whether these two conditions are related to existence or progression of glaucoma. Both the Blue Mountains Eye Study (Wang et al. 1997) and the Beaver Dam Eye Study (Klein et al. 1993) found migraine to be a risk factor for glaucoma, but the definition of migraine differed in those two investigations and has been disputed. The Swedish Early Manifest Glaucoma Trial found neither migraine nor Raynaud’s syndrome to be risk factors for progression of glaucoma (Leske et al. 2003). It is uncertain whether sleep apnoea is associated with glaucoma. Two clinical studies (Mojon et al. 2000; Girkin et al. 2006) have suggested that such a relationship does exist, whereas other investigations (Geyer et al. 2003; Bendel et al. 2008; Roberts TV et al. 2009b) have not found any connection. It has long been known that use of eye drops containing cortisone increases IOP. Moreover, oral corticosteroid therapy has been shown to raise the risk of ocular hypertension and glaucoma (Garbe et al. 1997). The results of a subsequent study (Mitchell et al. 1999) suggest that nasal sprays and inhalants containing corticosteroids increase the risk of ocular hypertension and glaucoma, particularly in people with a family history of glaucoma. The patients in the cited investigations had both ocular hypertension and glaucoma, and apparently no studies have focused solely on patients with glaucoma. Therefore, it seems reasonable to assume that the risk of glaucoma posed by corticosteroids is mediated indirectly through ocular hypertension. No associations have been found between glaucoma and physical activity (Passo et al. 1991), smoking, body mass index (BMI), alcohol or coffee consumption, or diet. The basis for the glaucoma diagnosis is optic nerve damage. Such damage is almost always associated with visual field loss. However, damage to the optic disc can occur either with or without accompanying visual field damage (the latter is called preperimetric glaucoma). Also, visual field defects without any identifiable optic disc damage are seen in rare cases involving an unusually small disc. It can be difficult to detect the glaucomatous damage in such a disc, particularly if the disease is bilateral and thus there is no healthy disc for comparison. Therefore, it is of fundamental importance to assess the size of the optic disc during an examination. Exact measurement is difficult to achieve and is seldom of clinical interest. To estimate disc size, the height of the split beam can be adjusted to coincide with the vertical (or horizontal) disc diameter, and the readings are converted according to the auxiliary lens that is used (Lim et al. 1996). Another simple method is to compare optic disc diameter (DD) with disc-to-fovea distance (DM) measured from the centre of the disc to the fovea. The mean of the ratio of DM to DD is 2.5 (Mok & Lee 2002). With increasing experience, it is often possible to estimate the size of the optic disc without relying on measured values. In this context, it can suffice to roughly divide discs into these five classes: very large, large, medium sized, small and very small. A large optic disc will usually have a large physiologic cup (excavation) that can easily be mistaken for glaucomatous damage (Heijl & Mölder 1993). The cup in a small optic disc will normally be very small or lacking, and thus it will be difficult to detect early glaucomatous changes. Therefore, when analysing the appearance of the optic disc, it is important not to concentrate on the size of the cup, but instead to focus on assessing the appearance of the neuroretinal rim and, if possible, also the thickness of the retinal nerve fibre layer (Fig. 1). A large normal optic disc with a large physiologic cup (excavation). The neuroretinal rim is intact and even in width. In glaucoma, a definite sign of optic disc damage is a focal thinning of the neuroretinal rim, which is called a notch (Fig. 2). Such a disc change is associated with localized thinning of the retinal nerve fibre layer in the same area. Glaucomatous optic disc showing notching of the neuroretinal rim (arrow). Another less reliable sign of optic disc damage in glaucoma is a general thinning of the neuroretinal rim (an enlarged cup). The size of the optic disc is of vital importance in this context. A measurement such as the cup-to-disc (C/D) ratio is of very little value, unless it is considered in relation to disc size. Moreover, this ratio offers low sensitivity as a measure in longitudinal follow-up, and thus it can be questioned whether C/D should be used at all. Nonetheless, the thickness of the neuroretinal rim can facilitate the analysis. According to the ISNT rule, in a normal rim the inferior (I) area is thickest, followed by the superior (S), nasal (N) and temporal (T) areas (Jonas et al. 1988a). Deviation from this rule should raise suspicion of glaucomatous damage, although it is neither a sensitive nor a specific sign of glaucoma (Sihota et al. 2008). It is important to notice any difference in size between the cups in the two eyes, but it is first necessary to
Purpose: Tafluprost is a new prostaglandin F2α (PGF2α) derivative in development for the treatment of glaucoma. Tafluprost is the first PGF2α analogue with a preservative‐free formulation.
This Acta Ophthalmologica supplement includes two papers describing the clinical effects of tafluprost (Taflotan®; Santen Oy, Helsinki, Finland), a new bi-fluorinated prostaglandin F2α analogue developed for the treatment of glaucoma. The first article reports an investigation into the systemic pharmacokinetics and intraocular pressure (IOP)-lowering effects of tafluprost in healthy volunteers (Uusitalo et al. 2008). The second paper compares the IOP-lowering efficacy of tafluprost in a conventional preserved formulation with that of preservative-free tafluprost in patients suffering from glaucoma or ocular hypertension (Hamacher et al. 2008). Tafluprost is the first prostaglandin analogue to be available in a preservative-free formulation. The efficacy and safety of tafluprost has been investigated in several clinical trials. A 6-month study showed that tafluprost 0.0015% once/day was at least as effective as timolol 0.5% twice/day (achieving IOP reductions of 5–7 mmHg and 4–6 mmHg, respectively). This effect was maintained for ≤ 12 months (Taflotan Summary of Product Characteristics; [2008]). Another 6-month study showed IOP reductions of 6–8 mmHg with tafluprost 0.0015% once/day and 7–9 mmHg with latanoprost 0.005% once/day (Taflotan Summary of Product Characteristics; [2008]). These data demonstrate that tafluprost is effective at lowering IOP. Preservatives are added routinely to multi-dose antiglaucoma medications. The most commonly used preservative is benzalkonium chloride (BAC). Historically, BAC has been used as a preservative and ocular penetration enhancer for topically applied medications because it destroys tight junctions and thus may facilitate paracellular diffusion across the ocular surface (Okabe et al. 2005; McCarey & Edelhauser 2007; Majumdar et al. 2008). There is a perception that BAC is required for ocular penetration and good drug activity. However, Pellinen & Lokkila (2008) found equivalent concentrations of tafluprost acid in the aqueous humour of rabbits following topical applications of preserved and preservative-free tafluprost solutions. Uusitalo et al. (2008) report comparable reductions in IOP by preservative-free and preserved formulations of tafluprost. Hamacher et al. (2008) compared the IOP-lowering efficacy of preserved versus preservative-free tafluprost eyedrops in patients diagnosed with either primary open-angle glaucoma or ocular hypertension. No differences were found between the two groups of patients in terms of the IOP-lowering efficacy of the medications throughout the 4-week treatment period of this study (Hamacher et al. 2008). Likewise, no differences in IOP reductions were found between BAC-preserved and BAC-free formulations of β-blockers (Baudouin & de Lunardo 1998; Bron et al. 2003; Easty et al. 2006) and travoprost (Lewis et al. 2007). These data provide clear evidence that BAC is not required for IOP reduction, at least not with lipophilic drugs such as prostaglandins. Virtually, all preservatives have inherent toxic properties associated with their mechanism as preservatives, and there is an increasing body of evidence to support the hypothesis that BAC has a concentration-dependent toxic action on the ocular surface (De Saint Jean et al. 1999; Debbasch et al. 2001). In vitro studies have demonstrated that high concentrations of BAC induce oxidative stress (Debbasch et al. 2001), promote the expression of inflammatory and apoptotic markers (De Saint Jean et al. 1999), and result in epithelial cell death (Rolando et al. 1991). In vivo models have also confirmed the adverse effects of BAC (Labbé et al. 2006). In rabbit models, preserved formulations of antiglaucoma medications display significantly more adverse effects than preservative-free formulations (Pisella et al. 2000). The relative toxicity of preserved antiglaucoma formulations appears to be directly proportional to their respective concentrations of BAC (Guenoun et al. 2005; Brasnu et al. 2008). In the two short-term studies reported in this supplement, both the preserved and preservative-free tafluprost formulations were generally well tolerated (Hamacher et al. 2008; Uusitalo et al. 2008). In clinical practice, many patients with glaucoma use several medications simultaneously, leading to substantial exposure to preservatives such as BAC. Ocular signs and symptoms have been reduced when patients switch from preserved to preservative-free formulations, or reduce the number of preserved eyedrops administered (Pisella et al. 2002; Jaenen et al. 2007). Thus, the data from the studies published in this supplement (Hamacher et al. 2008; Uusitalo et al. 2008) demonstrate that the preservative-free tafluprost formulation achieves a reduction in IOP equivalent to that obtained by the preserved formulation. Further larger-scale and longer-term studies are required to assess the effects of preservative-free tafluprost ophthalmic solution in the treatment of glaucoma. For patients suffering from dry or sensitive eyes, tafluprost seems to be a beneficial addition to the prostaglandin glaucoma medications group. The author has acted as a paid consultant to Santen Inc.
PURPOSE:Prostanoid F(2alpha) (PF(2alpha)) analogues are commonly used as first-line treatment of glaucoma. Tafluprost is a newly synthesized PF(2alpha) derivative and represents the first PF(2alpha) analogue with a fully preservative-free formulation.METHODS:A randomized, investigator-masked, single-centre, crossover phase I study evaluated the pharmacokinetics, efficacy and safety profiles of preserved and preservative-free tafluprost 0.0015% eyedrops in healthy volunteers. Both formulations were administered once/day for 8 days each. Plasma concentrations and, consequently, area under the curve (AUC(0-last)), maximum concentration (C(max)) and time to maximum concentration (t(max)) were determined for tafluprost acid, the biologically active metabolite. Intraocular pressure, adverse events, and ocular and systemic safety parameters were analysed.RESULTS:There were no statistically significant differences in pharmacokinetic parameters between preserved and preservative-free formulations after either single (day 1) or repeated (day 8) dosing. The mean (+/- standard deviation) results for preserved and preservative-free formulations on day 8 were, respectively: AUC(0-last) 581.1 +/- 529.9 pg/min/ml versus 431.9 +/- 457.8 pg/min/ml (p = 0.462); C(max) 31.4 +/- 19.5 pg/ml versus 26.6 +/- 18.0 pg/ml (p = 0.294), and median (range) t(max) 10 (5-15) for both. Generally, plasma concentrations of tafluprost acid were low at all time-points and were cleared rapidly from the circulatory system. There were no unexpected safety findings. The incidence of ocular hyperaemia was similar in both formulations and was of predominantly moderate severity with preserved tafluprost and mild severity with preservative-free tafluprost.CONCLUSIONS:Preservative-free tafluprost appeared to have similar pharmacokinetic properties to the preserved formulation and was generally well tolerated.
The purpose of the present study was to establish a method for objective measurements of visual readaptation after flash exposures and to define a model for measurements. Influences of target direction, luminance and velocity on optokinetic nystagmus (OKN) were investigated under scotopic conditions. Visual readaptation was measured using OKN as an indicator of visual perception after exposure to a flash. The interval between the triggering of the flash and the reoccurrence of OKN was defined as the visual readaptation time (RAT). A Goldmann perimeter hemisphere was used for flash stimulation. A horizontally moving vertical grating projected inside the hemisphere was used as the OKN stimulus. Eye movements were recorded by DC electrooculography (EOG). The dependence of RAT on the dose of the flash, the wavelength of the flash and the luminance of the OKN target were investigated. The precision of the measurement method was studied. This includes the analysis of the variance due to the experimental occasions, the repeated exposures, the sexes of the subjects, the methods for recognition of OKN and the ways of visual adaptation before measurements. The contributions of retinal receptor and the neural activity to RAT were investigated by electroretinography (ERG). The influences of target direction and luminance on binocular motion perception and OKN as well as monocular OKN were examined at various target velocities. The dependence of the frequency and amplitude of eye jerks during monocular OKN on target luminance and velocity were also examined. It was found that RAT increases with increasing doses of the flash or decreasing luminance of the grating. RAT is most extended after flashes near 520 nm. RAT does not differ between experimental occasions, between a manual and a semi-automatic method for recognition of OKN, between the sexes and between goggle adaptation and ordinary dark adaptation. There is a reduction of RAT due to repeated flash exposures. The data collected indicate that a well-defined model is crucial for measurements of RAT. The measurement of ERG showed that RAT is mediated by both retinal receptor and the neural activities. The receptor component depends on the wavelength of the flash while the neural component is wavelength-independent. Moreover, it was found that motion perception and OKN gain does not differ between right and left target directions. For a given target velocity, motion perception and OKN gain under both binocular and monocular viewing conditions increase with increasing luminance of the target with an exponential decay. The maximum OKN gain decreases as target velocity increases.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract. In a group of infants and children of very preterm delivery (gestational age 30 weeks or less, n = 411, Rigshospitalet Copenhagen 1983–89) 13 got blind due to retinopathy of prematurity (3.2%) while another 13 with sequelae retained useful vision of at least one eye. One child later acquired bilateral retinoblastoma, with a free interval of one year from a protracted course of ROP stage 2–3 eventually to regress. The 411 surviving subjects being recruited from a total of 515 of a similarly low gestational age, the survival rate in the 7-year period under study was just below 80%. No doubt, the high survival rate in this very pre-term group is of importance for the risk of developing retinopathy of prematurity, but the role of the ophthalmologist in controlling the infants is also emphasized. Generally, stricter observation schemes are recommended. - Probably, the ROP frequency in the sample of 23.6% is an underestimate.
Abstract. Frequency and natural history of retinopathy of prematurity (ROP) were prospectively studied in 142 preterm infants with birth weight (BW) less than 1501 g and/or gestational age (GA) below 33 weeks, who were born in Malmö 1986–1990. ROP developed in 27 (19%) of the 142 infants. The frequency of the ROP was significantly higher in infants with BW ≤ 1000 g (54%) and in those with GA ≤ 28 weeks (40%) than above these values. Infants with ROP had, compared with those without ROP, significantly lower BW, lower GA, lower Apgar score at 1 and 5 min, longer period of oxygen-therapy and higher frequency of neonatal complications. Five infants with stage 3 ROP were treated with cryotherapy; four with moderate changes showed good regression, the fifth with a severe stage 3 progressed and became blind. Up to 5 years follow-up revealed a significantly higher frequency of strabismus (40% vs 8%), myopia (25% vs 4%), and amblyopia (33% vs 6%) in infants with ROP than in those without ROP. Astigmatism and anisometropia were also frequent in children with ROP.
Abstract. The aim of this study was to examine the relationship between neonatal clinical conditions and the development of senso‐motoric handicaps. Two hundred and sixty‐two infants with a birth weight < 1500 g, born in or referred to the Karolinska/S:t Göran's Children Hospital from September 1988 to april 1992 were studied prospectively. The total survival was 83%. Preliminary results of the Griffiths' test of these infants showed an average cognitive ability of the same level as for fullterms except for those pre‐term infants who had suffered from the combination of chronic lung disease and leucomalacia. The incidence of moderate to severe senso‐motoric disability is up to the present time 5%.
138 premature infants born 1989-1991 have been examined by the ophthalmologist in Children's Hospital, University of Helsinki. The mean gestational age was 27.3 weeks and the mean birth weight 986 grams. Twenty-four cases of ROP were found. Seven of them got cryocoagulation treatment in both eyes for ROP 3 with plus disease. Only one child became blind. The risk to get ROP was 17.4% in the whole material and was highest among the most immature infants. The cryocoagulation treatment appeared an effective therapy to prevent blindness.
The incidence of retinopathy of prematurity (ROP) was studied in prematures in the southern part of Sweden during one year. Nine hospitals participated in the prospective study. During the period 23,745 children were born in the region. One hundred and ninety-three of 214 prematures of gestational age < or = 32 weeks and/or birth weight < or = 1500 g, were subjected to ophthalmic investigation. The incidence of ROP among the prematures under study was calculated to 9% (17 children). Six of them had severe ROP (3%). Some risk factors associated to ROP are discussed.
Abstract. Retinopathy of prematurity (ROP) is a leading cause of severe visual impairment and blindness in infancy. Transscleral cryotherapy has been shown to be effective in arresting the progression of ROP into the sightthreatening fibrovascular stages of the disease. It is currently recommended that all eyes reaching ‘threshold’ ROP should be treated. If both eyes of an infant reach ‘threshold’, both eyes should be treated. For centers that handle a limited number of infants with ROP it is suggested that the cryotherapy should be done under general anesthesia.
Results are presented from a case material of 22 prematurely born infants (43 eyes) who received cryotherapy for retinopathy of prematurity (ROP); 20 eyes were treated at stage 3, 14 at stage 3 plus, and nine at stage 4A. Follow-up examinations at the age of 26 to 52 months (average 38 months) showed regression of ROP in all eyes and visual acuities of 6/60 or better. The timing of cryotherapy is discussed. The present experience indicates treatment earlier than recommended by the US Cryotherapy of Retinopathy of Prematurity Study Group. There are, as yet, no reliable clinical criteria that can predict which eyes will progress from stage 3 to stages 4 or 5 (tractional retinal detachment or retrolental fibroplasia). Hence, infants at risk should be repeatedly examined and a progression towards impending retinal detachment diagnosed.
Retinopathy of prematurity (ROP) is a leading cause of severe visual impairment and blindness in infancy. Transscleral cryotherapy has been shown to be effective in arresting the progression of ROP into the sight-threatening fibrovascular stages of the disease. It is currently recommended that all eyes reaching 'threshold' ROP should be treated. If both eyes of an infant reach 'threshold', both eyes should be treated. For centers that handle a limited number of infants with ROP it is suggested that the cryotherapy should be done under general anesthesia.
Between 1987-89 fifteen premature infants with severe retinopathy of prematurity (ROP), at the age of ten months or less, were admitted as outpatients to the Department of Ophthalmology at the Orebro Medical Center Hospital. Initial examination of the infants showed that 6 eyes had stage 3+, 3 eyes had stage 4B and 21 eyes had stage 5 ROP. All 15 infants were born at gestational week 24-28 (mean value 26) and had a birth weight between 600 and 1310 g (mean 907 g). For stage 3+ cryotherapy was performed. For stage 4B and 5 buckling procedure and vitreous surgery was performed in an attempt to re-attach the retina. The children were followed 2-5.5 years. Postoperatively, the retinas of all eyes in stage 3+ and 4B were attached. Four retinas out of seventeen stage 5 eyes were later found to be centrally re-attached. One eye with stage 3+ and four eyes with stage 5 were not treated at all. At follow-up of stage 3+ and 4B, visual acuity was measurable in all eyes; in stage 5 only two out of four eyes with anatomically reattached retinas had perception of light.
Frequency and natural history of retinopathy of prematurity (ROP) were prospectively studied in 142 preterm infants with birth weight (BW) less than 1501 g and/or gestational age (GA) below 33 weeks, who were born in Malmo 1986-1990. ROP developed in 27 (19%) of the 142 infants. The frequency of the ROP was significantly higher in infants with BW less-than-or-equal-to 1000 g (54%) and in those with GA less-than-or-equal-to 28 weeks (40%) than above these values. Infants with ROP had, compared with those without ROP, significantly lower BW, lower GA, lower Apgar score at 1 and 5 min, longer period of oxygen-therapy and higher frequency of neonatal complications. Five infants with stage 3 ROP were treated with cryotherapy; four with moderate changes showed good regression, the fifth with a severe stage 3 progressed and became blind. Up to 5 years follow-up revealed a significantly higher frequency of strabismus (40% vs 8%), myopia (25% vs 4%), and amblyopia (33% vs 6%) in infants with ROP than in those without ROP. Astigmatism and anisometropia were also frequent in children with ROP.
Three studies of late outcome in groups of consecutively admitted very low birthweight or very pre-term infants have recently been reported from Rigshospitalet, Copenhagen. The periods were 1976-78, 1980-82, and 1984-87. The incidences of blindness due to retinopathy of prematurity (ROP) and of motor deficit due to cerebral palsy (CP) are analysed in this report. For the present purpose selection within the three groups made them more, although not entirely, comparable. In spite of marked changes in the use of mechanical ventilation, and in survival rate, the incidences of ROP as well as CP remained constant, at about 5% and 10% of the survivors, respectively. The actual numbers are too small for clearcut conclusions but the analysis supports two previously formed notions: 1) According to monitoring of blood gases deviating oxygen and carbon dioxide tensions do not appear as prime factors in inducing neither ROP nor CP, and 2) a very preterm infant of given size and maturity has become less exposed to ROP and CP over the years.
Registration of visual impairment is compulsory in Denmark for the age group 0-17 years. With birth years 1974-91 141 subjects were in the register with retinopathy of prematurity as basic disease, giving a frequency of 13.1 per 100 000 liveborn. Compared with other countries this is a high figure, and the trend over the period is a slight annual increase. Further analysing the data for trends in time the material was subdivided chronologically into thirds, each group comprising 47 subjects. Birth weight and gestational age showed a decline: median values in the three groups were 1250, 1100, and 960 g, and 30, 28, and 27 weeks, respectively. Associated CNS handicaps were recorded in 17, 38, and 34%. Visual impairment was serious in all groups, the median corrected acuity of the better eye being below 1/60. Geographically there was a striking shift towards a Copenhagen area preponderance of heavy ROP cases, with one of the two NICUs to account for the main part of registered cases in the most recent period.
