Skip to main content

The eye and systemic disease

Medical Professionals

Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find one of our health articles more useful.

Continue reading below

The role of the eye in diagnosing systemic disease

An ocular manifestation of a systemic disease or congenital condition may be its first visible presentation. The eye is a modified ball and socket joint with a transparent front viewing window allowing us to view signs which may suggest or confirm the presence of systemic disease. Awareness of these associations assists early diagnosis and may help anticipate or avoid complications.

This article first considers conditions which may affect the eye, then considers conditions of the eye which may be associated with particular conditions.

For details on how to assess the structure and function of the eye, see the separate Examination of the Eye article. Where findings are not in keeping with what you would expect or are difficult to elicit, it is safer to refer.

Part 1: conditions which may affect the eye

The following conditions affect the eye to an extent that they may first present through their ocular manifestations, or their ocular manifestations are likely to be significant in confirming the diagnosis.

Continue reading below

Endocrine/metabolic conditions

Diabetes mellitus1

Diabetes may first present on eye examination. Diabetes affects small blood vessels and can be particularly destructive in the eye. At the root of most diabetic eye problems lie reduced blood supply due to small vessel blockage leading to poor delivery of oxygen, together with raised blood glucose acting as a tissue poison. The end result is hypoxic damage to the tissues of the eye, particularly the retina, which may swell or grow new compensatory blood vessels which bleed easily. Severe sight impairment can result.

Signs of diabetic eye disease
These include:

  • Cotton wool spots (areas of retinal ischaemia with oedema).

  • Hard exudates (fatty deposits).

  • Microaneurysms (appearing as small red dots on the retina).

  • Small flame haemorrhages from damaged blood vessel walls.

  • Signs of new blood vessel formation on the back of the eye.

  • Diabetes - also a cause of early cataracts, due to excess glucose interfering with the metabolism of the crystalline lens.

The blood vessels on the diabetic fundus may reveal the health of microvasculature elsewhere in the body - eye disease, kidney disease and damage to small blood vessels in the feet tend to run in parallel, so when the eyes are deteriorating the kidneys are usually doing the same and the feet are becoming at risk from diabetic neuropathy. For greater detail on diabetic eye disease, see the separate Diabetic Retinopathy and Diabetic Eye Problems article.


The first signs of hypertension are often seen in the eye where blood vessels are clearly visible. It is not unusual for an optician to be the first to diagnose hypertension. The changes result from hypertension-induced atherosclerosis blocking the small blood vessels of the retina.

  • The earliest sign is narrowing of the vessels, referred to as 'silver wiring' because of the characteristic appearance. The arteries then swell and press on the veins where they cross over, causing them to look 'nipped' at the crossings.

  • Later blockage causes areas of ischaemic swelling (cotton wool spots) and superficial haemorrhages.

  • In extreme cases papilloedema develops, probably due to an increase in intracranial pressure. A macular star refers to the radial streaks of exudates that arise around the macula in severe hypertensive retinopathy.

  • Severe retinal changes are normally associated with a diastolic pressure >110 mm Hg and/or a systolic pressure of >220 mm Hg.

The fatty deposits in the retinal vessels remain when blood pressure is reduced; however, retinopathy resolves when blood pressure is treated. Changes develop within 48 hours of blood pressure rising and resolve in 2-10 weeks of it being lowered.

Complications of hypertensive retinopathy include optic neuropathy and central vein or artery occlusions.


Graves' disease may cause proptosis, which may be the first sign of the condition. This may be unilateral or bilateral. The ocular complications of thyroid eye disease may include corneal ulceration and visual loss3 .


Corneal arcus may be present at birth, but usually appears in patients aged over 50; it results from cholesterol deposits and can be associated with hyperlipidaemia.


Optic atrophy is common. There may be nystagmus.

Cushing's syndrome

Iatrogenic Cushing's syndrome may be associated with steroid-induced cataracts (this is not the case for Cushing's disease) and susceptible individuals may also develop glaucoma. Occasionally, a secreting pituitary tumour can cause bitemporal hemianopia.

Inflammatory and autoimmune conditions4

Connective tissue disorders

Those disorders which particularly affect joints can also inflame the eye, causing scleritis or uveitis. These include:

Acute anterior uveitis is a particular feature in AS, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis and sarcoidosis. In AS, it may occur in up to 30% of patients. In Crohn's disease and ulcerative colitis, it may be accompanied by conjunctivitis, episcleritis and (rarely) retinal complications (periphlebitis).

Multiple sclerosis

Often the first nerve to be affected by the acute demyelination of multiple sclerosis (MS) is the optic nerve, causing optic neuritis. Not all optic neuritis is MS, but repeated episodes warrant investigation.

  • Around 16% of optic neuritis patients presenting with no systemic abnormalities and a normal MRI will go on to develop MS.

  • About 50% of patients presenting with a first episode of optic neuritis but no other signs of MS have demyelinating lesions on MRI.

  • There is evidence of present or past optic neuritis in 70% of MS patients.

Myasthenia gravis

Myasthenia gravis often presents as ptosis. The picture is of fluctuating, asymmetric external ophthalmoplegia with ptosis and weak eye closure. Patients often have an inability to maintain upward gaze.

Cicatricial pemphigoid5

Most patients have cicatrising conjunctivitis where bullae are progressively replaced by conjunctival ulceration, shrinkage and scarring. These patients may also complain of dry eye and of adhesions within the conjunctiva and between the upper and lower lids.

Continue reading below

Infective conditions6

Ocular presentation can be associated with a number of chronic infections including tuberculosis, syphilis and toxoplasmosis.


This an also cause retinochoroiditis, although more than 60% of the population have antibodies to it and have presumably been exposed. Active infection in the eye is more common when there is an immune deficiency such as AIDS, or after transplant.

Fungal infections of the eye

These may lead to severe inflammation, with cotton wool 'fluff' in the back of the eye and visual loss. They are unusual in healthy individuals and their presence suggests immune deficiency or intravenous drug use. The latter occurs when intravenous drugs are diluted with lemon juice.


There are many ophthalmic features associated with AIDS and, very occasionally, suspicion of AIDS is raised by a first presentation with ophthalmological problems. The ocular problems can be summarised as follows:

Cat scratch disease

Occasionally, cat scratch disease neuroretinitis can occur and, more rarely, other ocular features - eg, uveitis, retinitis and retinal detachment.


Loss of hair and lagophthalmos are commonly seen in leprosy, as well as a neurotrophic keratitis. Occasionally, there is uveitis.

Lyme disease

Photophobia, pain, conjunctivitis and peri-ocular oedema are common in Lyme disease. More unusually, patients develop keratitis, uveitis, optic neuritis, neuroretinitis and motor nerve palsies. It can also predispose to cataract formation.


Acquired syphilis commonly results in keratitis. Less commonly, there is uveitis, chorioretinitis and neuroretinitis. Babies with congenital syphilis tend to have uveitis and keratitis; later on there is a pigmentary retinopathy

Congenital conditions8


This is a congenital condition of lack of pigmentation and includes the iris. Individuals with albinism have a rather transparent iris so that the red reflex is easily seen, although its colour varies from blue to brown. Most patients have deteriorating or poor vision with nystagmus. They are also at increased risk of ocular melanoma.

Down's syndrome

This condition involves multiple physical signs and associations. Ocular features include Brushfield's spots (small white spots on the periphery of the iris which are found sometimes in unaffected children). Children with Down's syndrome commonly have an upward slant to the eyes and have epicanthal folds at the inner corners of the eyes. They may have nystagmus or congenital cataracts and frequently have poor vision with short sight and/or squint. As they become older they are more likely to have sticky eyes, blepharitis and conjunctivitis and, in their teens and twenties, they are more at risk of developing cataracts and keratoconus.

Ehlers-Danlos syndrome (type 6)

The eyes of these patients with Ehlers-Danlos syndrome (type 6) are particularly susceptible to trauma. They frequently have blue sclerae and a microcornea. A misplaced lens, keratoconus, high myopia and retinal detachment are also seen.

Marfan's syndrome

Lens dislocation, myopia, retinal detachment and anomalies with the iridocorneal angle and pupil function are common in Marfan's syndrome.

Myotonic dystrophy

Early cataracts and ptosis are often found; there may also be abnormalities of eye movements and pupillary function.


In neurofibromatosis-1 there may be eyelid neurofibromas as well as nodules on the iris. Optic nerve neuroma can cause unilateral sight loss. Proptosis can occur and there may be abnormalities of colour vision. Occasionally, there are other tumours.


Patients with neurofibromatosis-2 develop early cataracts; some also develop ophthalmoplegia and intraocular hamartomas.

Retinitis pigmentosa

In retinitis pigmentosa, abnormal pigmentation is seen in the eye.

Tuberous sclerosis

Retinal astrocytomas occur in 50% of patients with tuberous sclerosis. Less commonly, hypopigmented spots develop on the iris and retina; raised intracranial pressure can cause papilloedema and a sixth nerve palsy.


Cancer can arise in or metastasise to the eye. The most common primary eye tumour is a choroidal melanoma. See the separate articles Eye and Optic Nerve Tumours, Retinal Tumours and Retinoblastoma.

Haematological conditions9


Haemorrhage, cotton wool spots, subconjunctival haemorrhage and, if vitamin B12 is low, optic neuropathy may occur. The severity is correlated with the severity of the anaemia.


Sickle cell disease and thalassaemias can result in ocular disease. Problems include vascular occlusions, anastomoses and proliferation, vitreous haemorrhage and retinal detachment.

Hyperviscosity states

These may cause haemorrhages, cotton wool spots and retinal vein change. Polycythaemia and multiple myeloma may cause optic disc swelling as well as cysts in the iris and ciliary body. Corneal crystals may also occur.


Similar findings to anaemia as well as pigment changes in the retina ('leopard spots') and spontaneous haemorrhage. Infiltration results in a variety of symptoms depending on where it occurs.

Sickle cell disease

Sickle cell disease causes abnormal retinal vessel formation which may lead to bleeding into the retina.

Skin conditions


Many patients with rosacea have chronic blepharitis and recurrent meibomian cysts. Occasionally there is also severe conjunctivitis and keratitis.

Less common conditions affecting the eye8


In this condition, one iris is a different colour from the other. It may be genetically inherited or acquired by disease or injury. It is associated with Waardenburg's syndrome (with deafness and a white streak of hair) and with Hirschsprung's disease.

Kearns-Sayre syndrome

A rare mitochondrial myopathy characterised by chronic progressive external ophthalmoplegia, cardiac conduction abnormalities and pigmentary retinopathy.

Idiopathic intracranial hypertension

Ophthalmic features may include frequent transient visual obscurations (up to 30 a day) diplopia, visual field defects and disc swelling which is usually bilateral.

Progressive supranuclear palsy

Progressive ophthalmoplegia in progressive supranuclear palsy is associated with dementia and truncal stiffness.

Sturge-Weber syndrome

Patients with Sturge-Weber syndrome frequently have ipsilateral glaucoma and a diffuse choroidal haemangioma. Occasionally, there is an ipsilateral episcleral haemangioma.

Vogt-Koyanagi-Harada (VKH) syndrome

In VKH syndrome there is anterior uveitis, along with skin changes. Harada's disease, additionally, has neurological features, and retinal detachments predominate.

Von Hippel-Lindau (VHL) disease

In VHL disease there may be capillary haemangiomas of the retina or the optic nerve head. Vessel leakage can cause visual deterioration

Granulomatosis with polyangiitis (GPA)

Ophthalmic features of GPA include nasolacrimal duct obstruction and dacrocystitis. Patients with the condition may also develop scleritis, peripheral ulcerative keratitis (± peripheral corneal thinning) and orbital pseudotumour.

Part 2: eye conditions and their associations

This section looks at systemic diseases affecting the eye from the opposite perspective, looking at presenting features and listing the conditions with which they may be associated.


Most cataracts are age-related but they are also associated with underlying conditions. They are more common in diabetes and Down's syndrome. They may be associated with steroid use, certain rare hormone deficiencies, previous eye trauma, congenital rubella and many rare congenital conditions. The list below offers examples but is not exhaustive.

Uveitis 4 6

Although many cases of uveitis are idiopathic, there are well recognised associations with systemic disease, particularly in atypical presentations, repeat presentations and immunocompromised patients.

Uveitis might be expected in any disease process which has the capacity to affect joints, given that the eye is a modified joint. Examples include inflammatory disorders such as rheumatoid arthritis, AS), infections (eg, tuberculosis, candidiasis) and with infestations (eg, toxoplasmosis, toxocariasis).

Acute anterior uveitis is associated with HLA-B27 (36% in one study)11 .

Central retinal vein occlusion12

Central retinal vein occlusion (CRVO) is associated with hypertension, diabetes, smoking, hyperlipidaemia, hyperviscosity states (particularly in patients aged less than 45 years), glaucoma, thrombophilia and vasculitis.

There may be an underlying haematological problem (eg, factor V Leiden, myeloma or antiphospholipid syndrome) or systemic inflammation (eg, rheumatoid arthritis, AS).

Central retinal artery occlusion13 14

Central retinal artery occlusion (CRAO) should prompt a search for a source of atherosclerosis, emboli or inflammatory causes (eg, giant cell arteritis, GPA, systemic lupus erythematosis, Kawasaki disease and pancreatitis). It is a common presenting feature of carotid artery stenosis.

Haematological causes include protein S deficiency, protein C deficiency and antithrombin deficiency as well as antiphospholipid syndrome, leukaemia and lymphoma. CRAO also been known to occur in migraine.

Amaurosis fugax4

Amaurosis fugax is due to transient ischaemia and may be a feature of embolic, thrombotic, vasospastic, or haematological problems. These include transient ischaemic attacks, giant cell arteritis, Takayasu's arteritis and sickle cell disease. It is also seen in carotid artery stenosis.

Pupillary abnormalities

Pupillary abnormalities may indicate a number of diseases or intoxication (cocaine: dilation, opioids: constriction). Horner's syndrome results from unilateral interruption of the sympathetic system on one side of the face, causing ptosis, miosis and lack of sweating on that side of the face. The path of the sympathetic fibres is so tortuous that it is a poor localising sign but it is a very good lateralising sign15 .

Abnormal eye movements

Abnormal eye movements and squints are found in many conditions affecting the cranial nerves or their corresponding brainstem nuclei. These include cerebrovascular accidents, aneurysms and diabetes.

Transient paralysis of cranial nerves III, IV or VI may occur during ophthalmoplegic migraines and may go on for days or weeks. These are rare and recovery is full.

Dr Mary Lowth is an author or the original author of this leaflet.

Further reading and references

  1. Diabetic Retinopathy; Columbia University Department of Ophthalmology, 2021
  2. Tsukikawa M, Stacey AW; A Review of Hypertensive Retinopathy and Chorioretinopathy. Clin Optom (Auckl). 2020 May 5;12:67-73. doi: 10.2147/OPTO.S183492. eCollection 2020.
  3. McAlinden C; An overview of thyroid eye disease. Eye Vis (Lond). 2014 Dec 10;1:9. doi: 10.1186/s40662-014-0009-8. eCollection 2014.
  4. Johns K et al; Ocular Manifestations of Systemic Disease, 2009
  5. Tolaymat L, Hall MR; Cicatricial Pemphigoid
  6. Roberts A; Eye Infections, 2010.
  7. Gichuhi S, Arunga S; HIV and the eye. Community Eye Health. 2020;33(108):76-78. Epub 2020 Mar 30.
  8. Genetic and Rare Diseases Information Centre; Eye Diseases, 2021.
  9. Reynolds S et al; Hematological Disorders and the Retina, 2009
  10. Nizami AA, Gulani AC; Cataract
  11. Accorinti M, Iannetti L, Liverani M, et al; Clinical features and prognosis of HLA B27-associated acute anterior uveitis in an Italian patient population. Ocul Immunol Inflamm. 2010 Apr;18(2):91-6. doi: 10.3109/09273941003597268.
  12. Sinawat S, Bunyavee C, Ratanapakorn T, et al; Systemic abnormalities associated with retinal vein occlusion in young patients. Clin Ophthalmol. 2017 Feb 23;11:441-447. doi: 10.2147/OPTH.S128341. eCollection 2017.
  13. Varma DD, Cugati S, Lee AW, et al; A review of central retinal artery occlusion: clinical presentation and management. Eye (Lond). 2013 Jun;27(6):688-97. doi: 10.1038/eye.2013.25. Epub 2013 Mar 8.
  14. Farris W, Waymack JR; Central Retinal Artery Occlusion
  15. Horner's Syndrome; Atlas of Ophthalmology, 2021

Article history

The information on this page is written and peer reviewed by qualified clinicians.

symptom checker

Feeling unwell?

Assess your symptoms online for free