At the completion of this article, the reader should be able to…
• Differentiate age-related
macular degeneration (AMD) from
its common mimickers.
• Interpret OCT and FAF imaging findings in early, intermediate, and advanced AMD.
• Identify hallmark features of
central serous chorioretinopathy, vitelliform dystrophy, and macular telangiectasia type 2.
• Recognise when urgent referral to an ophthalmologist is warranted.
Stefan Siskos
BHlthSci MOrth
Clinical Coordinator,
Vision Eye Institute
Box Hill, Victoria
Differentiating age-related macular degeneration from other causes of macular pathology can be challenging – but the stakes are high, and with new treatment options for geographic atrophy on the horizon, accurate diagnosis is more important than ever, writes Stefan Siskos.
Age-related macular degeneration (AMD) is one of the leading causes of blindness in Australia. It’s estimated that by 2030 1.7 million Australians over the age of 50 will present with signs of AMD.1 Even more alarmingly, in the absence of adequate treatment or prevention, approximately 330,000 cases may progress to advanced disease.1 Early and accurate diagnosis can drastically improve visual outcomes, as delayed intervention in AMD has been shown to be detrimental to visual acuity recovery.2
The good news is: our clinical arsenal is expanding. The increasing availability of diagnostic tools such as optical coherence tomography (OCT) and fundus autofluorescence (FAF) have been pivotal in early screening and diagnosis of AMD and its mimickers. While a thorough and precise patient history lays the foundation in our clinical workflow, it is now seldom just enough. Connecting clinical history with our imaging tools is essential for differential diagnosis. In an environment where early detection can improve visual outcomes, the ability to interpret each imaging modality is pivotal for best care.
To gain confidence differentiating AMD mimickers, we firstly need to understand the risk factors, pathophysiology and clinical findings of AMD itself.
AMD (early and advanced)
Risk Factors
Age-related macular degeneration. The first word in the diagnosis – ‘age’ – indicates one of the major risk factors. AMD is most frequent in individuals aged 65 years and older.3 The progression to advanced AMD can also be attributed to age, with those over 80 having a higher risk of advanced disease.1
A second major risk factor is genetics. Those with a known family history of AMD are at a greater risk of developing the condition.4
When considering AMD, it is also valuable to evaluate your patients’ lifestyle factors, which can affect their risk profile. Both smoking5 and poor diet6,7 contribute to either the development or progression of AMD. Tobacco use has been shown to accelerate the onset of late-stage AMD by five to 10 years compared to individuals who have quit or never smoked.5
Finally, the Age-Related Eye Disease Studies (AREDS 1 and 2) highlighted the link between diet and AMD. Individuals who consumed a high antioxidant diet reduced the risk of AMD progression compared to those who had suboptimal nutrition.6,7
Pathophysiology
The pathophysiology of early AMD is well documented. The retinal pigment epithelium (RPE), or ‘caretaker’ cells, become deficient at removing the protein and lipid waste material from photoreceptors following visual processing. Rather than the waste material passing Bruch’s membrane through to the choroid, the waste is deposited at the RPE level. This cellular waste we all know as ‘drusen’. As the disease progresses, the RPE undergoes further oxidative stress, and cell death eventually commences. It is at this crossroad point that the advanced labels ‘dry’ and ‘wet’ can apply.
Once RPE death commences, the photoreceptors follow suit. This process is geographic atrophy (GA), or ‘dry AMD’ – loss of the RPE and photoreceptor complex in the absence of neovascularisation.
‘Wet AMD’ is characterised by choroidal neovascularisation (CNV) into the retinal tissue. Vascular endothelial growth factor (VEGF) promotes the proliferation of fragile blood vessels into the subretinal space causing capillary leakage and haemorrhage. Left untreated, the haemorrhage is converted to fibrotic scar tissue and the retinal architecture is severely compromised.
Clinical imaging
Considering the natural history of AMD, when utilising OCT imaging we would expect to see disruption at the level of the RPE, photoreceptors and Bruch’s membrane. Drusen and RPE changes are common in the early and intermediate forms of AMD1 (Figure 1A). Pigment epithelial detachments (PED)1 (Figure 1B) present as the disease progresses, and it’s not until we see the advanced (wet) stage where subretinal and intraretinal fluid emerge (Figure 1C). Haemorrhaging on OCT scanning can be a subtle finding. There is often a ‘fuzzy’ area at the level of the RPE (Figure 1D).
As dry AMD is an atrophic process, many of the other findings apparent in the other stages of AMD are absent. Areas of geographic atrophy exhibit a ‘waterfall effect’ on OCT scanning. The RPE and photoreceptor junction ordinarily absorbs the light wavelength transmitted on OCT, and absence of the junction produces a pattern reminiscent of a waterfall (Figure 1E).
Perhaps a more precise method to detect dry AMD is the use of FAF. This technique uses specific light wavelengths that excite lipofuscin and fluorophores which appear in retinal disease.8 The corresponding excitation produces an image demonstrating RPE malfunction or death. Areas of stressed RPE produce hyper-fluorescence (bright white), while hypo-autofluorescence (black) is associated with RPE death. Specifically for GA and dry AMD, areas of photoreceptor and RPE loss appear hypo-fluorescent. The surrounding edge is typically hyper-fluorescent, indicating GA progression as growth (Figure 1F).
Bringing the picture together
When patients present with suspected AMD, it is most important to consider their age and family history. Wet AMD can present with sudden visual disturbances (such as distortion or scotoma) in one eye, but thorough examination of both eyes is vital, as we know AMD occurs bilaterally. It would be unusual to have disease exclusive to one eye, with normal findings in the contralateral eye. When utilising OCT, consider the appearance of the RPE, photoreceptors and Bruch’s membrane. Changes associated with these structures are most prevalent in AMD.
Finally, treating wet AMD with high suspicion is desirable, as early referral and treatment provides greater visual outcomes.2
Central Serous Chorioretinopthy (CSCR)
Risk Factors
Similar to AMD, central serous chorioretinopathy (CSCR) has a well-recognised list of risk factors. Interestingly, many of these risk factors stand in direct contrast to AMD risk factors. CSCR affects men much more commonly than women,9,10 with a mean age of 40.9. Corticosteroid exposure, from tablets, to topical creams or inhalers is a further risk factor.11 If the trigger is not exogenous, we need to consider endogenous factors. Stress, anxiety and type-A personalities have been shown to be a significant influence.11 Sleep apnoea is thought to be another contributing factor, as an elevated stress response occurs during apnoeic episodes.11
Pathophysiology of CSCR
The pathophysiology of CSCR is not as well understood compared to AMD. It is thought that steroid exposure affects the permeability of the choroid and dysfunction of the RPE pump,11 leading to a collection of subretinal fluid. Self-resolution over four-to-six months is common9 with greater improvement apparent once the steroid trigger is addressed.
Clinical imaging
OCT is the key imaging modality supporting diagnosis of CSCR. A key finding is a large, usually sub foveal mound of subretinal fluid (Fig 2A). It’s not uncommon for extrafoveal pockets of subretinal fluid to be present. PEDs are not as common in acute cases, although their presence is more often noted in chronic CSCR.11
FAF imaging also assists with the diagnosis of CSCR. It’s common to find a hyperfluorescent area which corresponds to the patch of subretinal fluid (Figure 2B). In chronic cases, FAF is slightly different. Hyper-fluorescence is seen, but there are also hypo-fluorescent areas indicating persistent disease. A ‘gravity’ or ‘draining’ effect can also be noted in these chronic cases (Figure 2C).
Bringing the picture together
CSCR is one of the few conditions where flagging the risk factors can almost assure correct diagnosis. Young, stressed males with reduced vision and metamorphopsia. Most acute cases are unilateral, and when examining the unaffected eye, findings are typically unremarkable. Although subretinal fluid presents with both CSCR and wet AMD, the absence of other AMD markers (drusen, haemorrhage) swings the suspicion away from the more sinister diagnosis. Interestingly, patients with acute onset CSCR can usually be refracted back to good visual acuity.
Best’s dystrophy/adult vitelliform dystrophy
Risk Factors
Genetic predisposition is the largest contributor to development of Best’s dystrophy.12 Best’s dystrophy presents with a mutation in the BEST1 gene.12 Presentation is in the juvenile years of life, but diagnosis is often made much later on.12 Adult vitelliform dystrophy (AVD) is thought to be a subtype of Best’s dystrophy with a much later presentation.12 The genetic link is not as strong as Best’s, but it may be a factor nonetheless.
Pathophysiology
The exact pathophysiology of AVD is uncertain. Similarly to AMD, it’s believed a dysfunction of RPE metabolism causes the build-up of material in the subfoveal space.12 Lipofuscin, macrophages and oxidative byproducts produce the classic egg yolk appearance12 (Figure 3A).
Clinical imaging
OCT imaging provides impressive assessment in AVD. We most commonly find a subfoveal cumulation of lipofuscin which is hyper-reflective. Drusen and other RPE material can be found at the base of lesion (Figure 3B). The remaining RPE around the lesion is normal.
As disease progresses, some AVD lesions turn hypo-reflective on OCT scanning (Figure 3C).
FAF is an excellent tool for imaging AVD. We frequently see a discrete hyper auto-fluorescent subfoveal lesion which corresponds to the lipofuscin collection (Figure 3D).
Bringing the picture together
With a vague list of risk factors, diagnosis of AVD is mainly sought via imaging and fundoscopy. The central egg yolk presentation, hyper fluorescence on FAF and large lipofuscin mound on OCT are pathognomonic. Apart from the central lesion, no other macular abnormalities are typically present, which acts as a differentiating factor compared to AMD. While both AVD and AMD are commonly bilateral, the unilateral cases of AVD is another flag to raise suspicion on the mimicker.
Finally, patients with AVD rarely indicate acute visual changes, as the condition is slow progressing. In contrast, patients with advancing AMD can often pinpoint a time where a distinct visual decline occurred.
Macular telangiectasia type 2
Risk Factors
Macular telangiectasia (MacTel) is perhaps the most mysterious of the mimickers. Risk factors are poorly understood; however, age and genetics are thought to be involved in the development of the condition.13
Pathophysiology
As MacTel is a relatively poorly understood condition, the pathophysiology of the disease is not concrete. The widely accepted theory involves disorder of the Muller cells14. These retinal glial cells are responsible for inner retinal metabolism, and act as ‘scaffolding’ for the retinal layers.14 Dysfunction and disorganisation of the Muller cells causes retinal atrophy and many of the clinical signs present in MacTel.14
Clinical imaging
OCT imaging is extremely valuable when suspecting MacTel. Cystic cavities commonly appear in the inner retinal layers. These spaces do not cause retinal thickening typical of subretinal or intraretinal fluid but rather produce a thinning effect (Figure 4A). As the condition matures, retinal cells collapse and cavities disappear. Retinal atrophy, photoreceptor loss and capillary pigmentary plaques develop (Figure 4B).
FAF imaging provides insights when imaging MacTel. A subtle hyper auto-fluorescent patch can present at the temporal edge of each maculae (Figure 4C). Finally, capillary blunting and wide angle junctions are also apparent on FAF imaging and fundoscopy (Figure 4D).
Bringing the picture together
MacTel presents with a peculiar set of symptoms. Despite physical changes demonstrated on OCT, early disease sufferers can be asymptomatic. Once symptomatic, patients complain of difficulty reading and commonly note the start of each word is blurry or missing (due to dysfunction of the temporal macular region). Comparatively, AMD patients have large central disturbances with metamorphopsia. Using OCT imaging, MacTel exhibits cystic ‘cookie cutter’ retinal thinning. As we know with AMD, this is juxtaposed. Retinal thickening associated with retinal haemorrhage, fluid and PEDs is frequent.
Referral of AMD and mimickers
Above all, suspicion of wet AMD requires urgent referral. This stands true for the mimickers as well, as CNV can be a rare complication of the discussed masquerades. Delay or failure to refer can be detrimental to long-term visual acuity.
In the absence of wet AMD or CNV, urgent referral is not crucial. Referral patterns can be guided by both the patient and clinician. For example, those with suspected CSCR often push for early referral, as they are the young working demographic that notice an immense visual change. In contrast, elderly patients with intermediate AMD or AVD often are guided by the clinician, as slow visual changes are often not perceived. We see an aspect of tolerance in these cases, as aging often brings other health issues which take precedence over their sight.
One major benefit of referral is the potential to access novel treatments. Multiple dry AMD therapies currently are on the horizon, and clinical trials using gene therapy are underway for MacTel. At a minimum, referral of these patients allows baseline imaging and formal registration of their diagnosis. This opens potential pathways to next-gen treatments or trials.
References
1.Deloitte Access Economics . Macular Degeneration Foundation; 2011. Eyes on the Future. A Clear Outlook on Age-Related Macular Degeneration. 145 pages.
2. Lim JH, Wickremasinghe SS, Xie J, Chauhan DS, Baird PN, Robman LD, Hageman G, Guymer RH. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol. 2012 Apr;153(4):678-86, 686.e1-2. doi: 10.1016/j.ajo.2011.09.013. Epub 2012 Jan 14. PMID: 22245460; PMCID: PMC4869322.
3. Mitchell, P, Smith, W, Attebo, K, Wang, JJ. 1995 ‘Prevalence of age‐related maculopathy in Australia: The Blue Mountains Eye Study’. Ophthalmology 102:1450‐1460.
4. Fajnkuchen, F, Cohen, SY 2008, ‘Update on the genetics of age‐related macular degeneration’, Journal of French Ophthalmology, 31 (6 Pt 1): 630‐637
5. Tan, J, Mitchell, P, Kifley, A, et al 2007, ‘Smoking and the long‐term incidence of age‐related macular degeneration: The Blue Mountains Eye Study’, Archives of Ophthalmology, 125(8): 1089‐1095.
6. AREDS ‐ 2007, ‘The relationship of dietary carotenoid and vitamin A, E, and C intake with age‐related macular degeneration in a case‐control study’, Archives of Ophthalmology, Report Number 22, 125(9):1225‐1232.
7. AREDS – 2001, ‘A randomized, placebo‐controlled, clinical trial of high‐dose supplementation with vitamins C and E, beta carotene, and zinc for age‐related macular degeneration and vision loss’, Archives of Ophthalmology, Report Number 8, 119(10): 1417‐1436.
8. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging: review and perspectives. Retina. 2008 Mar;28(3):385-409. doi: 10.1097/IAE.0b013e318164a907. PMID: 18327131.
9. Kanda P, Gupta A, Gottlieb C, Karanjia R, Coupland SG, Bal MS. Pathophysiology of central serous chorioretinopathy: a literature review with quality assessment. Eye (Lond). 2022 May;36(5):941-962. doi: 10.1038/s41433-021-01808-3. Epub 2021 Oct 15. PMID: 34654892; PMCID: PMC9046392.
10. Liew G, Quin G, Gillies M, Fraser-Bell S. Central serous chorioretinopathy: a review of epidemiology and pathophysiology. Clin Exp Ophthalmol. 2013 Mar;41(2):201-14. doi: 10.1111/j.1442-9071.2012.02848.x. Epub 2012 Sep 21. PMID: 22788735.
11. Daruich A, Matet A, Dirani A, Bousquet E, Zhao M, Farman N, Jaisser F, Behar-Cohen F. Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. Prog Retin Eye Res. 2015 Sep;48:82-118. doi: 10.1016/j.preteyeres.2015.05.003. Epub 2015 May 27. PMID: 26026923.
12. Nipp GE, Lee T, Sarici K, Malek G, Hadziahmetovic M. Adult-onset foveomacular vitelliform dystrophy: epidemiology, pathophysiology, imaging, and prognosis. Front Ophthalmol (Lausanne). 2023 Aug 10;3:1237788. doi: 10.3389/fopht.2023.1237788. PMID: 38983024; PMCID: PMC11182240.
13. Charbel Issa P, Gillies MC, Chew EY, Bird AC, Heeren TF, Peto T, Holz FG, Scholl HP. Macular telangiectasia type 2. Prog Retin Eye Res. 2013 May;34:49-77. doi: 10.1016/j.preteyeres.2012.11.002. Epub 2012 Dec 3. PMID: 23219692; PMCID: PMC3638089.
14. Newman E, Reichenbach A. The Muller cell: a functional element of the retina. Trends Neurosci. 1996;19(8):307–312. doi:10.1016/0166- 2236(96)10040-0.
