Ophthalmology – Iritis-Uveitis in Children

Basics

Description

Uveitis refers to intraocular inflammation. In children, it can involve different parts of the eye and may be classified anatomically.

Anterior uveitis involves the iris and ciliary body and includes iritis and iridocyclitis. Intermediate uveitis mainly involves the pars plana and vitreous, as in pars planitis. Posterior uveitis involves the retina and/or choroid and may also affect the optic nerve and vitreous. Panuveitis refers to inflammation involving multiple segments of the eye.

Childhood uveitis is less common than adult uveitis but may be particularly dangerous because some forms are asymptomatic despite active inflammation.

Epidemiology

Childhood uveitis is uncommon.

Reported incidence is approximately 4–7 cases per 100,000 children, with prevalence around 30 per 100,000.

A large proportion of cases are idiopathic, but juvenile idiopathic arthritis (JIA) is the most important systemic association with noninfectious anterior uveitis in children.

Risk Factors

Important risk factors include:

• Juvenile idiopathic arthritis
• Autoimmune disease
• HLA-B27-associated disease
• Congenital or acquired infections
• Ocular trauma
• Immunosuppression
• Exposure to infectious agents

JIA-Related Risk Factors

Children at particularly high risk for JIA-associated uveitis include those with:

• Oligoarticular JIA
• Young age at arthritis onset
• Positive ANA
• Negative rheumatoid factor
• Female sex

The ocular inflammation may occur independently of joint activity.

Genetics

Genetic predisposition contributes to several causes of childhood uveitis.

HLA-B27 is associated with acute anterior uveitis and with systemic disorders such as:

• Ankylosing spondylitis
• Reactive arthritis
• Psoriatic arthritis
• Inflammatory bowel disease-associated arthritis

Genetic susceptibility often interacts with environmental or infectious triggers.

General Prevention

The most important preventive measure is regular ophthalmologic screening of children at risk, especially those with JIA.

Because JIA-associated uveitis may occur in a completely white, quiet, asymptomatic eye, relying on symptoms can lead to delayed diagnosis and irreversible complications.

Prevention also includes appropriate treatment of systemic disease and avoidance or early treatment of infections when possible.

Pathophysiology

The mechanism depends on the underlying cause.

In autoimmune disease, inflammation is thought to result from dysregulated immune responses directed against ocular tissues.

The exact mechanism of JIA-associated uveitis remains incompletely understood.

Chronic inflammation can damage:

• Cornea
• Iris
• Trabecular meshwork
• Lens
• Vitreous
• Retina
• Optic nerve

This explains the broad range of potential complications.

Etiology

Anterior Uveitis

Important causes include:

• Juvenile idiopathic arthritis
• Idiopathic anterior uveitis
• HLA-B27-associated disease
• Trauma
• Behçet disease
• Sarcoidosis
• Kawasaki disease
• Tubulointerstitial nephritis and uveitis syndrome
• HSV or VZV
• Syphilis
• Tuberculosis
• Lyme disease
• Toxoplasmosis and other infections

Masquerade syndromes must also be considered, including:

• Retinoblastoma
• Leukemia
• Lymphoma
• Juvenile xanthogranuloma
• Coats disease
• Intraocular foreign body

JIA-Associated Uveitis

JIA is the most important cause of chronic noninfectious anterior uveitis in children.

The highest risk occurs with oligoarticular JIA.

The ocular disease may:

• Precede arthritis
• Occur during active arthritis
• Continue when joint disease is inactive

There is often no relationship between joint symptoms and ocular inflammatory activity.

The eye can appear externally normal despite significant inflammation.

A substantial proportion of affected children require prolonged treatment.

HLA-B27-Associated Uveitis

Children with enthesitis-related arthritis may develop HLA-B27-associated anterior uveitis.

Unlike classic JIA-associated uveitis, this form is more likely to be:

• Symptomatic
• Acute
• Painful
• Red
• Photophobic

Intermediate Uveitis

Possible causes include:

• Idiopathic intermediate uveitis
• Pars planitis
• Sarcoidosis
• Inflammatory bowel disease
• Multiple sclerosis
• Lyme disease

Intermediate uveitis is relatively uncommon in JIA.

Posterior Uveitis

Infectious causes are particularly important.

Toxoplasmosis is one of the most common infectious causes of posterior uveitis in children.

Other causes include:

• Toxocariasis
• Tuberculosis
• Syphilis
• Lyme disease
• Bartonella
• Fungal infection
• Bacterial infection
• HSV
• VZV
• CMV

Noninfectious causes include:

• Sarcoidosis
• Vogt-Koyanagi-Harada disease
• Sympathetic ophthalmia
• Masquerade syndromes

Panuveitis

Panuveitis may be caused by:

• Infection
• Systemic inflammatory disease
• Autoimmune disorders
• Masquerade syndromes

Because multiple ocular compartments are involved, extensive systemic evaluation may be necessary.

Commonly Associated Ocular Conditions

Childhood uveitis can be associated with:

• Band keratopathy
• Cataract
• Posterior synechiae
• Peripheral anterior synechiae
• Glaucoma
• Cystoid macular edema
• Chorioretinal scarring
• Retinal detachment
• Hypotony
• Vitreous hemorrhage
• Permanent vision loss

Diagnosis

History

History may provide the most important clues to the underlying cause.

Ask about:

• Eye redness
• Pain
• Photophobia
• Floaters
• Blurred vision
• Reduced vision
• Joint pain or swelling
• Skin rash
• Oral ulcers
• Fever
• Weight loss
• Recent infections
• Exposure to tuberculosis
• Tick exposure
• Travel
• Trauma
• Family history of autoimmune disease

Importantly, absence of ocular symptoms does not exclude active uveitis, particularly in JIA.

Physical Examination

A complete pediatric and ophthalmic examination should be performed.

Visual Acuity

Age-appropriate visual acuity testing is essential.

Young children may require:

• Fixation assessment
• Picture-based testing
• Matching symbols

Amblyopia may coexist and complicate interpretation.

Intraocular Pressure

IOP may be:

• Low during active ciliary body inflammation
• Elevated from chronic inflammation
• Elevated from steroid response
• Elevated from angle damage or synechiae

Both the disease and its treatment can therefore cause glaucoma.

Conjunctiva and Sclera

Possible findings include:

• Ciliary flush
• Episcleritis
• Scleritis
• Conjunctival nodules

The eye may nevertheless appear completely quiet in chronic JIA-associated uveitis.

Cornea

Possible findings include:

• Corneal edema
• Keratic precipitates
• Band keratopathy
• Interstitial keratitis
• Dendritic or geographic epithelial lesions in herpetic disease

Keratic precipitates may be small and nongranulomatous or larger and greasy in appearance, termed mutton-fat KPs.

Anterior Chamber

Slit-lamp examination may reveal:

• Cells
• Flare
• Fibrin
• Hypopyon

Anterior chamber cells are graded according to the number seen in a standardized slit beam.

Flare represents leakage of protein into the aqueous because of breakdown of the blood-aqueous barrier.

A true hypopyon contains inflammatory white blood cells. A pseudohypopyon can occur with tumor cells and should raise concern for a masquerade syndrome.

Iris

Important findings include:

• Posterior synechiae
• Peripheral anterior synechiae
• Iris nodules
• Iris neovascularization
• Irregular pupil

Posterior synechiae occur when the iris adheres to the anterior lens capsule.

Lens

Chronic inflammation and corticosteroid treatment may both lead to cataract formation.

Gonioscopy

Gonioscopy can identify:

• Peripheral anterior synechiae
• Angle closure
• Neovascularization
• Inflammatory debris

It is particularly important in children with elevated IOP.

Vitreous

The vitreous may contain:

• Inflammatory cells
• Haze
• Hemorrhage
• Membranes

These findings indicate intermediate or posterior segment involvement.

Retina

Possible retinal findings include:

• Cystoid macular edema
• Cotton-wool spots
• Retinal hemorrhages
• Vascular sheathing
• Neovascularization
• Retinal detachment

Choroid

Choroidal inflammatory lesions may occur in systemic inflammatory and infectious disease.

Certain inflammatory disorders may produce small yellow-white lesions at the level of the retinal pigment epithelium and choroid.

Pars Plana

Intermediate uveitis may produce:

• Snowballs
• Snowbanking
• Peripheral neovascularization

Snowbanking refers to white inflammatory exudates over the pars plana.

Optic Nerve

Possible findings include:

• Optic disc edema
• Optic atrophy
• Neovascularization
• Infiltration

Optic nerve involvement may substantially worsen the visual prognosis.

Diagnostic Tests and Interpretation

The workup should be directed by the history and examination, rather than using a broad laboratory panel in every child.

Laboratory Testing

Possible tests include:

• CBC with differential
• ESR and/or CRP
• ANA
• ACE
• Serum calcium
• Syphilis serology
• Tuberculosis testing
• Lyme serology when epidemiologically appropriate
• HLA-B27 when clinically indicated
• Urinalysis

Additional targeted studies may be appropriate based on the suspected diagnosis.

Urinalysis and TINU

Urinalysis can be particularly useful when tubulointerstitial nephritis and uveitis syndrome is suspected.

Renal abnormalities may precede, accompany, or follow the ocular disease.

Chest Imaging

Chest radiography may be considered when evaluating for:

• Sarcoidosis
• Tuberculosis

Further chest imaging may be needed when suspicion remains high.

Ocular Ultrasound

B-scan ultrasonography can be useful when media opacity prevents adequate visualization of the posterior segment.

It can identify:

• Retinal detachment
• Vitreous abnormalities
• Mass lesions

OCT

Optical coherence tomography is especially useful for detecting and monitoring:

• Cystoid macular edema
• Epiretinal membrane
• Structural macular damage

Fluorescein Angiography

Fluorescein angiography may demonstrate:

• Retinal vasculitis
• Macular edema
• Capillary leakage
• Neovascularization

Wide-field angiography may be particularly useful for detecting peripheral inflammation.

Other Investigations

Depending on the clinical context, additional evaluation may include:

• MRI of brain or orbits
• Sacroiliac or hand imaging
• Lumbar puncture
• ANCA
• HIV testing
• Stool testing for parasites
• Skin testing for tuberculosis
• ERG
• VEP
• Visual fields
• Aqueous or vitreous sampling
• Tissue biopsy

Differential Diagnosis

Important masquerade and alternative diagnoses include:

• Retinoblastoma
• Leukemia
• Lymphoma
• Trauma
• Retained intraocular foreign body
• Coats disease
• Juvenile xanthogranuloma
• Retinal dystrophies
• Infectious retinitis

Atypical inflammation, poor response to therapy, or pseudohypopyon should increase concern for a masquerade syndrome.

Treatment

Treatment depends on:

• Anatomic location
• Severity
• Underlying cause
• Presence of infection
• Risk of complications

The major goals are to suppress inflammation, prevent structural damage, treat the cause, and preserve visual development.

Topical Corticosteroids

Topical corticosteroids are first-line therapy for many forms of anterior noninfectious uveitis.

Frequency depends on severity and may range from several times daily to very frequent dosing in severe disease.

Treatment must be tapered according to clinical response.

Prolonged corticosteroid use can cause:

• Cataract
• Ocular hypertension
• Glaucoma

Cycloplegic Therapy

Cycloplegics are used to:

• Relieve pain from ciliary spasm
• Reduce photophobia
• Prevent or break posterior synechiae

The specific agent and frequency depend on the degree of inflammation.

Periocular Corticosteroids

Periocular steroid injections may be considered when:

• Topical treatment is insufficient
• Intermediate or posterior inflammation is present
• Macular edema is significant

Potential complications must be considered carefully in children.

Systemic Corticosteroids

Systemic corticosteroids may be required for:

• Severe bilateral disease
• Posterior uveitis
• Panuveitis
• Sight-threatening inflammation
• Disease inadequately controlled with local therapy

Long-term systemic corticosteroid exposure is undesirable in children because of effects on:

• Growth
• Bone health
• Metabolism
• Immune function

Therefore, steroid-sparing therapy should be considered early when chronic treatment is expected.

Immunomodulatory Therapy

Systemic immunomodulatory therapy should be managed by physicians experienced with these medications, usually in collaboration with pediatric rheumatology.

Methotrexate

Methotrexate is a common first-line steroid-sparing agent for chronic JIA-associated uveitis when topical therapy is inadequate or prolonged steroid exposure would be required.

Biologic Therapy

Biologic agents, particularly anti-TNF therapy, may be used for refractory disease.

Adalimumab is an important treatment for JIA-associated uveitis when conventional immunomodulation is inadequate.

Other agents may be considered in selected cases.

Additional Immunosuppressive Agents

Options may include:

• Mycophenolate mofetil
• Azathioprine
• Cyclosporine
• Tacrolimus
• Rituximab in selected refractory cases
• Alkylating agents for severe resistant disease

Therapy is individualized according to diagnosis and response.

Infectious Uveitis

Infectious causes require specific antimicrobial treatment.

Corticosteroids should not be used as stand-alone therapy when active infection is present.

Depending on the infection, treatment may involve:

• Antivirals
• Antibiotics
• Antituberculous therapy
• Antiparasitic medication
• Antifungal therapy

Infectious disease consultation may be appropriate.

Referral

Children without an obvious isolated traumatic cause generally benefit from multidisciplinary evaluation.

Referral may include:

• Pediatric rheumatology
• Infectious disease
• Oncology
• Neurology
• Nephrology
• Genetics

depending on the suspected etiology.

Surgical Treatment

Band Keratopathy

Visually significant band keratopathy may be treated with EDTA chelation after inflammation is adequately controlled.

Cataract Surgery

Cataract surgery may be required when lens opacity significantly limits vision.

Ideally, inflammation should be well controlled before surgery.

These children are at increased risk for:

• Postoperative inflammation
• Posterior synechiae
• Glaucoma
• Posterior capsule opacification

Glaucoma Surgery

Glaucoma that cannot be controlled medically may require surgery.

Retinal Procedures

Retinal laser or retinal detachment repair may be necessary for posterior segment complications.

Drug-Delivery Implants

Local sustained-release drug-delivery systems may be considered in carefully selected refractory cases.

Inpatient Considerations

Most childhood uveitis is managed as an outpatient.

Hospital admission may be required when:

• Severe systemic disease is present
• Intravenous antimicrobial therapy is needed
• High-dose intravenous corticosteroids are required
• A serious masquerade or systemic inflammatory disorder is being evaluated

Ongoing Care

Follow-Up

Children require frequent ophthalmologic examinations, particularly when inflammation is active.

Follow-up should monitor:

• Visual acuity
• Amblyopia
• Anterior chamber cells and flare
• IOP
• Cataract
• Synechiae
• Band keratopathy
• Macular edema
• Retinal disease
• Medication toxicity

Systemic Monitoring

Children receiving systemic immunosuppression require regular monitoring appropriate to the medication.

Because children grow, weight-based drug doses must be reassessed periodically.

Coordination among ophthalmology, rheumatology, primary care, and other specialists is essential.

Amblyopia

Amblyopia deserves special attention in pediatric uveitis.

Vision may be reduced not only by inflammation but also by:

• Cataract
• Corneal opacity
• Refractive error
• Strabismus

These factors can interfere with visual development even after the inflammation has been controlled.

Patient and Family Education

Parents should understand that:

• Uveitis may be present without symptoms
• Regular eye examinations are essential
• Treatment may need to continue for years
• Medications must not be stopped abruptly without medical advice
• Glaucoma and cataract can result from both the disease and its treatment

Families should be encouraged to maintain close follow-up even when the child’s eyes appear normal.

Prognosis

Early recognition and aggressive control of inflammation can substantially reduce the risk of permanent visual loss.

Prognosis depends on:

• Underlying etiology
• Duration before diagnosis
• Location of inflammation
• Presence of complications
• Response to treatment
• Adherence to follow-up

Children with chronic asymptomatic anterior uveitis may already have complications at the time of diagnosis if screening has been inadequate.

Complications

Major complications include:

• Band keratopathy
• Cataract
• Posterior synechiae
• Secondary glaucoma
• Cystoid macular edema
• Hypotony
• Optic disc edema
• Vitreous hemorrhage
• Epiretinal or vitreoretinal membranes
• Retinal detachment
• Phthisis bulbi
• Amblyopia
• Permanent visual loss

The most important clinical pearl is that JIA-associated uveitis can be severe despite a completely white, painless eye, making scheduled slit-lamp screening essential for children at risk.

Ophthalmology – Iris Nevus

Basics

Description

An iris nevus is a benign melanocytic tumor arising from the iris stroma. Iris melanocytic lesions form a spectrum ranging from harmless freckles and nevi to malignant iris melanoma.

Iris nevi can vary considerably in:

• Size
• Shape
• Thickness
• Degree of pigmentation
• Circumscribed versus diffuse appearance

A key distinction is that an iris nevus distorts or replaces the normal iris stromal architecture, whereas an iris freckle is a superficial area of pigmentation that does not alter the underlying iris structure.

Iris freckles are extremely common and have essentially no malignant potential.

Iris nevi usually become clinically apparent during childhood, puberty, or young adulthood and often remain stable for many years.

Alert

A pigmented iris lesion showing documented progressive enlargement should raise concern for iris melanoma.

Other concerning features include:

• Secondary glaucoma
• Angle involvement
• Tumor seeding
• Prominent intrinsic vessels
• Hyphema
• Increasing thickness

Special Variant – Iris Melanocytoma

Iris melanocytoma is a deeply pigmented variant of melanocytic nevus.

It is usually benign but may undergo spontaneous necrosis.

Necrotic tumor cells and pigment can disperse into the anterior chamber and obstruct the trabecular meshwork, producing secondary glaucoma. This is sometimes called melanocytomalytic glaucoma.

Melanocytoma may also have an associated ciliary body component.

Malignant transformation is possible but uncommon.

Pediatric Considerations

Iris nevi are often first detected during childhood, particularly in the preteen or adolescent years.

Most remain stable into adulthood.

Because many lesions are discovered incidentally, baseline photography is particularly valuable in children to allow accurate comparison over time.

Geriatric Considerations

An iris nevus discovered in an older patient may have been present for decades.

A newly noticed lesion in an older adult is not automatically malignant, but suspicious features or documented growth deserve careful evaluation.

Epidemiology

Iris freckles are very common and can be seen in approximately half or more of the general population.

True iris nevi are less common, occurring in roughly 5% of individuals.

Most are benign and remain stable.

Risk Factors

Reported associations include:

• White race
• Light iris color, particularly blue, gray, or green
• Inferior location of the lesion

Most iris nevi and many iris melanomas are located in the inferior half of the iris.

Sectoral iris nevi may be associated with ocular melanocytosis.

General Prevention

There is no proven method to prevent iris nevi.

Reasonable preventive measures include:

• Limiting excessive ultraviolet exposure
• Wearing UV-protective sunglasses
• Regular ophthalmic follow-up for suspicious lesions

The most important strategy is documenting a lesion early so that subsequent growth can be recognized.

Etiology

The exact cause is unknown.

Iris nevi arise from benign proliferation of melanocytes within the iris stroma.

Commonly Associated Conditions

Most iris nevi occur in otherwise normal eyes.

Some may be associated with:

• Sectoral ocular melanocytosis
• Iris pigment epithelial cysts
• Secondary cataract
• Rare secondary glaucoma

Diagnosis

History

Most patients are asymptomatic.

The lesion may be:

• Noticed by the patient
• Noticed by a family member
• Found incidentally during a routine ophthalmic examination

Important historical questions include:

• How long has the lesion been present?
• Has its size or color changed?
• Is there a previous photograph?
• Has there been pain, redness, or blurred vision?
• Has the patient ever been told the IOP is elevated?
• Is there a history of ocular melanoma or melanocytosis?

Documented stability strongly favors a benign nevus.

Physical Examination

Iris nevi have a broad range of appearances.

They may be:

• Small or large
• Flat or mildly elevated
• Dome-shaped
• Circumscribed or sectoral
• Pigmented or nonpigmented
• Uniform or heterogeneous in coloration

Possible secondary changes include:

• Corectopia
• Ectropion uveae
• Localized cataract
• Associated iris pigment epithelial cyst
• Intrinsic vascularity

Some benign nevi may have visible vessels, so vascularity alone does not establish malignancy.

Secondary Glaucoma

Glaucoma is uncommon with a simple iris nevus.

Therefore, elevated IOP in an eye with a melanocytic iris lesion should raise suspicion for:

• Iris melanoma
• Angle involvement
• Tumor seeding
• Melanocytoma with pigment dispersion

Unilateral unexplained glaucoma in association with an iris lesion warrants careful gonioscopy.

Sector Iris Nevus

A sector nevus extends radially from the pupillary margin toward the anterior chamber angle.

It may involve one or several clock hours.

Some authors consider this a localized manifestation of ocular melanocytosis.

Tapioca Nevus

A tapioca nevus has a multinodular surface composed of multiple small pale or pigmented elevations resembling tapioca pudding.

This appearance can resemble tapioca melanoma, so documentation of stability is particularly important.

Diffuse Iris Nevus and Cogan–Reese Syndrome

The term “diffuse iris nevus” has sometimes been used in connection with Cogan–Reese syndrome.

However, Cogan–Reese syndrome is part of iridocorneal endothelial syndrome and is not a true melanocytic nevus.

Diagnostic Tests and Interpretation

Slit-Lamp Examination

Slit-lamp examination evaluates:

• Pigmentation
• Thickness
• Surface architecture
• Intrinsic vessels
• Corectopia
• Ectropion uveae
• Hyphema
• Tumor seeding

Careful serial examinations are essential.

Anterior Segment Photography

Baseline photography is one of the most useful tools in managing an iris nevus.

Serial photographs allow detection of subtle:

• Growth
• Shape change
• Color change
• New vascularity
• Pupillary distortion

Documented enlargement is one of the strongest indicators of malignant transformation.

Intraocular Pressure

IOP should be measured at every evaluation.

New or progressive elevation should prompt investigation for angle involvement or malignant transformation.

Gonioscopy

Gonioscopy is used to assess:

• Extension into the anterior chamber angle
• Abnormal pigmentation of the trabecular meshwork
• Tumor seeding
• Associated angle mass

Angle involvement is an important feature distinguishing a suspicious lesion from an uncomplicated nevus.

Transillumination

Transillumination helps assess whether the apparent iris lesion extends posteriorly into the ciliary body.

This is particularly important for thicker or peripheral tumors.

Ultrasound Biomicroscopy

UBM is useful for:

• Measuring lesion thickness
• Determining posterior extent
• Detecting ciliary body involvement
• Distinguishing a solid nevus from a cystic lesion
• Providing a baseline for future comparison

It is especially useful for larger or more heavily pigmented lesions.

Anterior-Segment OCT

AS-OCT can image smaller, superficial iris lesions.

It is particularly helpful for lightly pigmented or nonpigmented lesions.

However, deeply pigmented or thick lesions may cause significant posterior shadowing, limiting assessment of their full depth.

Fine-Needle Aspiration Biopsy

FNAB is not needed for routine stable iris nevi.

It may be considered when:

• The diagnosis remains uncertain
• The lesion has suspicious features
• Differentiation from melanoma would alter management

Because low-grade melanoma can resemble a nevus cytologically, samples should be interpreted by an experienced ocular cytopathologist.

Pathological Findings

Iris nevi are usually composed predominantly of low-grade spindle melanocytic cells.

Some borderline lesions are difficult to distinguish histologically from low-grade melanoma.

For this reason, clinical behavior over time, especially documented growth, remains extremely important.

Differential Diagnosis

Important differential diagnoses include:

• Iris melanoma
• Iris melanocytoma
• Ocular melanocytosis
• Iris pigment epithelial cyst
• Adenoma of the iris pigment epithelium
• ICE syndrome
• Iris lymphoma
• Iris metastasis
• Iris granuloma
• Juvenile xanthogranuloma
• Retained anterior chamber foreign body

The most clinically important distinction is between iris nevus and iris melanoma.

Features Suggesting Melanoma Rather Than Nevus

Concern for melanoma increases with:

• Documented growth
• Increasing thickness
• Secondary glaucoma
• Angle involvement
• Tumor seeding
• Prominent intrinsic or feeder vessels
• Spontaneous hyphema
• Increasing pupillary distortion
• Progressive ectropion uveae

A stable lesion without these features is much more likely to remain benign.

Treatment

Medication

There is no medication required for an uncomplicated iris nevus.

Observation

Observation is the standard management.

Baseline assessment should ideally include:

• Slit-lamp examination
• Anterior segment photography
• IOP measurement
• Gonioscopy
• UBM when appropriate
• Transillumination
• AS-OCT in selected lesions

Follow-up is then used to establish whether the lesion remains stable.

Follow-Up Interval

A suspicious or newly documented lesion may initially be reassessed at approximately 6 months.

Once long-term stability is established, follow-up can often be extended to 6–12 month intervals, depending on its characteristics.

Higher-risk lesions require closer surveillance.

Documented Growth

If a melanocytic iris lesion shows unequivocal progressive growth, it should no longer be managed as a simple nevus.

The patient should be evaluated for iris melanoma and referred to an ocular oncologist when appropriate.

Management of Elevated IOP

Topical glaucoma medications may be used if IOP elevation occurs.

However, because secondary glaucoma is unusual with a benign nevus, the lesion must be reassessed carefully for malignant transformation or angle involvement.

Associated Hyphema

If inflammation or hyphema accompanies a lesion, cycloplegics and topical anti-inflammatory therapy may be used when appropriate.

The cause of the bleeding must still be investigated.

Surgery

Routine surgical excision is not indicated for a stable iris nevus.

Treatment is reserved for lesions that:

• Demonstrate documented growth
• Develop convincing malignant features
• Produce significant complications requiring intervention

Such lesions should be managed according to principles used for iris melanoma.

Ongoing Care

Follow-Up Recommendations

Patients should undergo periodic ophthalmic examinations.

Monitoring may include:

• Slit-lamp examination
• Anterior segment photography
• Gonioscopy
• IOP measurement
• UBM
• Transillumination
• AS-OCT when useful

The precise testing schedule depends on the lesion’s size, location, and level of suspicion.

Patient Education

Patients should understand that most iris nevi are benign and remain stable throughout life.

They should also understand why periodic monitoring is important.

They should return earlier than scheduled if they notice:

• Increase in size
• Change in pupil shape
• New pain
• Blurred vision
• Redness
• Visible bleeding in the eye

Avoiding excessive sun exposure and using UV-protective eyewear is reasonable.

Prognosis

The overall prognosis is excellent.

Most iris nevi remain stable and never become malignant.

A small proportion of suspicious or borderline lesions may enlarge over time and ultimately prove to be melanoma.

Therefore, the goal of management is not to remove every iris nevus, but to document stability and promptly identify the uncommon lesion that begins to grow.

Complications

Possible complications include:

• Secondary cataract
• Pupillary distortion
• Ectropion uveae
• Rare secondary glaucoma
• Pigment dispersion from melanocytoma
• Rare malignant transformation into iris melanoma

The most important clinical principle is: a stable iris nevus is usually benign, but documented progressive growth or secondary glaucoma should prompt evaluation for iris melanoma.

Ophthalmology – Iris Melanoma

Alert

Any pigmented iris lesion should be examined carefully for features suggesting malignancy, especially tumor seeding, secondary glaucoma, intrinsic tumor vessels, documented growth, and angle involvement.

These findings are much more concerning for iris melanoma than for a stable iris nevus.

Basics

Description

Iris melanoma is a malignant melanocytic tumor arising from the iris stroma. It is uncommon and accounts for only a small proportion of all uveal melanomas.

The tumor may be pigmented or nonpigmented and can vary considerably in size, shape, and appearance.

Important clinical forms include:

• Circumscribed iris melanoma
• Diffuse iris melanoma
• Tapioca melanoma
• Trabecular meshwork melanoma

Iris melanoma may cause:

• Corectopia
• Ectropion uveae
• Secondary glaucoma
• Spontaneous hyphema
• Anterior chamber inflammation
• Tumor seeding onto the iris or angle

More than 80% of iris melanomas arise in the inferior half of the iris.

Although iris melanoma generally has a lower metastatic risk than choroidal melanoma, it can metastasize, particularly to the liver, and less commonly to other organs.

Pediatric Considerations

Iris melanoma is rare in children and young adults, but among younger patients who do develop uveal melanoma, the iris represents a relatively larger proportion of cases than it does in older adults.

Epidemiology

Iris melanoma represents approximately 4–5% of uveal melanomas.

Uveal melanoma itself is uncommon, with an incidence of only several cases per million population per year.

Secondary elevation of intraocular pressure is relatively common in established iris melanoma and may occur because of:

• Direct tumor invasion of the angle
• Tumor seeding
• Pigment or tumor-cell obstruction of aqueous outflow

Risk Factors

Important associations include:

• White race
• Light-colored iris
• Inferior iris location
• Ocular melanocytosis
• Preexisting suspicious iris nevus

Features that increase concern for malignant transformation of a nevus include:

• Documented enlargement
• Pigment dispersion onto adjacent iris
• Angle involvement
• Secondary glaucoma
• Intrinsic vessels
• Tumor seeding

Genetics

Iris melanomas may demonstrate chromosomal abnormalities involving chromosomes 3, 6, and 8.

As with other uveal melanomas, certain cytogenetic features are associated with different metastatic risks.

Monosomy 3 is generally considered a higher-risk feature, whereas disomy 3 is associated with a lower metastatic risk.

Fine-needle aspiration biopsy may be used in selected cases for cytologic or molecular analysis.

General Prevention

There is no proven method to prevent iris melanoma.

Reasonable measures include:

• Limiting excessive ultraviolet exposure
• Wearing UV-protective eyewear
• Regular ophthalmic monitoring of suspicious iris lesions

The most important preventive strategy is early recognition of malignant transformation in a previously observed iris lesion.

Pathophysiology

Iris melanoma develops from malignant transformation of melanocytes within the iris stroma.

The tumor may remain localized or spread:

• Across the iris surface
• Into the anterior chamber angle
• Into the trabecular meshwork
• Into the ciliary body
• Extraocularly in advanced disease

Tumor cells may shed into the anterior chamber and produce visible seeding on the iris or angle.

Angle infiltration and seeding can obstruct aqueous outflow and produce secondary glaucoma.

Etiology

The exact cause is unknown.

Genetic susceptibility, melanocytic abnormalities, and environmental factors may contribute, but no single cause has been established.

Clinical Types

Circumscribed Iris Melanoma

This is the most common presentation.

It appears as a relatively well-defined mass within the iris stroma.

Features may include:

• Nodular or dome-shaped configuration
• Variable pigmentation
• Distortion of the pupil
• Intrinsic vessels
• Ectropion uveae
• Local angle involvement

Localized lesions without extensive seeding may be amenable to surgical excision.

Diffuse Iris Melanoma

Diffuse melanoma spreads across a broad portion of the iris rather than forming a single discrete mass.

It may produce:

• Acquired hyperchromic heterochromia
• Diffuse iris thickening
• Loss of normal iris architecture
• Progressive secondary glaucoma
• Extensive angle infiltration

Because the tumor may be subtle, the diagnosis can be delayed.

Tapioca Melanoma

This rare form has multiple small translucent or lightly pigmented nodules scattered over the iris surface.

The appearance has been compared with tapioca pudding.

It may be mistaken for inflammatory or benign nodular iris disease.

Trabecular Meshwork Melanoma

This form primarily involves the anterior chamber angle and trabecular meshwork without an obvious iris mass.

Patients may initially present with unilateral secondary glaucoma.

It can be mistaken for:

• Pigmentary glaucoma
• Other secondary glaucomas

Unexplained unilateral glaucoma with abnormal angle pigmentation should therefore prompt careful gonioscopic examination.

Diagnosis

History

Patients may be asymptomatic, with the lesion found during routine examination.

Possible symptoms include:

• Visible iris spot or mass
• Change in iris color
• Distorted pupil
• Blurred vision
• Eye pain
• Redness
• Symptoms of elevated IOP

Pain and visual loss often occur when secondary glaucoma develops.

A history of a previously documented iris nevus is particularly useful because growth over time is one of the strongest signs of malignancy.

Physical Examination

A complete ophthalmic examination should include:

• Visual acuity
• IOP measurement
• Slit-lamp examination
• Gonioscopy
• Transillumination
• Dilated examination

Concerning features include:

• Documented tumor growth
• Intrinsic tumor vessels
• Feeder vessels
• Corectopia
• Ectropion uveae
• Tumor seeding
• Secondary glaucoma
• Hyphema
• Angle invasion

Secondary Glaucoma

Elevated IOP is an important warning sign.

Glaucoma is unusual in a simple iris nevus, so unilateral glaucoma associated with an iris lesion should raise suspicion for melanoma.

Possible mechanisms include:

• Direct angle invasion
• Trabecular obstruction by tumor cells
• Tumor seeding
• Pigment dispersion
• Neovascular mechanisms in advanced disease

Tumor Seeding

Tumor cells may appear as fine pigmented or nonpigmented deposits on:

• The iris surface
• The anterior chamber angle
• Other anterior segment structures

Seeding is best identified with careful slit-lamp examination and gonioscopy.

Its presence strongly supports malignant behavior.

Diagnostic Tests and Interpretation

Anterior Segment Photography

Serial slit-lamp photographs are extremely useful.

They document:

• Tumor size
• Pigmentation
• Vascularity
• Pupillary distortion
• Growth over time

Documented enlargement is one of the most important criteria for treatment.

Ultrasound Biomicroscopy

UBM is very useful for evaluating iris melanoma.

It can:

• Measure tumor thickness
• Determine posterior extension
• Detect ciliary body involvement
• Distinguish solid tumors from cysts
• Assess angle involvement

Anterior-Segment OCT

AS-OCT may be useful for smaller, superficial, particularly nonpigmented iris lesions.

Its limitation is posterior shadowing, especially with larger or heavily pigmented tumors.

Gonioscopy

Gonioscopy is essential to determine:

• Angle involvement
• Trabecular pigmentation
• Tumor seeding
• Extent in clock hours

This information can significantly alter treatment planning and prognosis.

Transillumination

Transillumination may help determine whether the lesion extends posteriorly into the ciliary body.

Fine-Needle Aspiration Biopsy

FNAB may be useful when the diagnosis remains uncertain.

It can provide material for:

• Cytology
• Cytogenetic analysis
• Molecular prognostic testing

Interpretation should ideally be performed by an experienced ocular pathologist because low-grade melanomas may be difficult to distinguish from nevi histologically.

Systemic Evaluation

Because iris melanoma can metastasize, patients require systemic assessment.

The liver is the most important metastatic site in uveal melanoma.

Systemic surveillance is usually coordinated with ocular oncology and medical oncology and may include:

• Physical examination
• Liver function testing
• Liver imaging
• Other imaging based on risk and institutional protocol

Modern surveillance schedules vary according to tumor biology and metastatic risk.

Differential Diagnosis

Important mimics include:

• Iris nevus
• Iris melanocytoma
• Iris pigment epithelial cyst
• Adenoma of the iris pigment epithelium
• ICE syndrome
• Iris lymphoma
• Iris metastasis
• Iris granuloma
• Juvenile xanthogranuloma
• Retained anterior chamber foreign body
• Inflammatory iris nodules

The most important distinction is usually between iris nevus and iris melanoma.

Nevus Versus Melanoma

Features favoring melanoma include:

• Documented growth
• Larger size
• Greater thickness
• Intrinsic vascularity
• Ectropion uveae
• Corectopia
• Tumor seeding
• Angle involvement
• Secondary glaucoma
• Spontaneous hyphema

A stable, small lesion without these features is more likely to be benign.

Treatment

There is no established systemic medication that eradicates a localized primary iris melanoma.

Treatment is primarily local and depends on:

• Tumor size
• Location
• Circumscribed versus diffuse configuration
• Angle involvement
• Seeding
• Secondary glaucoma
• Visual potential

Observation

Small indeterminate lesions without clear malignant features may be observed closely.

Serial examination should include:

• Slit-lamp photography
• UBM
• Gonioscopy
• IOP measurement

Documented growth generally warrants treatment.

Surgical Excision

Localized circumscribed melanoma may be treated with surgical excision.

Procedures include:

• Iridectomy
• Iridocyclectomy
• Iridogoniocyclectomy

The choice depends on whether the tumor extends into:

• The angle
• Ciliary body
• Adjacent structures

Excision is most appropriate when the tumor is sufficiently localized and there is no extensive seeding.

Plaque Brachytherapy

Plaque radiotherapy is an important globe-preserving treatment.

It may be considered for:

• Larger tumors
• Diffuse tumors
• Tumors not suitable for excision
• Angle involvement
• Anterior chamber seeding
• Eyes in which preservation of useful vision is especially important

Radiation allows treatment of tissue beyond the visibly apparent tumor margin.

Enucleation

Enucleation is now reserved for advanced cases.

Indications may include:

• Extensive diffuse melanoma
• Involvement of a large portion of the iris and angle
• Severe uncontrolled secondary glaucoma
• Painful blind eye
• Extensive tumor seeding
• Extraocular extension in selected circumstances

Visual status of the fellow eye should be considered before proceeding.

Management of Glaucoma

Glaucoma should initially be treated medically when possible.

Filtering surgery such as trabeculectomy is generally avoided in eyes with active or incompletely controlled melanoma, because creating a surgical fistula could theoretically facilitate extraocular tumor spread.

When pressure cannot be controlled medically, options may include cyclodestructive procedures or other carefully selected interventions coordinated with an ocular oncologist.

Postoperative Treatment

After local excision or radiotherapy, topical medications may be used to control:

• Inflammation
• Pain
• Posterior synechiae

Cycloplegics and corticosteroid-containing regimens may be prescribed depending on the procedure and postoperative findings.

Follow-Up

Patients require long-term ocular surveillance.

Follow-up commonly includes:

• Slit-lamp examination
• Gonioscopy
• IOP measurement
• Anterior segment photography
• UBM
• Transillumination when appropriate

After treatment, follow-up is often performed approximately every 6 months, although intervals depend on tumor risk and stability.

Patient Monitoring

Monitoring focuses on:

• Tumor regression
• Recurrence
• New seeding
• Progressive angle involvement
• Secondary glaucoma
• Cataract
• Radiation complications

Systemic metastatic surveillance should continue long term.

Patient Education

Patients should understand that iris melanoma is malignant but generally has a better metastatic prognosis than choroidal melanoma.

They should be educated regarding the importance of:

• Long-term eye follow-up
• Lifelong systemic surveillance
• Reporting new eye pain or visual loss
• Monitoring previously suspicious iris lesions

Avoiding excessive ultraviolet exposure is reasonable.

Prognosis

The metastatic risk of iris melanoma is lower than that of choroidal or ciliary body melanoma.

Reported long-term metastatic rates are relatively low, but risk is not zero.

Features associated with a worse prognosis include:

• Older age
• Secondary glaucoma
• Angle involvement
• Extraocular extension
• More diffuse disease
• Higher-risk cytogenetic features

Early, localized lesions generally have a favorable ocular and systemic prognosis when appropriately treated.

Complications

Potential complications include:

• Secondary glaucoma
• Cataract
• Recurrent tumor
• Tumor seeding
• Angle invasion
• Radiation-related keratopathy
• Neovascular glaucoma
• Need for eventual enucleation
• Metastatic disease

After plaque radiotherapy, cataract is a particularly common late complication.

The key clinical warning is: an iris lesion with documented growth, intrinsic vessels, tumor seeding, angle involvement, or secondary glaucoma should be considered suspicious for iris melanoma until proven otherwise.

Ophthalmology – Iris Atrophy

Basics

Description

Iris atrophy is thinning or loss of iris tissue that can occur in a wide variety of ocular disorders. It may involve the iris stroma, iris pigment epithelium, or both.

The pattern, laterality, and associated ocular findings are particularly useful in determining the underlying cause.

Pediatric Considerations

In children, iris atrophy or iris transillumination abnormalities may suggest congenital or developmental disorders such as:

• Axenfeld–Rieger syndrome
• Ocular albinism

Pregnancy Considerations

Iris atrophy associated with uveitis during pregnancy may occur with infectious or inflammatory disorders such as:

• Herpes simplex virus (HSV)
• Varicella-zoster virus (VZV)
• Fuchs uveitis syndrome

The underlying disorder should be identified because treatment considerations may differ during pregnancy.

Epidemiology

The incidence and prevalence of iris atrophy depend entirely on the underlying disease.

ICE syndrome is rare, whereas iris atrophy is common in several forms of anterior uveitis.

In Fuchs uveitis syndrome, iris stromal atrophy is a characteristic and frequent finding.

Risk Factors

Important risk factors include:

• Chronic or recurrent anterior uveitis
• Herpetic eye disease
• Herpes zoster ophthalmicus
• Glaucoma
• Pigment dispersion syndrome
• Previous ocular trauma
• Previous intraocular surgery
• Intraocular lens–iris chafing
• Congenital anterior segment abnormalities
• Ocular ischemia

Genetics

Axenfeld–Rieger syndrome is usually inherited in an autosomal dominant pattern.

Ocular albinism and related forms of albinism have several inheritance patterns depending on the underlying genetic disorder.

Pathophysiology

The mechanism of iris atrophy varies according to its cause.

Chronic Inflammation

Repeated or persistent inflammation can destroy the iris stroma, producing:

• Loss of normal iris architecture
• Stromal thinning
• Pigment loss
• Transillumination defects

Herpetic Uveitis

HSV and VZV-associated anterior uveitis can produce ischemic and inflammatory damage to the iris, often resulting in characteristic sectoral or patchy atrophy.

Axenfeld–Rieger Syndrome

Iris abnormalities result from abnormal development of the anterior segment.

Ocular Albinism

Reduced iris pigmentation results from abnormal melanin production or melanosome abnormalities, producing prominent iris transillumination.

Pigment Dispersion Syndrome

Posterior bowing of the iris allows the posterior iris pigment epithelium to rub against the lens zonules. This produces loss of pigment and characteristic radial or spoke-like transillumination defects.

ICE Syndrome

Abnormal corneal endothelial cells proliferate over the anterior chamber angle and iris. Contraction of this membrane causes progressive iris distortion and atrophy.

Etiology

Important causes include:

• Herpes simplex anterior uveitis
• Herpes zoster anterior uveitis
• Fuchs uveitis syndrome
• Pigment dispersion syndrome
• Pigmentary glaucoma
• Pseudophakic pigment dispersion from iris–IOL chafing
• Ocular trauma
• Previous ocular surgery
• ICE syndrome
• Axenfeld–Rieger syndrome
• Ocular albinism
• Ischemic iridopathy
• Diabetes-associated iris ischemia
• Ocular ischemic syndrome
• Systemic vascular disorders

Commonly Associated Conditions

Iris atrophy is frequently associated with:

• Anterior uveitis
• Glaucoma
• Cataract

These associated conditions may ultimately be more important for vision than the iris atrophy itself.

Diagnosis

History

A careful history is essential because iris atrophy is a clinical sign rather than a single disease.

Ask about:

• Recurrent red eye
• Eye pain
• Photophobia
• Previous episodes of uveitis
• Blurred or decreased vision
• History of elevated IOP or glaucoma
• Herpes simplex infection
• Herpes zoster ophthalmicus
• Ocular trauma
• Previous ocular surgery
• Cataract surgery and intraocular lens implantation
• Family history of congenital ocular abnormalities

The age at onset and whether the condition is unilateral or bilateral can significantly narrow the differential diagnosis.

Physical Examination

Visual Acuity and Intraocular Pressure

Both should be carefully documented.

Elevated IOP can accompany:

• HSV anterior uveitis
• VZV anterior uveitis
• Fuchs uveitis syndrome
• Chronic anterior uveitis
• ICE syndrome
• Axenfeld–Rieger syndrome
• Pigment dispersion syndrome

Therefore, glaucoma must always be considered in a patient with iris atrophy.

Laterality

Laterality provides an important diagnostic clue.

Usually unilateral:

• ICE syndrome
• Herpetic anterior uveitis
• Fuchs uveitis syndrome, although bilateral cases occur
• Trauma or surgical injury

Usually bilateral:

• Axenfeld–Rieger syndrome
• Ocular albinism
• Pigment dispersion syndrome

Slit-Lamp Examination

Iris atrophy can be subtle on routine examination.

Retroillumination or transillumination is particularly useful for demonstrating areas of pigment loss.

The pattern of iris atrophy can provide an important clue to the diagnosis.

Pupillary Margin Atrophy

Atrophy around the pupillary margin, particularly when associated with persistent pupillary dilation, can occur with HSV anterior uveitis.

Sectoral Iris Atrophy

Sectoral or patchy iris atrophy strongly suggests herpetic anterior uveitis, particularly VZV or HSV.

Diffuse Iris Atrophy

Diffuse stromal atrophy is characteristic of Fuchs uveitis syndrome.

Heterochromia may result, although it is not always clinically obvious.

Radial or Spoke-Like Atrophy

Radial transillumination defects suggest pigment dispersion syndrome.

They result from mechanical rubbing between the posterior iris pigment epithelium and the lens zonules.

Corectopia and Iris Holes

The combination of:

• Corectopia
• Ectropion uveae
• Progressive iris atrophy
• Pseudopolycoria

should raise suspicion for ICE syndrome.

Similar developmental abnormalities can occur with Axenfeld–Rieger syndrome, but that disorder is usually bilateral and congenital.

Corneal Examination

The cornea can provide important clues to the underlying diagnosis.

Corneal Edema

Corneal edema, especially in a unilateral eye with iris distortion and peripheral anterior synechiae, suggests ICE syndrome.

Keratic Precipitates

Keratic precipitates indicate current or previous anterior segment inflammation.

Diffuse KPs may occur in:

• Herpetic anterior uveitis
• Fuchs uveitis syndrome

Gonioscopy

Gonioscopy should be performed whenever possible.

Peripheral Anterior Synechiae

PAS may indicate:

• Previous or chronic uveitis
• ICE syndrome
• Other causes of secondary angle closure

Heavy Trabecular Pigmentation

Marked pigmentation of the trabecular meshwork supports pigment dispersion syndrome.

Lens Examination

Cataract may be evidence of:

• Chronic uveitis
• Previous ocular inflammation
• Previous trauma
• Previous intraocular surgery

In pseudophakic patients, consider mechanical iris chafing from an intraocular lens when the iris atrophy corresponds to the position of an IOL component.

Posterior Segment Examination

The optic nerve should be carefully examined for glaucomatous cupping.

The retina should be evaluated for evidence of:

• Ocular albinism
• Retinal or choroidal ischemia
• Other manifestations of ocular ischemic syndrome

Diagnostic Tests

Laboratory Testing

Routine laboratory testing is usually unnecessary.

Testing should instead be directed toward the suspected underlying cause.

When the diagnosis of viral anterior uveitis is uncertain, aqueous humor PCR may be useful for detecting viral DNA, particularly:

• HSV
• VZV

Other targeted investigations may be appropriate depending on the clinical presentation.

Photography

Slit-lamp photographs can document:

• Iris architecture
• Corectopia
• Areas of stromal atrophy
• Progressive changes

Transillumination photographs are particularly useful for documenting pigment epithelial defects.

Anterior-Segment Imaging

When mechanical iris chafing is suspected, ultrasound biomicroscopy (UBM) or other anterior-segment imaging can help determine the relationship between the iris and:

• Intraocular lens
• IOL haptics
• Crystalline lens
• Other anterior segment structures

Differential Diagnosis

The major differential diagnoses include:

• Herpes simplex anterior uveitis
• Herpes zoster anterior uveitis
• Fuchs uveitis syndrome
• Pigment dispersion syndrome
• Pigmentary glaucoma
• Pseudophakic iris chafing
• Previous ocular trauma
• Iatrogenic iris damage
• ICE syndrome
• Axenfeld–Rieger syndrome
• Ocular albinism
• Diabetic ischemic iridopathy
• Ocular ischemic syndrome

Treatment

There is generally no treatment that restores already atrophied iris tissue. Management is directed toward the underlying disease and its complications.

Uveitis

Active inflammation may require topical corticosteroids or other anti-inflammatory therapy depending on the cause.

When herpetic disease is suspected or confirmed, appropriate systemic antiviral therapy may be required.

Steroids in infectious uveitis should be used in the appropriate clinical context and generally with treatment directed at the underlying infection when indicated.

Glaucoma

Elevated IOP should be treated appropriately.

Management may include:

• Topical pressure-lowering medications
• Laser treatment in selected disorders
• Glaucoma surgery when medical treatment is inadequate

Patients with uncontrolled IOP or progressive optic nerve/visual field damage should be referred to a glaucoma specialist.

Cataract

Visually significant cataract may require cataract extraction.

Surgical planning should take into account the underlying cause of iris atrophy, particularly when there is:

• Chronic uveitis
• Poor pupillary dilation
• Iris instability
• Extensive iris defects
• Glaucoma

Issues for Referral

Referral should be considered for patients with:

• Uncontrolled glaucoma
• Progressive visual field loss
• Significant corneal disease
• Uncertain uveitis etiology
• Suspected ICE syndrome
• Suspected congenital anterior segment dysgenesis

Children with suspected Axenfeld–Rieger syndrome or albinism may require pediatric and genetic evaluation.

Ongoing Care

Follow-Up

Follow-up frequency depends on the underlying condition.

Patients should be monitored for the major complications associated with iris atrophy, particularly:

• Glaucoma
• Cataract
• Recurrent or chronic uveitis
• Progressive visual loss

Patients with glaucoma require serial assessment of IOP, optic nerve structure, OCT when appropriate, and visual fields.

Patient Education

Patients should understand that iris atrophy is usually a sign of an underlying ocular disorder rather than an isolated disease.

Regular follow-up is important because glaucoma may progress without producing early symptoms.

Patients prescribed glaucoma medications should be counseled regarding adherence.

When a hereditary disorder such as Axenfeld–Rieger syndrome or albinism is identified, genetic counseling may be appropriate.

Prognosis

The prognosis depends primarily on the underlying cause and associated complications.

Iris atrophy itself may remain stable or progress depending on the disorder. Visual prognosis is usually determined by associated conditions such as:

• Glaucoma
• Cataract
• Chronic uveitis
• Corneal disease
• Ocular ischemia

Key clinical clue: the pattern of iris atrophy is diagnostically useful—sectoral atrophy suggests herpetic uveitis, diffuse stromal atrophy suggests Fuchs uveitis syndrome, radial transillumination defects suggest pigment dispersion syndrome, and progressive iris distortion with corectopia/pseudopolycoria suggests ICE syndrome.

Ophthalmology – Iridocorneal Endothelial (ICE) Syndrome

Basics

Description

Iridocorneal endothelial (ICE) syndrome is a rare, acquired disorder of the anterior segment characterized by abnormal proliferation of the corneal endothelium. It usually affects one eye and occurs most often in young to middle-aged women.

The abnormal endothelial cells spread from the posterior corneal surface across the anterior chamber angle and onto the iris. As this abnormal membrane contracts, it can produce progressive iris distortion, peripheral anterior synechiae, angle closure, corneal edema, and secondary glaucoma.

The three major clinical variants are progressive iris atrophy, Cogan–Reese syndrome, and Chandler syndrome. All three may produce corneal disease and glaucoma, although the dominant clinical features differ.

Epidemiology

ICE syndrome is uncommon, and its exact incidence and prevalence are not known.

It can affect individuals of any race but has a strong female predominance. Most patients are diagnosed in young or middle adulthood.

The disease is almost always unilateral.

Pediatric Considerations

ICE syndrome is extremely uncommon in children, although isolated pediatric cases have been reported.

Geriatric Considerations

Older patients may have substantial visual impairment from chronic corneal edema, glaucomatous optic nerve damage, or both.

Pregnancy Considerations

If glaucoma is present, medications may need to be adjusted during pregnancy or breastfeeding because some pressure-lowering agents may not be appropriate.

Risk Factors

No definite environmental or genetic risk factors have been established.

Unlike many corneal dystrophies, ICE syndrome is not considered an inherited disorder.

General Prevention

There is no known way to prevent ICE syndrome.

The main preventive strategy is early recognition and close follow-up to reduce the risk of irreversible vision loss from glaucoma or corneal decompensation.

Etiology

The exact cause is unknown.

A possible viral mechanism, particularly involving herpes simplex virus, has been proposed. HSV DNA has been detected in the corneal endothelium of some affected eyes, but a definitive causal relationship has not been established.

Pathophysiology

The central abnormality is a population of pathologic corneal endothelial cells that behave more like epithelial cells than normal endothelium.

These abnormal cells proliferate and form a membrane that extends:

Corneal endothelium → anterior chamber angle → iris

As the membrane contracts, several structural changes can develop.

Peripheral anterior synechiae form as the iris is pulled toward and adheres to the angle. Progressive angle closure can obstruct aqueous outflow and lead to secondary angle-closure glaucoma.

The same membrane can pull on the iris and produce:

• Corectopia
• Iris stromal atrophy
• Pseudopolycoria
• Iris nodules
• Distortion of normal iris architecture

At the corneal level, abnormal endothelial pump function causes stromal and epithelial edema and may eventually produce chronic corneal decompensation.

Clinical Variants

Progressive Iris Atrophy

This form is dominated by marked iris changes.

Typical findings include progressive iris stromal atrophy, severe corectopia, pseudopolycoria, and broad peripheral anterior synechiae.

Angle closure tends to be prominent, and secondary glaucoma is common.

This variant often produces the most dramatic iris distortion.

Cogan–Reese Syndrome

Cogan–Reese syndrome, also called iris nevus syndrome, is characterized by pigmented iris abnormalities.

Patients may have a diffuse iris nevus-like lesion or multiple nodules over the iris surface.

The appearance can mimic an iris melanoma, making careful examination important.

Glaucoma and corneal edema can also occur.

Chandler Syndrome

Chandler syndrome is characterized primarily by corneal disease.

The corneal endothelium may have a characteristic hammered-silver appearance, and corneal edema is often the major cause of symptoms.

Compared with the other variants, iris abnormalities may be less prominent and glaucoma may be somewhat less frequent.

Commonly Associated Conditions

The major associated ocular conditions are:

• Secondary angle-closure glaucoma
• Progressive peripheral anterior synechiae
• Corneal edema
• Corneal endothelial failure
• Iris atrophy
• Corectopia
• Pseudopolycoria

There is no established systemic syndrome consistently associated with ICE.

Diagnosis

History

Patients usually present with symptoms in one eye.

Common complaints include:

• Blurred vision
• Fluctuating vision
• Vision worse in the morning
• Ocular discomfort
• Pain
• Halos around lights
• Visible change in pupil shape
• Progressive visual loss from glaucoma

Morning blurring is often related to increased corneal edema after overnight eyelid closure.

Pain may result from epithelial edema, bullous changes, or elevated IOP.

Physical Examination

A complete anterior segment and glaucoma examination is essential.

Cornea

Slit-lamp examination may show:

• Corneal edema
• Abnormal endothelial appearance
• Reduced corneal clarity
• Bullous epithelial change in advanced disease

The endothelial surface may look irregular or hammered silver.

Iris

Possible findings include:

• Corectopia
• Iris stromal atrophy
• Pseudopolycoria
• Iris nodules
• Diffuse nevus-like pigmentation
• Irregular pupil shape

The pattern often helps determine the clinical subtype.

Anterior Chamber Angle

Gonioscopy is very important.

Findings may include:

• Broad peripheral anterior synechiae
• Progressive synechial angle closure
• Abnormal membrane extending across the angle

In some eyes, synechiae can extend unusually far anteriorly, including beyond Schwalbe’s line.

Intraocular Pressure

IOP may be normal early in the disease.

As the angle progressively closes, IOP may rise and secondary glaucoma may develop.

The glaucoma can become severe and difficult to control.

Diagnostic Tests and Interpretation

Visual Acuity

Visual acuity may be reduced because of:

• Corneal edema
• Cataract
• Glaucomatous damage

Fluctuating vision can occur as corneal edema varies.

Visual Field Testing

Visual fields are indicated when glaucoma is suspected or established.

Defects reflect the degree of glaucomatous optic neuropathy.

Optic Nerve Imaging

OCT of the retinal nerve fiber layer and optic nerve can help detect and follow glaucoma progression.

Serial optic disc photography may also be useful.

Specular Microscopy

Specular microscopy can demonstrate the characteristic abnormal endothelial cells.

Findings may include:

• Irregular cell size
• Abnormal cell shape
• Loss of the normal hexagonal endothelial pattern
• Characteristic ICE-cell appearance

This test can strongly support the diagnosis.

Pachymetry

Pachymetry is useful for measuring corneal thickness and following progression of corneal edema.

Differential Diagnosis

Fuchs Endothelial Corneal Dystrophy

Fuchs dystrophy can produce similar corneal edema and endothelial changes, but it is usually:

• Bilateral
• Associated with guttae
• Not associated with progressive iris distortion or broad PAS

Posterior Polymorphous Corneal Dystrophy

Posterior polymorphous dystrophy can also resemble ICE syndrome, but it is generally:

• Bilateral
• Familial
• Present earlier in life

Axenfeld–Rieger Syndrome

Axenfeld–Rieger syndrome may produce angle and iris abnormalities, but it is usually congenital and bilateral.

Systemic findings such as dental or craniofacial abnormalities may also be present.

Iris Melanoma

Cogan–Reese syndrome may resemble an iris melanoma.

Progressive mass growth, intrinsic tumor vessels, secondary cataract, and localized angle invasion may favor melanoma.

Treatment

Treatment is directed mainly at corneal edema and glaucoma.

There is no therapy that reliably eliminates the abnormal endothelial membrane itself.

Corneal Edema

Mild corneal edema can be treated with hypertonic sodium chloride 5% drops or ointment.

These therapies may reduce epithelial edema and improve vision temporarily.

They do not correct the underlying endothelial dysfunction.

If corneal decompensation becomes visually significant, endothelial keratoplasty may be required.

Glaucoma

Topical glaucoma medications are generally used initially.

Because the angle becomes progressively closed by PAS and abnormal endothelial membrane, medical treatment may eventually become insufficient.

Laser Trabeculoplasty

Laser trabeculoplasty is generally not effective because the problem is not primarily an open trabecular meshwork with increased resistance. Instead, there is progressive structural angle closure.

Laser Peripheral Iridotomy

Laser peripheral iridotomy usually does not halt progression.

ICE-related angle closure is not primarily caused by pupillary block, so the abnormal endothelial membrane continues to contract even after an iridotomy.

Surgical Treatment

Trabeculectomy

Trabeculectomy may be performed when medications fail.

An antimetabolite such as mitomycin C may improve surgical success.

However, trabeculectomy can fail because abnormal endothelial tissue may proliferate over the internal filtering ostium.

Glaucoma Drainage Devices

Tube shunts are often considered in refractory ICE-associated glaucoma.

They may be more successful than trabeculectomy in some patients because the drainage pathway is less vulnerable to direct closure by the endothelial membrane.

Even so, tube positioning must be carefully planned because the corneal endothelium is already compromised.

Corneal Transplantation

Persistent corneal edema and endothelial failure may require corneal transplantation.

Modern endothelial procedures such as:

• DSAEK
• DMEK

may be used when appropriate.

Because the underlying ICE process can remain active, recurrent endothelial failure or graft decompensation can occur.

Cataract Surgery

Cataract surgery may be more complicated because of:

• Poor pupillary dilation
• Iris distortion
• PAS
• Fragile iris tissue
• Corneal endothelial dysfunction

Extra care is required to protect the corneal endothelium.

Iris Reconstruction

Iris reconstruction may be considered when severe corectopia or iris defects cause:

• Glare
• Photophobia
• Cosmetic concerns

The iris can be friable and technically difficult to repair.

Artificial iris implantation may be considered in selected patients.

Ongoing Care

Follow-Up Recommendations

ICE syndrome is progressive, so long-term follow-up is required.

Patients with mild disease and no glaucoma may be monitored periodically, often annually.

Patients with glaucoma or significant corneal disease require more frequent follow-up.

Patient Monitoring

Follow-up should assess:

• Visual acuity
• IOP
• Gonioscopic angle changes
• Optic nerve appearance
• Visual fields
• OCT of the retinal nerve fiber layer
• Corneal edema
• Corneal thickness
• Progression of iris abnormalities

Referral to a glaucoma specialist or corneal specialist may be needed when complications become significant.

Patient Education

Patients should understand that ICE syndrome is a chronic, usually unilateral, progressive condition.

They should be informed that the two major threats to vision are:

• Glaucoma
• Corneal decompensation

They should seek prompt evaluation for worsening pain, halos, blurred vision, or sudden reduction in vision.

Prognosis

The visual prognosis depends mainly on the severity of glaucoma and the degree of corneal endothelial failure.

Patients with well-controlled IOP and manageable corneal edema may maintain useful vision for many years.

Advanced glaucoma can cause irreversible visual loss even if corneal clarity is restored later.

Corneal transplantation can improve vision, but repeated graft failure or rejection can limit the final outcome.

Complications

Important complications include:

• Secondary angle-closure glaucoma
• Progressive optic nerve damage
• Permanent visual field loss
• Chronic corneal edema
• Bullous keratopathy
• Corneal decompensation
• Cataract
• Surgical complications
• Graft failure after endothelial keratoplasty

The key clinical concept is that ICE syndrome is an acquired, usually unilateral disease in which abnormal corneal endothelial cells spread over the angle and iris, producing corneal edema, progressive iris distortion, peripheral anterior synechiae, and potentially severe secondary glaucoma.

98. Ophthalmology – Intraoperative Floppy Iris Syndrome (IFIS)

Basics

Description

Intraoperative floppy iris syndrome (IFIS) is an abnormal iris behavior encountered during cataract surgery. It may be suspected before surgery when the pupil dilates poorly, but it is primarily an intraoperative diagnosis.

The classic features are:

• Billowing of the iris stroma during normal irrigation
• Prolapse of the iris toward or through the corneal incisions
• Progressive intraoperative miosis
• Poor maintenance of pupillary dilation despite mechanical stretching

Pupillary stretching alone is often ineffective because the problem is not simply a small pupil, but loss of normal iris dilator tone.

Epidemiology

IFIS occurs more commonly in men than women, largely because medications strongly associated with IFIS are frequently prescribed for benign prostatic hyperplasia.

In the United States, IFIS has historically been reported in approximately 2–3% of cataract operations, although the true frequency varies depending on patient population and medication exposure.

Risk Factors

The strongest risk factor is exposure to α1-adrenergic antagonists, especially drugs with strong activity at the α1A receptor.

The medication most strongly associated with IFIS is tamsulosin (Flomax). A very high proportion of patients exposed to tamsulosin may demonstrate some degree of IFIS during cataract surgery.

Other α1 antagonists associated with IFIS include:

• Alfuzosin
• Silodosin
• Terazosin
• Doxazosin
• Naftopidil

Nonselective α1 antagonists generally appear to carry a lower risk than tamsulosin.

Other reported medication associations include:

• Finasteride
• Dutasteride
• Saw palmetto
• Certain antipsychotic medications

The relationship is strongest and best established with α1 blockers, particularly tamsulosin.

Important Medication History

Patients should be asked specifically about both current and previous use of medications associated with IFIS.

This is important because IFIS may occur:

• After only a short period of drug exposure
• Even when the medication was discontinued long before cataract surgery

Therefore, simply asking whether the patient is currently taking tamsulosin is not sufficient.

General Prevention

The most important preventive measure is preoperative recognition.

The ophthalmic surgeon should know whether the patient has ever taken medications associated with IFIS so that the surgical technique and equipment can be planned accordingly.

Avoiding unnecessary exposure to high-risk medications before cataract surgery may reduce risk, but many patients require these drugs for important systemic conditions.

Stopping the medication shortly before surgery does not reliably prevent IFIS.

Pathophysiology

The iris dilator muscle is partly controlled by α1A-adrenergic receptors.

Selective α1A antagonists such as tamsulosin reduce sympathetic stimulation of the iris dilator muscle.

This may produce:

• Reduced iris dilator tone
• Poor pharmacologic dilation
• Increased iris mobility
• Progressive pupillary constriction during surgery

Chronic exposure may also be associated with structural or functional changes in the iris dilator muscle, which helps explain why IFIS can persist even after the medication is discontinued.

Etiology

IFIS is most commonly associated with exposure to medications that antagonize α1 receptors.

Even relatively brief exposure has been associated with the syndrome.

The condition can persist long after discontinuation, so the relationship cannot always be prevented simply by stopping the medication before surgery.

Commonly Associated Conditions

Conditions commonly treated with medications associated with IFIS include:

• Benign prostatic hyperplasia
• Prostate-related urinary symptoms
• Urinary retention
• Hypertension
• Hair loss
• Certain psychiatric disorders

Because benign prostatic hyperplasia becomes increasingly common with age, IFIS is particularly relevant in the elderly male cataract population.

Geriatric Considerations

Benign prostatic hyperplasia is extremely common in older men.

As a result, a substantial number of elderly men presenting for cataract surgery have current or previous exposure to α1 blockers.

Every older cataract patient, especially a man, should therefore be asked specifically about medications used for urinary or prostate symptoms.

Diagnosis

History

The most important diagnostic step before surgery is a careful medication history.

Ask about:

• Tamsulosin
• Alfuzosin
• Silodosin
• Terazosin
• Doxazosin
• Other prostate or urinary medications
• Finasteride or dutasteride
• Saw palmetto
• Antipsychotic medications

Past use is just as important as current use.

Physical Examination

Poor or slow pharmacologic pupillary dilation before cataract surgery may suggest an increased risk of IFIS.

However, a patient can have apparently adequate preoperative dilation and still develop IFIS intraoperatively.

Therefore, the absence of a small pupil before surgery does not rule out the syndrome.

Intraoperative Findings

The classic intraoperative findings are:

Billowing Iris

The iris becomes unusually mobile and undulates with irrigation currents.

Iris Prolapse

The floppy iris may move toward or prolapse through the main corneal incision or side-port wounds.

Progressive Miosis

The pupil gradually becomes smaller during the operation despite initially adequate dilation.

Poor Response to Stretching

Mechanical stretching of the pupil may temporarily enlarge it but usually does not provide stable dilation throughout surgery.

Differential Diagnosis

A small pupil before surgery can also result from:

• Previous ocular trauma
• Chronic uveitis
• Posterior synechiae
• Previous infection
• Chronic miotic therapy
• Pseudoexfoliation
• Other iris structural abnormalities

Iris prolapse can also occur because of:

• Poor wound construction
• Very short corneal tunnels
• Excessive intraocular pressure
• Excessive irrigation pressure

The combination of billowing, prolapse, and progressive miosis, especially in a patient with α1-blocker exposure, strongly supports IFIS.

Treatment and Surgical Management

Management begins with anticipating the syndrome before the operation.

The surgeon should modify the pharmacologic, viscoelastic, fluidic, and mechanical aspects of cataract surgery according to severity.

Stopping the Associated Medication

Stopping tamsulosin or another α1 antagonist before surgery may improve pharmacologic dilation in some patients, but it does not reliably reduce the severity of IFIS.

For this reason, many surgeons do not routinely discontinue these medications.

Any decision to stop a systemic medication should also consider why the medication was prescribed and should generally be coordinated with the prescribing physician.

Preoperative Atropine

Preoperative atropine may improve pupillary dilation and help maintain iris tone in selected patients.

However, atropine does not reliably prevent IFIS, especially in more severe cases.

Therefore, it should not be relied upon as the sole preventive strategy.

Intracameral Adrenergic Agents

Intracameral adrenergic stimulation can improve iris tone.

Agents may include preservative-free intracameral epinephrine or phenylephrine, depending on availability and surgical protocol.

These drugs may:

• Improve pupillary dilation
• Increase iris rigidity
• Reduce progressive miosis
• Reduce iris billowing

Only appropriate preservative-free intracameral preparations should be used.

Ophthalmic Viscoelastic Devices

Highly cohesive ophthalmic viscoelastic devices can mechanically stabilize the iris and maintain pupillary dilation.

A highly viscous OVD such as sodium hyaluronate 2.3% may help:

• Expand the pupil
• Push the iris away from the surgical incision
• Reduce iris billowing

Other viscoelastic formulations that remain in the anterior chamber during higher fluid flow may also be useful.

Repeated reinjection may sometimes be necessary during surgery.

Wound Construction

A well-constructed, sufficiently long corneal tunnel helps reduce iris prolapse.

Short, unstable, or poorly positioned incisions may make iris prolapse more likely.

Careful wound architecture is therefore an important component of IFIS management.

Fluidics

Lower and more controlled fluidic parameters can reduce movement of the floppy iris.

The surgeon may reduce:

• Irrigation pressure
• Aspiration flow
• Vacuum

Gentler fluidics decrease turbulence and reduce the tendency of the iris to billow or prolapse.

Pupil Expansion Rings

Mechanical pupil expansion is often the most reliable treatment for moderate or severe IFIS.

Devices include various pupillary expansion rings, with the Malyugin ring being one commonly used example.

These rings provide stable enlargement of the pupil throughout surgery and reduce the risk of progressive miosis.

Iris Hooks

Iris retractors or hooks can also mechanically enlarge and stabilize the pupil.

They are especially useful when:

• The pupil is very small
• The iris is markedly floppy
• A pupil expansion ring is unsuitable
• Asymmetric dilation is desired

Mechanical expansion should be used early rather than after substantial intraoperative miosis or repeated iris prolapse has already occurred.

Why Pupillary Stretching Alone Is Usually Inadequate

Simple mechanical stretching may enlarge the pupil temporarily but does not correct the underlying loss of iris dilator tone.

Consequently, the pupil may constrict again during surgery.

For this reason, stable mechanical devices such as iris hooks or pupil expansion rings are usually more effective in significant IFIS.

Patient Education

Patients taking or previously exposed to α1 blockers should be informed that these medications may complicate cataract surgery.

They should be instructed to tell their ophthalmologist if they have ever taken medications such as:

• Tamsulosin
• Alfuzosin
• Silodosin
• Terazosin
• Doxazosin

This history remains important even if the medication was stopped months or years earlier.

Prescribing physicians should also be aware of the association and, when practical, may consider ophthalmic evaluation in patients with known cataract before initiating long-term α1-blocker therapy.

Prognosis

When the surgeon knows about the risk beforehand and uses appropriate surgical modifications, cataract surgery can usually be completed successfully.

The greatest difficulty occurs when significant IFIS develops unexpectedly.

Preoperative recognition therefore substantially improves surgical safety.

Complications

IFIS increases the risk of intraoperative complications, particularly when it is unanticipated.

Potential complications include:

• Posterior capsule rupture
• Vitreous loss
• Iris trauma
• Iris prolapse
• Irregular or damaged pupil
• Prolonged surgery
• Increased postoperative inflammation

The complication rate is highest when the surgeon is unaware of prior exposure to an associated medication.

High-Yield Clinical Pearls

IFIS classically causes billowing iris, iris prolapse, and progressive intraoperative miosis.

Tamsulosin is the medication most strongly associated with IFIS.

Ask about previous as well as current α1-blocker use.

Stopping tamsulosin shortly before surgery does not reliably eliminate the risk.

Preoperative atropine may help but does not reliably prevent IFIS.

Intracameral adrenergic agents, controlled fluidics, cohesive viscoelastic, iris hooks, and pupil expansion rings are important management strategies.

The greatest surgical risk occurs when IFIS is unexpected rather than when it is recognized and planned for in advance.

Ophthalmology – Interstitial Keratitis (IK)

Basics

Description

Interstitial keratitis (IK), also called immune stromal keratitis, is a nonsuppurative inflammatory process involving the corneal stroma. Unlike infectious corneal ulcers, the overlying epithelium is generally intact during the active phase, and there is no primary stromal melting.

The condition is frequently accompanied by stromal neovascularization. Active disease commonly causes pain, photophobia, tearing, redness, and reduced vision.

Chronic inflammation may eventually produce:

• Corneal scarring
• Stromal thinning
• Lipid deposition
• Persistent or “ghost” stromal vessels
• Irregular astigmatism and permanent visual impairment

Many cases are associated with an underlying infectious or systemic inflammatory disorder.

Etiology

Historically, congenital syphilis was considered the classic cause of interstitial keratitis worldwide.

In contemporary ophthalmic practice, however, important causes include:

• Herpes simplex virus
• Varicella-zoster virus
• Syphilis
• Tuberculosis
• Lyme disease
• Cogan syndrome
• Sarcoidosis
• Other infectious and autoimmune disorders

In some patients, no specific cause is identified.

Risk Factors

Risk factors are primarily those associated with the underlying disease.

These include exposure to:

• Sexually transmitted infection
• Tuberculosis
• Tick-borne disease
• Herpes viruses
• Parasitic infections

Systemic inflammatory and autoimmune conditions can also predispose to stromal inflammation.

Pathophysiology

Interstitial keratitis is usually produced by an immune-mediated inflammatory reaction within the corneal stroma.

A common mechanism is a delayed-type, or type IV, hypersensitivity response against microbial antigens or other inflammatory targets within the cornea.

The inflammatory response produces:

• Lymphocytic stromal infiltration
• Corneal edema
• New blood vessel formation
• Subsequent fibrosis and scarring

In late disease, active inflammation disappears but the residual vascular channels remain as ghost vessels.

Diagnosis

History

A careful systemic and ophthalmic history is essential because IK is often a manifestation of another disease.

Ask about:

• Onset and duration of symptoms
• Unilateral versus bilateral disease
• Pain and photophobia
• Previous episodes
• Contact lens use
• Ocular trauma
• Previous herpes infection
• Sexually transmitted infections
• Travel history
• Tick exposure
• Tuberculosis exposure
• Hearing loss
• Vertigo or tinnitus
• Autoimmune disease

Review of Systems

A targeted systemic review can provide important diagnostic clues.

Constitutional Symptoms

Fever, night sweats, chills, or weight loss may suggest tuberculosis or systemic inflammatory disease.

Skin and Mucous Membranes

Look for:

• Erythema migrans in Lyme disease
• Vesicular eruptions in HSV or VZV
• Oral or genital ulceration
• Skin findings of syphilis
• Features of leprosy in endemic settings

Dental and ENT Findings

Congenital syphilis may be associated with:

• Hutchinson incisors
• Abnormal molars
• Saddle-nose deformity
• Sensorineural hearing loss

Cogan syndrome commonly produces:

• Tinnitus
• Vertigo
• Progressive hearing impairment

Respiratory Findings

Shortness of breath may suggest sarcoidosis, whereas chronic cough may suggest tuberculosis.

Musculoskeletal Findings

Migratory joint pain may occur with Lyme disease.

Neurologic Findings

Cranial nerve abnormalities can occur with:

• Herpes infection
• Lyme disease
• Syphilis
• Cogan syndrome
• Leprosy

Physical Examination

A complete ophthalmic examination should include:

• Visual acuity
• Pupillary examination
• Intraocular pressure
• Ocular motility
• Slit-lamp examination
• Dilated fundus examination

Corneal Findings

The characteristic finding is a stromal inflammatory infiltrate beneath an intact or minimally disrupted epithelium.

Other findings may include:

• Stromal edema
• Deep or superficial stromal vessels
• Corneal scarring
• Lipid deposition
• Ghost vessels
• Reduced corneal sensation
• Late stromal thinning

Scarring may be:

• Diffuse
• Sectoral
• Central
• Peripheral
• Circumferential
• Multifocal

Corneal Neovascularization

Corneal vascularization is a common feature.

During active inflammation, vessels may be engorged and accompanied by stromal haze.

Once inflammation resolves, vessels may become empty and difficult to see clinically, leaving ghost vessels embedded within the stroma.

These vessels are important because they increase the risk of corneal graft rejection if keratoplasty is later required.

Anterior Segment Findings

Associated findings may include:

• Conjunctival injection
• Scleritis
• Anterior uveitis
• Fine keratic precipitates
• Posterior synechiae
• Iris atrophy

Certain findings can suggest specific causes. For example, reduced corneal sensation and iris atrophy support a herpetic etiology.

Posterior Segment Findings

Depending on the systemic cause, the posterior segment may show:

• Retinal vasculitis
• Choroiditis
• Optic nerve abnormalities
• Salt-and-pepper retinal pigmentary changes in congenital syphilis

Diagnostic Testing

Slit-Lamp Examination

Slit-lamp examination remains the primary diagnostic method.

The clinician should characterize:

• Location and depth of stromal inflammation
• Presence of vessels
• Corneal sensation
• Epithelial integrity
• Associated anterior chamber inflammation
• Degree of scarring

Confocal Microscopy

Confocal microscopy may be useful when unusual infectious causes such as:

• Acanthamoeba
• Fungal keratitis

remain in the differential diagnosis.

Laboratory Evaluation

Testing should be guided by clinical suspicion.

Possible investigations include:

Syphilis

• RPR or VDRL
• Confirmatory treponemal testing such as TP-PA or another treponemal assay

Tuberculosis

• Interferon-gamma release assay or tuberculin skin testing
• Chest imaging when indicated

Lyme Disease

• Two-tier serologic testing when epidemiologically appropriate

Herpetic Disease

HSV serology is generally of limited diagnostic value because prior exposure is common. PCR or other direct testing may be more useful in selected atypical cases.

Sarcoidosis

Appropriate chest imaging and targeted laboratory evaluation may be considered.

Differential Diagnosis

Important infectious causes include:

• Syphilis
• Tuberculosis
• Lyme disease
• Leprosy
• Brucellosis
• Chlamydial disease
• HSV
• VZV
• Epstein-Barr virus
• Mumps
• Rubella
• Acanthamoeba
• Onchocerciasis
• Other parasitic disease

Important noninfectious causes include:

• Cogan syndrome
• Sarcoidosis
• Autoimmune disease
• Lymphoproliferative disease
• Idiopathic stromal inflammation

Syphilitic Interstitial Keratitis

Congenital Syphilis

Congenital syphilitic IK is classically associated with Hutchinson triad:

Interstitial keratitis + sensorineural deafness + Hutchinson teeth

Ocular disease typically appears in childhood or adolescence rather than at birth.

The disease is commonly bilateral, although one eye may be affected before the other.

Active findings can include:

• Diffuse stromal inflammation
• Deep vascularization
• Stromal edema
• Iritis

A characteristic vascularized stromal area may produce a salmon-patch appearance.

Late findings include:

• Corneal scarring
• Ghost vessels
• Irregular astigmatism
• Secondary degenerative changes

Acquired Syphilitic IK

Acquired syphilitic interstitial keratitis is much less common.

It tends to be:

• More often unilateral
• More sectoral
• Less severe than congenital disease

Diagnosis requires appropriate syphilis testing and systemic evaluation.

Tuberculous Interstitial Keratitis

Tuberculosis-associated IK is usually immune-mediated rather than caused by direct active corneal infection.

It tends to be:

• Unilateral
• Peripheral
• Sectoral
• Sometimes associated with stromal thinning

Associated ocular findings may include:

• Uveitis
• Scleritis
• Retinal vasculitis
• Choroiditis
• Conjunctival inflammation

Lyme-Associated Interstitial Keratitis

Lyme disease is caused by Borrelia burgdorferi and transmitted by Ixodes ticks.

Corneal findings may include:

• Bilateral stromal infiltrates
• Poorly defined stromal opacities
• Mild anterior uveitis
• Later vascularization and scarring

Associated systemic findings include:

• Erythema migrans
• Fatigue
• Migratory arthritis
• Cranial neuropathies
• Cardiac conduction abnormalities
• Optic neuritis in some patients

Herpes Simplex Interstitial Keratitis

HSV stromal keratitis is an important cause of IK.

It is usually:

• Unilateral
• Sectoral or diffuse
• Associated with reduced corneal sensation

Disease may initially resemble disciform keratitis and later develop:

• Stromal infiltrates
• Deep neovascularization
• Anterior uveitis
• Scarring
• Lipid keratopathy

Herpes Zoster Interstitial Keratitis

VZV-associated disease commonly develops after herpes zoster ophthalmicus.

Corneal manifestations include:

• Anterior stromal infiltrates
• Disciform keratitis
• Immune ring infiltrates
• Reduced corneal sensation
• Deep neovascularization
• Lipid deposition
• Stromal scarring

The inflammatory process is largely immune mediated.

Cogan Syndrome

Cogan syndrome is an important cause of nonsyphilitic interstitial keratitis associated with audiovestibular disease.

The classic syndrome consists of:

• Interstitial keratitis
• Vertigo
• Tinnitus
• Sensorineural hearing loss

Hearing loss may progress rapidly and can become permanent.

Typical Cogan Syndrome

Typical disease involves:

• IK
• Vestibular symptoms
• Hearing loss

The eye disease is often bilateral and may cause sudden:

• Pain
• Tearing
• Photophobia

Corneal inflammation may begin superficially and peripherally before progressing deeper into the stroma.

Atypical Cogan Syndrome

Atypical forms may include ocular inflammatory disease other than classic IK, such as:

• Scleritis
• Episcleritis
• Posterior uveitis
• Retinal vasculitis
• Optic disc edema
• Orbital inflammation

Systemic vasculitis may also occur.

Reported systemic complications include:

• Aortitis
• Aortic insufficiency
• Coronary involvement
• Cerebral ischemia

Patients with suspected Cogan syndrome should receive prompt systemic evaluation because early treatment may reduce the risk of permanent hearing loss.

Treatment Principles

Management requires two simultaneous strategies:

1. Control the corneal inflammation
2. Treat the underlying disease

Before using corticosteroids aggressively, active infection must be identified and appropriately treated.

Topical Corticosteroids

Topical corticosteroids are commonly used for immune-mediated stromal inflammation.

They reduce:

• Stromal inflammatory cells
• Edema
• Neovascularization
• Scarring

Treatment should be tapered slowly according to the inflammatory response.

Steroids should be used with appropriate antimicrobial coverage when an infectious cause such as herpes is involved.

Cycloplegics

Cycloplegic agents are useful when anterior uveitis accompanies IK.

They help:

• Reduce ciliary spasm
• Relieve pain
• Reduce photophobia
• Prevent posterior synechiae

Treatment of Syphilis

Ocular syphilis requires systemic antibiotic therapy, generally managed as neurosyphilis according to current infectious-disease guidelines.

Intravenous penicillin is the standard treatment in patients without contraindications.

Topical corticosteroids and cycloplegics may be added for active ocular inflammation but do not replace systemic antimicrobial therapy.

Patients should also be evaluated for other manifestations of syphilis and managed in collaboration with infectious-disease specialists when appropriate.

Treatment of Tuberculosis

Tuberculosis-associated disease requires appropriate multidrug antituberculous therapy when active or clinically relevant infection is established.

Treatment typically involves combinations of agents such as:

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol

The exact regimen should be directed by infectious-disease or pulmonary specialists.

Topical corticosteroids may be used to control stromal inflammation after adequate antimicrobial therapy has been established.

Treatment of Lyme Disease

Patients with untreated systemic Lyme disease require appropriate antibiotic therapy.

Depending on the clinical manifestation, treatment may involve:

• Doxycycline
• Ceftriaxone
• Other guideline-directed antibiotic regimens

Topical corticosteroids and cycloplegics may be used for associated immune-mediated ocular inflammation.

Treatment of Herpetic Stromal Keratitis

HSV stromal keratitis is usually treated with topical corticosteroids together with antiviral therapy.

Antiviral therapy may include:

• Acyclovir
• Valacyclovir
• Famciclovir
• Topical antiviral therapy in selected cases

Steroids should not be given unopposed when active herpetic infection is suspected.

Antiviral Prophylaxis

Patients with recurrent HSV stromal keratitis may benefit from long-term oral antiviral prophylaxis.

This can reduce the risk of recurrent ocular herpes, particularly in patients with repeated stromal episodes or those undergoing corneal transplantation.

Treatment of Cogan Syndrome

Cogan syndrome often requires both ocular and systemic therapy.

Treatment may include:

• Topical corticosteroids
• Cycloplegics
• High-dose systemic corticosteroids
• Steroid-sparing immunosuppressive therapy when necessary

Because hearing loss may progress rapidly, suspected cases warrant prompt:

• Audiometry
• ENT evaluation
• Rheumatologic evaluation
• Cardiovascular assessment when systemic vasculitis is suspected

Surgery

Corneal transplantation may be necessary when chronic disease causes visually significant scarring.

Options include:

• Deep anterior lamellar keratoplasty (DALK)
• Penetrating keratoplasty

DALK may be appropriate when disease is primarily stromal and the endothelium remains healthy.

Corneal Neovascularization and Graft Risk

Active or extensive corneal vascularization significantly increases the risk of corneal graft rejection.

Ideally, inflammation should be controlled before transplantation.

In herpetic disease, perioperative and postoperative antiviral prophylaxis may reduce recurrence.

Follow-Up

Patients with active disease should initially be followed closely, often weekly, until the inflammatory response is clearly controlled.

At each examination, monitor:

• Visual acuity
• Stromal inflammation
• Corneal edema
• Neovascularization
• Epithelial integrity
• Corneal thinning
• IOP
• Anterior chamber inflammation

Once stable, follow-up intervals can be extended.

Patient Monitoring

The treatment goal is to suppress inflammation with the lowest effective corticosteroid exposure while preventing:

• Progressive corneal scarring
• Stromal thinning
• Secondary glaucoma
• Cataract
• Recurrence

Patients with infectious causes should also be followed by the appropriate systemic specialist.

Prognosis

Prognosis depends strongly on the underlying cause and the degree of central corneal involvement.

Vision may recover well if:

• Inflammation is recognized early
• The underlying cause is treated promptly
• Central scarring is limited

Longstanding disease may result in permanent visual reduction from:

• Stromal scarring
• Irregular astigmatism
• Lipid keratopathy
• Corneal thinning
• Persistent vascularization

Complications

Major complications include:

• Corneal scarring
• Corneal neovascularization
• Lipid keratopathy
• Irregular astigmatism
• Stromal thinning
• Secondary uveitis
• Cataract
• Secondary glaucoma
• Permanent visual impairment
• Corneal graft rejection after transplantation

In systemic diseases such as Cogan syndrome or syphilis, nonocular complications such as hearing loss, neurologic disease, or systemic vasculitis may be more consequential than the corneal disease itself.

Ophthalmology – Internuclear Ophthalmoplegia

Basics

Description

Internuclear ophthalmoplegia (INO) is a disorder of horizontal eye movements caused by a lesion of the medial longitudinal fasciculus (MLF).

The MLF normally carries signals from the abducens nucleus of one side to the contralateral oculomotor nucleus, allowing the two eyes to move together during horizontal gaze.

In a typical INO, when the patient looks to one side:

• The abducting eye moves normally
• The contralateral eye has impaired adduction
• The abducting eye often develops horizontal abducting nystagmus

INO is named according to the eye with impaired adduction.

Thus, a right INO means that the right eye fails to adduct normally during left gaze.

Partial and Complete INO

INO can vary in severity.

A partial INO may show only slowing of the adducting saccade rather than complete failure of adduction.

This subtle form is more common than complete paralysis and may require careful examination of rapid horizontal saccades.

A more severe lesion may prevent the affected eye from adducting beyond the midline.

Convergence

Convergence is often preserved in a typical INO because convergence uses a pathway that can bypass the damaged internuclear fibers.

Preserved convergence helps distinguish an MLF lesion from a primary medial rectus or oculomotor nerve disorder.

However, convergence may be impaired when the lesion extends into nearby midbrain structures.

Anatomy

The horizontal gaze pathway begins in the paramedian pontine reticular formation (PPRF) and abducens nucleus.

When looking to the right, for example:

1. The right PPRF activates the right abducens nucleus.
2. Motor neurons directly activate the right lateral rectus.
3. Internuclear neurons cross the midline.
4. They ascend in the left MLF.
5. They activate the left oculomotor medial rectus subnucleus.
6. The left medial rectus contracts.

A lesion of the left MLF therefore produces impaired left-eye adduction during right gaze.

Pathophysiology

INO usually results from either:

• Demyelination, or
• Ischemic injury of the MLF

The lesion is generally located in the pons or midbrain.

The characteristic abducting nystagmus is thought to result from an imbalance in conjugate gaze commands and an adaptive increase in neural drive to overcome the weak adduction of the opposite eye.

Epidemiology

The exact incidence and prevalence are unknown.

INO is relatively common in patients with multiple sclerosis, particularly when demyelinating lesions involve the brainstem.

Both unilateral and bilateral forms occur.

Risk Factors

Risk factors are essentially those of the underlying disorder.

Important associations include:

• Multiple sclerosis
• Cerebrovascular disease
• Hypertension
• Diabetes mellitus
• Smoking and other vascular risk factors
• Brainstem tumors
• Head trauma
• Central nervous system infection
• Drug toxicity or overdose

Etiology

Multiple Sclerosis

Multiple sclerosis is one of the most important causes, especially in younger patients.

MS-associated INO is commonly:

• Bilateral
• Asymmetric
• Associated with other neurologic findings

A bilateral INO in a young adult should strongly raise suspicion for demyelinating disease.

Brainstem Stroke

Small ischemic infarcts of the pons or midbrain are another major cause.

Stroke-associated INO is particularly common in older adults and is often unilateral.

Acute onset with additional neurologic symptoms should trigger urgent evaluation for cerebral ischemia.

Other Causes

Less common causes include:

• Brainstem hemorrhage
• Brainstem tumor
• Trauma
• Encephalitis
• Hydrocephalus
• Neurosarcoidosis
• Chiari malformation
• Nutritional or metabolic disease
• Sedative or anticonvulsant toxicity

Certain medications or drug overdoses may occasionally cause reversible internuclear eye movement abnormalities.

Commonly Associated Conditions

INO may coexist with:

• Multiple sclerosis
• Optic neuritis
• Lacunar stroke
• Brainstem hemorrhage
• Brainstem tumor
• Skew deviation
• Other brainstem ocular motor syndromes

Because the MLF lies near several vestibular and ocular motor pathways, associated abnormalities are common.

Diagnosis

History

Many patients with mild INO are asymptomatic.

When symptoms occur, patients may report:

• Horizontal diplopia
• Blurring during rapid gaze shifts
• Difficulty tracking moving objects
• Oscillopsia
• Vertical or oblique diplopia if skew deviation is also present

Symptoms may be most noticeable when looking toward the side opposite the affected eye.

Physical Examination

The defining finding is impaired adduction of one eye during conjugate horizontal gaze.

For example, in a right INO:

• Looking right may be normal.
• Looking left causes poor or slow adduction of the right eye.
• The left eye abducts and often develops nystagmus.

The deficit may range from subtle slowing to complete inability to cross the midline.

Saccadic Testing

Rapid horizontal saccades are particularly useful for detecting partial INO.

The examiner asks the patient to alternate fixation rapidly between two horizontal targets.

The affected eye shows:

• Delayed adduction
• Reduced adduction velocity
• Disconjugate horizontal saccades

This may be more sensitive than asking the patient simply to follow a slowly moving target.

Abducting Nystagmus

The abducting eye commonly shows coarse horizontal nystagmus.

This finding strongly supports INO but is not essential for the diagnosis.

The nystagmus usually becomes most prominent during gaze away from the side of the affected MLF.

Skew Deviation

A vertical ocular misalignment may accompany INO because the MLF also carries vestibular pathways.

This is called skew deviation.

It may produce vertical or oblique diplopia in addition to the horizontal symptoms of INO.

Bilateral INO

When both MLFs are involved, both eyes demonstrate impaired adduction.

Bilateral INO is particularly associated with multiple sclerosis, although vascular and other brainstem diseases can also cause it.

WEBINO Syndrome

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is a severe bilateral form.

Features include:

• Bilateral INO
• Exotropia in primary gaze
• Marked bilateral adduction deficits
• Often impaired convergence

The term “wall-eyed” refers to the divergent position of the eyes.

One-and-a-Half Syndrome

A larger pontine lesion can involve both:

• The ipsilateral PPRF or abducens nucleus, and
• The ipsilateral MLF

This produces one-and-a-half syndrome.

For example, with a right-sided lesion:

• Neither eye can look to the right because of the right horizontal gaze palsy.
• During left gaze, the right eye cannot adduct because of the right MLF lesion.
• The only preserved horizontal movement is abduction of the left eye.

Thus, three of the four horizontal half-movements are impaired.

Pseudo-INO

Not every apparent adduction deficit represents a true MLF lesion.

The most important mimic is myasthenia gravis, sometimes called pseudo-INO.

Features suggesting myasthenia include:

• Variable or fatigable weakness
• Ptosis
• Changing ocular motility pattern
• Orbicularis weakness
• Absence of a corresponding brainstem lesion

Myasthenia can closely mimic the adduction deficit and abducting nystagmus of true INO.

Other Differential Diagnoses

Other considerations include:

• Partial third-nerve palsy
• Medial rectus weakness
• Restrictive orbital disease
• Thyroid eye disease
• Duane syndrome
• Mechanical restriction after orbital trauma
• Ocular motor apraxia in selected neurologic disorders

A complete neurologic and ocular motor examination helps differentiate these conditions.

Diagnostic Tests and Interpretation

MRI

MRI of the brain with attention to the brainstem is the preferred imaging test.

Small MLF lesions may be visible on:

• T2-weighted imaging
• FLAIR sequences
• Diffusion-weighted imaging for acute infarction
• Post-gadolinium imaging for active demyelination or inflammation

The lesion is often small.

In some clinically definite cases, conventional MRI may appear normal.

CT

CT is much less sensitive than MRI for small brainstem lesions and may fail to demonstrate the cause of INO.

It is therefore not the preferred study when an MLF lesion is suspected.

Stroke Evaluation

In patients with acute-onset INO and suspected vascular disease, investigation may include:

• Diffusion-weighted MRI
• Vascular imaging
• ECG
• Cardiac evaluation
• Blood pressure assessment
• Diabetes and lipid screening
• Other standard stroke investigations

Management should proceed according to the overall neurologic presentation.

Multiple Sclerosis Evaluation

When demyelination is suspected, workup may include:

• MRI brain and spinal cord
• Gadolinium-enhanced imaging
• Lumbar puncture for oligoclonal bands in selected cases
• Neurologic examination for additional demyelinating signs

INO can occasionally be the presenting manifestation of MS.

Infrared Oculography

Specialized eye movement recording can objectively demonstrate slowed adduction velocity.

This may be useful in research or diagnostically difficult cases but is usually unnecessary because INO is primarily a clinical diagnosis.

Treatment

There is no specific ocular medication that repairs the MLF.

Treatment is aimed at the underlying disorder.

Multiple Sclerosis

Management of MS-associated INO is directed by neurology.

An acute demyelinating relapse may be treated with systemic corticosteroids when indicated.

Long-term disease-modifying therapy is based on the overall MS diagnosis rather than on the INO alone.

Stroke

Stroke-related INO requires standard cerebrovascular management.

This may include:

• Antiplatelet therapy when appropriate
• Treatment of hypertension
• Diabetes control
• Lipid lowering
• Smoking cessation
• Evaluation for cardioembolic or vascular causes

Symptomatic Diplopia

While the neurologic lesion recovers, diplopia may be managed with:

• Temporary occlusion
• Fresnel prism in selected cases
• Ground-in prism when deviation becomes stable

Because the alignment may change during recovery, temporary measures are usually preferred initially.

Botulinum Toxin and Surgery

Persistent symptomatic strabismus is uncommon but may occasionally require:

• Botulinum toxin
• Strabismus surgery

Surgical treatment should generally be delayed until the neurologic condition and ocular deviation have remained stable.

Referral

Patients should generally be referred to neurology or neuro-ophthalmology, especially when:

• The onset is acute
• There are additional neurologic symptoms
• MS is suspected
• Stroke is suspected
• Imaging is abnormal
• The diagnosis is uncertain

Follow-Up

Follow-up depends on the etiology and neurologic status.

Patients with stable or improving isolated INO may be reassessed over several months.

A 3–6 month ophthalmic reassessment is often reasonable for documenting recovery of eye movements and diplopia.

More urgent or frequent follow-up is required when the underlying neurologic disease is active.

Patient Education

Patients should understand that INO is a brainstem eye movement disorder, not a primary extraocular muscle problem.

The significance depends on the cause.

A younger patient may require evaluation for demyelinating disease, whereas an older patient with sudden onset may require urgent evaluation for stroke.

New neurologic symptoms such as weakness, numbness, dysarthria, severe vertigo, or difficulty swallowing should prompt immediate medical attention.

Prognosis

The prognosis depends on the underlying cause.

Recovery can be substantial in:

• Small ischemic lesions
• Drug-related cases
• Infectious or inflammatory disease successfully treated
• Some demyelinating attacks

INO may persist when caused by:

• Larger stroke
• Multiple sclerosis with permanent axonal injury
• Brainstem tumor
• Severe trauma
• Hemorrhage

Even when some eye movement abnormality remains, diplopia may improve because of neural adaptation and improved ocular alignment.

High-Yield Clinical Pearls

INO = impaired adduction of one eye + abducting nystagmus of the fellow eye during horizontal gaze.

INO is named for the eye that fails to adduct.

The lesion is in the medial longitudinal fasciculus.

Convergence is often preserved in classic INO.

Young patient + bilateral INO → think multiple sclerosis.

Older patient + acute unilateral INO → think brainstem ischemic stroke.

WEBINO = bilateral INO + primary-position exotropia.

One-and-a-half syndrome = ipsilateral horizontal gaze palsy + ipsilateral INO.

Myasthenia gravis is the classic cause of pseudo-INO.

MRI is the preferred imaging test because small MLF lesions can easily be missed on CT.

Ophthalmology – Intermediate Uveitis and Pars Planitis

Basics

Description

Intermediate uveitis (IU) is an inflammatory disorder in which the predominant inflammation involves the vitreous, pars plana, ciliary body, and peripheral retina. The anterior chamber may also be involved, but vitreous inflammation is usually the dominant feature.

Pars planitis is a subset of intermediate uveitis in which there is no identifiable infectious or systemic inflammatory cause. It is classically associated with inflammatory aggregates in the vitreous called snowballs and exudative plaques over the pars plana called snowbanks.

IU is often bilateral, although the severity can differ considerably between the two eyes.

Epidemiology

Intermediate uveitis accounts for approximately 15% of uveitis cases.

There is no strong sex predilection.

Disease is bilateral in roughly 70–90% of patients, although involvement may be asymmetric.

Pars planitis represents a large proportion of idiopathic intermediate uveitis.

It has traditionally been described as having two age peaks:

• Childhood and adolescence, approximately 5–15 years
• Young adulthood, approximately 20–40 years

Risk Factors

No specific environmental risk factor has been clearly established for idiopathic pars planitis.

Genetics

Associations have been reported with:

• HLA-DR15
• HLA-DR51

These associations support an immune-mediated mechanism but are not diagnostic.

Pathophysiology

The pathogenesis is not completely understood.

The disease is thought to represent an immune-mediated inflammatory response against ocular antigens.

Inflammation frequently centers around the peripheral retinal veins, producing retinal periphlebitis.

Persistent inflammatory cells in the vitreous can organize into snowballs, while chronic inflammation over the pars plana may produce fibroinflammatory exudates known as snowbanks.

Longstanding inflammation may ultimately lead to structural complications such as macular edema, epiretinal membrane, cataract, retinal neovascularization, and retinal detachment.

Commonly Associated Conditions

Intermediate uveitis can be associated with systemic or infectious disease.

Important associations include:

• Multiple sclerosis
• Sarcoidosis
• Syphilis
• Tuberculosis
• Lyme disease
• Toxocariasis
• Bartonella infection
• HTLV-related disease in selected populations

By definition, pars planitis has no identified systemic or infectious cause.

Diagnosis

History

The most common symptoms are:

• Floaters
• Blurred or decreased vision

Patients often have a relatively white and quiet eye, despite substantial vitreous inflammation.

Some patients experience:

• Photophobia
• Mild redness
• Mild ocular discomfort

Redness and anterior segment inflammation are more commonly prominent in children.

Physical Examination

A complete uveitis examination should include careful evaluation of the anterior chamber, vitreous, peripheral retina, macula, and optic nerve.

Typical findings include:

Anterior Vitreous Cells

Inflammatory cells within the vitreous are the defining clinical feature.

The amount of vitreous haze should also be assessed because it correlates with inflammatory activity.

Snowballs

Snowballs are rounded whitish aggregates of inflammatory cells suspended within the inferior vitreous.

They are commonly located near the inferior peripheral retina.

Although characteristic, they are not absolutely specific for pars planitis.

Snowbanks

Snowbanks are broad, gray-white inflammatory exudates involving the pars plana, most often inferiorly.

They represent fibroglial and inflammatory tissue.

Snowbank formation generally indicates more substantial or chronic disease and is associated with a higher risk of complications such as peripheral retinal neovascularization.

Retinal Periphlebitis

Peripheral retinal venous inflammation may appear as:

• Vascular sheathing
• Tortuosity
• Leakage on fluorescein angiography
• Peripheral nonperfusion in more severe cases

The retinal veins are the most commonly involved vessels.

Pediatric Considerations

Children may have more pronounced anterior chamber inflammation than adults.

Because young children may not report floaters or blurred vision reliably, disease can remain undetected until complications develop.

Children are particularly vulnerable to:

• Amblyopia
• Cataract
• Band keratopathy
• Glaucoma

Therefore, careful long-term monitoring is essential.

Diagnostic Tests and Interpretation

Laboratory Evaluation

The laboratory workup should be guided by clinical findings and systemic symptoms.

Commonly considered tests include:

• CBC with differential
• ESR and/or CRP
• Syphilis serology
• Tuberculosis screening
• ACE or other testing when sarcoidosis is suspected
• Lyme serology when epidemiologically appropriate
• Bartonella testing when clinically indicated

Testing should be tailored rather than indiscriminately broad.

Chest Imaging

A chest radiograph may be obtained when sarcoidosis or tuberculosis is suspected.

If suspicion for sarcoidosis remains high despite a normal radiograph, chest CT may provide greater sensitivity.

Fluorescein Angiography

Fluorescein angiography is particularly useful for detecting:

• Cystoid macular edema
• Retinal periphlebitis
• Peripheral vascular leakage
• Areas of capillary nonperfusion
• Retinal neovascularization
• Optic disc leakage

Peripheral angiographic abnormalities may be more extensive than suggested by ophthalmoscopy alone.

Optical Coherence Tomography

OCT is now central to monitoring intermediate uveitis.

It is especially useful for identifying and following:

• Cystoid macular edema
• Epiretinal membrane
• Vitreomacular traction
• Macular structural damage

Because CME is a major cause of visual loss, serial OCT is often more useful than visual acuity alone.

Ultrasound Biomicroscopy

UBM may help visualize:

• Pars plana exudates
• Anterior vitreous abnormalities
• Ciliary body changes

It can be particularly useful when the pupil is small or direct visualization of the pars plana is difficult.

Diagnostic Vitrectomy

Diagnostic pars plana vitrectomy may be considered when there is concern for:

• Intraocular lymphoma
• Chronic endophthalmitis
• Unusual infectious uveitis
• Atypical or treatment-resistant inflammation

Vitreous samples can undergo cytology, flow cytometry, culture, and molecular testing according to the suspected diagnosis.

Pathological Findings

Histopathology may show lymphocytic inflammation around retinal veins.

Snowbank tissue is composed of a mixture of:

• Fibroglial tissue
• Inflammatory cells
• Extracellular material

The pathological findings are generally nonspecific and must be interpreted in clinical context.

Differential Diagnosis

Important differential diagnoses include:

• Primary vitreoretinal lymphoma
• Chronic endophthalmitis
• Sarcoid uveitis
• Infectious uveitis
• Fuchs uveitis syndrome
• Vogt–Koyanagi–Harada disease
• Retinal vasculitis of other causes
• Toxocariasis

In an older patient with new vitreous inflammation, vitreoretinal lymphoma must be considered carefully.

Treatment

Treatment depends on:

• Cause
• Severity
• Visual symptoms
• Presence of macular edema
• Degree of vitreous haze
• Structural complications

If an infectious cause is identified, the infection must be treated specifically, and immunosuppression should be used cautiously.

Corticosteroids

For noninfectious disease causing visual symptoms or complications, corticosteroids remain an important first-line therapy.

Periocular Corticosteroids

Posterior sub-Tenon corticosteroid injections may be used for:

• Unilateral or asymmetric disease
• Macular edema
• Moderate inflammation

They provide high local concentrations while reducing systemic exposure.

Potential complications include:

• Elevated IOP
• Cataract
• Globe perforation
• Ptosis
• Local tissue atrophy

Oral Corticosteroids

Systemic corticosteroids may be used when:

• Disease is bilateral and severe
• Local therapy is inadequate
• There is extensive retinal vasculitis
• Sight-threatening complications are present

Long-term systemic steroid dependence should generally prompt consideration of steroid-sparing immunomodulatory therapy.

Intravitreal Corticosteroids

Intravitreal corticosteroid therapy may be considered in refractory cases, particularly when cystoid macular edema is prominent.

Potential complications include:

• Cataract
• Ocular hypertension
• Glaucoma
• Endophthalmitis

Long-acting steroid implants may also be considered in selected chronic noninfectious cases.

Immunomodulatory Therapy

Steroid-sparing therapy is appropriate when inflammation is:

• Chronic
• Recurrent
• Steroid-dependent
• Resistant to corticosteroids
• Producing unacceptable steroid-related adverse effects

Agents may include:

• Methotrexate
• Mycophenolate mofetil
• Azathioprine
• Cyclosporine
• Tacrolimus

Biologic therapy may be used in selected refractory cases under specialist supervision.

Laser and Cryotherapy

Peripheral laser photocoagulation or cryotherapy was historically used to treat:

• Snowbank-associated neovascularization
• Peripheral ischemic retina
• Persistent inflammatory exudates

Today, these treatments are used selectively, especially when neovascularization or ischemia is present.

They are not routine therapy for every case of pars planitis.

Pars Plana Vitrectomy

Pars plana vitrectomy may be useful for:

• Persistent dense vitreous opacities
• Chronic vitreous inflammation
• Epiretinal membrane
• Vitreomacular traction
• Retinal detachment
• Persistent CME in selected cases
• Diagnostic uncertainty

Vitrectomy can reduce the inflammatory load and improve media clarity.

Cystoid Macular Edema

CME is the most important cause of visual impairment in intermediate uveitis.

Treatment may involve:

• Periocular corticosteroids
• Intravitreal corticosteroids
• Systemic corticosteroids
• Immunomodulatory therapy
• Vitrectomy in selected refractory cases

OCT should be used to document response.

Cataract

Cataract may result from:

• Chronic inflammation
• Corticosteroid therapy

Cataract surgery should ideally be performed when inflammation has been well controlled for a sustained period.

Perioperative corticosteroid or other anti-inflammatory therapy is commonly used to minimize postoperative recurrence.

Glaucoma

Both open-angle and angle-closure glaucoma may occur.

Mechanisms include:

• Chronic inflammation
• Peripheral anterior synechiae
• Steroid response
• Pupillary block

IOP should be monitored carefully throughout treatment.

Follow-Up

Patients require long-term ophthalmic follow-up because intermediate uveitis often follows a chronic relapsing-remitting course.

Monitoring should include:

• Visual acuity
• Anterior chamber activity
• Vitreous cells and haze
• Peripheral retinal examination
• OCT for CME
• IOP
• Cataract progression
• Retinal neovascularization

Referral

Depending on the suspected cause, referral may be appropriate to:

• Rheumatology
• Neurology
• Infectious disease
• Pulmonology
• Retina or uveitis specialists

Patients with neurologic symptoms or findings suggestive of demyelinating disease may require evaluation for multiple sclerosis.

Prognosis

Intermediate uveitis often has a prolonged course, lasting many years, with periods of exacerbation and remission.

A minority of patients experience spontaneous resolution.

Visual prognosis depends primarily on:

• Severity of inflammation
• Development of CME
• Retinal ischemia
• Cataract
• Glaucoma
• Retinal detachment

Pars planitis generally has a favorable long-term visual prognosis when inflammation and complications are appropriately controlled.

The presence of extensive snowbanking or chronic CME is associated with a less favorable outcome.

Complications

Important complications include:

• Cystoid macular edema
• Cataract
• Secondary glaucoma
• Band keratopathy
• Epiretinal membrane
• Peripheral retinal neovascularization
• Vitreous hemorrhage
• Retinal detachment
• Chronic vitreous opacification
• Permanent visual impairment

The most important practical point is that intermediate uveitis describes the anatomic location of inflammation, whereas pars planitis specifically refers to idiopathic intermediate uveitis without an identifiable infectious or systemic cause.

Ophthalmology – Idiopathic Orbital Inflammatory Syndrome (Orbital Pseudotumor)

Basics

Description

Idiopathic orbital inflammatory syndrome (IOIS), historically called orbital pseudotumor, is a noninfectious, non-neoplastic inflammatory disorder of the orbit in which no specific local or systemic cause can be identified.

It is fundamentally a diagnosis of exclusion. Before labeling orbital inflammation as idiopathic, important mimics such as infection, thyroid eye disease, lymphoma, sarcoidosis, IgG4-related disease, granulomatosis with polyangiitis, and metastatic or primary orbital tumors must be considered.

IOIS can involve virtually any orbital structure, either alone or in combination. According to the predominant site, it may present as:

• Orbital myositis
• Dacryoadenitis
• Posterior scleritis
• Diffuse orbital fat inflammation
• Apical orbital inflammation

Some patients have diffuse disease involving several compartments simultaneously.

Epidemiology

The exact incidence and prevalence are uncertain.

IOIS accounts for a minority of orbital inflammatory disorders, historically estimated at approximately 5% of orbital disease in some series.

It most commonly presents between 40 and 60 years of age, but it can occur at virtually any age.

Children may be affected and can present somewhat differently from adults, including a greater tendency toward bilateral disease and systemic symptoms.

Risk Factors

No consistent risk factor has been established.

Some patients have coexisting autoimmune or inflammatory disorders, but in many cases the relationship is uncertain.

Reported associations include:

• Rheumatoid arthritis
• Systemic lupus erythematosus
• Crohn disease
• Ankylosing spondylitis
• Diabetes mellitus

The presence of another autoimmune disorder should prompt careful consideration of whether the orbital disease is truly idiopathic.

Genetics

No specific hereditary pattern has been established.

IOIS is generally considered sporadic.

General Prevention

There is no known primary preventive strategy because the inciting cause remains uncertain.

Prevention of complications depends on:

• Prompt recognition
• Appropriate imaging
• Exclusion of dangerous mimics
• Adequate treatment of inflammation
• Long-term follow-up when the diagnosis remains clinical rather than histologic

Pathophysiology

The underlying mechanism is incompletely understood.

IOIS is thought to represent a heterogeneous group of immune-mediated inflammatory processes involving orbital tissues.

Possible mechanisms include:

• Autoimmune inflammation
• T-cell-mediated immune activation
• Cytokine-mediated tissue injury
• Fibroinflammatory responses

Because different orbital compartments can be involved, IOIS likely represents more than one biological process rather than a single uniform disease.

Chronic or recurrent inflammation may eventually produce fibrosis and permanent restriction of orbital structures.

Etiology

By definition, there is no identifiable specific cause.

Thus, when a definite infectious, neoplastic, autoimmune, vasculitic, or systemic inflammatory disorder is discovered, the diagnosis should be revised accordingly.

Commonly Associated Conditions

Most cases are isolated.

However, patients may have or later develop systemic inflammatory disease.

Reported associations include:

• Crohn disease
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Ankylosing spondylitis
• Other autoimmune disorders

This is one reason long-term follow-up is valuable.

Diagnosis

History

The classic presentation is abrupt onset of painful orbital inflammation.

The most characteristic symptom is:

Periorbital or orbital pain.

Pain is common enough that its absence should make the clinician more cautious about the diagnosis.

Other symptoms include:

• Diplopia
• Blurred vision
• Pain with eye movement
• Eyelid swelling
• Orbital fullness
• Redness
• Proptosis
• Reduced vision in severe disease

The onset is often acute or subacute.

Important Historical Questions

A detailed history should assess for:

• Fever
• Constitutional symptoms
• Sinus disease
• Recent infection
• Immunosuppression
• Previous malignancy
• Autoimmune disease
• Thyroid disease
• Pulmonary symptoms
• Neurologic symptoms
• Previous orbital inflammation
• Trauma or surgery

A complete review of systems is particularly important because apparently idiopathic orbital inflammation may eventually prove to be part of a systemic disorder.

Pediatric Considerations

Children may have:

• Bilateral disease
• Sequential involvement of both orbits
• Fever
• Constitutional symptoms

Because orbital cellulitis is an important and potentially dangerous mimic in children, infection must be carefully excluded before corticosteroid therapy is started.

Physical Examination

A complete ophthalmic and orbital examination is required.

Possible findings include:

• Tender eyelid edema
• Pink-red eyelid erythema
• Conjunctival injection
• Chemosis
• Proptosis
• Painful restricted eye movement
• External ophthalmoplegia
• Reduced visual acuity
• Relative afferent pupillary defect if the optic nerve is involved
• Optic disc swelling
• Choroidal folds
• Choroidal detachment in posterior scleritis

The degree and location of inflammation depend on the affected orbital compartment.

Orbital Myositis

When an extraocular muscle is predominantly involved, patients often present with:

• Acute orbital pain
• Pain worsened by eye movement
• Diplopia
• Restricted ocular motility
• Localized tenderness

Unlike classic thyroid eye disease, IOIS-associated myositis may involve the muscle belly and tendon insertion.

Dacryoadenitis

Lacrimal gland involvement may cause:

• Superotemporal eyelid swelling
• Pain
• S-shaped upper eyelid contour
• Displacement of the globe
• Tenderness over the lacrimal gland

Because the lacrimal gland is a common site for lymphoma, IgG4-related disease, sarcoidosis, and epithelial tumors, the threshold for biopsy is relatively low in atypical or persistent cases.

Posterior Scleritis

Posterior scleritis may occur within the IOIS spectrum.

Features can include:

• Severe deep ocular pain
• Reduced vision
• Pain with eye movement
• Choroidal folds
• Exudative retinal detachment
• Optic disc edema

B-scan ultrasonography may demonstrate the classic T-sign, caused by fluid around the optic nerve adjacent to thickened posterior sclera.

Orbital Apex Disease

Inflammation involving the orbital apex can threaten vision.

Possible findings include:

• Optic neuropathy
• Decreased visual acuity
• Dyschromatopsia
• Relative afferent pupillary defect
• Visual field loss
• Multiple cranial nerve deficits

This presentation often requires urgent treatment and careful exclusion of alternative causes.

Diagnostic Tests and Interpretation

Laboratory Testing

No laboratory test confirms IOIS.

Laboratory studies are mainly used to identify mimicking systemic disorders.

Depending on the presentation, investigations may include:

• CBC with differential
• ESR and CRP
• ANA
• ANCA
• ACE
• Serum protein electrophoresis
• LDH
• Thyroid studies
• IgG4 level
• Infectious testing when indicated

Testing should be directed by history and examination rather than performed indiscriminately.

Imaging

All suspected cases require orbital imaging.

IOIS should not be diagnosed solely from symptoms and examination.

CT

CT may demonstrate:

• Poorly defined soft-tissue inflammation
• Orbital fat stranding
• Enlargement of extraocular muscles
• Lacrimal gland enlargement
• Apical involvement
• Contrast enhancement

Bone destruction is atypical and should raise concern for malignancy, invasive infection, or another alternative diagnosis.

MRI

MRI is particularly useful for defining soft-tissue extent.

Typical inflammatory tissue may show:

• Low to intermediate signal on T1
• Variable signal on T2
• Contrast enhancement after gadolinium

Signal characteristics can vary with the amount of active inflammation versus fibrosis.

More fibrotic disease may appear relatively low signal on T2.

Ultrasonography

Orbital ultrasonography is less frequently used today but remains useful in selected situations.

For suspected posterior scleritis it may reveal:

• Posterior scleral thickening
• Fluid in Tenon’s space
• The characteristic T-sign

Biopsy

Orbital biopsy is not mandatory in every classic case, but it is critical when the presentation is atypical.

Biopsy should be strongly considered when there is:

• Poor or incomplete steroid response
• Steroid dependence
• Recurrent disease
• Painless orbital mass
• Atypical imaging
• Bone erosion
• History of malignancy
• Persistent lacrimal gland enlargement
• Progressive disease despite treatment
• Diagnostic uncertainty

A low threshold for biopsy is particularly appropriate for lacrimal gland disease, because biopsy can often be obtained relatively safely and several important neoplasms may present with inflammatory features.

Pathological Findings

Histopathology is generally nonspecific.

Findings may include:

• Lymphocytes
• Plasma cells
• Histiocytes
• Variable fibroblast proliferation
• Variable fibrosis

The pathology should also be examined for evidence of:

• Lymphoma
• IgG4-related disease
• Granulomatous inflammation
• Vasculitis
• Infection
• Neoplasia

Differential Diagnosis

Important alternatives include:

• Orbital cellulitis
• Thyroid eye disease
• IgG4-related orbital disease
• Sarcoidosis
• Granulomatosis with polyangiitis
• Orbital lymphoma
• Metastatic tumor
• Primary orbital neoplasm
• Tolosa-Hunt syndrome
• Posterior scleritis
• Cavernous sinus disease
• Orbital fungal infection
• Lymphoproliferative disease

The differential diagnosis is especially broad in patients with recurrent, painless, or steroid-resistant disease.

Treatment

Treatment depends on severity and on confidence that infection and malignancy have been excluded.

The traditional first-line treatment is systemic corticosteroid therapy.

Corticosteroids

Oral prednisone has traditionally been started at approximately 1–1.5 mg/kg/day, followed by a gradual taper according to clinical response.

A dramatic improvement in pain and swelling within the first several days is common.

However:

A steroid response does not prove IOIS.

Lymphoma, sarcoidosis, and several other orbital disorders may temporarily improve with corticosteroids.

Therefore, steroid responsiveness should never substitute for appropriate diagnostic evaluation.

Steroid Taper

Relapse may occur during dose reduction.

A slower taper may be necessary when inflammation returns at lower doses.

Repeated rebound inflammation, prolonged steroid dependence, or incomplete response should prompt reconsideration of the diagnosis and often biopsy.

Intravenous Corticosteroids

IV corticosteroids may be used for severe disease, particularly when there is:

• Optic neuropathy
• Orbital apex involvement
• Marked vision loss
• Severe diffuse inflammation

Treatment should be closely monitored because high-dose systemic steroids have substantial metabolic and infectious risks.

NSAIDs

Nonsteroidal anti-inflammatory drugs may be useful in:

• Mild disease
• Steroid tapering
• Patients with recurrent symptoms at very low steroid doses

Some clinicians may try NSAIDs first in limited orbital myositis, although corticosteroids remain more commonly used for significant disease.

Intralesional Corticosteroids

Local corticosteroid injection, such as triamcinolone, may be considered in selected localized lesions, particularly lacrimal gland inflammation.

This is an off-label strategy and carries risks including:

• Globe perforation
• Vascular occlusion
• Elevated IOP
• Skin or fat atrophy
• Local tissue injury

It should be used only by clinicians experienced in orbital injection techniques.

Observation

Mild inflammation may occasionally resolve spontaneously.

Observation can be considered when:

• Symptoms are limited
• Vision is unaffected
• Imaging is reassuring
• Serious alternative diagnoses have been excluded

Close follow-up is still required.

Steroid-Resistant or Steroid-Dependent Disease

Patients who fail corticosteroid therapy should not simply be given progressively stronger immunosuppression without reconsidering the diagnosis.

Where feasible, tissue biopsy should precede long-term immunomodulatory treatment.

Potential steroid-sparing therapies include:

• Methotrexate
• Azathioprine
• Mycophenolate
• Cyclosporine
• Tacrolimus
• Cyclophosphamide in selected severe cases
• Biologic therapy in carefully selected refractory disease

Choice of agent depends on disease pattern, comorbidities, and specialist experience.

Orbital Radiotherapy

Low-dose orbital radiotherapy may be considered in selected cases that are:

• Corticosteroid-resistant
• Corticosteroid-dependent
• Intolerant of systemic immunosuppression

When tissue is safely accessible, biopsy should generally be obtained before radiation treatment.

Surgery

Surgery is primarily used for diagnostic biopsy, rather than complete excision.

Diffuse inflammatory tissue is often poorly demarcated and complete excision may cause:

• Diplopia
• Optic nerve injury
• Ptosis
• Sensory deficits
• Scarring

Therefore, extensive resection is usually inappropriate.

Inpatient Considerations

Most patients can be managed as outpatients.

Admission may be appropriate when:

• High-dose IV corticosteroids are required
• Severe optic neuropathy is present
• Significant comorbidities make systemic steroid therapy unsafe
• Deep orbital biopsy requires postoperative observation
• Infection cannot yet be confidently excluded

Follow-Up

Close follow-up is required during active treatment.

Monitoring should assess:

• Pain
• Visual acuity
• Pupillary function
• Color vision
• Proptosis
• Ocular motility
• Diplopia
• Optic nerve function
• Response to therapy
• Steroid-related adverse effects

Long-term follow-up is advisable even after apparent resolution.

Long-Term Monitoring

Some patients initially labeled as having idiopathic orbital inflammation later develop evidence of a specific systemic or orbital disease.

Therefore, follow-up every 6–12 months after resolution may be reasonable in recurrent or atypical cases.

Particular attention should be paid to:

• Recurrence
• Contralateral orbital involvement
• New systemic inflammatory symptoms
• New lymphadenopathy
• Persistent lacrimal gland enlargement

Patient Education

Patients should understand that IOIS is often a clinical diagnosis of exclusion.

They should be told that:

• Symptoms may recur
• Additional testing or biopsy may eventually become necessary
• Corticosteroid response does not completely exclude tumor or systemic disease
• New visual loss, worsening pain, or recurrent proptosis requires prompt reassessment

Patients receiving corticosteroids should also be counseled about potential complications including hyperglycemia, hypertension, infection, mood changes, osteoporosis, and gastrointestinal effects.

Prognosis

Most patients respond well to therapy and recover without major permanent visual dysfunction.

The prognosis is less favorable when there is:

• Orbital apex involvement
• Optic neuropathy
• Multiple recurrences
• Marked fibrosis
• Delayed diagnosis
• Incomplete response to corticosteroids

Chronic inflammation may produce permanent orbital fibrosis and restriction.

Complications

Potential complications include:

• Permanent diplopia
• Restrictive ophthalmoplegia
• Orbital fibrosis
• Optic neuropathy
• Permanent visual loss
• Ptosis
• Proptosis
• Recurrence
• Steroid toxicity
• Immunosuppressive treatment complications
• Surgical biopsy complications such as hemorrhage, infection, diplopia, sensory loss, ptosis, or rarely visual loss

The most important diagnostic principle is that orbital pseudotumor should remain a diagnosis of exclusion—atypical, recurrent, painless, or steroid-resistant disease warrants renewed investigation and often biopsy.