The eye and systemic disease

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 the only organ in which vascular disease can be observed in vivo. This may enable a clinician to observe signs of systemic disease. Awareness of these associations assists early diagnosis and may help to reduce the risk of 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 do not fit with those expected or are difficult to elicit, referral should be considered.

Diabetes mellitus¹

Diabetes affects small blood vessels and can be particularly destructive in the eye leading to diabetic retinopathy. This is caused by small vessel blockage causing blood supply, leading to poor delivery of oxygen. Raised blood glucose also acts directly to damage tissue. ²³

The end result is hypoxic damage to the tissues of the eye, particularly the retina, which may become oedematous or grow new compensatory blood vessels which bleed easily. Severe sight impairment can result. Diabetic retinopathy accounts for 80% of visual loss in patients with diabetes.³

77.3% of people with type 1 diabetes and 25.1% of those with type 2 diabetes have diabetic retinopathy on examination.⁴

Examination findings in diabetic eye disease 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 is 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 - as the eyes develop diabetic retinopathy, renal impairment and diabetic neuropathy often develop in a similar timeframe. For greater detail on diabetic eye disease, see the separate Diabetic retinopathy and diabetic eye problems article.

Hypertension⁵

Vascular changes from hypertension can be seen in vivo in the eye. The changes result from hypertension-induced atherosclerosis affecting the blood vessels, as well as fibrinoid necrosis of the choroidal arterioles.

Hypertensive retinopathy can be characterised as mild, moderate or severe.

• In mild disease there is narrowing of the vessels, referred to as 'silver wiring' because of the characteristic appearance. The arteries then swell and compress the veins where they cross over, causing "arteriovenous nicking".

• Moderate disease causes haemorrhages, micro-aneurysms, cotton wool spots (caused by micro-infarcts from obstructed blood vessels) and hard exudates (lipid deposits).

• Severe disease is demonstrated by the development of papilloedema, 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.

Malignant hypertension definitions differ but the 2020 international hypertension societies define it as a severe elevation of blood pressure, typically above 200/120 mm Hg, accompanied by advanced bilateral retinopathy characterized by retinal haemorrhages, cotton wool spots, and papilledema. ⁶

Retinopathy often stabilises with treatment of hypertension; however, arteriole narrowing and vessel crossing changes often remain. ⁶Visual loss is rare but complications of hypertensive retinopathy can include optic neuropathy and central vein or artery occlusions, particularly if left untreated. Malignant hypertension retinopathy with papilloedema has a strong correlation with increased cardiovascular morbidity and mortality.⁷

Hyperthyroidism

Graves' disease may cause proptosis due to an inflammatory orbital process and remodelling of surrounding connective tissue. This may be the first sign of the condition and may be unilateral or bilateral. The ocular complications of thyroid eye disease include corneal ulceration and visual loss.⁸

Hyperlipidaemia

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.

Acromegaly

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.

Connective tissue disorders

Those disorders which particularly affect joints can also inflame the eye, causing scleritis or uveitis. They are also often associated with dry eyes due to dysfunction of the lacrimal and meibomian glands. These include:

• Rheumatoid arthritis (often with episcleritis, scleritis and dry eyes).

• Systemic lupus erythematosus (keratoconjunctivitis sicca, ulcerative keratitis, and (rarely) scleritis, retinal vasculitis, or optic neuropathy).

• Behçet's disease (usually oral ulceration is the predominant feature).

• Ankylosing spondylitis (AS). Up to 25% of patients with AS develop iritis at some time.

• Reactive arthritis - (conjunctivitis and uveitis).

• Crohn's disease.

• Ulcerative colitis.

• Sarcoidosis (conjunctival granulomas and posterior uveitis). Less commonly, there may be fundal granulomas, neovascularisation and papilloedema.

• Sjögren's syndrome (most commonly as keratoconjunctivitis sicca and occasionally as episcleritis or scleritis).

• Systemic sclerosis: eyelid tightening and telangiectasia are common.

• The inflammation of small arteries in giant cell arteritis may cause sudden unilateral transient or permanent visual loss.

• Polyarteritis nodosa: ulcerative keratitis and scleritis are common. Patients may also develop an orbital pseudotumour and occlusive retinal periarteritis.

• Psoriatic arthritis: this may be associated with uveitis, conjunctivitis, keratitis or keratoconjunctivitis sicca.

• Dermatomyositis: produces purple coloration and oedema of the eyelids with oedema of the conjunctiva.

• Stevens-Johnson syndrome: conjunctivitis is common. There may also be mild anterior uveitis, superficial punctate keratopathy and (rarely) panophthalmitis.

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

The optic nerve may be the first to be affected by the acute demyelination of multiple sclerosis (MS) resulting in optic neuritis.¹¹

• Around 18% of optic neuritis patients presenting with no systemic abnormalities and a normal MRI will go on to be diagnosed with MS in the first year.¹²

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

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 pemphigoid¹³

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.

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

Toxoplasmosis

This can cause retinochoroiditis. Up to 85% of children born with congenital toxoplasmosis eventually develop ocular involvement, even when the infection is subclinical at birth. The prevalence of ocular toxoplasmosis in people who contract toxoplasmosis postnatally varies with geographical location, having been found to be between 2 and 18%.¹⁴

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 occur in more than a million people worldwide each year and are increasing in incidence. This is thought to be due to the increasing number of patients with risk factors such as immunosuppression, use of medical devices, widespread use of antimicrobials, and, at the time of the study, hospitalised patients with COVID-19. ¹⁵They are more common in LEDCs than MEDCs.¹⁶

HIV/AIDS¹⁷

There are many ophthalmic features associated with AIDS. The ocular problems can be summarised as follows:

• External disease: Kaposi's sarcoma (eyelids and conjunctiva), multiple molluscum lesions, severe herpes zoster ophthalmicus, squamous cell carcinoma.

• Cornea: herpes viruses, microsporidial keratoconjunctivitis, bacterial and fungal keratitis, cytomegalovirus keratitis.

• Various forms of uveitis, generally severe.

• Retinitis, HIV retinopathy, choroiditis, B-cell intraocular lymphoma.

• Neuro-ophthalmological problems - for example, cranial nerve palsies, pupillary abnormalities, squints, visual field defects, and visual hallucinations.

Cat scratch disease

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

Leprosy (Hansen's Disease)

Ocular involvement in HD is estimated at 70–75% worldwide. About 10–50% suffer from severe ocular symptoms and loss of vision occurs in approximately 5% of cases. Ocular changes may persist or worsen even after patients are considered cured.¹⁸

Lyme disease

Up to a half of those with confirmed Lyme disease have been shown to have ocular manifestations, most commonly diplopia and strabismus, but also anterior segment findings, including conjunctivitis, keratitis, and cataracts, (23.76%), posterior segment findings, which included retinitis, chorioretinitis, neuroretinitis, posterior uveitis, intermediate uveitis, and retinal vasculitis, (19.66%), third cranial nerve palsy (18.65%), and optic nerve findings (10.76%).¹⁹

Syphilis

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.

Other infectious causes ²⁰

Infections which are more common worldwide but very rare in the UK can cause ocular manifestations. These include:

• Avian influenza virus - conjunctivitis

• Zika virus - anterior uveitis, retrobulbar pain, congenital Zika disease (visual impairment)

• Ebola virus - uveitis, optic neuropathy

• Nipah virus - diplopia, photophobia, Horner syndrome, abnormal Doll's eye, retinal artery occlusion

• Dengue virus - uveitis, retrobulbar pain, optic neuropathy, photophobia, conjunctival injection

• Chikungunya virus - uveitis, sub-conjunctival haemorrhage, maculopathy, vasculitis, optic neuropathy, endophthalmitis, photophobia, conjunctival injection

Albinism²¹

Ocular symptoms in albinism are the most significant clinical feature. They include photophobia, refractive errors, foveal hypoplasia, horizontal nystagmus, strabismus and reduced stereopsis.

Down's syndrome²²

Ocular features include Brushfield's spots (small white spots on the periphery of the iris). Children with Down's syndrome commonly have epicanthal folds at the inner corners of the eyes.

They are more likely to have strabismus, amblyopia, accommodation defects, refractive errors, nasolacrimal duct obstruction, nystagmus, keratoconus, congenital cataracts, and retinal and optic nerve abnormalities.

Ehlers-Danlos syndrome (type 6)

The eyes of 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.

Neurofibromatosis-1

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.

Neurofibromatosis-2

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 Optic nerve and eye tumours, Retinal tumours and Retinoblastoma.

Anaemia

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.

Haemoglobinopathies

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.

Leukaemia

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.

Rosacea

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

Heterochromia

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.

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.

Cataracts²³

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.

• Metabolic abnormalities:

  • Poorly controlled diabetes.

  • Phosphofructokinase deficiency.

  • G6PD deficiency.

  • Hyperuricaemia associated with dehydration and chronic renal disease.

• Other systemic disease:

  • Muscular dystrophy.

  • Atopic dermatitis.

  • Neurofibromatosis-2.

  • Congenital rubella.

  • Lowe's syndrome.

  • Refsum's disease.

  • Hypoparathyroidism.

• Drug exposure:

  • Steroids (including prolonged use of topical steroids).

  • Chlorpromazine.

  • Busulfan.

  • Amiodarone.

  • Gold.

  • Allopurinol.

Uveitis

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 (for example, tuberculosis, candidiasis) and with infestations (for example, toxoplasmosis, toxocariasis).

Acute anterior uveitis is associated with HLA-B27.²⁴

Central retinal vein occlusion²⁵

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 (for example, factor V Leiden, myeloma, or antiphospholipid syndrome) or systemic inflammation (for example, rheumatoid arthritis, AS).

Central retinal artery occlusion ²⁶

Central retinal artery occlusion (CRAO) is an ophthalmic emergency. It may be caused by atherosclerosis, emboli or inflammatory causes (for example, giant cell arteritis, GPA, systemic lupus erythematosis, and polyarteritis nodosa, among others).²⁷

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 fugax

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 are found in a number of conditions. 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 sign.

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 with full recovery.

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