Age-related macular degeneration (AMD) is the leading cause of severe visual loss in adults in the developed world. AMD affected over 1.7 million people in US alone in 2004. Owing to the rapid aging of the population, the number is expected to increase to 3 million by the year of 2020 [1]. AMD is classified as either dry (nonexudative, atrophic) or wet (exudative, neovascular) form. Individuals with dry AMD typically experience a gradual visual reduction, while those with wet AMD often suffer a more precipitous and profound visual loss. Although most AMD patients (about 90%) have the dry form of disease, the wet form accounts for 80-90% of legal blindness rendered by AMD. [2]. The recent introduction of anti-vascular endothelial growth factor (VEGF) therapies, i.e. pegaptanib, ranibizumab and bevacizumab, has revolutionized the management of wet AMD. About 95% patients treated with ranibizumab showed visual improvement and stabilization [3,4]. However, in order to maintain the therapeutic effect, those patients may require frequent intravitreal injection, often monthly, over an extended period of time.

This tremendously increased frequency in intravitreal administration of therapeutic agents will likely result in a rise of its associated complications. Endophthalmitis is one of the devastating complications that physicians should actively avoid. It has been recommended that prior to intravitreal injections; the ophthalmologist should identify and treat patients with comorbidities that predispose to endophthalmitis, specifically patients with active blepharitis. These recommendations originated from panel discussions to establish guidelines for intravitreal injections, and are followed in many randomized multicenter clinical trials, which notably include blepharitis as a contraindication to trial enrollment or treatment [5,6].

Blepharitis is an inflammation of the eyelid margins which can result in patient discomfort, decline in visual function and cosmetic distress.. It is also known to be commonly associated with dry eye syndrome and rosacea. The etiology of blepharitis can be infectious (commonly caused by Staphylococcus aureus) or inflammatory. It is categorized as anterior or posterior. The former is most often a product of bacterial growth or sebaceous gland malfunction, whereas the latter is almost always associated with dysfunction of the meibomian glands (MGD). According to a 2008 Canadian consensus statement on the identification and management of blepharitis, staphylococcal bacteria were involved in both anterior and posterior blepharitis [7]. Physicians are aware that blepharitis is one of the most common disorders encountered in eyecare practice. [8] However; there is extremely little literature about the prevalence or incidence of blepharitis.

Blepharitis-associated staphylococcal colonization in the eyelids may pose a significant threat for endophthalmitis, a severe complication of intravitreal injections. As patients with age-related macular degeneration may be subject to frequent intravitreal injections, it is important to know how frequently this population develops blepharitis. The purpose of this study is to determine the prevalence and severity of blepharitis amongst patients with age-related macular degeneration (AMD).

This observational study was approved by the Cleveland Clinic Institutional Review Board (IRB). The clinical investigation was conducted in compliance with International Conference on Harmonization (ICH), Good Clinical Practices (GCP) guidelines, and other applicable guidelines and regulatory requirements.

The inclusion criteria were age greater than 18 years, of either sex, with either dry or active wet AMD, presenting to a retina specialist's office for routine eye evaluation. From February to July 2009, a total of 50 patients participated in the study, which included 21 male, 29 female, age 78.1 ± 8.48 years, with both dry (n=21) and wet (n=29) AMD. The written informed consent was obtained prior to any study related procedures were performed.

A self-reported survey was designed to evaluate and score (0-4) the frequency and severity of five common symptoms associated blepharitis reported by patients (Table 1). Subjects were also asked whether they had any history of rosacae, atopic conditions, dry eye syndrome or blepharitis. Current ophthalmic medications were also recorded. All findings were subject to the accurate recall of the participants.

Table 1: Questionnaire for the Symptoms of Blepharitis.

Each participating patient was also seen in a clinical setting by a blinded ophthalmologist investigator, and the ocular surface signs of blepharitis (Table 2) were assessed with slit lamp biomicroscopy and the severity was scored on a range of 0-4.

Table 2: Investigator-rated Assessment of Blepharitis Signs.

Total symptom and sign scores were also calculated and normalized to a scale of 0-10.Severity of symptoms and signs were then categorized as normal (0), mild (0.1-3.3), moderate (3.4-6.6), severe (6.7-10). The incidence and severity of blepharitis symptoms and signs were calculated and compared.

In this patient population with AMD, 32% had a history of dry eye or blepharitis prior to examination and 26% had a history of rosacae or atopic conditions. During the period of study, 29 patients (58%) were not on any kind of topical ophthalmic medications. Eighteen patients (36%) were using artificial tears, and four patients were using no more than two kinds of topical glaucoma drops. And only one patient was using over-the-counter allergy eye drops (Table 3).

Table 3: Usage of ophthalmic medications during the study.

Prevalence and severity of subjective symptoms of blepharitis

Self-reported patient surveys showed that among respondents, 86% reported experiencing at least one of the symptoms and 66% reported more than one symptom (Figure 1) at the investigation time. Mean number of symptoms experienced is 2.62 out of a total of 5 symptoms. The most commonly reported symptom was eyelid itching, and the least common symptom was swollen or heavy eyelids (Figure 2). The severity of individual blepharitis symptom was usually in the mild to moderate range (Figure 3).

Figure 1: Prevalence of symptoms of blepharitis.

Figure 2: Prevalence of individual symptoms of blepharitis.

Figure 3: Severity of individual symptoms of blepharitis.

Prevalence and severity of clinical signs of blepharitis

Blinded clinical evaluation demonstrated similar findings with a high prevalence of blepharitis in participating AMD patients. About 94% had at least one of the clinical signsblepharitis and 92% showed more than one clinical sign (Figure 4). Mean number of signs found is 3.38 out of a total of 4 signs. The most common finding was abnormal secretion expressed from the Meibomian gland, and the least common sign was lid debris (Figure 5).The severity of individual clinical sign were also usually in the mild to moderate range (Figure 6).

Figure 4: Prevalence of clinical signs of blepharitis.

Figure 5: Prevalence of individual clinical signs of blepharitis.

Figure 6: Severity of individual clinical signs of blepharitis.

Comparison of the prevalence and severity of blepharitis symptoms and signs

Self-reported patient surveys and blind investigator examinations demonstrated similar-high prevalence of blepharitis (86% and 94% respectively) (Figure 1 and Figure 4). The prevalence of clinical findings was slightly higher than that of self-reported symptoms. Fourteen percent of total patients reported no symptoms, and six percent had no clinical signs of blepharitis. Normalized data demonstrated that most patients had mild to moderate disease based on both symptoms and clinical exam findings (Figure 7). The incidences were 50% and 36% for mild, 32% and 50% for moderate, and only 4% and 8% for severe symptoms and signs of blepharitis, respectively. The comparable severity scores of blepharitis symptoms and signs are shown in Figure 8. Self-reported symptom scores (2.65 ± 2.16) were generally lower than clinical examination scores (4.08 ± 2.06) (p < 0.001, paired t-test).

Figure 7: Comparison of blepharitis symtoms and signs – prevalence.

Figure 8: Comparison of blepharitis symptoms and signs – severity. * p < 0.05.

The purpose of this study was to determine the prevalence of disease in the AMD patient population, and to further determine the impact, if any, this would have on clinical trial recruitment for studies utilizing intravitreal injections. Based on self-reported findings and investigator exam findings, the prevalence of blepharitis is high in the AMD patient population. This is significant due to the frequent intravitreal injections commonly used in the management of these patients. Additionally, most of the symptoms and clinical findings were classified as mild or moderate. This is the first reported prevalence numbers for this age group and diagnosis.

Self-reported symptoms were generally less severe than clinical findings. We hypothesized that this may be partly attributed to the acceptance of ocular insults as part of normal aging by older individuals. In addition, blepharitis and dry eye disease are chronic conditions and it is quite possible that while symptoms may remit and relapse, the clinical signs would remain even when symptoms were not prominently reported.

Regarding the prevalence of blepharitis, there is little data available on this subject despite clinical awareness that blepharitis is one of the most common disorders encountered in ophthalmologic practice. In the survey by Lempand colleagues of 5019 adults, 79% reported at least one symptom which was verified in our patient series (86%).8 The percent of patients reporting two symptoms was 63%; similar to the 66% we obtained in our study). Interestingly, when stratified by age, Lemp reported lower percentage of patients manifesting symptoms as the age increased (83% in patients 18-49 years old versus 70% of patient 65 and older), but this was not found in our series (86% reported at least one symptom with average age of 78.1 years). This might partially be due to selection bias given that our patients were derived from an ophthalmology clinic while Lemp's data was derived from a randomized phone system in patients with and without ocular disorders. For the purposes of potential AMD patients requiring intravitreal injections, our population is likely more relevant for testing the hypothesis than the population tested in the Lemp study.

This is the first study to confirm that the clinical signs and symptoms of blepharitis are highly prevalent in patients with age related macular degeneration. Whether these findings lead to a higher risk of endophthalmitis following intravitreal injection cannot be confirmed in this report. Further studies utilizing a larger study population should be conducted to determine whether AMD patients with symptoms and signs of blepharitis have an associated higher risk of endophthalmitis following injections.

Dr Werdich and Ms Ruez have no relevant financial disclosures. Dr Singh is a consultant for Genentech, Oraya Therapeutics, and Inspire Pharmaceuticals.

Research support for this project was provided by an unrestricted grant from the Research to Prevent Blindness Foundation to the Cole Eye Institute.