Eye Manifestations In Connective Tissue Disorders

Dr. Amar Patil

PG Medicine

Introduction

Connective tissue disease refers to a group of disorders involving the protein-rich tissue that supports organs and other parts of the body. Examples of connective tissue are fat, bone, and cartilage. These disorders often involve the joints, muscles, and skin, but they can also involve other organs and organ systems, including the eyes, heart, lungs, kidneys, gastrointestinal tract, and blood vessels.

• Many connective tissue diseases have abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one’s own body tissues (autoimmunity).

• Ocular inflammation is seen as part of a number of systemic diseases with autoimmune processes heading the list. Inflammation can affect any part of the eye starting from the cornea anteriorly to the retina, uveal tract and sclera posteriorly.

• In some conditions, uveitis or scleritis is the heralding presentation and in others it determines the need for more aggressive immunosuppressive therapy.

• The incidence, severity, and disease course of uveitis and scleritis are variable with many factors contributing to the natural history of the disease, including gender, the underlying systemic disease, and the extent of the inflammatory process.

Anatomy of Eye

Sclera

• Sclera forms the posterior 5/6th of the opaque part of the external fibrous tunic of the eyeball. In the anterior part it is covered by bulbar conjunctiva.

• Histologically sclera consists of 3 layers: ( image)

i)Episcleral tissue – it is a thin dense vascularised layer of connective tissue which covers the sclera proper.

ii) Sclera proper – it is an avascular structure which consists of dense bundles of collagen fibres. The branch of collagen tissue cross each other in all directions.

• iii) Lamina fusca – it is inner most part of sclera which blends with supra choroidal and supra ciliary laminae of the uveal tract.

Episcleritis• It is benign inflammation of the episclera involving the overlying

tenons capsule but not the underlying sclera.

• Types :

i. Simple episcleritis

ii. Nodular episcleritis

• Symptoms and Signs: Redness and ocular discomfort described as gritty or burning sensation. Rarely mild photophobia and lacrimation can occur

• Treatment :

i. Topical artifical tears: 0.5% carboxy methyl cellulose

ii. Topical NSAIDs: keratolac 0.3%

iii. Topical mild corticosteroid eye drops: fluorometholone.

iv. Cold compresses

v. Systemic NSAIDs: indomethacin (25mg three times a day)

Scleritis

• Scleritis refers to a chronic inflammation of the sclera proper.

• It is a comparatively serious disease which may cause visual impairment and even loss of the eye if treated inadequately.

• Its incidence is much less than that of episcleritis. It usually occurs in elderly patients (40-70 years) involving females more than the males.

Etiology :

• Autoimmune collagen disorders : Rheumatoid arthritis, is the most common association. Overall about 5% cases of scleritis

• Metabolic disorders like gout and thyrotoxicosis have also been reported to be associated with scleritis.

• Infections : Herpes zoster ophthalmicus, chronic staphylococcal and streptococcal infection.

• Granulomatous diseases: Tuberculosis, syphilis, sarcoidosis, leprosy can also cause scleritis.

• Miscellaneous conditions like irradiation, chemical burns, behcet'sdisease and rosacea are also implicated

Symptoms:

• Patients complain of moderate to severe pain which is deep and boring in character and often wakes the patient early in the morning .

• Ocular pain radiates to the jaw and temple. It is associated with localised or diffuse redness, mild to severe photophobia and lacrimation.

• Occasionally there occurs diminution of vision.

• Types

i. Non-necrotizing anterior diffuse scleritis

ii. Non-necrotizing anterior nodular scleritis

iii. Anterior necrotizing scleritis with inflammation

iv. Anterior necrotizing scleritis without inflammation (scleromalaciaperforans)

v. Posterior scleritis

Treatment:

• Non-necrotising scleritis - It is treated by topical steroid eyedrops and systemic indomethacin 100 mg daily for a day and then 75 mg daily until inflammation resolves.

• Necrotising scleritis - It is treated by topical steroids and heavy doses of oral steroids tapered slowly. In non-responsive cases, immuno-suppressive agents like methotrexate or cyclophosphamide may be required.

• To distinguish from episcleritis and scleritis phenylephrine 2.5% eye drops is used. The instillation of one or two drops in the affected eye will constrict the superficial episcleral vessels but not the deeper scleral vessels .

Rheumatoid Arthritis• Rheumatoid arthritis is a chronic inflammatory disease of unknown

etiology marked by symmetric ,peripheral polyarthritis.

• Ocular manifestations of this autoimmune disease vary and are mainly

i) Keratoconjunctivitis sicca

ii) Episcleritis

iii) Scleritis

iv) Keratitis

v) Uveitis

vi) Scleromalacia perforans.(Necrotising scleritis)

Their appearance, as well as their severity are related to RA chronicity and resistance to therapy

Keratoconjunctivitis sicca (Dry eye syndrome)

• It is the most common eye sign of RA with a percentage of 10% - 35%.

• Dry eye can be either “aqueous deficient ” or “evaporative” type.

• Gender plays a key role with 90% of the patients being females

• Pathology:

i) It is caused by infiltration of the lacrimal gland by T and B lymphocytes, leading to a secondary atrophy of the gland which is responsible for the decrease of tears.

ii) Females with primary Sjogren’s syndrome (without any underlying autoimmune problem) have elevated levels of antinuclear antibody(ANA)and autoantibodies directed against Ro/SSA and La/SSB autoantigens. This is thought to be secondary to higher estrogen levels in women, which, being immune stimulatory, result in accelerated humoral and cell mediated response

iii) The evaporative type of dry eye is secondary to tear film instability and higher rate of evaporation. This is thought to be due to relative androgen deficiency. Androgens play a role at various stages in lipid metabolism. Meibomian glands are target organs for androgens. Decreased levels of androgens therefore lead to altered lipid component of meibomian secretions. This alters tear film composition and leads to evaporative dry eye.

iv) Similarly, men on antiandrogen therapy(such as for prostate cancer) are more commonly affected than others . Therefore, female gender has been identified as a risk factor for the development of dry eye .

• Symptoms and Signs:

i) The patients complain of a burning sensation of the eye, pain and blurred vision.

ii) Foreign body sensation described as gritty feeling in eyes, and there is also a hyperaemia of the conjunctiva (red eye).

iii) Mucus discharge and crusts are not uncommon.

iv) So the dominant findings of Keratoconjunctivitis sicca are two: diminished corneal tear meniscus and abnormal Schirmer’s test.

• Treatment:

i) The primary goal in managing dry eye is to replenish or preserve

the tear film. The treatment is a combination of several actions.

ii) The patients should avoid dry environments and

overexposure to the sun.

iii) Natural tear substitutes are used

iv) In extreme cases occlusion of the lacrimal drainage, tarsorrhaphymay be required in order to eliminate the problem.

Episcleritis

• Scleritis and episcleritis are the second most common ocular manifestation of rheumatoid arthritis with RA being the most common autoimmune etiology associated with scleritis.

• Occurs in 4% - 10% of RA patients.

• There are two forms of episcleritis: Simple episcleritis and the Nodular episcleritis. The nodular is characterized by the presence of subconjunctival nodules that are mobile over the sclera. The simple (diffuse) episcleritis is more common.

• Symptoms and Signs:

I. The symptoms include sudden onset, with mild photophobia and discomfort, no visual impairment.

II. Also mild pain may radiate into cheek,eye brows, temples.

III. The signs of episcleritis include bright red appearance of the eye with engorged blood vessels.

IV. Also, there is no tenderness on palpation(Painless).

• Treatment:

I. Topical/oral steroids or NSAIDs.

II. Initial treatment of episcleritis should be focused on relieving discomfort and stopping progression of the disease.

Scleritis

• Scleritis occurs with the same percentage as episcleritis does.

• In RA it is 4% - 10%. RA is a common cause of Scleritis.

• Scleritis may be diffuse, nodular, or necrotizing. Patients with non-necrotizing scleritis usually have mild joint disease whereas necrotizing disease tends to affect patients with severe long-standing rheumatoid disease with extra-articular manifestations, most notably rheumatoid nodules.

• Necrotizing scleritis without inflammation is a sign of long-standing RA.

Symptoms and Signs

• Scleritis may have similar symptoms to episcleritis but Scleritis has a gradual onset with a deep, boring pain which may radiate into cheek, eyebrows and temples.

• Scleritis causes blurred vision and photophobia.

• Patients may have decreased visual acuity and tender nodules over the sclera.

• There is more pain than in episcleritis and also there is tenderness on palpation.

• The Scleritis patient will complain of pain while the Episcleritis-patient will not.

Treatment:

• Initial treatment is by topical steroids.

• If there is non-necrotizing disease then treatment with topical and oral NSAIDs.

• Also periocular steroid injections may be used in non-necrotizing and necrotizing disease but their effects are usually transient.

• Corticosteroids by systemic route are used when NSAIDs are contraindicated or ineffective. Cytotoxic/immunomodulatory agents (such as cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil) are usually necessary if the activity of the disease is not fully controlled with steroids or they are used in order to reduce the dose of corticosteroid in patients requiring long term treatment.

• Immunosuppressive agents, including inhibitors of calcineurin: cyclosporine and tacrolimus have been used as a long term treatment.

• Monoclonal antibody/biological agents, such as infliximab and rituximab are promising. Infliximab as an antagonist of TNF inhibits the referred factor or serum or on the surface of target cells and suppress the inflammatory process and rituximab as a monoclonal anti-CD20 antibody for B lymphocytes eliminates the specific B memory lymphocytes thereby inhibiting activation of antigen reactive cells preventing their operation to create inflammation .

• Subconjunctival triamsinolone has also been used.

• The penetrating scleromalacia is a type of necrotizing scleritis without inflammation, which typically may occur in older women with RA on longer duration.

• The term penetrating is surprising since the penetration of the ball is extremely unlikely and the integrity of the bulb remains thin but with an intact layer of fibrous tissue.

• It forms necrosis of the sclera near the limbus without vascular congestion. It has been very slow progress by scleral thinning and uncovering the underlying choroid.

• The treatment may be effective in the initial stages, otherwise the phthisis of the bulb follows.

Scleromalacia Perforans

Keratitis

• Keratitis is another very important aspect of the ocular manifestations. Corneal disease in patients with RA can be an isolated complication, but it is mostly associated with keratoconjunctivitissicca (a form of anterior scleritis).

Symptoms and Signs

• Keratitis is being characterized by pain with photophobia, foreign body sensation, red eye, tearing and decreased vision.

• Keratitis is caused by infiltration by inflammatory cells and maybe characterized by corneal opacification or by corneal vascularization, which can lead to ulceration.

• Peripheral ulcerative keratitis (PUK) is also associated with RA, which may lead to rapid corneal keratolysis, perforation of the globe and visual failure and is associated with systemic vasculitis in more than 50% of cases , which carries a high mortality rate and needs early and aggressive treatment.

• The clinical presentation of PUK is variable, it may present after intraocular surgery or arise de novo, and typically patients describe a non-specific foreign body sensation with pain, watering eye and reduced visual acuity.

• The peripheral cornea has morphological and immunological characteristics that predispose to autoimmune inflammation. Unlike the central avascular cornea, the peripheral is provided with nutrients from the capillary.

• The vascular architecture of limbus is suitable for IgM accumulation, complement C1 and immunocomplexes. The deposition of immune complexes triggers the classical complement pathway, which in turn induces chemotaxis of inflammatory cells, particularly neutrophils and macrophages. These cells can release collagenases and other proteases that destroy the corneal stroma.*

• Moreover, the proinflammatory cytokines such as interleukin-1 ,stimulates stromal keratocytes to produce metalloproteinases, which may accelerate destructive procedure.

• PUK described local imbalance in the ratio of the levels of a particular collagenase (MMP-1) and the inhibitor (TIMP-1) and it has been suggested that this imbalance is responsible for the rapid keratolysis*

*Silva, B.L., Cardozo, J.B., Marback, P., Machado, F.C., Galvão, V. and Santiago, M.B. (2010) Peripheral Ulcerative Keratitis: A Serious Complication of Rheumatoid Arthritis. Rheumatology International, 30, 1267-1268.

Treatment

• Without treatment, the disease maybe self-limited.

• Treatment includes NSAIDs, topical/oral/IV corticosteroids and Cytotoxics .

• Systemic administration of corticosteroids are used to treat acute phase and cytotoxic immunomodulators (cyclophosphamide, methotrexate, azathioprine) for long-term treatment.

• In cases of perforation PUK application corneal tissue glue or amniotic membrane patch or keratoplasty.

• Systemic administration of cyclosporin as an immunosuppressant, when the RA is in advanced stages. The decision regarding the duration of treatment depends on whether associated with underlying systemic vasculitis, response to treatment. Particular caution is required when prescribing topical steroids to prevent further thinning of the cornea*.

*Patel, S.J. and Lundy, D.C. (2002) Ocular Manifestations of Autoimmune Disease. 66.

Uveitis

• Uveitis (anterior uveitis/iridocyclitis, intermediate uveitis, posterior uveitis/chorioretinitis, panuveitis) are several forms of intraocular inflammation that may occur in rheumatoid arthritis .

• The clinical signs are reduced visual acuity, inflammatory infiltration of the anterior chamber, synechiae and miosis .

• Treatment includes cycloplegics, topical steroids and immunosuppressants.

Systemic Lupus Erythematous

• Systemic lupus erythematous is an autoimmune disease in which the organs and cells undergo damage initially mediated by tissue binding autoantibodies and immune complexes.

• Ocular manifestations cause significant morbidity in their own right, but can also be a useful indicator of underlying systemic disease activity. Although early recognition and treatment have led to a reduction in severe ocular complications. Ocular involvement in SLE is still a potentially blinding condition.

• Gender plays a key role with women being nine times more commonly affected than men*

*MariaM.Choudhary et al, Gender and Ocular Manifestations of Connective Tissue Diseases and Systemic Vasculitides Journal of Ophthalmology Volume 2014, Article ID 403042, 8 pages

• Ocular manifestations in SLE are fairly common, potentially sight threatening and may be the presenting feature of their disease .

• SLE may affect almost any part of the eye and visual pathway. Additionally drugs used in the treatment of SLE may cause ocular problems such as cataract or retinopathy.

Pathology

• SLE may cause ocular disease by a number of mechanisms including immune complex deposition and other antibody related mechanisms, vasculitis and thrombosis. Immune complex deposition has been identified in blood vessels of the conjunctiva, retina, choroid, sclera, ciliary body, in the basement membranes of the ciliary body and cornea, in the peripheral nerves of the ciliary body and conjunctiva*.

• Antibody dependent cytotoxicity may cause retinal cell death and demyelination of the optic nerve. Pathogenic circulating antibodies include anti-phospholipid antibodies (APLA) and antineuronalantibodies

* Karpik AG, Schwartz MM, Dickey LE, Streeten BW, Roberts JL. Ocular immune reactants in patients dying with systemic lupus erythematosus. Clin Immunol Immunopathol 1985;35:295–312

Symptoms and signs

i. Pain (often accompanied by visible inflammation or redness) usually indicates significant external/anterior segment disease.

ii. Problems with vision (blurring, distortion, double vision usually indicates posterior segment/neuro-ophthalmic disease).

Causes of Red Eye in SLE

i. Common - Dry eye (kerato-conjunctivitis sicca)

ii. Less common – Episcleritis, Scleritis, Conjunctivitis (non-infective)

iii. Rare - Keratitis (other than kerato-conjunctivitis sicca)

Anterior uveitis

Causes of loss of vision in SLE

• Anterior segment - Severe kerato-conjunctivitis sicca

• Lens - Cataract (secondary to inflammation and/or

corticosteroids)

• Vitreous - Vitreous haemorrhage (secondary to proliferative

retinopathy)

• Retina - Severe vaso-occlusive retinopathy

Central retinal vein occlusion (CRVO)

Branch retinal vein occlusion (BRVO)

Central retinal arteriole occlusion (CRAO)

Branch retinal arteriole occlusion (BRAO)

Exudative retinal detachment

Toxic maculopathy (secondary to malarial

treatment)

• Choroid - Lupus choroidopathy

Choroidal effusion

Choroidal infarction

Choroidal neovascular membranes

Neuro-ophthalmic - Optic neuritis

Anterior ischaemic optic neuropathy

Posterior ischaemic optic neuropathy

Optic chiasmopathy

Cortical infarcts

• External eye disease

i) Eyelid disease - SLE (and discoid lupus erythematosus) can present with a discoid lupus-type rash over the eyelids. These discrete raised scaly lesions must be distinguished from the much more common chronic blepharitis (inflammation of lid margins). These lesions usually respond well to systemic but not topical antiinflammatory therapy.

ii) Lacrimal system disease - Dry eye syndrome (keratoconjunctivitissicca) is the most common ocular feature of SLE (around a third of patients) and is often associated with secondary Sjogren’s syndrome . Usually, symptoms are relatively mild (irritation, redness) but severe pain and visual loss may occur. A reduced tear film and corneal changes are evident on slit-lamp examination. Tear production can be assessed by the Schirmer test. Milder forms of dry eye can be treated with artificial tear drops.

iii) Orbital disease - Rare ocular presentations include orbital masses, periorbital oedema, orbital myositis, acute orbital ischemia and infarction are rare presentations of SLE. A biopsy is often necessary to confirm the diagnosis. Treatment is with systemic immunosuppression

• Anterior segment disease

i) Corneal disease - Although the most common, the changes of dry eye syndrome are not the only corneal manifestation of SLE. Recurrent corneal erosions (large breaks in the corneal epithelium) typically present as a painful watery eye that comes on at waking and improves over the course of the day.

Another corneal presentation is punctate epithelial loss. This may respond to systemic antimalarials suggesting that this may be an autoimmune rather than a dry eye phenomenon*. Peripheral ulcerative keratitis is rare and is an ominous marker of the presence of active systemic vasculitis. Acute unilateral corneal stromal infiltration and oedema has been reported and responds rapidly to topical corticosteroid therapy.*

*Foster CS. Ocular surface manifestations of neurological and systemic disease. Int Ophthalmol Clin 1979;19:207–42.

ii) Episcleral and scleral disease - Episcleritis (superficial) and scleritis(deeper inflammation of the sclera) are both seen in SLE, and may be the presenting feature of the disease. Episcleritis usually presents with mild, if any, irritation and redness due to injection of the superficial blood vessels.

Scleritis is much more painful, may be sight threatening and requires urgent assessment by an ophthalmologist. The pain is so severe that it can wake the patient from sleep; it may be described as an ‘ache’ or ‘boring’ and may be generalized to the whole eye or the side of the face..

• Anterior scleritis may be diffuse or nodular in distribution. Rarely it may result in significant destruction (necrotizing scleritis) leaving an area of scleral thinning.

• Posterior scleritis does not cause a red eye (unless it extends anteriorly) but may cause visual problems, with blurring, change in refraction and double vision. Although features may be present on fundoscopy (oedema, choroidal detachments, exudative retinal detachments), the diagnosis is most easily confirmed on B-scan ultrasonography.

• Episcleritis does not usually require treatment, although artificial tears may be soothing. The presence of scleritis may indicate activity of the underlying disease and requires systemic therapy, ranging from non steroidal anti-inflammatory drugs like flurbiprofen to corticosteroids and other immunosuppressive agents (e.g. cyclophosphamide, azathioprine, methotrexate, cyclosporin or mycophenolate)

iii) Other anterior segment complications - Conjunctival inflammation is uncommon. It presents with irritation, redness and may be associated with lid follicles

• Posterior segment disease

i) Retinal disease - Retinal disease affects around 10% of SLE patients, reflecting a reduction in frequency associated with improved control of systemic disease. Mild retinopathy may be asymptomatic but more severe disease may cause loss of vision, field defects, distortion or floaters. Such visual symptoms are therefore an indication for urgent ophthalmic review. The retinal signs often parallel the severity of systemic inflammation, and may indicate inadequate control of the systemic disease. The presence of APA is associated with more severe retinopathy and vascular occlusions.*

*R. R. Sivaraj et al, Ocular manifestations of systemic lupus erythematosus, Rheumatology 2007;46:1757–1762,Advance Access publication 5 August 2007

• Mild lupus retinopathy consists of cotton–wool spots, perivascular hard exudates, retinal haemorrhages and vascular tortuosity.

• Other retinal presentations include large vessel occlusions (central and branch retinal vein occlusions, central and branch retinal arteriole occlusions) that are more common in the presence of APA, pigmentary changes (pseudo-retinitis pigmentosa) and exudative retinal detachments secondary to choroidal disease.

• The mainstay of treatment for significant retinal disease is systemic immunosuppression. Initial treatment is usually with oral corticosteroids (e.g. prednisolone 1mg/kg/day), but may be preceded by intravenous methylprednisolone (e.g. 500mg–1g daily for 3 days).

• ii) Choroidal disease - Choroidal disease is less common than retinopathy but is probably underdiagnosed as a cause of visual loss in SLE.

Neuro-ophthalmic disease

Optic nerve disease - Optic nerve disease occurs in around 1% of patients with SLE , and includes optic neuritis and ischemic optic neuropathy.

Optic neuritis presents acutely with unilateral loss of vision associated with pain that is worse with eye movements. The prognosis is worse in SLE associated optic neuritis, with more than half having a persistent central scotoma and progressing to optic atrophy. Pathological studies demonstrate infarction of the optic nerve secondary to extensive arteriolar fibrinoid necrosis . Acute optic neuritis may also be bilateral and associated with transverse myelopathy

In contrast to optic neuritis, optic neuropathy in SLE typically presents with bilateral, acute painless loss of vision associated with an altitudinal or arcuate field defect, with or without optic disc swelling. This is due to occlusion of the small vessels of the optic nerves, which leads to demyelination in mild cases or axonal necrosis in more severe cases

• Bilateral optic neuropathy that improves with immunosuppressive treatment is suggestive of a more generalised CNS vasculiticpathology .

• Visual prognosis following optic neuropathy is generally poor, although good outcomes have been reported. Recurrence usually worsens the prognosis. Occasional improvement following early treatment with corticosteroids or pulsed cyclophosphamide have been reported, with some patients needing anticoagulation in addition to immunosuppression.

Polymyositis and Dermatomyositis

• Polymyositis and Dermatomyositis are a group of autoimmune diseases characterized by inflammation of the skeletal muscles ; when there is dermatological involvement , the condition is referred to as dermatomyositis.

• Genetic factors play an important role and a strong association has been identified with human leukocyte antigens HLA-B8 and DR3 and DR52.

• Inflammatory myositis is relatively rare compared to other rheumatologic diseases with around 5 new cases per million being reported annually.

• Women are more commonly affected than men.

• Around 15% of the cases are associated with an underlying malignancy.

• Ocular manifestations are as follows;

i. Heliotrope rash or purplish discoloration of the eyelids is the most common ocular manifestation.

ii. Pediatric case reports exist about retinal vasculitis.

iii. Occasional cases of internuclear ophthalmoplegia have also been reported.

iv. Involvement of the extraocular muscles is extremely rare and can cause pain and ophthalmoplegia.

iv. The associated peri-orbital redness and oedema producing ptosis, chemosis, and exophthalmos may initially be mistaken for infective orbital cellulitis.

v. Additional features seen are conjunctivitis and iritis , episcleritis and uveitis with glaucoma.

• No gender differences have been observed in the incidence or severity of ocular problems in the patient population.

Visual loss from optic neuropathy

• Optic neuropathy has been described in patients with dermatomyositis, but only in association with retinopathy usually producing multiple cotton wool spots is the most common finding and may be asymptomatic.

• Pathology:

i) Retinal involvement is believed to be due to vasculitis with endothelial disruption and platelet thrombi.

• Retinopathy is believed to be more common in children with dermatomyositis because accompanying vasculitis is more common at a younger age.

ii) Decreased vision has been attributed to retinopathy and infarction within the retinal nerve fibre layer.

iii) Intraretinal haemorrhages and macular exudates have also been described as causing decreased vision in patients with dermatomyositis.

• Signs and symptoms

I. Blurred vision in both eyes that is gradually progressing.

II. The relative afferent pupillary defect, dyschromatopsia, visual field defects and optic disc oedema in the absence of retinopathy give evidence that the visual loss is from an optic neuropathy and not a retinopathy.

• Treatment

I. Corticosteroid therapy (oral/iv)

II. Immunosupressants (high dose)

Marfan’s syndrome

• Marfan's syndrome (MFS) is an autosomal dominant connective tissue disorder, caused by mutations in FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin.

• Abnormalities in this protein often lead to a myriad of skeletal, cardiovascular, and ocular abnormalities.

• Around 41% of the patients with MFS are initially seen for an ocular pathology and diagnosed by an ophthalmologist.

• Ocular manifestations include;

i. Ectopia lentis

ii. Cataracts

iii. Myopia

iv. Astigmatism

v. Strabismus

vi. Retinal detachment

vii. Glaucoma

Ectopia lentis

Found in 50–80% of the eyes.

• Signs and symptoms

I. Fluctuating blurred vision.

II. Monocular diplopia

III. Pain

IV. Characteristically, lens tend to be displaced in superior-temporal direction and often bilateral.

V. Phacodonesis and/or iridodonesis may commonly present even in the absence of evident lens dislocation.

VI. Develop cataracts several decades earlier compared to unaffected

individuals.

• Treatment

I. Surgical management of these cases with anterior lensectomy, limited vitrectomy, and iris/scleral-fixated intraocular lenses or aphakic correction are indicated where ametropia cannot be achieved by optical refraction or when the refractive status becomes unstable, in the presence of significant anisometropia, complete dislocation of the lens and lens-induced glaucoma or uveitis.

Myopia

Present in around 40% of the cases.

• Pathology

i. These patients develop lenticular myopia resulting from spherophakia and axial myopia resulting from globe elongation.

Astigmatism

• Pathology

i. Combined effect of corneal toxicity and lens subluxation. The cornea is typically flat in these patients.

ii. Anterior chamber angle in these patients is usually wide with immature trabecular meshwork and displacement of schlemm'scanal.

iii. Sphincter and dilator muscle of the iris are usually underdeveloped causing eccentric pupil or mydriasis. Iris transillumination defects may present in some cases.

Strabismus

• Incidence in strabismus in patients with MFS is increased compared to general population.

• Specifically, exotropia has been reported in up to 11.7% of patients with MFS, whereas esotropia has been found in 2.1% of patients.

• Pathology

i. Abnormal afferent visual inputs to cortical centers caused by ectopialentis and craniofacial abnormalities may contribute to the higher prevalence of strabismus in MFS.

Retinal detachment

• Common ocular complication.

• The incidence of retinal detachment in MFS ranges from 5% to 11% and more commonly seen in younger adults.

• This risk further increases (38%) with the presence of ectopia lentis or following surgical extraction of the lens.

Glaucoma

• Around 35% of the patients develop glaucoma during their lifetime and primary open-angle glaucoma is the most common.

• Other causes of glaucoma in these patients are lens dislocation and surgery.

• Overall treatment

i. Patients must be closely followed up for complications such as glaucoma, retinal detachment, cataract, and amblyopia.

ii. Awareness and prompt recognition of the ocular manifestations of MFS by the general ophthalmologist, especially in the absence of family history and distinct musculoskeletal features, may not only enable the improvement and preservation of sight, but by relevant referrals to the internists and comprehensive management by a multidisciplinary team including a geneticist, orthopedics, and cardiologist, may also improve the morbidity and mortality of these patients.

Osteogenesis imperfecta

• Osteogenesis imperfecta is a genetic disorder of connective tissue characterized by increased bone fragility and usually associated with hearing loss , abnormalities of dentition and blue sclera.

• Ocular manifestations include;

i. Blue sclera

ii. Blindness

iii. Retinal detachment

• Most affected individuals have mutation in either the COL1A1 or COL1A2 genes that encode the chains of type I procollagen.

Blue sclera

• The sclera can vary in color from normal to a slightly bluish to a bright blue.

• Pathology

i. The blue sclera result from thinning of abnormal sclera , leading to the transmission of the uveal tissue to the observer.

• Treatment

I. Vitrectomy

Blindness

• Blindness usually results from corneal opacity , secondary glaucoma and hyperplasia of the vitreous.

Retinal detachment

• Pathology

i. Patients with osteogenesis imperfecta are more prone to retinal detachment because decreased scleral rigidity leads to increases tractional forces on the peripheral retina.

• Treatment

For uncomplicated cases the standard for repair is ;

I. Scleral buckling surgery

II. Pneumatic retinopexy

III. Primary vitrectomy

For acute or chronic macular-sparing shallow retinal

detachments without proliferating vitreoretinopathy;

I. Laser photocoagulation

Scleroderma

• Scleroderma is a generalized connective tissue disease of unknown origin with heterogeneous manifestations

• It is characterized by abnormal fibroblast proliferation leading to deposition of extracellular matrix in the skin, blood vessels, and viscera.

• This results in stiffening of the connective tissue structures in the skin and body organs.

• Symtoms and signs

i. Telangiectasia

ii. Eyelid changes : dermal sclerosis of the eyelids and Lid stiffness is associated with woody texture on palpation and difficulty with lid eversion.

iii. Conjunctival changes: This comprises of vascular congestion, telangiectasia and varicosities of conjunctival vessels, intravascular sludging, and loss of fine vessels.

iv. Lacrimal function changes :A tear defect of varying severity.

V. Iris changes :punctate defects of the iris pigment epithelium appearing as Spotty areas of transillumination in all zones of the iris

Vi. Fundus changes : There will be retinal arterial sclerosis with constriction of the affected venous branch due to sclerosis of the adjacent arterial adventitial sheath.

• Treament

• Telangiectasia such as those on the face, can be treated with local laser therapy. Sun exposure should be minimized as it can worsen telangiectasias.

• Lacrimal function changes :Topical lubricants

Stills Disease

• It is a rare systemic autoinflammatory disease characterized by the classic triad of persistent high spiking fevers, joint pain , and a distinctive salmon-colored rash.

• Symptoms and signs

i. Iridocyclitis :This iridocyclitis is commonly of a quiet sero-fibrinous non-granulomatous type.

Fine posterior synechiae commonly develop

and may be seen extending as filmy grey bands

from the anterior surface of the iris near

the pupil margin to the anterior lens capsule.

• The quiet insidious nature of the iridocyclitis is characteristic.

• There is no pain . The inflammation may subside for long periods-months or years and then recur.

• Iridocyclitis is sub-acute in nature with definite redness of the eye, photophobia and some discomfort.

Treatment

• It is mainly by mydriatics and cortisone. Suppressing inflammation and preventing adhesions is the main stay of the treatment.

• Cortisone and hydrocortisone 1 percent drops and ointment is used. Drops should be instilled 2- or 4-hrly during the day and the ointment before going to sleep at night.

ii. Band Keratopathy (Corneal Band Opacity).-This is a striking feature and common complication of the ocular inflammation occurs in still's disease only in association with iridocyclitis.

• The opacity usually extends across the cornea in the inter-palpebral area, more below than above the centre of the

pupil and is subepithelial at the

level of bowman's membrane.

• It consists of closely-grouped grey dots interspersed with clear round lacunae of varying sizes. These clear fenestrations are said to be caused by the corneal nerve filaments which perforate bowman's membrane to form the subepithelial plexus.

Treatment

• Subconjunctival injections of cortisone.

• Chelation : EDTA(Edetate Disodium)

• If there is sufficiently gross opacity, lamellar keratoplasty might seem to be indicated.

iii. Cataract :This forms the third feature of what might be called the "ocular triad" of Still's disease.

• It is seen typically as a complicated cataract, usually first in the posterior lens cortex and then in the anterior cortex, and it matures rapidly, causing profound interference with vision.

• Treatment : Repeated needling operations ,but only when the iridocyclitis has been fully controlled and the eye has been free from inflammation for some months.

iv. Fibrinous exudate : inflammatory deposits on the lens capsule in the pupillary area can also cause considerable interference with vision and may be followed by localized subcapsular opacities.

V. Secondary glaucoma: It is another possible complication. Extensive adhesions between iris and lens result in seclusio pupilli and iris bombe which must be promptly relieved by iridectomy.

vi. Hypotony can also occur as a terminal event when the ciliary body is so disrupted by prolonged inflammation that the ciliary processes can no longer produce aqueous humour, phthisis bulbi then gradually develops.

Behcet’s Disease

• Behçet’s disease (BD) is a chronic, relapsing inflammatory disorder of unknown etiology and characterized by obstructive vasculitis. It can involve both the arteries and veins of almost any organ and characterized by recurrent oral and genital aphthous ulcers, ocular inflammation, and skin lesions.

• The frequency of ocular involvement in patients with BD is approximately 70%-90% . The ocular disease manifests approximately in 2-3 years after the initial symptoms noted.

• Males are more frequently involved, has an earlier disease onset, and has a more severe disease.

Occular Manifestations – Symptoms and Signs

• The characteristic ocular involvement is a relapsing remitting panuveitis.

• The ocular inflammatory episodes in BD are characteristically associated with a sudden severe onset of visual loss. Severity and number of repeated inflammatory attacks involving the posterior segment determine the extent of permanent structural changes and the resultant rate of irreversible visual loss. Because of that, Behçetpanuveitis is a medical emergency, which must be treated immediately.

ANTERİOR SEGMENT:

• Iridocyclitis ± hypopyon, Secondary glaucoma ,Secondary cataract

• Less frequent findings:

Episcleritis,Scleritis,Conjunctivitis, Subconjunctival haemorrhage,-Conjunctival ulcers, Filamentary keratitis,Corneal immune ring opacity.

POSTERİOR SEGMENT:

• Vitritis, Retinal perivasculitis, Retinal hemorrhage and infarction due to occlusive vasculitic attacks, Retinitis, Diffuse retinal or optic disc edema, Optic disc hyperemia, Venous engorgement, Cystoid macular edema, Macular ischemia, Macular scarring, Pigment epithelial changes,Epiretinal membrane formation.

End stage ocular disease:

• Optic atrophy, Vascular attenuation and sheathing, Diffuse retinal atrophy.

Treatment

• The primary goals of management are symptom control, early suppression of inflammation and prevention of end-organ damage. Even though therapy of acute disease is essential, to prevent or at least to decrease the number of repetitive ocular and systemic inflammatory episodes is important.

• Many treatment modalities have been tried in ocular BD with varying claims of success. For the time being, the most commonly used agents are corticosteroids, cytotoxic drugs, colchicine, and tacrolimus.

Ehler‘s Danlos Syndrome

• It’s a heterogenous group of inherited connective tissue disorders Characterized by hyperextensible skin, hypermobile joints and connective tissue/ cutaneous fragility.

• These symptoms are result of gene mutations affecting the structure of various collagen types.

• Mainly affecting the eye , as 80% of eye is made up of collagen.

• The frequency of Ehler's Danlos syndrome has been estimated at 1 case in 50,000 to 1 case in 200,000 and prevalence is reported to be 1 case in approximately 400,000.

• Type 6, the ocular form, affects 2%of patients and is inherited in an autosomal recessive pattern.

Signs and symptoms

• Keratoconus-Abnormal corneal curvature occurs when it becomes cone shaped, usually occurs in 2nd & 3rd decade of life.

• Angioid streaks - These are cracks in the Bruch's membrane or anchoring membrane of retina. The streaks usually radiate from optic disc .

• High myopia- characterizd by shortsightedness. Results because cornea is to steep to focus point of light rays entering the pupil in front of the retina.

• Blue sclera-bluish appearance attributed to a thinning of sclera, noticeable at the limbus.

.

• Posterior staphyloma- is a streching or distortion in the posterior aspect of eye. Scleral tissue bubbles which results in a significant myopic shift i.e, increased shortsightedness

• Retinal detachments-preceded by a shower of sparks & floaters are trapped debris in vitreous of the eye. Blue sclera-bluish appearance attributed to a thinning of sclera, noticeable at the limbus.

• Macular degeneration-contains the highest concentration of vision receptors, when the macula atrophies causing pigment changes and decrease in keen vision to occur.

• Glaucoma- increase in intraocular pressure which leads to vision impairment till blindness, as well as a progressive loss of peripheral vision.

• Cataracts - the lens tissue discolours naturally resulting in cloudy lens.

• Dry eye - results in when normal coating of tears on the eye is diminished.

Treatment

i) Medical care

• Eye drops are used for dry eye.

ii) Surgical care

• Corneal transplant is required for keratoconus.

• Corrective lenses are an effective treatment for high myopia

Systemic Vasculitidies

• The vasculitic syndromes have been classified by the predominant sizes of the blood vessels most commonly involved.

• Ophthalmic manifestations are protean and nonspecific and are secondary to vasculitis of the ophthalmic circulation.

• Conjunctivitis, episcleritis, and scleritis are the most common presentations. The patients typically present with painful red eye except in episcleritis where the condition might be painless and usually self-limiting

• Cicatrizing conjunctivitis resulting in symblepharon more commonly of the upper eyelid can be seen in uncontrolled disease .

• Scleritis associated with systemic vasculitis requires more aggressive treatment than idiopathic scleritis or from other etiologies.

• Retinal arterial involvement can be in the form of central retinal artery occlusion or a branch of it. Involvement of posterior ciliarycirculation can cause ischemic optic neuritis.

Sjogren’s Syndrome

• It is a chronic ,slowly progressive autoimmune disease characterized by lymphocytic infiltration of the exocrine glands resulting in xerostomia and dry eyes.

• Occular Manifestations: Keratoconjunctivitis sicca

• Signs and Symptoms

i. Sandy gritty feeling under eyelids

ii. Accumulation of secretions in thick strands at the inner canthi

iii. Decreased tearing

iv. Redness ,Itching and increased photosensitivity.

v. Slit lamp examination shows punctate corneal ulcerations .

Treatment

i. Tear drops – Hydroxypropyl methylcellulose

ii. Corneal ulcerations – Eye patching and boric acid ointment.

Scleritis Anterior Uveitis Posterior Uveitis

Rheumatoid arthritis Rheumatoid arthritis Idioapthic

SLE SLE Sarcoidosis

Behcet’s disease Ankylosing spondylosis Behcet’s disease

Sarcoidosis Sarcoidosis

Dermatomyositis Reiters syndrome

Wegner,s granulomatosis Spondyloarthritis

Spondyloarthritis

Panuveitis

Idiopathic

Behcet’s disease

Sarcoidosis

Ankylosing spondylosis

Rheumatological Emergency : i) Scleromalacia Perforans(RA)ii) Acute iridocyclitis ( seronegative

spondyloarthritis) iii) Retinal vein thrombosis(Antiphospholipid

syndrome)

References• MariaM.Choudhary et al, Gender and Ocular Manifestations of Connective Tissue Diseases and Systemic

Vasculitides Journal of Ophthalmology Volume 2014, Article ID 403042.

• Foster CS. Ocular surface manifestations of neurological and systemic disease. Int Ophthalmol Clin1979;19:207–42

• Karpik AG, Schwartz MM, Dickey LE, Streeten BW, Roberts JL. Ocular immune reactants in patients dying with systemic lupus erythematosus. Clin Immunol Immunopathol 1985;35:295–312

• R. R. Sivaraj et al, Ocular manifestations of systemic lupus erythematosus, Rheumatology 2007;46:1757–1762,Advance Access publication 5 August 2007

• Silva, B.L., Cardozo, J.B., Marback, P., Machado, F.C., Galvão, V. and Santiago, M.B. (2010) Peripheral Ulcerative Keratitis: A Serious Complication of Rheumatoid Arthritis. Rheumatology International, 30, 1267-1268.

• Waduthantri S. Ocular manifestations of Marfan's syndrome. Med J DY Patil Univ [serial online] 2017 [cited 2017 Jul 21];10:118-9.

• Diamantis Almaliotis et al, Ocular Manifestations in Rheumatoid Arthritis Open Journal of Ophthalmology, 2016, 6, 170-175 .

• R.H.West et al, Ocular involvement in scleroderma British Journal of Ophthalmology, 1979, 63, 845-847.

• Yonca Aydın Akova and Sirel Gür Güngör et al, Ocular Involvement in Behçet’s Disease ,review article.

• Kasper et al,Harrisons’s Principles of internal medicine 19th edition.

Thank you

Seronegative Spondyloarthropathies

• Ankylosing spondylitis:

Occular features occur in 25% of the patients

i. Uveitis

• Occular pain,redness and blurred vision.

• It classically alternates between the two eyes.

ii. Scleritis and conjunctivitis may rarely occur.

Reiters Syndrome:

i. Bilateral mucopurulrnt conjunctivitis(58%)

ii. Non granulomatous anterior uveitis

iii. Keratitis

iv. Anterior scleritis and episcleritis

Psoriatic arthritis:

• Anterior uveitis(7 – 20%) – Non granulomatous.

• Scleritis is srare.