A Clinical Review on the Holism of Ophthalmology – The Associations Between Systemic Diseases and Ocular Conditions

This is an up-to-date review on the holism of ophthalmology, covering the associations between eyes and systemic diseases. Ophthalmology teaching in the undergraduate medical curriculum is often very brief, which seems reasonable in view of other specialties such as internal medicine which have many life-and-death issues and numerous diseases across a wide spectrum of subspecialties. By contrast, ophthalmology gives the impression of being more specialized. However, the value which vision holds in people’s hearts is usually underestimated when compared to life or limb. Moreover, the severity of visual impairment in relation to its impact on daily life is also often not proportional; in other words, mild visual impairment may have a detrimental effect on daily life, functionally and emotionally. This review aims to provide an overview of ocular pathologies that are associated with systemic diseases with emphasis on cardiovascular and autoimmune conditions. In addition, we discuss the potential role of retinal microvascular analysis in the prevention and management of cardiovascular diseases, which has been gaining attention in recent years. Copyright Royal Medical Society. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISBN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, 2015, 23(1):38-47. doi:10.2218/resmedica.v23i1.1240 Res Medica 2015, Volume 23, Issue 1


Introduction
A survey of 11,000 people in 11 countries, conducted by Bausch & Lomb (one of the eye-care giants), demonstrated that rather than losing sight, 67% of people would rather lose 10 years of life, 68% would rather sacrifice a limb, 78% would rather lose their ability to hear and 79% would rather lose their sense of taste. 1 However, while facing numerous life-and-death issues in the medical field, we often forget that there are things that a patient may weigh even more importantly than life -such as vision.
Vision is the dominant sensory modality that the majority of human beings use to interpret the world.The ability to see provides us with a sense of security.We often only appreciate this after it's gone, which may occur even following minor issues, such as the changes in refractive error and the need for new glasses.Nevertheless, the "minor issue" of uncorrected refractive error is the commonest global cause of moderate-to-severe visual impairment according to World Health Organization, 2 even though refractive-error correction is neither difficult nor expensive.
There is also relatively less emphasis in our undergraduate curriculum on the active detection and timely referral of ocular presentations in systemic diseases and the correlation of ocular features with systemic diseases.Therefore, this review seeks to provide a non-exhaustive overview of the holism of ophthalmology to attempt to, at least in part, redress this balance.

Methods
The studies that are cited in this clinical review were retrieved from PubMed and Ovid (Embase).Titles and abstracts retrieved from search strategies were screened based on the sequence of "sort by relevance", then full texts were accessed for selected studies.Three main search methods were applied: 1) Usage of "all fields" of keywords pertaining to particular anatomical structures of the eye (e.g.retina) and "systemic diseases" or the specific name of known associated systemic diseases (e.g."diabetes mellitus"), with or without the use of filters such as "review", "meta analysis", "published in the last 5 years" and "published in the last 10 years".Relevant studies with higher evidence levels such as meta-analyses and reviews, which can portray the holism of ophthalmology through the association with systemic diseases, were given highest priority during selection of references.
2) Single search terms, e.g."Vogt Koyanagi Harada disease", "drug-induced uveitis" and "peripheral ulcerative keratitis", applied to "all fields" were used only once a specific system disease was confirmed to have ophthalmological associations and further information was desired.
3) To provide evidence of specific facts such as ten anatomic layers of retina, more specific keywords like "ten layers of retina" under "all fields" with filters such as "review" were used.
Some references were manually searched from the studies that were selected in the first round of abstract screening and some from the "similar articles" and "find similar" sections on PubMed and Ovid (Embase) respectively.Relevant websites, mainly http://emedicine.medscape.comand http://www.uptodate.com,with contents strongly evidence-based, were cited.
Emphasis has been placed on cardiovascular and autoimmune diseases, as these two groups can be commonly encountered in all specialties due to the high prevalence of cardiovascular diseases and the multi-systemic involvement of autoimmune diseases.

A. CARDIOVASCULAR DISEASES 1. Retina
The ocular component that is best known to have associations with cardiovascular disease is the retina.The retina, the innermost layer of the globe, is divided into outer retinal pigment epithelium (RPE) and inner neurosensory layer. 3It is associated with diabetes mellitus, hypertension, arteriosclerosis, coronary heart disease and cerebrovascular diseases.] (i) Diabetic Retinopathy Diabetic retinopathy (DR), the most important ocular manifestation of diabetes mellitus, is classified into non-proliferative retinopathy, proliferative retinopathy and maculopathy. 7Patients are usually asymptomatic until advanced stages where blurring of vision, metamorphopsia, floaters and sudden visual loss may occur. 8The severity of retinopathy is related to the duration of diabetes, a younger age at diagnosis, higher glycosylated hemoglobin levels, higher systolic blood pressure, use of insulin, presence of proteinuria, and low body mass. 9herefore, the signs of diabetic retinopathy (Table 1), of which most are easily detected on direct fundoscopy, should be actively sought, especially in those with the aforementioned risk factors. 7,8,10 ot and blot hemorrhages.
• Macular oedema.Diabetic Maculopathy/ Diabetic macular oedema (DME) Clinically significant if any of the below occurs: • Retinal thickening occurs at or within 500 microns of the center of macula.
• Hard exudates at or within 500 microns of the center of macula, if associated with thickening of adjacent retina but not residual hard exudates remaining after disappearance of retinal thickening.
• Zone(s) of retinal thickening at least 1 disc area, any part of which is within 1 disc diameter of the center of macula.
Visual impairment and blindness are still major concerns in type I diabetes (DM1), despite strict glycemic control and use of laser photocoagulation 4 .The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) showed that wider retinal arterioles were associated with 10-fold increase in the incidence of DR in patients with type 2 diabetes (DM2) [odds ratio, OR=1.78]. 11This was further supported by a prospective cohort study (OR=4.79). 12A cross-sectional study demonstrated that lower retinal fractals (a self-similarity characteristic of retinal vasculature where the overall shape and structure will persist regardless of changes in magnification) 13 were associated with proliferative retinopathy (OR=1.45),neuropathy (OR=1.42),nephropathy (OR=1.39),but not macrovascular disease. 14Therefore, retinal arteriolar caliber and fractals might be useful in predicting the microvascular damage caused by diabetes, without being limited to intrinsic retinal changes.

(ii) Retinal Venous Occlusion
Retinal venous occlusion (RVO) is the second most common retinal venous disease after DR and an important cause of visual morbidity and blindness. 15ranch RVO can be asymptomatic or produce metamorphopsia or relative scotoma, and on occasion may only be detected incidentally on fundoscopy. 16Central RVO classically presents as sudden painless monocular visual loss or dense central scotoma, although non-ischemic type may be more subtle and present as intermittent episodes of blurred vision. 16Retinal signs of RVO are easily detected on direct ophthalmoscopy (Table 2) and hence can be diagnosed clinically. 15,17 Arteriosclerosis.
A 2014 meta-analysis evidenced that, apart from the immutable risk factor of advancing age, the other risk factors for RVO are all systemic (Table 2). 15,17etabolic syndrome greatly increases the risk of RVO, especially if end-organ damage due to diabetes or hypertension has occurred. 15The role of thrombophilic risk factors remains controversial, although congenital thrombophilic diseases, hyperhomocysteinemia and anticardiolipin antibodies can all increase the risk of RVO. 15 Therefore, in elderly patients with cardiovascular risk factors that present with sudden painless visual loss, RVO should be among the top differential diagnoses.

(iii) Hypertensive Retinopathy (HR)
In individuals with elevated BP, visual loss can occur due to hypertensive retinopathy (HR). 18Hence, ophthalmoscopy has long been adopted as part of the evaluation of hypertensive patients. 18,19 R can be classified into mild, moderate and malignant according to population-based data (Table 3). 18ssociations with clinical CVA, subclinical CVA, cognitive decline, coronary heart disease, congestive heart failure, and cardiovascular mortality may exist once patients develop mild HR and increase proportionally with severity. 18,20 n algorithm has been designed to provide specific management plan according HR severity.

(iv) Transient monocular visual field loss (TMVL)
Transient monocular visual field loss (TMVL), typically sudden and painless, 21 is divided into embolic (eTMVL) and non-embolic (neTMVL). 22isual field loss can be sectorial (''curtain effect'') or altitudinal, which strongly suggests vascular etiology. 23,24This may follow the horizontal meridian in a branch retinal arterial occlusion or follow the vertical meridian in a posterior ciliary arterial occlusion, which will also require investigation to exclude a possible occipital stroke 22 .eTMVL is associated with increased stroke risk and hence requires urgent assessment. 22The source of emboli can be the heart, carotid artery or aorta. 22here might be co-existing atrial fibrillation, past or recent cardiac ischemia, metabolic syndrome and hypercoagulability. 22r central retinal arterial occlusion (CRAO), fundoscopy can be carried out to detect a fibrinplatelet thrombus or cholesterol embolus (a Hollenhorst plaque) within the lumen of the central retinal artery (15-29% detection rate on direct ophthalmoscopy) and retinal infarction with a cherry red spot (during acute phase, 90% of all cases with permanent visual loss and 59% of transient cases). 22,25Other acute phase signs of CRAO include retinal opacities (59%), visible emboli (15%), disc oedema (11%), disc pallor (11%), attenuated retinal arteries (11%), cotton-wool spots (7%), and attenuated veins (7%). 22TMVL is thought to be associated with retinal vasospasm, which, if observed during direct fundoscopy, is diagnostic. 22Hence, a broader differential diagnoses of secondary vasospasm should be considered when suspecting neTMVLincluding autoimmune diseases (e.g.giant cell arteritis, systemic lupus erythematosus and rheumatoid arthritis); infectious diseases (e.g.bacterial meningitis); vascular diseases (e.g.subarachnoid hemorrhage and intracerebral hemorrhage); and other causes (e.g.malignancy and beta blocker usage). 22

(v) Cardiovascular Diseases
According to the World Health Organization, cardiovascular disease, particularly ischemic heart disease, cerebrovascular diseases and diabetes mellitus are within the top 10 causes of mortality since 2000 and will continue as such at least till 2030, irrespective of the income levels. 26,27 009 review summarized the relationship between retinal vascular caliber with various systemic factors, such as age, hypertension, obesity, coronary artery disease, smoking, and systemic inflammation. 28ecent data also demonstrated a potential genetic contribution. 28tinal vascular caliber is usually quantified on digitized or digital retinal images with computerassisted programs, and cannot be accurately measured clinically as yet. 29However, it is important to be aware of the rapidly growing importance of the role of non-invasive retinal microvasculature analysis on the prediction, prevention and monitoring of cardiovascular diseases, which has the potential for significant impact on morbidity and mortality in the future. 6,28e reduction in flicker light-induced retina-arterial vasodilation, which has been shown to be endothelium-and nitric-oxide-dependent, has also been shown to be associated with cardiovascular risk factors, such as diabetes mellitus. 6Multiple reviews concluded that since endothelial dysfunction precedes the development of morphological vascular changes, the assessment of endothelial function could have a diagnostic value, especially in patients with cardiovascular risk factors. 6,29

Optic nerve (i) Ischaemic optic neuropathy (ION)
Ischaemic optic neuropathy (ION), a major cause of blindness or severe visual impairment, was discussed in detail in a 2009 review. 30Non-arteritic anterior ischemic optic neuropathy (NA-AION) is by far the most common type among the 6 distinct clinical categories of ION and one of the most prevalent and visually crippling diseases in the middle-aged and elderly. 30NA-AION is associated with arterial hypertension, arterial hypotension, diabetes mellitus, hyperlipidemia, ischemic heart disease, atherosclerosis, and arteriosclerosis. 30The majority of cases present with sudden, painless visual deterioration, particularly loss of the nasal fields, discovered upon waking up in the morning. 30,31Photophobia is common in bilateral cases. 30Other signs which may be elicited during clinical examination include relative afferent pupillary defects in unilateral cases, optic disc oedema, splinter hemorrhage on the optic disc or in the peripapillary region, serous retinal detachment, and macular edema. 30teritic AION (A-AION), although less common, is an ocular emergency that is almost invariably caused by giant cell arteritis (GCA), with the single strongest risk factor being age. 32GCA, which is associated with increased cardiovascular risk, is mainly a clinical diagnosis and has to be actively sought, especially in elderly patients, based on the American College of Rheumatology 1990 criteria (Table 4), which have a sensitivity of 95.3% and specificity of 90.7%. 33A-AION requires early diagnosis and immediate treatment with systemic high dose corticosteroids to reduce the risk of further visual loss. 31,34 le 4 -The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis 33 Old Criteria of 5 Classification Tree of 6 Criteria • age greater than or equal to 50 years at disease onset.
• new onset of localized headache.
• temporal artery tenderness or decreased temporal artery pulse.
• * elevated erythrocyte sedimentation rate (Westergren) greater than or equal to 50 mm/hour.
• biopsy sample including an artery, showing necrotizing arteritis, characterized by a predominance of mononuclear cell infiltrates or a granulomatous process with multinucleated giant cells.
• age greater than or equal to 50 years at disease onset.
• new onset of localized headache.
• temporal artery tenderness or decreased temporal artery pulse.
• biopsy sample including an artery, showing necrotizing arteritis, characterized by a predominance of mononuclear cell infiltrates or a granulomatous process with multinucleated giant cells.
• * claudication of the jaw or tongue or on deglutition.
* = Differences between old and new criteria, either removed or newly added.

B. AUTOIMMUNE DISEASES 1. Uvea
The uvea consists of the iris, ciliary body and choroid. 35Uveitis, most often unilateral and idiopathic, is characterized by the potentially sight-threatening intraocular inflammation of the uveal tract, although inflammation of adjacent tissues, such as the retina, optic nerve and vitreous humor may also occur. 36Uveitis is the commonest ophthalmological finding in the practice of rheumatology and clinical immunology and requires urgent evaluation by ophthalmologists due to the risk of blindness if treatment is delayed. 358][39][40][41][42][43] The International Uveitis Study Group has also proposed a simplified clinical classification based on suspicion of infection in order to facilitate the evaluation and diagnosis of uveitis. 40,44 he presentation of uveitis and its relationship with systemic diseases is summarized in Table 5. 35,40- 42,45,46 §  • Eye redness.
• Independent of underlying disease course (e.g.inflammatory bowel disease).

Intermediate uveitis
• Similar to posterior uveitis.
Posterior uveitis • Blurred vision to severe visual loss.
• Less likely to be red and painful.
• Cardinal part of the underlying systemic disease (e.g.Behcet's disease).
• Combination of symptoms and signs above.
• Cardinal part of the underlying systemic disease (e.g.Vogt-Koyanagi Harada syndrome and Behcet's disease).
As the underlying systemic causes of uveitis are usually autoimmune or inflammatory diseases, corticosteroids and other immunosuppressants are often indicated and this may lead to side effects, such as cataract, glaucoma, central obesity, metabolic diseases, opportunistic infections, and liver and renal toxicity.
Although more than half of uveitis cases have no identifiable cause, all types of uveitis (based on anatomic classification) can be drug-induced. 47,48 e culprits can be systemic, intraocular or topical medications that are commonly encountered, such as cidofovir, sulfonamides, bisphosphonates, anti-vascular endothelial growth factor, triamcinolone, metipranolol, theBacillus Calmette-Guérin vaccine and the MMR vaccine. 47The strength of association between causative drugs and uveitis are scored and categorized according to Naranjo's Classification Criteria. 47,49 Cornea, Conjunctiva and Eyelid Many systemic diseases that affect the cornea also involve the conjunctiva.Systemic inflammatory disorders, which might be life-threatening, such as connective tissue diseases, autoimmune diseases of the lacrimal system, and graft-versus-host-disease (GVHD) can affect the cornea and potentially lead to blindness.50,51 Prompt referral to an ophthalmologist consultation is therefore recommended.[50][51][52][53][54][55][56][57] (i) Keratoconjunctivitis sicca (KCS) The commonest ocular finding in these patients is keratoconjunctivitis sicca (KCS) 50,51 .KCS can be synonymous with dry eye disease (DED) or refer only to DED caused by aqueous tear deficiency.50,[58][59][60] Dry eye disease (DED) is a multifactorial disease that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface, accompanied by increased osmolarity of the tear film and inflammation.58 The common symptoms are dryness, irritation, foreign body sensation, photophobia, and itching.61 DED is usually classified by aetiologies, which can be due to pathological or systemic factors.It is generally divided into aqueous deficiency, which largely depends on lacrimal gland function (e.g.Sjogren syndrome, ageing, sarcoidosis, lymphoma and cicatricial diseases) and evaporative causes (e.g.meibomian gland dysfunction, disorders of lid aperture and globe congruity, contact lens wear, allergic conjunctivitis and vitamin A deficiency).58,[62][63] DED is usually diagnosed via ocular surface dye staining, fluorescein tear break-up time, the Schirmer test or symptom questionnaires, although newer methods with higher sensitivity and specificity have been reported, e.g.tear film osmolarity, tear fluid protein immunoassays, and fluorescein tear clearance.64,65 A diagnostic algorithm was designed and deemed better than single test alone. 65,66 Monnies questionnaire is one of the earliest and most widely used DED screening tools with 87 -98% sensitivity reportedly and 87 -97% specificity.67,[68][69] (ii) Other Corneal/Conjunctival/Eyelid Involvements In GVHD, apart from KCS, the cornea may show filamentary keratitis, superficial punctate keratitis, corneal ulcers, and peripheral corneal melting which may lead to perforation in severe cases.51 Severe dry eye syndrome may occur and later develop conjunctival scarring, keratinization, and cicatrization, which can be detected by on clinical examination. 51 Eyd changes leading to scleroderma-like appearance may occur, including poliosis (loss of melanin in eyelashes), madarosis (loss of eyelashes), vitiligo, lagophthalmos, and entropion.51 Nevertheless, all the layers of the eye can be involved in ocular GVHD, although posterior eye involvement is very rare.51 Peripheral ulcerative keratitis (PUK) although rare, might be an indicator of more severe and widespread systemic vasculitis.50 Sclerosing keratitis, the peripheral thickening and opacification of the corneal stroma adjacent to the site of inflammation secondary to scleritis, may be associated with rheumatoid arthritis.71 It is one of the commonest ocular complications (38%) of juvenile idiopathic arthritis.72 3. Sclera Scleritis is an uncommon, heterogeneous group of diseases characterized by inflammation of the sclera, which may be caused by local or systemic infections or immune mediated diseases.73,74 Rheumatoid arthritis remains the commonest disease that is associated with all types of scleritis.74 There are various etiologies of scleritis but the systemic autoimmune or vasculitic diseases are implicated in half of all cases.[74][75][76] All of these cause scleral inflammation, which results to readily detectable changes in the visible coats of episclera and conjunctiva.
However, episcleritis and scleritis may be distinguished based on history and physical examinations. 77oth scleritis and episcleritis can present as red eye. 77However, scleritis is more likely to present as a sudden onset of deep, severe periorbital pain with radiation to the temple and jaw and often wakes patients at night.50% of cases have underlying systemic symptoms.By contrast, episcleritis is usually painless and less likely to have systemic symptoms. 77 Orbit, Extraocular muscles and Eyelids (i) Graves' Ophthalmopathy (GO) Graves' ophthalmopathy (GO), also known as thyroid eye disease, is the commonest (25%) extra-thyroidal manifestation of Grave's Disease (GD).78 Bilateral GO usually occurs simultaneously or within 18 months of hyperthyroidism in GD, although occasionally GO and GD can happen separately with many years in between.79 Clinical presentations of GO and GD are described in table 6. 80 Cigarette smoking is the strongest modifiable risk factor of GO and exists in dosedependence relationship, so smoking history should be taken in detail.81 • Pain.
• Edema and erythema of the periorbital tissues and conjunctivae.
• Visual field loss.
• Thyroid acropachy (clubbing of the fingers and toes).

Conclusion
There are multiple systemic diseases and therapies that are associated with ocular problems in all parts of the eye.A high index of suspicion is necessary to actively detect these conditions and refer patients timeously when indicated to allow the highest possibility of visual recovery.In addition, the role of retinal microvascular analysis, including retinal vascular caliber, fractals, arteriovenous ratio and flicker light-induced retina-arterial vasodilation, should be further pursued to improve the prediction, prevention and management of cardiovascular disease worldwide.
What are known already: What this study adds/ highlights: • Ocular diseases with cardiovascular associations include diabetic retinopathy, retinal venous and artery occlusion, hypertensive retinopathy, transient monocular visual field loss, and ischemic optic neuropathy.
• The commoner systemic diseases that have ocular associations are cardiovascular diseases (diabetes mellitus, hypertension and hyperlipidemia) and autoimmune or inflammatory diseases (rheumatoid arthritis, spondyloarthropathies, inflammatory bowel diseases, Wegener granulomatosis ).
• Vision is actually considered more important than lifespan or loss of a limb in the majority of people.
• Retinal microvascular analysis has the potential to develop an important role in the prediction, prevention, monitoring and prognosis of cardiovascular diseases.
• Certain medications (systemic, intraocular and topical) are important but often-overlooked causes of uveitis.

Table 1 -
Signs of Different Types of Diabetic

Table 2 -
Clinical Signs and Systemic Risk Factors of Retinal Venous Occlusion 15, 17 Clinical Signs 18

Table 3 -
Classification of Hypertensive

Table 5 -
Presentations of Uveitis and Its Relationship with Systemic Diseases