The eye can be affected in a number of systemic diseases. Problems in the eye may be a first presentation of the systemic disease or patients with known systemic problems may need to have their eyes specifically checked for complications. This is a very broad topic and this record serves only as a guide. Awareness of these associations is the first step in diagnosis and management of these often complex patients.
For details on how to assess the structure and function of the eye, see separate article Examination of the Eye. Where findings are not in keeping with what you would expect or are difficult to elicit, it is safer to refer.
Common eye problems and their systemic associations
Cataracts are largely age-related but may also be associated with a number of situations such as:
- Metabolic abnormalities, eg in poorly controlled diabetes, phosphofructokinase deficiency and G6PD deficiency, hyperuricaemia associated with dehydration and renal failure.
- Other systemic disease, eg muscular dystrophy, atopic dermatitis and neurofibromatosis-2, congenital rubella, Lowe's syndrome, Refsum's disease and hypoparathyroidism, to name just a few.
- Drug exposure, particularly in steroid use (including prolonged use of topical steroids), as well as with chlorpromazine, busulfan, amiodarone, gold and allopurinol.
Uveitis is inflammation of the uveal tract comprising the iris, ciliary body and choroid. It can be classified as anterior uveitis, posterior uveitis or panuveitis. Although many cases are idiopathic, one-off episodes, there are also well recognised associations with systemic diseases which should be sought and ruled out, particularly in atypical presentations and immunocompromised patients. Broadly, uveitis can be associated with systemic diseases and syndromes (eg sarcoidosis, Behçet's syndrome, Reiter's syndrome, etc; see under 'Inflammatory' heading below), with infections (eg tuberculosis, candidiasis, herpes zoster, and syphilis) and with infestations (eg toxoplasmosis, toxocariasis, pneumocystosis). Recurrent acute anterior uveitis is associated with HLA-B27 in 60% of cases.
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 inflammation (see under 'Inflammatory' heading, below).
Central retinal artery occlusion (CRAO) should prompt a search for a source of atherosclerosis, emboli or inflammatory causes (eg giant cell arteritis, polyarteritis nodosum, Wegener's granulomatosis, systemic lupus erythematosis, Kawasaki's disease and pancreatitis). Haematological causes include protein S, protein C or antithrombin deficiency as well as antiphospholipid syndrome, leukaemia and lymphoma. The oral contraceptive pill and cocaine have also been associated with CRAO. It has also been known to occur in migraines.
Amaurosis fugax is the painless, transient loss of all or part of the vision of an eye, lasting just seconds or minutes. It 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 disease and sickle cell disease.
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 no use as a 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.
Common systemic problems and their eye associations
Every diabetic should have their eyes examined on diagnosis and then annually, preferably with retinal photography as laid down in the National Service Framework (NSF) for diabetes, unless they are under the care of an ophthalmologist. Even those who are blind should have their fundi inspected, as it may indicate other disease. The underlying pathology of many of the complications of diabetes is a leakage of the basement membrane, resulting in exudates, haemorrhages and microaneurysms. Poorly controlled diabetes may also result in premature cataracts due to excess glucose interfering with the metabolism of the crystalline lens. For greater detail on diabetic eye disease, see separate article Diabetic Retinopathy and Diabetic Eye Problems. It can be summarised as follows:
- Background retinopathy shows microvascular leakages seen as haemorrhages (tiny red dots) and exudates (well-defined yellow patches). Eyesight is normal.
- Pre-proliferative retinopathy is characterised by cotton wool spots ('fluffy' creamy patches) and irregularity of the veins. Vision remains normal.
- Proliferative retinopathy shows evidence of neovascularisation of the disc (NVD - little tufts of vessels growing on the disc) or neovascularisation elsewhere (NVE) on the retina. Although eyesight is still normal, it is a sight-threatening situation.
- Advanced diabetic retinopathy shows bleeding from the neovascularisation ± the complications of this (eg retinal traction or detachment). The vision will have acutely deteriorated.
- Maculopathy may be early and diffuse, moderate or severe and ischaemic. There may be spots and cotton wool haemorrhages. Eyesight is reduced.
All diabetics should be screened (depending on local policy, there may be a mobile screening unit or a dedicated screening clinic) and all but background retinopathy need referral to an ophthalmologist.
Hypertension may produce no abnormalities if caught early but examination of the fundi is part of the initial assessment of the patient.
- Grade I - mild narrowing or sclerosis of retinal arteries and they are more tortuous. This is called copper wiring or sometimes silver wiring.
- Grade II - thickening of the small arteries pushes on the veins so that the veins appear nipped as they cross the arteries. This is also called A-V nipping.
- Grade III - in addition to A-V nipping, there are haemorrhages or cotton wool spots. The latter are exudates.
- Grade IV - is papilloedema which is swelling of the optic nerve head. It is rarely seen these days and may be associated with the severe headache of hypertensive encephalopathy. A macular star refers to the radial streaks of exudates that arise around the macula in severe hypertensive retinopathy.
Grades III and IV are indicative of severe, accelerated or 'malignant' retinopathy. Severe retinal changes are normally associated with a systolic pressure of >220 mm Hg and/or a diastolic pressure >110 mm Hg, often with proteinuria. Treatment of the hypertension (though avoiding a rapid reduction which can precipitate vascular occlusion or a cerebrovascular event) results in resolution of the retinal signs if not left too long. Complications of hypertensive retinopathy include optic neuropathy and central vein or artery occlusions.
The ocular complication of carotid stenosis is most commonly amaurosis fugax and, to a lesser extent, retinal artery occlusion. Ocular ischaemic syndrome is a more unusual occurence whereby patients complain of a gradual (usually unilateral) loss of vision over several weeks or months. Examination reveals diffusely red eye, corneal oedema, an element of uveitis and rubeiosis iridis (new vessels growing on the iris). Fundoscopy shows venous dilation, micro-aneurysms, proliferative retinopathy and macular oedema. These patients are treated with steroids, mydriatics, laser and, occasionally, surgical intervention.
This may be associated with Sjögren's syndrome, most commonly manifesting itself as keratoconjunctivitis sicca and occasionally as episcleritis or scleritis. Peripheral ulcerative keratitis can occur, eventually resulting in a corneal melt (ie the corneal ulcer erodes through to the anterior chamber). This is initially managed with systemic steroids and bandage contact lenses but these patients may go on to need a corneal graft.
There are a number of ophthalmic features relating to thyroid disease and particularly thyrotoxicosis. See separate article Thyroid Eye Disease.
Ocular features include loss of eyelash and eyebrow hair (madarosis) and blepharitis. Occasionally, these patients suffer from chronic keratoconjunctivitis sicca, keratoconus and early-onset cataract.
This common condition manifests itself in a number of ways, most of which involve some degree of ophthalmological problem.
- Visual aura - occurs in 99% of migraines with aura (typical and prolonged) as well as in retinal migraines which are characterised by recurrent monocular visual disturbance ± various types of scotoma. Visual disturbances are also the hallmark of ocular migraines or acephalic migraines (those without headaches).
- Diplopia - transient paralysis of III, IV or VI may occur during ophthalmoplegic migraines and may go on for days or weeks. These are rare and recovery is full.
Other associations between the eye and systemic disease
The eye may be affected by a very wide number of conditions, being intimately associated with the neurological, vascular and metabolic systems among others. Listed below are a few more commonly found associations, with a brief outline of associated eye problems. More information is available in the dedicated article for each conditions.
- AIDS - 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:
- 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, eg cranial nerve palsies, pupillary abnormalities, squints, visual field defects and visual hallucinations.
- Cat-scratch disease - occasionally, neuroretinitis can occur and, more rarely, other ocular features, eg Parinaud's oculoglandular syndrome, uveitis, retinitis and retinal detachment.
- Chlamydial infection - conjunctivitis in both adults and infants (one of the causes of ophthalmia neonatorum).
- Leprosy - madarosis (loss of hair) and lagophthalmos are commonly seen as well as a neurotrophic keratitis. Occasionally, there is uveitis.
- Lyme disease - photophobia, pain, conjunctivitis and peri-ocular oedema are common. More unusually, patients develop keratitis, uveitis, optic neuritis, neuroretinitis and motor nerve palsies. It can also predispose to cataract formation.
- Syphilis - acquired syphilis commonly results in madarosis and 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.
- Tuberculosis - these patients may have a grumbling uveitis or choroiditis. Occasionally, there are solitary choroidal granulomas.
Acute anterior uveitis is a feature in ankylosing spondylitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis and sarcoidosis. In ankylosing spondylitis, 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). Sarcoidosis patients also have conjunctival granulomas and posterior uveitis. More uncommonly, there may be fundal granulomas, neovascularisation and papilloedema.
- Cicatricial pemphigoid - the majority of these patients have cicatrising conjunctivitis where bullae are progressively replaced by conjunctival ulceration, shrinkage and scarring. These patients may also complain of dry eye, adhesions within the conjunctiva and between the upper and lower lids. Occasionally, there may be a sight-threatening keratopathy.
- Myasthenia gravis - the picture of fluctuating, asymmetric external ophthalmoplegia with ptosis and weak eye closure is a classic feature of myasthenia. Patients often have an inability to maintain upgaze, and demonstrate Cogan's lid-twitch sign (when the patient first looks down for a short period and then makes a saccade back to primary position: the upper eyelid elevates excessively during this upward saccade, sometimes causing a transient lid retraction and then twitches or slowly droops back to a ptotic position).
- Sjögren's syndrome - these patients often present with keratoconjunctivitis sicca and, occasionally, with an Adie's pupil.
- Systemic lupus erythematosus - keratoconjunctivitis sicca and madarosis are common in these patients. They may also get an ulcerative keratitis and, rarely, scleritis, retinal vasculitis or optic neuropathy.
- Anaemia - haemorrhage, cotton wool spots, subconjunctival haemorrhage and, if vitamin B12 is low, optic neuropathy may occur. The severity of these features is correlated with the severity of the anaemia.
- Haemoglobinopathies - sickle cell disease and thalassaemias can result in ocular disease - usually more severe in thalassaemias. Problems include vascular occlusions, anastomoses and proliferation, vitreous haemorrhage and retinal detachment.
- Hyperviscosity states - these may cause (usually asymptomatic) haemorrhages, cotton wool spots and retinal vein change. Polycythaemia and multiple myeloma may cause optic disc swelling as well as cysts in various parts of the eye (iris, 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 (eg infiltration of the orbit may cause proptosis, infiltration of the optic nerve may cause optic neuropathy ± disc swelling and so on).
Inherited or genetic
- Albinism - this refers to a lack of melanin synthesis and these patients fall into one of two types:
- Ocular albinism (X-linked and recessive): the lack of pigmentation is confined to the eye.
- Oculocutaneous albinism (recessive): the hair is white and the skin very pale. A few of these patients can actually synthesise some melanin.
- Ehlers-Danlos syndrome (type 6) - the eyes of these patients are particularly susceptible to trauma. They also frequently have blue sclerae and a microcornea (affecting refractive error). A misplaced lens (ectopia lentis), keratoconus, high myopia and retinal detachment are some of the other problems seen in this patient group.
- Marfan's syndrome - ectopia lentis, myopia, retinal detachment and anomalies with the iridocorneal angle and pupil function are common problems. Occasionally, they are found to have other problems such as a small round lens, a flat cornea, keratoconus or a large cornea.
- Myotonic dystrophy - early cataracts and ptosis are often found; more unusually, there may also be abnormalities of the movements of the eyes, pupillary function abnormalities and a low intraocular pressure.
- Neurofibromatosis-1 - there may be eyelid neurofibromas as well as Lisch's nodules (little nodules seen on the iris) or an optic nerve neuroma, which can cause unilateral blindness. In children, asymmetrical, uncorrectable visual loss may occur. Proptosis can occur and abnormalities of colour vision. Occasionally, there are other neural orbital and intraocular tumours.
- Neurofibromatosis-2 - many of these patients get presenile cataracts; some additionally develop ophthalmoplegia and intraocular hamartomas.
- Tuberous sclerosis - retinal astrocytomas occur in 50% of these patients. Less commonly, hypopigmented spots develop on the iris and retina and raised intracranial pressure can cause papilloedema and a sixth nerve palsy.
Endocrine or metabolic
- Acromegaly - bitemporal hemianopia and optic atrophy are often found in these patients due to an enlarged pituitary gland. Occasionally, there is an associated 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.
- Homocystinuria - patients often have ectopia lentis and may also be prone to high myopia and retinal detachment.
- Behçet's syndrome - tends to present with oral ulceration as the predominant feature but there may also be some loss of vision and floaters due to vitritis (inflammation within the vitreous). Anterior uveitis may have a rapid and dramatic onset. It tends to settle in a few weeks but may require the help of an ophthalmologist and steroid drops. Up to 25% of patients with the disease suffer from uveitis at some time. Occasionally, an occlusive retinal periphlebitis or retinal oedema may complicate the picture.
- Dermatomyositis - produces purple coloration and oedema of the eyelids with oedema of the conjunctiva.
- Giant cell arteritis - this may present as sudden unilateral painful deterioration in vision (leading to blindness and becoming bilateral if left untreated), sometimes associated with scalp tenderness, jaw claudication, headache, polymyalgia rheumatica and nonspecific symptoms, eg neck pain, weight loss, fever, malaise, depression, etc.
- Kearns-Sayre syndrome - these patients have a symmetrical ptosis and external ophthalmoplegia as well as 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.
- Multiple sclerosis (MS) - there are clear associations between this and acute optic neuritis which may be the first indication that there is a problem. 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.
- Polyarteritis nodosa - peripheral ulcerative keratitis and scleritis are common ocular problems in these patients. More unusually, they may develop an orbital pseudotumour and occlusive retinal periarteritis.
- Psoriatic arthritis - this may occasionally be associated with uveitis, conjunctivitis, keratitis or keratoconjunctivitis sicca.
- Reiter syndrome - conjunctivitis and acute anterior uveitis are common ophthalmic features.
- Rosacea - many of these patients suffer from chronic blepharitis and recurrent meibomian cysts. Occasionally there is also severe conjunctivitis and keratitis.
- Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy) - is characterised by progressive ophthalmoplegia associated with progressive dementia, stiff neck and trunk.
- Stevens-Johnson syndrome - transient membranous conjunctivitis is common. This may be associated with mild anterior uveitis, superficial punctate keratopathy and, rarely, panophthalmitis.
- Sturge-Weber syndrome - these patients frequently have ipsilateral glaucoma and a diffuse choroidal haemangioma. Occasionally, there is also an ipsilateral episcleral haemangioma.
- Systemic sclerosis - eyelid tightening and telangiectasia are common; they may also suffer from keratoconjunctivitis sicca.
- Vogt-Koyanagi-Harada syndrome (VKH) - anterior uveitis is one of the features characterising the Vogt-Koyanagi syndrome (along with skin changes). Harada's disease, additionally, has neurological features, and retinal detachments predominate.
- von Hippel-Lindau syndrome - there may be capillary haemangiomas of the retina or the optic nerve head. Vessel leakage can cause visual deterioration
- Wegener's granulomatosis - ophthalmic features commonly include nasolacrimal duct obstruction and dacrocystitis but these patients may also develop scleritis, peripheral ulcerative keratitis (± peripheral corneal thinning) and an orbital pseudotumour.
- Wilson's disease - gives the Kayser-Fleischer ring that is a copper-coloured ring at the periphery of the cornea. It requires slit lamp examination and may not be apparent until there are neurological symptoms.
Pregnancy and the eye
Physiological changes: a shift in the hormonal and fluid status may result in some self-limiting changes which are no cause for concern. These occur at several points:
- External changes - the conjunctiva may become more injected and increased pigmentation can occur around the cheeks and eyes (chloasma) - both reversible postpartum.
- Cornea - slight oedema and a steepening of the curvature can result in a minor shift in refractive error of the eye - wait several weeks postpartum before going to an optician for a new prescription, as this usually resolves.
- Intraocular pressure - this drops after 20 weeks of gestation but should return to normal within 2 months postpartum.
- Visual fields - an asymptomatic reduction may occur through an unknown mechanism but any symptomatic problems should be taken seriously and investigated.
Effect on pre-existing pathology: the mother may have pre-existing pathology that is affected by pregnancy. The most common is diabetic eye disease. Pregnancy is a major risk factor for progression of diabetic retinopathy and these patients should be followed much more closely throughout their pregnancy. Ideally, a preconception review should take place to assess baseline retinopathy and establish a monitoring plan.
- No pre-existing diabetic retinopathy: single baseline assessment at the start of pregnancy will do.
- Non-proliferative diabetic retinopathy: ophthalmological review needed every trimester.
- Proliferative diabetic retinopathy: monthly ophthalmological review recommended.
- Macular oedema: many cases resolve after pregnancy - often seen in conjunction with proteinuria and hypertension.
Other important conditions encountered, which may be worsened by pregnancy, include pituitary adenomas, meningiomas and other intracerebral tumours (eg craniopharyngiomas). Toxoplasmosis may be reactivated during pregnancy and both Grave's disease and migrainous headaches often worsen during pregnancy. On the other hand, ocular problems in sarcoidosis, ankylosing spondylitis, Vogt-Koyanagi-Harada (VKH) syndrome and MS often stabilise or even improve during pregnancy. Some conditions, such as immune-mediated uveitis, vary depending on the individual and may stay the same, improve or get worse.
New eye pathology: ophthalmological problems can arise in a little under a third of cases of toxaemia of pregnancy, characterised hypertensive retinopathy, optic neuropathy, retinal detachment and occipital cortical changes. In HELLP syndrome (H aemolysis, EL evated liver enzymes, L ow P latelet count),10% of severe cases show bilateral retinal detachments and vitreous haemorrhage and there may also be pupillary mydriasis, ptosis and nystagmus. Other new problems arising in pregnancy include central serous retinopathy, ocular vascular disorders (eg branch or retinal artery or vein occlusions, Purtscher-like retinopathy, the ocular effects of disseminated intravascular coagulation and thrombotic thrombocytopenic purpura), ptosis (usually unilateral) and, unusually, diabetic retinopathy in gestational diabetes.
The principle concern relating to the fetus of pregnant women with eye problems is the medication used to treat these diseases. There is little known regarding the effects of ophthalmic medications in pregnancy and whilst breast-feeding. Topical drops can be absorbed into the conjunctival vessels or nasal mucosa and pass through the placenta. They are excreted through breast milk although there are very little published data concerning the effects. Drops are more readily absorbed than ointment. Occluding the nasolacrimal duct (by putting firm pressure just medial to the medial canthus), avoiding instillation of a succession of drops and blowing the nose after drop instillation may all help to reduce systemic absorption.The following table should only be used as a guide; bear Hippocrates' wise words in mind, primum non nocere and think hard before prescribing in these women. If in doubt, ring the National Teratology Information Service.
|Use with caution||Anaesthetics, steroids, brimonidine, miotics (except for demecarium).||Erythromycin, polymyxin B, quinolones, diagnostic dyes are probably alright.|
|Use if really necessary||Mydriatics if occasional use only, betablockers but stop pre-birth and whilst breast-feeding, prostaglandin analogues.||Prednisolone less than 40 mg per day.|
|Do not use||Antibiotics, antivirals, carbonic anhydrase inhibitors, demecarium.||Carbonic anhydrase inhibitors.|
Where illicit drugs have been used, several ophthalmic problems have been described in the newborn. Infants born with neonatal abstinence syndrome may be at particular risk of nystagmus. These babies benefit from early screening intervention (ophthalmic assessment and visual electrophysiology) to enable early diagnosis and management of ophthalmic problems.
Further reading & references
- Good Hope Hospital Eye Department; Excellent information resource with lots of good links
- Denniston AKO, Murray PI. Oxford Handbook of Ophthalmology (OUP), 2009.
- Kanski J. Clinical Ophthalmology; A Systematic Approach (5th Ed) Butterworth Heinemann (2003)
- Jackson TL; Moorfields Manual of Ophthalmology, Mosby (2008)
- National service frameworks and strategies - diabetes, NHS Choices
- National Screening Programme for Diabetic Retinopathy, UK Screening Portal; England
- Kunimoto DY, Kanitkar KD, Makar MS; The Wills Eye Manual (4th Ed), Lippincott, Williams and Wilkins (2004)
- Vestgaard M, Ringholm L, Laugesen CS, et al; Pregnancy-induced sight-threatening diabetic retinopathy in women with Type 1 Diabet Med. 2010 Apr;27(4):431-5.
- UK Teratology Information Service
- Hamilton R, McGlone L, MacKinnon JR, et al; Ophthalmic, clinical and visual electrophysiological findings in children born to Br J Ophthalmol. 2010 Jun;94(6):696-700. Epub 2010 Apr 21.
|Original Author: Dr Olivia Scott||Current Version: Dr Olivia Scott|
|Last Checked: 22/06/2011||Document ID: 2851 Version: 24||© EMIS|
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.