The Eye In Systemic Disease

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, please refer to our record on Examination of the Eye. Where findings are not in keeping with what you would expect or difficult to elicit, it is safer to refer.

Cataracts

Cataracts are largely age-related but may also be associated with a number of situations such as:

• Metabolic abnormalities e.g. in poorly controlled diabetes, phosphofructokinase deficiency and G6PD deficiency
• Other systemic disease e.g. 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, busulphan, amiodarone, gold and allopurinol.¹

Uveitis

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 (e.g. sarcoidosis, Behçet's syndrome, Reiter's syndrome etc, see below), infections (e.g. tuberculosis, candidiasis, herpes zoster) and infestations (e.g. toxoplasmosis, toxocariasis, pneumocystosis).

Central retinal vein occlusion

Central retinal vein occlusion is associated with hypertension, diabetes, smoking, hyperlipidaemia, hyperviscosity, glaucoma, thrombophilia and vasculitis.

Central retinal artery occlusion

Central retinal artery occlusion should prompt a search for a source of emboli or arteritis.

Amaurosis fugax

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

Pupillary abnormalities may indicate a number of diseases or intoxication. 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.

Diabetes

Every diabetic should have their eyes examined on presentation and then annually, preferably with retinal photography as laid down in the NSF on diabetes,^2,3 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 produce also result in premature cataracts due to excess glucose interfering with the metabolism of the crystalline lens. Diabetic eye disease is covered in greater detail in our dedicated record on The Eye in Diabetes Mellitus. 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 (little tufts of vessels) growing on the disc (NVD) or elsewhere on the retina (NVE). Although eyesight is still normal, it is a sight-threatening situation.
• Advanced diabetic retinopathy shows bleeding from the neovascularisation ± the complications of this (e.g. 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

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 diastolic pressure >110mmHg, often with proteinuria. Treatment of the hypertension (though avoiding a rapid reduction which can precipitate a vascular occlusion) results in resolution of the retinal signs if not left too long.

Carotid stenosis

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, microaneurysms, proliferative retinopathy and macular oedema. These patients are treated with steroids, mydriatics, laser and occasionally surgical intervention.

Rheumatoid arthritis

This may be associated with Sjogren's syndrome, most commonly manifesting itself as keratoconjunctivitis sicca, scleritis and episcleritis. More seriously, peripheral ulcerative keratitis can occur eventually resulting in a corneal melt (i.e. 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.

Thyrotoxicosis

There are a number of ophthalmic features relating to thyroid eye disease and particularly thyrotoxicosis. These most commonly include lid retraction with lid lag (the best way to demonstrate this is to ask the patient to follow your finger to look up then down - as the eye descends a glimpse of white sclera above the iris is seen), conjunctival chemosis and proptosis. Less commonly, keratoconjunctivitis, diplopia and optic neuropathy occur. An early and important sign of the latter is colour desaturation (things looked washed out). As the thyrotoxicosis is brought under control the exophthalmos sometimes gets worse.

Atopic eczema

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.

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 record of these conditions.

Infective

• AIDS⁴ - 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 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 e.g. 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 e.g. Parinaud ocularglandular 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 periocular oedema are common. More unusually, patients develop keratitis, uveitis, optic neuritis, neuroretinitis and motor nerve palsies.
• 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.

Inflammatory

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.

Autoimmune

• 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 the Cogan 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.
• 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.
• 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.

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.
  Popular opinion is that people with albinism have red eyes, but the colour of the iris varies from a dull grey to blue to brown (a brown iris is common in ethnic groups with darker pigmentation). Under certain lighting conditions, there is a reddish or violet hue reflected through the iris from the retina, similar to that which occurs when a flash photograph is taken of a person looking directly at the camera and the eyes appear red. With some types of albinism the red colour can reflect back through the iris as well as through the pupil. Vision is poor from birth and often continues to deteriorate with nystagmus and blindness being common. The Chediak-Higashi syndrome is associated with impaired vision and albinism. Children with Prader-Willi syndrome have blond hair and blue eyes but sight is preserved.
• 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 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 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 enlargening pituitary gland. Occasionally, there is an associated nystagmus.
• Cushing syndrome - iatrogenic Cushing syndrome may be associated with steroid-induced cataracts (this is not the case for Cushing 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.

Other problems

• 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.
• 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 non-specific symptoms e.g. neck pain, weight loss, fever, malaise, depression etc.
• 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 conjunctivitis and keratitis.
• Behçet disease - 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.
• Kearns-Sayre syndrome - these patients have a symmetrical ptosis and external ophthalmoplegia as well as pigmentary retinopathy.
• 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.
• Stevens-Johnson syndrome - transient membranous conjunctivitis is common.
• 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 telangectasia are common; they may also suffer from keratoconjunctivitis sicca.
• Vogt-Koyanagi-Harada syndrome (VKH) - anterior uveitis is one of the features characterising Vogt-Koyanagi disease (along with skin changes). Harada 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.
• Wegener granulomatosis - ophthalmic features commonly include nasolacrimal duct obstruction and dacrocystitis but these patients may also develop scleritis, peripheral ulcerative keratitis and an orbital pseudotumour.
• Dermatomyositis - produces purple coloration and oedema of the eyelids with oedema of the conjunctiva.
• 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.

The mother

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 post-partum.
• Cornea - slight oedema and a steepening of the curvature can result in a minor shift in refractive error of the eye - wait several weeks post-partum before going to an optician for a new prescription as usually resolves.
• Intraocular pressure - this drops after 20 weeks gestation but should return to normal within 2 months post partum.
• Visual fields - an asymptomatic reduction may occur through an unknown mechanism but any symptomatic problems should be taken seriously and investigated (see below).

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.

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,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 (e.g. branch or retinal artery or vein occlusions, Purtscher-like retinopathy, the ocular effects of disseminated intravascular coagulation and thrombotic thrombocytopaenic purpura), ptosis (usually unilateral) and unusually, diabetic retinopathy in gestational diabetes.

The baby

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 and pass through the placenta and are excreted through breast milk although there is very little published data concerning the effects. The following table should be only be used as a guide; bear Hippocrates' wise words in mind, primum non nocere and think hard before prescribing in these women.