OCULAR MANIFESTATIONS OF SYSTEMIC DISEASES

Jeannette TÓTH

Semmelweis University, Budapest

Dept. of Ophthalmology

INTRODUCTION

• The eyes are frequently involved in diseases affecting the rest of the body

• Ocular manifestations in certain multisystem disorders may offer a diagnostic clue

• Sometime the eye involvement may be subtle enough to avoid detection unless the clinicians knows to look for it

THE CORNEA RELATED TO SYSTEMIC DISEASES

• DISEASES OF THE SKIN AND MUCOUS MEMBRANES

Atopic dermatitis, cicatricial pemphigoid, epidermolysis bullosa, erythema multiforme

• DISORDERS OF COLLAGEN METABOLISM

Ehlers-Danlos syndrome, Marfan syndrome

THE CORNEA RELATED TO SYSTEMIC DISEASES

• COLLAGEN DISEASES

Dermatomyositis, periarteritis nodosa,

rheumatoid arthritis, SLE

• METABOLIC DISEASES

Amyloidosis, cystinosis, glycogen storage disease, gout, hyperlipidemia

CATARACT RELATED TO SYSTEMIC DISEASES

• CHROMOSOMAL DISORDERS

Alport syndrome, Crouzon syndrome, myotonic dystrophy,Trisomy 18, Turner syndrome

• DISEASES OF THE SKIN AND MUCOUS MEMBRANES

Atopic dermatitis, pemphigus

CATARACT RELATED TO SYSTEMIC DISEASES

• METABOLIC AND NUTRITION DISEASES

Aminoaciduria, diabetes mellitus, galactosemia, hypoparathyroidism, hypothyroidism, Wilson’s disease

• INFECTIOUS DISEASES

Congenital HSV, syphylis, CMV, rubella

• TOXIC SUBSTANCES

THE RETINA RELATED TO SYSTEMIC DISEASES

CARDIOVASCULAR DISEASESAortic arch syndrome, hypertension and toxaemia

of pregnancy, occlusive vascular disease

COLLAGEN DISEASESDermatomyosistis, periarteritis nodosa, SLE, temporal

arteritis, Wegener granulomatosis

ENDOCRINE DISEASESDiabetes mellitus, Cushing syndrome,

hyperthyroidism, hypothyroidism, hypoparathyroidism

THE RETINA RELATED TO SYSTEMIC DISEASES

DISEASES OF THE SKIN AND MUCOUS MEMBRANESPseudoxanthoma elasticum

GASTROINTESTINAL AND NUTRITIONAL DISEASESRegional enteritis, vitamin A deficiency

HEMATOLOGIC DISEASESAnaemias, leukemias, sickle cell disease, thrombocytopenia

INFECTIOUS DISEASESCandida retinitis, parasites, viral infections, tuberculosis, HIV, HSV, HZV,

CMV

PHAKOMATOSES

METABOLIC DISEASES

THYROID EYE DISEASE (Graves’ ophthalmopathy)

The diagnosis may not be obvious, although it is quite common!

The severity of the eye changes does not always relate to the severity of the endocrine problem

It is not known why some patients with thyroid imbalance have eye features and others do not

The link is immunological, though the details are unclear

Often the eye features develop out of phase with the thyroid

FEATURES OF THYROID EYE DISEASENot all patients have all the signs and symptoms!

Puffiness of lids and conjunctiva, often worse in the morning

Discomfort and redness

Watering

Upper lid

Retraction due to overaction of Müller’s muscle (Dalrymple’s sign)

Lag (Von Graefe’s sign)

FEATURES OF THYROID EYE DISEASE

Infiltrative ophthalmopathyEnlargement of extraocular muscles

Proliferation of orbital fat and connective tissue

Protrusion (with poor eyelid closure, if severe corneal damage)

Double vision, often worse in the morning

Visual failure from optic nerve compression (rare, but needs urgent treatment)!

PATHOGENESIS OF THYROID EYE DISEASE

The disease is not completely understood

The existing knowledge suggests that the disease is likely to be

autoimmune in origin and linked to autoimmune thyroid disease

Cigarette smoking is commoner among patients with Graves’

disease and smokers have a more severe ophthalmopathy

Orbital fibroblasts synthesize more glycosaminoglycans when

cultured under hypoxic conditions.

Glycosaminoglycans attract water swelling of extraocular

muscles

Infiltration of orbital tissue by immune cells ant their activation, with

subsequent cytokine release leads to local cell proliferation

OPHTHALMIC PROBLEMES IN NEUROLOGICAL DISORDERS

• Multiple sclerosis

• Stroke

• Intracranial tumors

• Benign intracranial hypertension

• Facial palsy

MULTIPLE SCLEROSIS (demyelinisation)

Optic (ON) neuritis is the most common manifestation (usually unilateral, but may be bilateral) and the presenting feature in about 25% of MS patients

About 60% of patients in the 20-40 years age group who present with ON will subsequently develop evidence of systemic demyelinisation!

SYMPTOMS OF OPTIC NEURITIS

Decreased visual acuity

Afferent pupillary defect (if unilateral or asymmetric)

Impairment of color vision

Pain with eye movements or pressure on the globe

Central or ceco-central visual field defect

STROKE

Homonymous hemianopia is the commonest finding

Often not recognized by the patient

Lesion within the optic path behind the chiasm (usually in the radiation passing through temporal and parietal areas to the occipital cortex)

Occlusion of the vertebrobasilar circulation may cause bilateral cortical lesions and marked visual disability

Many patients have reading difficulties

INTRACRANIAL TUMORS

A tumor close to the optic nerve, chiasm or radiation may affect visual acuity or visual field

Check both visual field and visual acuity in patients with vague, but persistent and progressive complaints

Headache is not always present!

Look for papilloedema or atrophy of one or both optic nerve heads

PAPILLOEDEMA

Is caused by impairment of axonic flow in the optic nerve

Does not impair visual acuity but increases the size of the blind spot

Optic atrophy implies death of nerve fibers and is associated with impairment of visual acuity, field or color vision

BENIGN INTRACRANIAL HYPERTENSION

Papilloedema

Raised intracranial pressure

No tumor

Syndrome found in plump young women with persistent headache and menstrual irregularities

Cause unknown

Therapy: diuretics

Long-term monitoring by a specialist

FACIAL PALSY

Weakness of eye closure

Patients at risk of corneal ulceration

Depending on severity of malfunction therapy consists of topical antibiotics (for lubrication and prevention of secondary infections), taping or temporary suturing of the eyelids

EYE PROBLEMS IN JOINT DISORDERS

Some patients with joint disorders have inflammation of the coats of the eye (e.g. episcleritis, scleritis), other condition are associated with internal inflammation (iritis), some are a cause of dryness of the eye (sicca)

Rheumatoid arthritis

Ankylosing spondylitis

Reiter syndrome

Sjögren syndrome

Juvenile arthritis

RHEUMATOID ARTHRITIS

Dry eye (discomfort, burning sensation)

Scleritis (necrosis of the sclera may occur)

Refer urgently the rheumatoid arthritis patient with a painful eye even if it is not particularly red!

EYE PROBLEMS IN JOINT DISORDERS

ANKYLOSING SPONDYLITIS

Occurs in younger patients with HLA B27 positivity, causes sacroiliitis

Patients have recurrent anterior uveitis

REITER’S SYNDROME

Ocular inflammation with oligoarticular arthritis and urethritis

Chlamydia, Yersinia, Salmonella may be the causative agent

SJÖGREN’S SYNDROME

Typically affects conjunctiva and oral mucosa

The ophthalmologist is frequently the first doctor to see the patient

DRY EYE!

JUVENILE IDIOPATHIC ARTHRITIS

Low grade iritis, that may lead to blindness, if not recognized and treatedChildren with inflammatory arthritis under 12 years of age are at riskScreening!COMPLICATIONS:•Cataract•Glaucoma•Band keratopathy•Phthisis bulbi

EYE PROBLEMS IN SKIN DISORDERS

ALLERGIC REACTIONS

Acute allergic reaction in atopic patients

Cell-mediated allergy (e.g. topical treatment)

SEBORRHOEIC DERMATITIS

Blepharitis

EYE PROBLEMS IN SKIN DISORDERS

ROSACEA

BLEPHARITIS

Severe corneal changes

PSORIASIS

Iritis in some patients

BLISTERING DISORDERS

• STEVENS-JOHNSON SYNDROME

• PEMPHIGOID

• EPIDERMOLYSIS BULLOSA

STEVENS-JOHNSON SYNDROMEAcute hypersensitivity vesiculobullous reaction of the skin and mucous membranesImmune complex deposition incited by medications or infectious agentsCorneal ulceration and severe pseudomembranous conjunctivitisSymblepharon, entropion, ectropion, trichiasis, dry eye, persistent conjunctival inflammation, corneal opacification

OCULAR CICATRICIAL PEMPHIGOID

Slowly progressive, chronic cicatrizing conjunctivitisIdiopathic, possibly a type II hypersensitivity reactionPresents in women over 60 with recurrent attacks of nonspecific conjunctival inflammationThere may be associated oral, pharyngeal or urethral mucosal lesions

INFECTIONS OF THE SKIN INVOLVING THE EYE

• HERPES ZOSTER– Often involves the eyelid– Cornea and uvea may be involved (secondary glaucoma)

• VARICELLA– Lid and corneal lesions

• IMPETIGO• WARTS• MOLLUSCUM CONTAGIOSUM• PUBIC LICE

HERPES ZOSTER (HZ)

Incidence: between 40 and 70 years

Healthy and immuno-compromized patients are affected

HZ ophthalmicus represents 10 - 15% of cases

HERPES ZOSTER

Any branch of the Vth cranial nerve may be affected

Ocular complications are related to infection of the naso-ciliary nerve

Eyelid cicatrization

Symblepharon

Keratitis

ANTERIOR UVEITIS WITH SECONDARY GLAUCOMA!

AIDS

TWENTY MILLION CASES WORLDWIDE IN 2000!

Retrovirus (HIV) which infects immunocompetent CD4+ cells

RESULTS IN CELLULAR IMMUNODEFICIENCY (T-CELL AND MACROPHAGE DEFICIT)Complications due

1) to the virus itself

2) to superinfection by opportunistic pathogens

OCULAR INVOLVEMENT IN AIDS

Ocular manifestations have been reported in up to 70% of individuals infected with HIV

Ocular manifestations almost invariably reflect systemic disease and may be the first sign of disseminated systemic infection

The most common ocular finding is HIV retinopathy, occurring in about 50%-70% of cases

HIV has been isolated from human retina, and its antigen has been detected in retinal endothelial cells

Endothelial infection may be responsible for the vascular alterations

INFECTIOUS AGENTS THAT AFFECT THE EYE IN AIDS

Cytomegalovirus (CMV) - retinitis

Herpes Zoster - retinal necrosis

Toxoplasma gondii - retinochoroiditis

Mycobacterium tuberculosis - multifocal choroiditis

Cryptococcus neoformans - multifocal choroiditis

Pneumocystis carinii- choroiditis

These agents can infect the ocular adnexa, anterior or posterior segment

Multifocal choroiditis is an alarming sign, since it frequently represents disseminated infection!

OCULAR MANIFESTATIONS OF AIDS

Clinically 75% of patients have ocular signs or symptoms

ANTERIOR SEGMENT COMPLICATIONSConjunctival teleangiectasia, giant molluscum,

High grade malignant lymphoma/Burkitt lymphoma

Kaposi sarcoma

Keratitis, keratoconjunctivitis (HZ)

OCULAR MANIFESTATIONS OF AIDS

POSTERIOR SEGMENT COMPLICATIONS

Vasculitis (direct effect of the virus)VIRUS INFECTIONS (MULTIPLE)

CMV retinitis

HSV acute retinal necrosisMYCOTIC AND PARASITIC INFECTIONS

Pneumocystis carinii

EYE PROBLEMS IN VASCULAR DISORDERS

• Hypertension

• Diabetes mellitus

• Hyperlipidaemia

• Hematological disorders

• Vasculitis

• Ischaemic optic nerve disease

• Retinal vascular occlusions

RETINAL FEATURES OF HYPERTENSION

Vessels (especially arterioles)

Narrowing

Thickening with silvering or tortuosity

Arteriovenous crossing change (nipping in of the vein)

RETINAL FEATURES OF HYPERTENSION

Hemorrhages

Cotton wool spots (microinfarcts)

Retinal edema and disc swelling

Hard exudates (lipid)

Macroaneurysms

DIABETIC RETINOPATHY

A sight-threatening chronic process based primarily

on damage to the retinal capillaries (microangiopathy)

Later the process involves larger vessels: venules,

arterioles and arteries

A certain degree of retinopathy develops in virtually

every diabetic patient

DIABETIC RETINOPATHY

• In type -1 (insulin-dependent) diabetes the first ophthalmologic examination should be performed 3 to 5 years after the diagnosis

• In type -2 diabetes (NIDDM) the beginning of the disease is usually not known, ophthalmologic examination is mandatory, as retinopathy or macular edema may already be present at diagnosis!

DIABETIC RETINOPATHY (pathogenic mechanisms)

• Capillary hypertension• Systemic hypertension• Insulin resistance• Increased vascular permeability• Endothelial dysfunction• Hyperglycemic pseudohypoxia• Non-enzymatic glycosylation

Capillary damage

Pericyte necrosis(capillaries and veins)

Endothelial damage

Capillary non-perfusion

Retinal ischaemia

Vasoactive factors

HyperperfusionAbnormal autoregulation

Hypertension

New vesselsGrowth factors

Hyperglycemia

NON-PROLIFERATIVE DIABETIC RETINOPATHY

MICROANEURYSMS and blot-and-dot hemorrhages

INCREASED VASCULAR PERMEABILITY (hard exudates)

ISCHAEMIA (cotton-wool spots: damage to axoplasmic flow in the nerve fiber layer)

NON-PROLIFERATIVE DIABETIC RETINOPATHY

Venous “beading”

IRMA (intraretinal microvascular anomalies)

Extensive capillary occlusion and ischaemia

PROLIFERATIVE DIABETIC RETINOPATHY

IS CHARACTERIZED BY NEWLY FORMED VESSELS (neovascularisation) which originate from vessels of the optic nerve or from the surface of the retina

Newly formed vessels are abnormal, extremely fragile vessels!

PROLIFERATIVE DIABETIC RETINOPATHY

Vascular buds grow into the vitreous cortex through the damaged internal limiting membrane of the retina

Shrinkage and retraction of the vitreous is complicated by vitreous hemorrhage and/or retinal detachment

ANTERIOR SEGMENT COMPLICATIONS OF DIABETES

Recurrent, non-healing corneal epithelial defects

Neovascular glaucoma (related to rubeosis iridis ang anterior chamber angle neovascularization)

HYPERLIPIDAEMIA

OCULAR SYMPTOMS

Corneal arc

Eruptive xanthoma

VASCULITIS

PERIARTERITIS NODOSA

WEGENER GRANULOMATOSIS

VASCULITIS

ARTERITIS TEMPORALIS (GIANT CELL ARTERITIS)

Arteritic ischemic optic neuropathy

Painless visual loss with altitudinal visual field defect

Age more than 55 years!

Elevated ESR!

PHAKOMATOSES

• Phakomatoses or neurocutaneous syndromes are a group of disorders featuring multiple discrete lesions of one or a few histologic types that are found in two or more organ systems, including skin or central nervous system or both.

• Eye involvement is frequent, and may constitute an important source of morbidity or provide information critical to diagnosis

• Neurofibromatosis (von Recklinghausen disease)• Tuberous sclerosis (Bourneville disease)• Angiomatosis of retina and cerebellum (von Hippel-Lindau)• Encephalotrigeminal angiomatosis (Sturge-Weber

syndrome)

NEUROFIBROMATOSIS

• Two genetically distinct form are recognized• NF-1, one of the commonest autosomal dominant

disorders. Variation in the spectrum and severity of expression are prominent features.

• NF-1 gene is a tumor suppressor gene (chromosome 17q12)

• Diagnostic features– Café au lait spots– Skin neurofibromas– Lisch nodules

NEUROFIBROMATOSIS 1 (NF-1)

• Associated ocular features

– Neurofibroma of eyelid and orbit

– Uveal melanocytic nevi

– Retinal glial hamartoma

– Congenital glaucoma

– Optic nerve glioma

NEUROFIBROMATOSIS 2 (NF-2)

The gene maps to chromosome 22

Diagnostic features

Schwannoma of VIII cranial nerve

Meningioma

Spinal nerve root tumors

Cutaneous neurofibroma (relatively rare)

Associated ocular features

Lens opacities - posterior capsular cataract developing during adolescence or young adulthood

TUBEROUS SCLEROSIS

Autosomal dominant trait, the responsible gene maps to chromosome 9q34

Skin lesions

Angiofibroma (adenoma sebaceum)

Seizures

Mental retardation in 50% of cases

Eye lesions

Astrocytic hamartoma (composed of nerve fibers and glial cells) may be flat or mulberry-like

VON HIPPEL-LINDAU DISEASE Autosomal dominant disease, maps to

chromosome 3p25

Diagnostic features

Retinal angioma supplied by dilated tortuous arteriole and venule, may be multiple

Cerebellar angioma

Associated ocular conditions

Retinal exudates, hemorrhage, retinal detachment

Associated general conditions

Kidney tumors (renal carcinoma)

Pheochromocytoma

Cysts in different organs

STURGE-WEBER SYNDROME

Is not genetically transmitted

Diagnostic features

Facial cutaneous angioma (consists of excessively numerous dilated capillaries in the dermis)

Cerebral calcification

Seizures

STURGE-WEBER SYNDROME

OCULAR FEATURESChoroidal involvement - increased number of choroidal vessels

Glaucoma is the most serious complication seen in children with SWS