Ophthalmology – Non-Physiologic Vision Loss

Basics

Description

Non-physiologic vision loss refers to visual symptoms that are not fully explained by identifiable ocular or neurologic disease.

Modern preferred terms include:

• Functional vision disorder
• Functional visual loss
• Non-organic visual loss

Older terms such as “hysterical” or “psychosomatic” are generally avoided.

Symptoms may arise in different contexts:

• Functional neurologic/psychogenic symptoms – symptoms are experienced as genuine and are not consciously produced
• Factitious disorder – symptoms are intentionally produced to assume a sick role
• Malingering – symptoms are intentionally produced for external gain

A functional component can also coexist with true organic disease.

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Epidemiology

Functional visual symptoms account for a small but important proportion of ophthalmic presentations.

Reported prevalence is approximately:

1–5% of patients presenting with visual complaints

It is seen particularly in:

• Children
• Adolescents
• Young adults

Functional symptoms are common in children and younger adults.

Historically, malingering has been reported more often in adults.

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Risk Factors and Associations

Potential associated factors include:

• Psychological stress
• Family or school conflict
• Anxiety
• Depression
• Trauma
• Major life changes
• Secondary gain
• Psychiatric illness
• Functional neurologic disorder

However:

The absence of an obvious psychological stressor does not exclude functional vision disorder.

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Associated Psychiatric Conditions

Some patients have coexisting psychiatric conditions, including:

• Anxiety disorders
• Depression
• Somatic symptom disorder
• Functional neurologic disorder
• Illness anxiety disorder
• Body dysmorphic disorder

Not every patient has a diagnosable psychiatric disorder.

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Pathophysiology

There is no structural lesion that adequately explains the visual deficit.

Symptoms may affect:

• Visual acuity
• Visual fields
• Ocular motility
• Accommodation
• Pupillary function
• Eyelid position
• Sensation

The modern understanding of functional neurologic symptoms emphasizes abnormal brain network function rather than deliberate symptom production.

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Possible Manifestations

Functional visual symptoms may include:

• Monocular or binocular visual loss
• Visual field constriction
• Central scotoma
• Diplopia
• Abnormal eye movements
• Spasm of the near reflex
• Functional ptosis
• Blepharospasm
• Altered facial or corneal sensation

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Diagnosis

The diagnosis should be based on positive examination findings showing internal inconsistency or preserved visual function, not simply on the absence of identifiable disease.

Before diagnosing functional visual loss, important organic causes must be excluded.

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History

Important questions include:

• Exact nature of visual symptoms
• Onset and duration
• Monocular versus binocular involvement
• Degree of functional disability
• Variability of symptoms
• Situational triggers
• School, work, or family stressors
• Associated neurologic symptoms
• Previous ocular or neurologic disease
• Medications
• Psychiatric history
• Potential external incentives

Observe:

• Affect
• Behavior
• Consistency between reported disability and observed function

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Important Clinical Principle

A patient’s emotional response to visual loss is not diagnostic.

Some patients with severe organic disease may appear unconcerned, while some patients with functional symptoms may be extremely distressed.

Diagnosis must rest on objective examination findings.

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Physical Examination

A complete ophthalmic examination should include:

• Best-corrected visual acuity
• Pupillary examination
• Color vision
• Ocular motility
• Alignment
• Slit-lamp examination
• Dilated fundus examination
• Visual fields

Look carefully for subtle organic disease.

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Functional Visual Acuity Loss

Visual acuity may appear dramatically reduced despite preserved visual behavior.

Possible patterns include:

• Similar acuity at different testing distances
• Better near than expected from distance acuity
• Improved performance when testing is altered or distraction is introduced
• Inconsistent responses during repeated testing

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Testing Visual Acuity

Start With the Smallest Line

Instead of beginning with large letters, start near the expected acuity level.

This may reveal unexpectedly good performance before the patient anticipates the test strategy.

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Near Visual Acuity

Near acuity may be disproportionately better than distance acuity.

For example:

• Severe claimed distance loss
• Relatively preserved reading ability

This discrepancy can support a functional component.

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Fogging Techniques

In suspected unilateral functional loss, the “good” eye can be blurred or fogged while binocular acuity is tested.

If the patient continues to read well, the supposedly poor eye must be contributing vision.

This is one of the most useful objective techniques.

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Prism Dissociation Test

A prism placed before one eye may produce two images if both eyes are seeing.

This can demonstrate preserved vision in an eye claimed to be profoundly impaired.

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Stereopsis

Preserved stereopsis provides evidence that both eyes have useful vision.

The degree of stereopsis can estimate a minimum level of binocular visual function.

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Optokinetic Nystagmus

An optokinetic drum or strip can elicit reflexive eye movements.

Presence of optokinetic nystagmus suggests at least moderate visual function.

It is useful particularly when cooperation is limited.

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Mirror Test

A large mirror can be moved or tilted in front of the patient.

Patients with useful vision often reflexively track their reflected image.

This test is particularly useful in young children.

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Menace and Navigation

Observe spontaneous behavior such as:

• Avoiding obstacles
• Reaching accurately for objects
• Navigating through the room
• Looking toward visual stimuli

Functional behavior inconsistent with claimed profound blindness is diagnostically useful.

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Visual Field Loss

The most common functional visual field pattern is:

Concentric constriction

sometimes described as:

• Tunnel vision
• Tubular visual field

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Tubular Visual Field

In true physiologic visual field constriction, the field should enlarge as testing distance increases.

In functional visual loss, the patient may report essentially the same field diameter at:

• 1 meter
• 2 meters
• Greater distances

This produces a geometrically impossible “tubular” field.

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Tangent Screen Testing

Tangent screen testing can demonstrate:

• Nonexpanding visual field with increased testing distance
• Inconsistent field boundaries

These findings strongly support a nonphysiologic pattern.

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Goldmann Perimetry

Possible functional findings include:

• Crossing isopters
• Spiraling isopters
• Inconsistent field size
• Marked variability during the same examination

These findings should be interpreted cautiously because poor attention can also cause inconsistent fields.

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Automated Perimetry

Automated fields may show:

• Poor reproducibility
• Cloverleaf patterns
• High false-negative responses
• Implausible defects

However:

An unreliable automated field is not by itself diagnostic of functional visual loss.

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Monocular Hemianopia

A monocular hemianopic defect that respects the vertical meridian is anatomically implausible because postchiasmal lesions cause homonymous defects involving corresponding halves of both eyes.

Such patterns may suggest functional loss.

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Monocular Diplopia

Functional diplopia may be suspected when:

• Diplopia persists after occlusion of the other eye
• Refraction, corneal, lenticular, and retinal causes are excluded
• Images have unusual or inconsistent separation

However, organic monocular diplopia must first be excluded.

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Ocular Motility Abnormalities

Functional ocular motor findings may include:

• Apparent horizontal gaze palsy
• Apparent vertical gaze palsy
• Convergence insufficiency
• Spasm of near reflex
• Voluntary nystagmus

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Spasm of the Near Reflex

Characterized by episodic:

• Convergence
• Accommodation
• Miosis

This may mimic:

• Bilateral abduction weakness
• Sixth nerve palsy

The presence of pupillary constriction during apparent abduction limitation is an important clue.

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Voluntary Nystagmus

Voluntary nystagmus is typically:

• High frequency
• Low amplitude
• Horizontal
• Sustained only briefly

It may be reproduced by some healthy individuals.

It can resemble:

• Ocular flutter
• Opsoclonus

but lacks associated neurologic disease.

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Functional Ptosis

Features may include:

• Active orbicularis contraction
• Brow depression
• Variable eyelid position
• Improvement with distraction

True neurologic and myogenic ptosis must be excluded.

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Pupils

A major clue to organic versus functional visual loss is the pupillary examination.

Profound unilateral optic nerve dysfunction should generally produce:

A relative afferent pupillary defect

If a patient claims severe unilateral visual loss with:

• Normal pupils
• No RAPD

then profound optic neuropathy or extensive retinal disease becomes less likely.

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Sensory Symptoms

Functional sensory symptoms may include:

• Reduced corneal sensation
• Facial numbness
• Hypersensitivity

These may not respect known neuroanatomic distributions.

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Objective Testing

Objective studies can be useful when the diagnosis remains uncertain.

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Visual Evoked Potentials

Visual evoked potentials may demonstrate preserved cortical visual responses.

Limitations include:

• Variability
• Dependence on attention and fixation
• Poor specificity

A normal VEP can support preserved visual pathway function but does not prove malingering or a functional disorder.

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Electroretinography

ERG may help exclude retinal disease.

Useful tests include:

• Full-field ERG
• Multifocal ERG

These may help identify subtle retinal disorders that can mimic functional visual loss.

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Optical Coherence Tomography

OCT can help identify subtle:

• Macular disease
• Retinal nerve fiber layer loss
• Ganglion cell abnormalities
• Optic neuropathy

A structurally normal OCT supports—but does not by itself prove—a functional diagnosis.

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Neuroimaging

MRI may be appropriate when:

• Visual loss is unexplained
• Field loss is reproducible
• There are neurologic signs
• Optic neuropathy or retrochiasmal disease is suspected

Imaging should be directed at the suspected anatomic pathway.

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Functional Overlay

Functional visual symptoms can coexist with organic disease.

This is sometimes called:

Functional overlay

Examples include:

• Mild optic neuropathy with claimed complete blindness
• Small retinal lesion with disproportionately severe field loss
• True amblyopia with additional functional visual symptoms

Therefore:

Finding some organic disease does not exclude a functional component, and diagnosing functional symptoms does not eliminate the possibility of coexisting organic disease.

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Differential Diagnosis

Always exclude subtle or early organic disease.

Important mimics include:

• Optic neuritis
• Ischemic optic neuropathy
• Leber hereditary optic neuropathy
• Compressive optic neuropathy
• Occipital lesions
• Migraine aura
• Occipital epilepsy
• Retinal dystrophies
• Macular dystrophies
• Acute zonal occult outer retinopathy
• Paraneoplastic retinopathy
• Paraneoplastic optic neuropathy
• Retinal toxicity
• Inflammatory retinal disease
• Cerebral infarction
• Intracranial mass

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Important Diagnostic Principle

The diagnosis should preferably be made by demonstrating:

What the patient can see

rather than merely showing that no lesion was found.

Positive signs of preserved visual function are much more reassuring and diagnostically robust.

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Functional Vision Disorder vs Malingering

These should not be considered synonymous.

Functional Vision Disorder

Symptoms are:

• Experienced as real
• Not consciously produced
• Often associated with stress or functional neurologic symptoms

Malingering

Symptoms are:

• Intentionally produced
• Motivated by external gain

Examples of external gain include:

• Financial compensation
• Avoiding work
• Legal advantage
• Obtaining drugs or services

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Factitious Disorder

Factitious symptoms are intentionally produced, but the primary motivation is:

• Assuming the sick role

rather than obvious external reward.

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Treatment

Reassurance

The mainstay of treatment for functional visual loss is:

Supportive, non-confrontational reassurance

Explain that:

• The examination shows that the visual pathways are functioning.
• No evidence of permanent ocular or neurologic damage has been identified.
• Recovery is expected.

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Positive Explanation

A useful approach is to frame the diagnosis positively:

• “Your visual system is structurally healthy.”
• “The testing shows that your eyes can see better than the initial measurements suggested.”
• “This type of visual problem often improves.”

Avoid implying that symptoms are fabricated.

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Avoid Confrontation

Do not accuse the patient of:

• Pretending
• Lying
• Seeking attention

Even when malingering is suspected, confrontation usually:

• Damages the therapeutic relationship
• Reduces cooperation
• Makes follow-up more difficult

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Children

In children, treatment often consists of:

• Reassurance
• Reducing anxiety
• Normalizing activity
• School reintegration
• Family support

Most children improve without intensive intervention.

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Psychological or Psychiatric Referral

Consider referral when:

• Symptoms persist
• Stressors are significant
• Anxiety or depression is suspected
• Functional neurologic symptoms are present
• There is major psychosocial dysfunction
• There is concern for self-harm

Referral should be presented supportively rather than as proof that symptoms are “imaginary.”

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Psychotherapy

Psychotherapy may help selected patients, particularly when there is:

• Functional neurologic disorder
• Anxiety
• Trauma
• Depression
• Persistent symptoms

Approaches may include:

• Cognitive behavioral therapy
• Stress management
• Treatment of underlying psychiatric conditions

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Safety Concerns

Urgent psychiatric or emergency referral is required when there is:

• Suicidal ideation
• Risk of self-harm
• Threats toward others
• Severe psychiatric decompensation

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Follow-Up

Reevaluation is appropriate if symptoms:

• Persist
• Worsen
• Change pattern
• Become anatomically consistent with organic disease

Repeat examination is important because early organic disease may occasionally be subtle.

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Prognosis

The prognosis is generally favorable.

More than half of patients improve or experience complete resolution.

Children often have particularly good recovery.

Recovery may occur:

• Rapidly
• Over several weeks
• Gradually over months

Persistent symptoms warrant reassessment for both:

• Functional contributors
• Previously occult organic disease

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Ophthalmology Pearls

• Functional vision disorder is diagnosed by positive evidence of preserved visual function, not simply by a normal eye exam.
• Modern terminology favors functional visual loss / functional vision disorder rather than “hysterical” vision loss.
• Functional symptoms are not the same as malingering.
• Malingering involves intentional symptom production for external gain; functional symptoms are not consciously produced.
• A severe unilateral claimed visual loss with a normal pupillary examination and no RAPD should raise suspicion for a non-organic component.
• Useful tests include fogging, prism dissociation, stereopsis, optokinetic nystagmus, mirror testing, and observation of navigation.
• A tubular visual field that does not enlarge with increased testing distance is strongly nonphysiologic.
• Crossing or spiraling isopters can suggest functional field loss.
• Always exclude subtle organic disease such as optic neuritis, retinal dystrophy, LHON, macular disease, or cerebral pathology.
• Functional symptoms can coexist with true ocular disease—functional overlay is real and important.
• Management should be supportive and non-confrontational, with reassurance that the visual system is capable of normal function.
• Persistent or worsening symptoms require reevaluation rather than assuming the diagnosis is permanently settled.

Ophthalmology – Non-Granulomatous Anterior Uveitis

Basics

Description

Non-granulomatous anterior uveitis (NGAU) is inflammation predominantly involving the anterior uveal tract:

• Iris → iritis
• Ciliary body → cyclitis
• Both → iridocyclitis

Typical symptoms include:

• Ocular pain
• Redness
• Photophobia
• Blurred vision

It may be:

• Infectious
• Immune-mediated
• Associated with systemic disease
• Limited to the eye
• Idiopathic

A classic slit-lamp feature is the presence of small, fine keratic precipitates (KPs) rather than the large “mutton-fat” KPs more typical of granulomatous inflammation.

Epidemiology

Reported incidence is approximately:

8–17 cases per 100,000 population

Important epidemiologic associations include:

• HLA-B27-associated uveitis – more common in younger adults, classically males with spondyloarthropathy
• Behçet disease – more common in populations from the Middle East and parts of Asia
• JIA-associated uveitis – more common in children, particularly girls with certain JIA phenotypes

Risk Factors

Important risk factors include:

• Ocular trauma
• HLA-B27 positivity
• HLA-B51 positivity
• Autoimmune disease
• Smoking
• Previous episodes of uveitis
• Certain infections
• Selected medications

Genetics

HLA-B27

Associated with:

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

HLA-B27-associated anterior uveitis is typically:

• Acute
• Unilateral
• Recurrent
• Painful
• Often associated with marked anterior chamber inflammation

HLA-B51

Associated particularly with:

Behçet disease

which may cause:

• Recurrent anterior uveitis
• Hypopyon
• Retinal vasculitis
• Panuveitis

Etiology

Common causes include:

• Idiopathic
• HLA-B27-associated disease
• JIA
• Herpetic anterior uveitis
• Fuchs uveitis syndrome
• Posner-Schlossman syndrome
• Behçet disease
• TINU syndrome
• Trauma
• Lens-induced inflammation
• UGH syndrome
• Drug-induced uveitis

A substantial proportion of cases remain idiopathic.

Classification by Clinical Course

Using standard uveitis terminology:

Acute

• Sudden onset
• Limited duration

Recurrent

• Repeated episodes
• Separated by periods of inactivity without treatment

Chronic

• Persistent inflammation
• Relapse soon after treatment is stopped

History

A targeted history is essential.

Ask about:

• Onset
• Duration
• Laterality
• Previous episodes
• Trauma
• Previous ocular surgery
• Previous treatment
• Response to corticosteroids
• Medication use
• Infectious exposures
• Autoimmune disease
• STI risk
• Intravenous drug use

Review of Systems

Constitutional

Ask about:

• Fever
• Chills
• Night sweats
• Weight loss

These may suggest:

• Infection
• Tuberculosis
• Malignancy
• Systemic inflammatory disease

Skin and Mucosal Symptoms

Ask about:

• Oral ulcers
• Genital ulcers
• Psoriatic plaques
• Erythema nodosum
• Vitiligo
• Rash
• Herpetic lesions

Important associations include:

• Behçet disease
• Psoriasis
• Reactive arthritis
• Sarcoidosis
• Syphilis
• VKH

Musculoskeletal Symptoms

Ask about:

• Inflammatory back pain
• Sacroiliac pain
• Morning stiffness
• Peripheral arthritis
• Enthesitis
• Tendon pain

These suggest:

• Ankylosing spondylitis
• Reactive arthritis
• Psoriatic arthritis
• IBD-associated arthritis

Gastrointestinal Symptoms

Ask about:

• Chronic diarrhea
• Bloody stool
• Abdominal pain

These may suggest:

• Inflammatory bowel disease
• Reactive arthritis

Genitourinary Symptoms

Ask about:

• Urethritis
• Genital ulcers
• Dysuria
• Epididymitis

These may be relevant to:

• Reactive arthritis
• Behçet disease
• Syphilis
• HSV

Renal Symptoms

Consider:

• Abnormal urinalysis
• Elevated creatinine
• Systemic symptoms

in suspected:

Tubulointerstitial nephritis and uveitis (TINU)

Neurologic Symptoms

Ask about:

• Headache
• Meningitic symptoms
• Cranial nerve palsies
• Sensory or motor symptoms

Possible associations include:

• Sarcoidosis
• Behçet disease
• Lyme disease
• Multiple sclerosis
• VKH
• Lymphoma

Physical Examination

External Examination

Assess:

• Skin
• Joints
• Oral cavity
• Lymph nodes
• Neurologic findings

Pupils

Possible findings include:

• Miosis
• Irregular pupil
• Posterior synechiae
• Seclusio pupillae

A fixed irregular pupil may indicate extensive synechiae.

Intraocular Pressure

IOP may be:

• Low from ciliary body shutdown
• Normal
• Elevated from trabeculitis, inflammation, or steroid response

Elevated IOP is particularly associated with:

• Herpetic anterior uveitis
• Fuchs uveitis syndrome
• Posner-Schlossman syndrome

Gonioscopy

Gonioscopy may reveal:

• Peripheral anterior synechiae
• Angle KPs
• Secondary angle closure
• Abnormal angle vessels

In Fuchs uveitis syndrome, abnormal angle vessels may predispose to bleeding during surgery.

Conjunctiva and Sclera

Typical finding:

Ciliary flush

Associated episcleritis or scleritis may suggest systemic inflammatory disease.

Cornea

Important findings include:

• Small punctate KPs
• Fine stellate KPs
• Corneal edema
• Reduced corneal sensation in herpetic disease
• Band keratopathy in chronic uveitis, especially JIA

Keratic Precipitates

In NGAU, KPs are usually:

• Fine
• Small
• Punctate
• Stellate

Large greasy “mutton-fat” KPs suggest granulomatous inflammation, although overlap can occur.

Iris Findings

Look for:

• Posterior synechiae
• Iris atrophy
• Transillumination defects
• Heterochromia
• Iris nodules
• Pupillary membranes

Posterior Synechiae

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

Complications include:

• Irregular pupil
• Seclusio pupillae
• Iris bombe
• Secondary angle closure

Cycloplegics help reduce this risk.

Hypopyon

Hypopyon may occur in:

• HLA-B27-associated uveitis
• Behçet disease
• Severe infectious uveitis
• Masquerade syndromes

A hypopyon should prompt careful consideration of infection before escalating immunosuppression.

Hyphema

Possible causes in an inflamed eye include:

• Herpetic disease
• Fuchs uveitis syndrome
• UGH syndrome
• Juvenile xanthogranuloma
• Neovascularization
• Leukemia

Anterior Chamber Cell Grading

Using SUN criteria with a 1 × 1 mm slit beam:

• 0: <1 cell
• 0.5+: 1–5 cells
• 1+: 6–15 cells
• 2+: 16–25 cells
• 3+: 26–50 cells
• 4+: >50 cells

Anterior Chamber Flare

Typical grading:

• 0: none
• 1+: faint
• 2+: moderate
• 3+: marked
• 4+: intense, often with fibrin

Lens and Anterior Vitreous

Look for:

• Posterior subcapsular cataract
• Lenticular precipitates
• Retained lens material
• IOL-related irritation
• Cyclitic membrane
• Anterior vitreous cells

Dilated Fundus Examination

A complete dilated examination is essential to exclude posterior disease.

Look for:

• Vitritis
• CME
• Retinal vasculitis
• Toxoplasmosis scars
• Retinal necrosis
• Choroidal lesions
• Snowballs/snowbanking
• Intraocular foreign body
• Retinal or choroidal infiltrates

Diagnostic Workup

A laboratory workup should be targeted, not indiscriminate.

Workup is particularly indicated when disease is:

• Bilateral
• Recurrent
• Severe
• Chronic
• Atypical
• Poorly responsive to treatment
• Associated with systemic symptoms

Common Initial Tests

Depending on presentation, consider:

• Syphilis serology
• TB testing
• HLA-B27
• Chest imaging for sarcoidosis/TB
• Lyme testing only when epidemiologically appropriate

HLA-B27 Testing

Useful particularly in:

• Recurrent acute unilateral anterior uveitis
• Young adults
• Inflammatory back pain
• Known spondyloarthropathy

JIA Evaluation

In a child with suspected JIA-associated uveitis, consider:

• ANA
• Rheumatologic assessment

JIA uveitis may be asymptomatic, making screening crucial.

TINU Evaluation

If TINU is suspected:

• Serum creatinine
• Urinalysis
• Urine β2-microglobulin

may be useful.

Renal consultation may be appropriate.

Vasculitis / Scleritis Workup

If uveitis is associated with:

• Scleritis
• Peripheral ulcerative keratitis
• Sinopulmonary disease
• Systemic vasculitic symptoms

consider targeted testing such as:

• ANCA
• ESR
• CRP

Imaging

OCT

OCT is useful for detecting and monitoring:

• Cystoid macular edema
• Epiretinal membrane
• Macular structural damage

Fluorescein Angiography

Useful when there is concern for:

• CME
• Retinal vasculitis
• Posterior segment inflammatory disease

B-Scan Ultrasonography

Useful when media opacity prevents visualization of the posterior segment.

Anterior Chamber or Vitreous Sampling

May be considered in selected cases for:

• HSV PCR
• VZV PCR
• CMV PCR
• Toxoplasma PCR
• Cytology for lymphoma or leukemia

This is particularly useful in atypical or treatment-resistant disease.

Differential Diagnosis

Important causes include:

• HLA-B27-associated anterior uveitis
• Ankylosing spondylitis
• Psoriatic arthritis
• IBD-associated uveitis
• Reactive arthritis
• JIA
• HSV
• VZV
• CMV
• Posner-Schlossman syndrome
• Fuchs uveitis syndrome
• Behçet disease
• TINU
• Traumatic iritis
• Lens-induced uveitis
• UGH syndrome
• Drug-induced uveitis
• Intraocular lymphoma
• Idiopathic anterior uveitis

Other infectious or granulomatous diseases such as syphilis, TB, and sarcoidosis can also present with anterior inflammation and should be considered when appropriate.

Treatment

First-Line – Topical Corticosteroids

The mainstay of treatment for noninfectious anterior uveitis is:

Topical corticosteroid therapy

Common choices include:

• Prednisolone acetate 1%
• Difluprednate 0.05%

Frequency depends on severity.

Severe inflammation may initially require very frequent dosing, then gradual tapering according to clinical response.

Important Treatment Principle

Do not taper corticosteroids based only on symptoms.

Taper according to:

• Anterior chamber cell count
• Flare
• Clinical course

Tapering too quickly may cause recurrence.

Cycloplegics

Cycloplegic or mydriatic agents are used to:

• Reduce ciliary spasm
• Relieve pain
• Prevent posterior synechiae
• Break fresh synechiae

Options include:

• Homatropine
• Cyclopentolate
• Atropine in severe disease

Herpetic Anterior Uveitis

If HSV or VZV is suspected, treatment generally includes:

• Systemic antiviral therapy
• Topical corticosteroid under antiviral cover
• IOP-lowering therapy when needed

Steroid monotherapy should be avoided when active herpetic disease is suspected.

Periocular Steroids

Sub-Tenon corticosteroid injection may be considered for:

• Chronic uveitis
• Significant CME
• Poor response to topical therapy
• Poor adherence

Monitor closely for:

• Steroid-induced ocular hypertension
• Cataract

Systemic Corticosteroids

Oral prednisone may be needed when inflammation is:

• Severe
• Bilateral
• Posteriorly extensive
• Refractory to topical/local therapy

Prolonged high-dose therapy should generally be avoided when steroid-sparing therapy is appropriate.

Steroid-Sparing Immunomodulatory Therapy

Consider when:

• Disease is chronic
• Relapses occur during steroid taper
• Long-term systemic corticosteroid is required
• Steroid toxicity develops

Options include:

• Methotrexate
• Mycophenolate mofetil
• Azathioprine
• Cyclosporine
• Tacrolimus
• Biologic therapy

These are usually managed with rheumatology or a uveitis specialist.

Biologic Therapy

Biologic agents, especially TNF-alpha inhibitors, may be particularly useful in:

• JIA-associated uveitis
• Behçet disease
• Spondyloarthropathy-associated uveitis
• Refractory noninfectious uveitis

Systemic infection screening is essential before biologic therapy.

Monitoring During Immunosuppression

Depending on the medication, monitoring may include:

• CBC
• Liver function
• Renal function
• Blood pressure
• Infection screening

Monitoring intervals depend on the specific drug and specialist protocol.

Glaucoma Management

Glaucoma may result from:

• Inflammatory trabeculitis
• Peripheral anterior synechiae
• Pupillary block
• Steroid response

Treatment may require:

• IOP-lowering drops
• Glaucoma specialist referral
• Surgery if uncontrolled

Cataract

Posterior subcapsular cataract may result from:

• Chronic inflammation
• Corticosteroid exposure

Cataract surgery is usually planned when inflammation has been well controlled.

Cystoid Macular Edema

CME is a major cause of reduced vision.

Treatment may include:

• Topical steroids
• Periocular steroid
• Intravitreal steroid
• Systemic anti-inflammatory treatment
• Steroid-sparing immunomodulation

Surgery

Possible procedures include:

• Cataract extraction
• Glaucoma surgery
• Vitrectomy in selected cases

Surgery is ideally performed when inflammation is well controlled.

Referral

Consider referral to:

• Uveitis specialist for recurrent or atypical disease
• Rheumatology for HLA-B27/JIA/systemic inflammatory disease
• Gastroenterology for IBD
• Pulmonology for sarcoidosis
• Retina specialist for CME or posterior involvement
• Glaucoma specialist for uncontrolled IOP

Follow-Up

During active inflammation, follow-up may initially be:

• Weekly
• Every 1–2 weeks

depending on severity.

Once the anterior chamber reaction improves and steroid dosing decreases, visits may be spaced out.

Patient Monitoring

Monitor:

• Visual acuity
• Anterior chamber cells
• Flare
• IOP
• Posterior synechiae
• Cataract
• CME
• Response to steroid taper

Prognosis

Prognosis depends on:

• Etiology
• Severity
• Recurrence
• Chronicity
• Treatment response
• Development of complications

Many acute unilateral cases have an excellent prognosis with appropriate treatment.

Chronic or recurrent disease may lead to permanent visual impairment.

Complications

Important complications include:

• Posterior synechiae
• Seclusio pupillae
• Iris bombe
• Secondary angle closure
• Steroid-induced glaucoma
• Chronic inflammatory glaucoma
• Posterior subcapsular cataract
• Cystoid macular edema
• Band keratopathy
• Hypotony in severe chronic disease

Ophthalmology Pearls

• NGAU = pain + photophobia + ciliary flush + anterior chamber cells/flare.
• Fine or stellate KPs favor a non-granulomatous pattern.
• HLA-B27 uveitis is typically acute, unilateral, recurrent, and can be severe with hypopyon.
• Anterior uveitis with high IOP should raise suspicion for herpetic disease, Fuchs uveitis syndrome, or Posner-Schlossman syndrome.
• Cycloplegics relieve pain and help prevent posterior synechiae.
• Always perform a dilated fundus examination to exclude posterior involvement.
• Laboratory testing should be targeted to the clinical picture, not ordered indiscriminately.
• Do not suppress presumed infectious uveitis with corticosteroids alone.
• CME, cataract, and glaucoma are major causes of long-term visual loss.
• Recurrent or steroid-dependent disease should prompt consideration of systemic immunomodulatory therapy.

Ophthalmology – Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)

Basics

Description

Non-arteritic anterior ischemic optic neuropathy (NAION) is an acute ischemic optic neuropathy caused by impaired perfusion of the anterior optic nerve head.

It classically presents with:

• Sudden
• Painless
• Unilateral visual loss
• Optic disc edema
• Relative afferent pupillary defect
• Characteristic visual field loss

NAION is one of the most common acute optic neuropathies in older adults.

Epidemiology

NAION most commonly occurs after age 50.

Reported incidence is approximately:

2–10 cases per 100,000 persons older than 50 years per year

Thousands of new cases occur annually in the United States.

It can also occur in younger adults, particularly when vascular or anatomic risk factors are present.

Risk Factors

Important associated risk factors include:

• Hypertension
• Diabetes mellitus
• Hyperlipidemia
• Obstructive sleep apnea
• Nocturnal hypotension
• Systemic hypoperfusion
• Small-vessel vascular disease
• Smoking
• Migraine in some patients

Anatomic susceptibility also plays a major role.

Medication Associations

Drugs reported in association with NAION include:

• Amiodarone
• Phosphodiesterase-5 inhibitors used for erectile dysfunction

The relationship between erectile dysfunction medications and NAION remains uncertain, and a direct causal relationship has not been definitively established.

Genetics

No consistent Mendelian genetic cause of typical NAION has been established.

Familial cases are uncommon.

Pathophysiology

NAION is believed to result from transient or sustained hypoperfusion of the:

Short posterior ciliary arterial circulation supplying the optic nerve head

This produces ischemia of the retrolaminar/prelaminar optic nerve.

Subsequent:

• Axonal swelling
• Optic disc edema
• Compartment-like crowding

may worsen ischemia in an already anatomically crowded disc.

“Disc at Risk”

The classic structural predisposition is a:

Small, crowded optic nerve head with a very small or absent physiologic cup

This is commonly called the:

“Disc at risk.”

The fellow eye often demonstrates this appearance.

A crowded disc may permit initial axonal swelling to compress adjacent capillaries and worsen ischemic damage.

Systemic Hypoperfusion

NAION is often first noticed on awakening.

This has led to the hypothesis that:

• Physiologic nocturnal blood pressure reduction
• Excessive nighttime antihypertensive effect
• Obstructive sleep apnea

may reduce optic nerve perfusion in susceptible patients.

However, blood pressure management must be individualized because uncontrolled hypertension is itself harmful.

Commonly Associated Conditions

Common associations include:

• Diabetes mellitus
• Hypertension
• Hyperlipidemia
• Obstructive sleep apnea
• Atherosclerotic vascular disease
• Migraine

Diagnosis

NAION is primarily a clinical diagnosis.

The typical patient has:

Acute painless monocular visual loss + swollen optic disc + corresponding visual field defect

History

Typical features include:

• Sudden visual loss in one eye
• Usually painless
• Often noticed on awakening
• Stable or mildly progressive decline over hours to days

Patients may describe:

• Blurred vision
• Dark area in the visual field
• Loss of upper or lower half of vision
• Reduced contrast
• Color desaturation

Pain

Significant orbital pain or pain with eye movement is unusual.

Its presence should raise consideration of:

• Optic neuritis
• Orbital disease
• Other inflammatory optic neuropathies

Visual Acuity

Visual acuity is variable.

Patients may retain relatively good central acuity despite a large visual field defect, or may develop marked central visual loss if the papillomacular fibers are affected.

Pupillary Examination

A unilateral or asymmetric case usually produces:

Relative afferent pupillary defect (RAPD)

Color Vision

Color vision is commonly reduced.

Patients may demonstrate:

• Dyschromatopsia
• Red desaturation
• Reduced color discrimination

The deficit often corresponds roughly with the degree of optic nerve dysfunction.

Visual Field Defect

The classic visual field abnormality is:

Altitudinal field loss

Most often:

• Inferior altitudinal defect

but superior altitudinal loss can also occur.

Other patterns include:

• Arcuate defects
• Central defects
• Nasal steps
• Generalized depression

Optic Disc Appearance

During the acute phase, examination shows:

• Optic disc edema
• Often segmental swelling
• Hyperemic or occasionally pale disc
• Peripapillary splinter or flame hemorrhages

Disc hemorrhages are common and support the diagnosis.

Fellow Eye

The fellow optic nerve commonly shows:

• Small disc
• Minimal or absent cup
• Crowded appearance

This is the classic disc at risk.

Critical Alert – Exclude Giant Cell Arteritis

In an older patient with acute ischemic optic neuropathy, the most important immediate distinction is between:

• NAION
• Arteritic anterior ischemic optic neuropathy (AAION) from giant cell arteritis

AAION is an ophthalmic emergency because the fellow eye can become involved rapidly, causing bilateral severe visual loss.

Symptoms Suggesting Giant Cell Arteritis

Ask specifically about:

• New headache
• Scalp tenderness
• Jaw claudication
• Constitutional symptoms
• Fever
• Weight loss
• Polymyalgia rheumatica symptoms
• Transient visual loss
• Diplopia

Absence of systemic symptoms does not completely exclude GCA.

NAION vs Arteritic AION

Features more suggestive of NAION include:

• Moderately reduced vision
• Hyperemic swollen disc
• Disc hemorrhages
• Crowded fellow disc
• Typical vascular risk factors

Features more suggestive of GCA/AAION include:

• Profound visual loss
• Chalky-white or pallid disc edema
• Older age
• Systemic GCA symptoms
• Markedly elevated inflammatory markers
• Retinal or choroidal ischemia

Laboratory Evaluation

Routine laboratory testing is not necessary for every classic NAION case.

However, in patients in whom GCA is possible—especially those over 50—obtain urgently:

• ESR
• CRP
• CBC with platelet count

If clinical suspicion remains high, management for GCA should not be delayed while waiting for confirmatory testing.

Visual Field Testing

Automated or kinetic perimetry is useful for:

• Documenting the baseline defect
• Monitoring recovery
• Demonstrating altitudinal or arcuate loss

Optical Coherence Tomography

OCT can document:

Acute stage

• RNFL thickening from disc edema

Chronic stage

• RNFL thinning
• Ganglion cell loss
• Optic atrophy

OCT is useful for structural follow-up but does not itself establish the vascular cause.

Fundus Photography

Useful for documenting:

• Optic disc edema
• Peripapillary hemorrhage
• Resolution of swelling
• Subsequent optic atrophy

Fluorescein Angiography

Fluorescein angiography is not usually necessary in straightforward cases.

It may show:

• Delayed disc filling
• Disc leakage

It can be useful when the diagnosis is uncertain or another retinal/choroidal ischemic process is suspected.

Neuroimaging

MRI is not routinely required in classic NAION.

Consider MRI of the brain and orbits when:

• Age is atypical
• Disc edema persists unusually long
• Progressive visual loss continues
• Pain is prominent
• Neurologic abnormalities are present
• A compressive or inflammatory optic neuropathy is suspected

Pathology

Pathologic studies demonstrate:

• Ischemic infarction of the anterior/retrolaminar optic nerve
• Subsequent axonal loss
• Optic nerve atrophy

Differential Diagnosis

Important differential diagnoses include:

• Arteritic AION from giant cell arteritis
• Optic neuritis
• Papillitis
• Papilledema
• Papillophlebitis
• Compressive optic neuropathy
• Infiltrative optic neuropathy
• Amiodarone-associated optic neuropathy
• Diabetic papillopathy
• Central retinal vein occlusion with disc edema

Amiodarone Optic Neuropathy

Amiodarone-associated optic neuropathy may resemble NAION but more often shows:

• Bilateral involvement
• Insidious onset
• Prolonged disc edema
• More gradual visual loss

Treatment

No Proven Vision-Restoring Therapy

At present, there is no established treatment proven to reliably restore vision after acute NAION.

Management therefore focuses on:

• Excluding GCA
• Optimizing systemic risk factors
• Reducing risk to the fellow eye
• Monitoring visual recovery
• Low-vision support when needed

Blood Pressure Management

Hypertension should be appropriately controlled.

However, avoid unnecessary excessive hypotension, particularly at night, in susceptible patients.

Medication timing should be discussed with the patient’s primary physician or cardiologist rather than changed independently.

Diabetes and Lipid Control

Optimize:

• Blood glucose
• HbA1c
• Lipids
• General cardiovascular health

These measures benefit overall vascular health, although they have not been proven to reverse existing NAION.

Obstructive Sleep Apnea

Patients with symptoms or risk factors for obstructive sleep apnea should be evaluated.

Relevant symptoms include:

• Loud snoring
• Witnessed apneas
• Daytime somnolence
• Morning headaches

Treatment of sleep apnea is important for systemic health and may potentially reduce recurrent hypoxic stress.

Aspirin

Aspirin has been investigated for prevention of fellow-eye NAION.

However:

There is no convincing evidence that aspirin reliably prevents NAION in the fellow eye.

Aspirin should be prescribed based on the patient’s general cardiovascular indications rather than specifically as NAION therapy.

Corticosteroids

Systemic corticosteroids have been studied, but evidence has not established them as standard therapy for NAION.

They should not be confused with the urgent high-dose corticosteroid treatment required for arteritic AION due to giant cell arteritis.

Anticoagulation

Anticoagulation has not been proven effective for routine NAION treatment.

It should only be used when there is another established medical indication.

Hyperbaric Oxygen

Hyperbaric oxygen has not demonstrated sufficient benefit to become standard treatment.

Optic Nerve Sheath Decompression

Optic nerve sheath decompression should not be performed for NAION.

Clinical trial evidence demonstrated:

• No visual benefit
• Potential worsening of visual outcomes

This procedure is considered potentially harmful in NAION.

Referral

Patients should be evaluated by an ophthalmologist, preferably:

• Neuro-ophthalmologist

when available.

Medical evaluation should address:

• Hypertension
• Diabetes
• Hyperlipidemia
• Sleep apnea
• Other vascular risk factors

Follow-Up

Typical follow-up may include:

• Early reassessment within 1–2 weeks
• Approximately 1 month
• Approximately 2–3 months

depending on clinical findings.

Course of Disc Edema

Optic disc edema usually resolves over approximately:

6–11 weeks

The disc subsequently develops:

• Segmental pallor
• Diffuse optic atrophy

Persistent swelling well beyond the expected period should prompt reconsideration of the diagnosis.

Patient Monitoring

Follow:

• Visual acuity
• Color vision
• Visual field
• Optic disc appearance
• OCT RNFL and ganglion cell measurements when useful

24-Hour Blood Pressure Monitoring

Ambulatory blood pressure monitoring is not routinely required.

It may be useful in selected patients when there is concern for:

• Excessive nocturnal hypotension
• Medication-related hypotension
• Marked blood pressure variability

Patient Education

Patients should understand that:

• The vision loss is caused by ischemic injury to the optic nerve.
• Recovery is variable.
• The damaged field may remain permanently reduced.
• The fellow eye is also at risk.

They should seek prompt assessment for new visual symptoms in the other eye.

Medication Counseling

Patients should discuss potentially relevant medications with their physicians, particularly:

• Antihypertensives taken at night
• Amiodarone
• PDE-5 inhibitors

Medications should not be stopped without medical supervision.

Prognosis

Visual loss generally becomes stable after the acute phase.

Many patients have persistent visual field defects.

A meaningful spontaneous improvement in visual acuity can occur in a subset of patients over several months.

Fellow-Eye Risk

The fellow eye has a significant but not inevitable risk of developing NAION.

A commonly cited risk is approximately:

15% over 5 years

Risk may be higher in patients with persistent systemic and anatomic risk factors.

Recurrence

Recurrence in the same eye is relatively uncommon because optic atrophy and tissue loss may reduce the crowding that contributed to the original event.

Complications

Potential consequences include:

• Permanent visual field defect
• Persistent reduction in visual acuity
• Dyschromatopsia
• Optic atrophy
• Bilateral visual impairment if the fellow eye later becomes involved

Ophthalmology Pearls

• NAION = sudden painless monocular visual loss + swollen optic disc + altitudinal visual field defect.
• Symptoms are frequently first noticed on awakening.
• The fellow eye often has a small cup-to-disc ratio—the classic “disc at risk.”
• Peripapillary splinter hemorrhages commonly accompany acute disc edema.
• In every older patient with acute ischemic optic neuropathy, exclude giant cell arteritis urgently.
• A pale, chalky swollen optic disc with profound visual loss should raise strong concern for arteritic AION.
• There is currently no proven vision-restoring treatment for NAION.
• Optimize modifiable risks, particularly diabetes, hypertension, hyperlipidemia, and obstructive sleep apnea.
• Avoid unnecessary systemic hypotension, especially excessive nocturnal hypotension.
• Aspirin, anticoagulation, steroids, and hyperbaric oxygen have not been proven to prevent or reverse typical NAION.
• Optic nerve sheath decompression is ineffective and potentially harmful.
• Disc edema usually resolves within several weeks and is followed by optic atrophy.
• Fellow-eye involvement occurs in roughly 15% over 5 years, making long-term risk-factor management important.

Ophthalmology – Neuroretinitis

Basics

Description

Neuroretinitis is an inflammatory optic neuropathy characterized by:

• Optic disc edema
• Subsequent development of macular hard exudates in a stellate or “macular star” pattern
• Variable visual loss

It is usually:

• Unilateral
• Painless
• Self-limited in immunocompetent patients

Bilateral disease can occur but is less common.

Historically called Leber idiopathic stellate neuroretinitis, many cases are now known to have an infectious or immune-mediated cause.

The most important infectious association is:

Bartonella henselae – cat-scratch disease

Epidemiology

Neuroretinitis:

• Can occur at any age
• Has no strong sex predilection
• Affects either eye with similar frequency

The true prevalence is uncertain.

Cat exposure is common among patients with Bartonella-associated neuroretinitis.

Risk Factors

Important historical risk factors include:

• Recent contact with cats, especially kittens
• Cat scratch or bite
• Flea exposure
• Recent febrile or flu-like illness
• Immunocompromised state
• Exposure to tuberculosis
• Tick exposure in Lyme-endemic areas
• Sexual risk factors relevant to syphilis or HIV
• Exposure to animals associated with zoonotic infections

A viral-like illness may precede otherwise idiopathic neuroretinitis.

Pathophysiology

The characteristic process begins with inflammation and leakage from the:

Optic nerve head

This causes:

• Optic disc edema
• Peripapillary retinal edema
• Leakage of lipid-rich fluid into the outer plexiform layer of the macula

As the fluid resolves, lipid deposits remain in a radial configuration around the fovea, producing the:

Macular star

Macular Star Formation

The macular star is often not present at the initial examination.

It typically develops days to several weeks after the onset of optic disc edema and visual symptoms.

Therefore:

Early neuroretinitis may resemble isolated optic neuritis or other causes of disc edema.

Etiology

Neuroretinitis may be:

• Infectious
• Postinfectious
• Immune-mediated
• Idiopathic

Infectious Causes

Important infectious causes include:

• Bartonella henselae
• Syphilis
• Tuberculosis
• Lyme disease
• Toxoplasmosis
• Toxocariasis
• Leptospirosis
• Brucellosis
• HIV-associated infections
• Viral infections

Other infectious etiologies should be considered according to:

• Geography
• Exposure history
• Immune status

Bartonella henselae

Bartonella henselae is the classic and most common identifiable cause of neuroretinitis in many regions.

It causes cat-scratch disease.

Transmission commonly involves:

• Cats, especially kittens
• Cat scratches
• Cat bites
• Fleas

A scratch is not always recalled.

Cat-Scratch Disease

Systemic manifestations may include:

• Fever
• Malaise
• Headache
• Regional lymphadenopathy

Ocular manifestations can include:

• Neuroretinitis
• Parinaud oculoglandular syndrome
• Retinitis
• Choroiditis
• Retinal vascular occlusion

Diagnosis

Diagnosis is based on the characteristic combination of:

Optic disc edema + delayed macular star formation

together with clinical and laboratory evaluation for an underlying cause.

History

Patients commonly report:

• Blurred vision
• Decreased central vision
• Central or paracentral scotoma
• Reduced color vision
• Metamorphopsia

Vision may range from near normal to profound impairment.

Pain

Unlike typical demyelinating optic neuritis:

Neuroretinitis is usually painless.

Pain with eye movement is less characteristic.

Systemic Symptoms

Ask about:

• Fever
• Malaise
• Recent viral-like illness
• Lymph node enlargement
• Cat exposure
• Cat scratches or bites
• Tick exposure
• Tuberculosis exposure
• Sexual history
• Rash
• Arthralgia
• Immunosuppression

Physical Examination

Visual Acuity

Visual acuity may range widely depending on:

• Severity of optic nerve involvement
• Macular edema
• Associated retinitis

Pupillary Examination

A unilateral or asymmetric case usually produces a:

Relative afferent pupillary defect

Color Vision

Acquired dyschromatopsia is common.

Patients may have:

• Reduced color saturation
• Red desaturation
• Generalized color discrimination loss

Optic Disc

Typical initial finding:

Optic disc edema

This may be:

• Diffuse
• Hyperemic
• Associated with peripapillary retinal edema
• Accompanied by small hemorrhages in some cases

Macular Star

The hallmark finding is:

Radially arranged hard exudates around the fovea

forming a star-shaped pattern.

These deposits may appear after the onset of disc edema, so repeat examination can establish the diagnosis.

Chorioretinal Lesions

Small focal chorioretinal lesions may occur, especially with infectious etiologies such as Bartonella.

Visual Field Defects

Possible defects include:

• Cecocentral scotoma
• Central scotoma
• Arcuate defect
• Altitudinal defect

The most typical pattern is central or cecocentral involvement.

Bilateral Disc Edema

Bilateral neuroretinitis is possible.

However, bilateral optic disc swelling should also raise concern for:

• Papilledema from raised intracranial pressure
• Hypertensive emergency
• Infiltrative disease
• Infectious optic neuropathy

Appropriate neuroimaging and, when indicated, lumbar puncture may be required.

Diagnostic Testing

Testing should be guided by history, examination, geography, and immune status rather than automatically ordering every possible serology.

Bartonella Serology

When cat-scratch disease is suspected, obtain:

• Bartonella henselae IgG
• Bartonella henselae IgM

A significantly elevated or rising IgG titer and/or compatible IgM supports recent infection.

Serology must be interpreted in clinical context.

Additional Laboratory Tests

Depending on the presentation, evaluation may include:

• CBC
• ESR
• CRP
• Syphilis serology
• HIV testing
• Tuberculosis testing
• Lyme serology when epidemiologically appropriate
• Toxoplasma serology
• Toxocara testing
• Sarcoidosis evaluation
• Leptospira testing
• Brucella testing

Autoimmune studies should be guided by systemic findings.

Syphilis

Syphilis is an important mimic because it can cause virtually any pattern of ocular inflammation.

Testing generally includes:

• Treponemal test
• Nontreponemal test

Ocular syphilis requires systemic treatment.

Tuberculosis

Consider tuberculosis when there is:

• Relevant exposure
• Endemic residence
• Systemic symptoms
• Suggestive ocular inflammation

Testing may include:

• Interferon-gamma release assay
• Tuberculin skin testing
• Chest imaging when appropriate

MRI

MRI of the brain and orbits with contrast may be performed when:

• The diagnosis is uncertain
• Visual loss is severe
• Neurologic symptoms are present
• Bilateral disc edema is present
• A compressive or demyelinating lesion must be excluded

MRI can demonstrate optic nerve or optic disc enhancement but may also be normal.

Optical Coherence Tomography

OCT is very useful for documenting:

• Optic disc edema
• Peripapillary RNFL thickening
• Macular edema
• Subretinal fluid
• Hard exudates
• Later optic nerve thinning

Serial OCT is useful for monitoring recovery.

Fluorescein Angiography

FA typically demonstrates:

• Leakage from optic disc vessels
• Progressive optic disc hyperfluorescence
• Late disc staining

It may also identify:

• Retinal vascular inflammation
• Focal chorioretinal lesions
• Macular leakage

Fundus Photography

Useful for documenting:

• Disc edema
• Macular star development
• Chorioretinal lesions
• Resolution over time

Visual Field Testing

Formal visual fields are useful for:

• Documenting central or cecocentral scotomas
• Monitoring recovery
• Identifying persistent deficits

Differential Diagnosis

Important differential diagnoses include:

• Bartonella neuroretinitis
• Demyelinating optic neuritis
• Anterior ischemic optic neuropathy
• Papilledema
• Hypertensive retinopathy
• Syphilis
• Tuberculosis
• Lyme disease
• Toxoplasmosis
• Toxocariasis
• Sarcoidosis
• Lupus
• HIV-related disease
• Leber hereditary optic neuropathy
• Infiltrative optic neuropathy
• Leukemia or lymphoma

Hypertensive Retinopathy

Severe hypertension can produce:

• Bilateral optic disc edema
• Cotton-wool spots
• Retinal hemorrhages
• Macular star

Therefore, blood pressure should always be checked in a patient presenting with a macular star.

Neuroretinitis vs Typical Optic Neuritis

Neuroretinitis

Usually:

• Painless
• Marked disc edema
• Macular star develops
• Often infectious or postinfectious
• Lower association with multiple sclerosis

Typical Demyelinating Optic Neuritis

Usually:

• Pain with eye movement
• Retrobulbar or mild disc edema
• No macular star
• Stronger association with demyelinating disease

Treatment

Treatment depends on the underlying cause.

Many idiopathic or uncomplicated Bartonella-associated cases in immunocompetent patients are:

Self-limited

and recover spontaneously.

Bartonella-Associated Neuroretinitis

The benefit of antibiotics in otherwise healthy patients with mild disease remains somewhat uncertain because spontaneous recovery is common.

Treatment is more strongly considered when there is:

• Severe visual loss
• Bilateral disease
• Significant macular involvement
• Systemic Bartonella disease
• Immunocompromise
• Persistent or progressive disease

Antibiotic Therapy

Antibiotics used for Bartonella infection may include:

• Doxycycline
• Rifampin
• Azithromycin
• Trimethoprim-sulfamethoxazole
• Other agents depending on age and systemic circumstances

For severe Bartonella neuroretinitis in adults, a commonly used specialist regimen is:

Doxycycline with rifampin

for several weeks.

Treatment should be individualized according to:

• Age
• Pregnancy status
• Immune status
• Systemic disease
• Infectious disease guidance

Immunocompromised Patients

Patients who are immunocompromised generally require treatment because they have:

• Greater risk of disseminated infection
• More prolonged disease
• More severe ocular involvement

Corticosteroids

Systemic corticosteroids may occasionally be considered as adjunctive therapy in severe inflammatory neuroretinitis.

However:

Corticosteroids should not be given alone when an untreated infectious cause remains possible.

When used for infectious neuroretinitis, they should generally be combined with appropriate antimicrobial therapy under specialist supervision.

Cause-Specific Treatment

If another infectious cause is identified, treat appropriately.

Examples include:

• Syphilis → systemic penicillin therapy
• Tuberculosis → multidrug antituberculous therapy
• Toxoplasmosis → appropriate antiparasitic therapy when indicated
• Lyme disease → guideline-directed antibiotic therapy

Referral

Patients should be evaluated by an:

• Ophthalmologist

Referral to a:

• Neuro-ophthalmologist
• Retina/uveitis specialist

is appropriate when:

• Diagnosis is uncertain
• Visual loss is severe
• Disease is bilateral
• Retinal lesions are prominent
• Recovery is atypical

Infectious disease consultation may be useful for complex infections.

Hospitalization

Most uncomplicated neuroretinitis can be treated as an outpatient.

Admission may be required for:

• Severe systemic infection
• Immunocompromised patients with disseminated disease
• Neurologic involvement
• Need for intravenous therapy
• Diagnostic uncertainty involving potentially life-threatening disease

Follow-Up

During the acute phase, follow-up should monitor:

• Visual acuity
• Pupillary response
• Color vision
• Visual field
• Optic disc edema
• Macular edema
• Macular exudates

Initial follow-up may occur every few weeks depending on severity.

Natural Course

Optic disc swelling generally resolves first.

Macular exudates may persist considerably longer.

They often resolve over:

Several months

and occasionally remain visible for many months.

Patient Education

Patients should understand that:

• Most cases have a favorable prognosis.
• Macular exudates resolve slowly.
• Vision may improve before the fundus appears completely normal.
• New neurologic or systemic symptoms require prompt evaluation.

Cat-Exposure Education

When Bartonella infection is suspected or confirmed:

• Avoid rough play with kittens.
• Wash scratches promptly.
• Avoid allowing cats to lick open wounds.
• Maintain appropriate flea control.

Cat ownership itself usually does not need to be eliminated.

Prognosis

The overall visual prognosis is usually good, especially in immunocompetent patients.

Many patients recover substantial central visual acuity over weeks to months.

Recovery may continue even while the macular star remains visible.

Poor Prognostic Factors

Residual impairment is more likely with:

• Severe initial optic nerve dysfunction
• Extensive macular involvement
• Recurrent disease
• Severe infectious disease
• Optic atrophy

Complications

Potential complications include:

• Persistent reduced visual acuity
• Central or cecocentral visual field defect
• Optic atrophy
• Dyschromatopsia
• Metamorphopsia
• Persistent macular abnormalities
• Rare permanent severe visual loss

Ophthalmology Pearls

• Neuroretinitis = optic disc edema followed by a macular star.
• The macular star may be absent initially and appear later, so early cases can be misdiagnosed.
• Bartonella henselae is the classic infectious association.
• Ask specifically about cat or kitten exposure, even if no scratch is remembered.
• Neuroretinitis is generally painless, unlike typical demyelinating optic neuritis.
• A central or cecocentral scotoma is common.
• Bilateral disc edema requires consideration of raised intracranial pressure and malignant hypertension, not just bilateral neuroretinitis.
• Always check blood pressure when a macular star is present.
• Bartonella neuroretinitis is often self-limited in immunocompetent patients, but severe or systemic disease may warrant antimicrobial treatment.
• Steroids should not be used alone when infectious neuroretinitis has not been excluded or treated.
• Visual prognosis is usually good, while the macular exudates may take months to disappear completely.

Ophthalmology – Neuroprotection in Glaucoma

Basics

Description

Neuroprotection in glaucoma refers to therapeutic strategies aimed at preserving retinal ganglion cells (RGCs), their axons, and optic nerve function independently of—or in addition to—lowering intraocular pressure (IOP).

Potential goals include:

• Preventing RGC injury
• Slowing RGC apoptosis
• Preserving optic nerve axons
• Maintaining visual field function
• Enhancing neuronal resistance to metabolic or ischemic stress
• Potentially promoting neuronal recovery or regeneration

At present, however:

IOP reduction remains the only clinically proven treatment strategy that consistently reduces the risk of glaucomatous progression.

No treatment has yet been definitively established as an independent neuroprotective therapy for glaucoma in routine clinical practice.

Why Neuroprotection Is Important

Glaucoma is a progressive optic neuropathy characterized by:

• Loss of retinal ganglion cells
• Loss of retinal nerve fiber layer
• Optic nerve head remodeling
• Progressive visual field loss

Although IOP is the most important modifiable risk factor, it does not completely explain glaucomatous damage.

Important observations include:

• Some patients with elevated IOP never develop glaucoma.
• Patients with normal-tension glaucoma develop glaucomatous optic neuropathy despite IOP measurements within the statistically normal range.
• Some patients continue to progress despite substantial IOP reduction.

Therefore, mechanisms independent of IOP probably contribute to retinal ganglion cell injury.

Pathophysiology

RGC death in glaucoma is multifactorial.

Mechanisms can broadly be divided into:

• IOP-dependent injury
• IOP-independent neuronal injury

These mechanisms interact rather than functioning as completely separate pathways.

IOP-Dependent Retinal Ganglion Cell Loss

Mechanical Theory

Elevated IOP can cause deformation of the:

Lamina cribrosa

This may produce:

• Posterior laminar bowing
• Compression of retinal ganglion cell axons
• Disturbance of axoplasmic transport
• Mechanical injury to optic nerve fibers
• Remodeling of connective tissue

Interruption of axonal transport may deprive RGCs of important neurotrophic factors.

Vascular Theory

Optic nerve damage may also be related to reduced perfusion.

A simplified concept is:

Ocular perfusion pressure ≈ arterial blood pressure − intraocular pressure

Reduced perfusion can result from:

• Increased IOP
• Low systemic blood pressure
• Nocturnal hypotension
• Vascular dysregulation
• Impaired autoregulation

This may be particularly relevant in some patients with normal-tension glaucoma.

Non-IOP-Dependent Mechanisms

Multiple cellular pathways have been implicated in glaucomatous neurodegeneration.

Important mechanisms include:

• Excitotoxicity
• Mitochondrial dysfunction
• Oxidative stress
• Neuroinflammation
• Loss of neurotrophic support
• Nitric oxide dysregulation
• Axonal transport failure
• Glial activation
• Apoptosis

Excitotoxicity

Glutamate is the major excitatory neurotransmitter of the central nervous system.

Excessive stimulation of glutamate receptors, particularly:

NMDA receptors

can result in excessive entry of:

• Calcium
• Sodium

into neurons.

Excess intracellular calcium may activate:

• Proteases
• Lipases
• Endonucleases
• Mitochondrial injury pathways

ultimately promoting apoptosis.

Although excitotoxicity is biologically plausible, targeting this pathway has not yet produced an established clinical neuroprotective treatment for glaucoma.

Retinal Ganglion Cell Apoptosis

A major final pathway of glaucomatous neuronal injury is:

Apoptosis

This is programmed cell death characterized by controlled intracellular signaling rather than acute necrosis.

Potential triggers include:

• Mechanical stress
• Ischemia
• Oxidative injury
• Mitochondrial dysfunction
• Neurotrophin deprivation
• Inflammatory mediators

Mitochondrial Dysfunction

Retinal ganglion cells have high energy requirements.

Mitochondrial dysfunction may lead to:

• Reduced ATP production
• Increased reactive oxygen species
• Abnormal calcium handling
• Greater susceptibility to metabolic stress
• Activation of apoptotic pathways

Mitochondrial vulnerability has therefore become an important area of glaucoma neuroprotection research.

Oxidative Stress

Oxidative stress occurs when production of:

Reactive oxygen species (ROS)

exceeds the antioxidant capacity of ocular tissues.

Consequences may include:

• Lipid peroxidation
• DNA damage
• Protein oxidation
• Mitochondrial dysfunction
• Trabecular meshwork injury
• RGC apoptosis

Neuroinflammation

Glaucoma is increasingly recognized as involving chronic neuroinflammatory signaling.

Potential components include:

• Activated microglia
• Astrocytes
• Complement activation
• Cytokines
• Tumor necrosis factor-alpha
• Other inflammatory mediators

Inflammation may initially be protective but become detrimental when chronically activated.

Complement System

Several complement components are upregulated in experimental glaucoma.

The complement system may participate in:

• Synaptic remodeling
• Clearance of damaged tissue
• Neuroinflammatory injury

Its exact role in human glaucoma remains under investigation.

Heat Shock Proteins

Heat shock proteins (HSPs) normally act as:

• Molecular chaperones
• Cellular stress-response proteins
• Anti-apoptotic mediators

Abnormal immune responses against heat shock proteins have been described in glaucoma.

Their role in disease progression remains incompletely defined.

Tumor Necrosis Factor-Alpha

TNF-α can be increased during optic nerve injury.

Potential effects include:

• Activation of inflammatory pathways
• Glial activation
• Mitochondrial dysfunction
• Promotion of RGC apoptosis

Nitric Oxide

Nitric oxide has normal physiologic roles in:

• Vascular regulation
• Neural signaling

Excessive nitric oxide production under pathologic conditions may contribute to:

• Oxidative/nitrosative stress
• Mitochondrial injury
• RGC loss

Loss of Neurotrophic Support

Healthy retinal ganglion cells depend on neurotrophic factors transported between the retina and brain.

Potential protective factors include:

• Brain-derived neurotrophic factor (BDNF)
• Nerve growth factor
• Ciliary neurotrophic factor

Glaucoma-associated axonal transport disruption may reduce delivery of these survival signals.

Diagnosis and Assessment of Neurodegeneration

There is currently no single clinical test that directly measures neuroprotection.

The effectiveness of a neuroprotective therapy would ideally be demonstrated by slower loss of:

• RGC structure
• Optic nerve axons
• Visual function

Visual Field Testing

Standard automated perimetry remains essential for determining functional progression.

Limitations include:

• Test-retest variability
• Learning effects
• Fatigue
• Slow rate of glaucomatous progression

As a result, proving a neuroprotective benefit may require large numbers of patients and long-term follow-up.

Optical Coherence Tomography

OCT provides objective structural measurements of:

• Peripapillary retinal nerve fiber layer
• Macular ganglion cell complex
• Ganglion cell–inner plexiform layer
• Optic nerve head parameters

Serial OCT can detect progressive structural loss, sometimes before clear visual field deterioration.

Optic Disc Photography

Serial optic nerve photography may document:

• Neuroretinal rim thinning
• Progressive cupping
• Disc hemorrhage
• Localized RNFL defects

It remains useful for longitudinal assessment.

Other Structural Technologies

Historically used technologies include:

• Scanning laser polarimetry
• Confocal scanning laser ophthalmoscopy

OCT has largely become the dominant structural imaging modality in routine glaucoma practice.

Detection of Apoptosing Retinal Cells

DARC – Detection of Apoptosing Retinal Cells

is an investigational imaging technique designed to visualize apoptotic retinal cells in vivo.

Its potential applications include:

• Earlier detection of active neurodegeneration
• Rapid assessment of treatment effects

It remains investigational and is not part of routine glaucoma management.

Requirements for a True Neuroprotective Therapy

An ideal neuroprotective agent should:

• Reach the retina and optic nerve at therapeutic concentrations
• Act on biologically relevant targets
• Improve neuronal survival
• Preserve retinal ganglion cell structure
• Preserve visual function
• Provide benefit independent of IOP lowering
• Demonstrate safety and efficacy in appropriately controlled human trials

The last requirement is particularly important.

A drug showing neuroprotection in animals is not automatically neuroprotective in humans.

Current Clinical Reality

Many compounds have shown promising neuroprotective effects in:

• Cell culture
• Retinal injury models
• Experimental glaucoma
• Animal studies

However, translation to human glaucoma has been difficult.

At present:

No pharmacologic therapy is established as a proven IOP-independent neuroprotective treatment for glaucoma.

Memantine

Memantine is an NMDA receptor antagonist originally developed for neurologic disease.

The rationale was to reduce glutamate-mediated excitotoxicity.

Experimental models suggested RGC protection.

However, large phase III glaucoma trials did not demonstrate sufficient clinical neuroprotective benefit to establish memantine as a glaucoma treatment.

Therefore:

Memantine is not recommended for routine glaucoma neuroprotection.

Brimonidine

Brimonidine is an α2-adrenergic agonist routinely used to lower IOP.

Experimental neuroprotective mechanisms include:

• Increased expression of neurotrophic factors
• Reduced excitotoxic injury
• Anti-apoptotic signaling

Some clinical observations, particularly in normal-tension glaucoma, have suggested possible benefit beyond IOP lowering.

However, limitations such as:

• High dropout rates
• Medication intolerance
• Difficulty separating IOP effects from true neuroprotection

mean that independent neuroprotection has not been conclusively proven.

Brimonidine should therefore be used primarily as an:

IOP-lowering medication

rather than prescribed specifically as a proven neuroprotectant.

Betaxolol

Betaxolol is a relatively β1-selective topical beta-blocker.

Experimental mechanisms proposed include:

• Reduced calcium influx
• Protection against excitotoxicity
• Improved retinal or optic nerve perfusion

Definitive independent neuroprotective benefit in humans has not been established.

Its proven role remains:

IOP reduction

Calcium Channel Blockers

Calcium channel blockers have been investigated because they may:

• Reduce intracellular calcium overload
• Reduce vasospasm
• Improve ocular blood flow

This concept may be of interest in some patients with vascular dysregulation or normal-tension glaucoma.

However:

There is insufficient evidence to recommend systemic calcium channel blockers specifically for glaucoma neuroprotection.

Systemic hypotension from these drugs could theoretically worsen optic nerve perfusion in susceptible patients.

Ginkgo Biloba

Ginkgo biloba extract has proposed:

• Antioxidant
• Vasoregulatory
• Mitochondrial

effects.

Small studies have explored its use, particularly in normal-tension glaucoma.

However:

• Evidence remains limited
• Preparations vary
• Drug interactions and bleeding risk must be considered

It is not an established glaucoma treatment.

Vitamin E

Vitamin E acts as an antioxidant and scavenger of lipid peroxyl radicals.

Although antioxidant therapy has theoretical appeal:

Vitamin E has not been proven to prevent glaucomatous RGC loss in clinical practice.

High-dose supplementation should not be recommended solely for glaucoma without another indication.

Neurotrophins

Potential neurotrophic therapies include:

• BDNF
• Nerve growth factor
• Ciliary neurotrophic factor

These can enhance neuronal survival experimentally.

Challenges include:

• Delivering adequate concentrations to RGCs
• Short duration of effect
• Receptor downregulation
• Potential activation of unwanted signaling pathways

They remain investigational.

Coenzyme Q10

Coenzyme Q10 is important in:

• Mitochondrial electron transport
• ATP production
• Antioxidant defense

Experimental studies have suggested possible protection against mitochondrial and oxidative injury.

However, definitive human evidence for glaucoma neuroprotection is lacking.

Nicotinamide

Nicotinamide (vitamin B3) has become an important area of modern glaucoma research because it supports:

• NAD metabolism
• Mitochondrial function
• Cellular energy homeostasis

Experimental glaucoma models have shown substantial RGC protection, and early human studies have investigated potential functional effects.

However:

Nicotinamide remains investigational for glaucoma neuroprotection and is not yet established as standard treatment.

High doses can also produce systemic toxicity and should not be self-prescribed for glaucoma.

Citicoline

Citicoline has been studied for possible:

• Neuroprotective
• Neuroenhancing
• Membrane-stabilizing

effects.

Small clinical studies have suggested possible improvement in electrophysiologic or functional parameters.

However:

• Evidence is not sufficient to establish long-term prevention of glaucoma progression.
• It is not a replacement for IOP-lowering therapy.

Glatiramer Acetate

Glatiramer acetate, used in multiple sclerosis, has shown neuroprotective effects in some experimental optic nerve injury models.

Its proposed mechanism involves:

• Immunomodulation
• Protective autoimmunity

It is not an established treatment for glaucoma.

Heat Shock Protein Modulation

Compounds that enhance protective heat shock protein pathways have shown experimental benefit.

For example, geranylgeranylacetone has been investigated for its ability to increase HSP expression.

This approach remains experimental.

Nitric Oxide Synthase Inhibitors

Nitric oxide pathway modulation has demonstrated potential neuroprotection in experimental models.

However:

• Nitric oxide has both protective and harmful physiologic roles.
• Systemic or ocular manipulation is complex.

No nitric oxide synthase inhibitor is established for glaucoma neuroprotection.

Photobiomodulation

Red or near-infrared light therapy has been investigated for potential:

• Mitochondrial stimulation
• Anti-inflammatory effects
• Antioxidant effects
• Anti-apoptotic effects

This remains an experimental strategy rather than standard glaucoma treatment.

Neuroregeneration

Neuroprotection aims to preserve surviving RGCs.

A more ambitious goal is:

Neuroregeneration

which would require:

• Regrowth of damaged axons
• Restoration of connections with central visual targets
• Functional reconstruction of the optic nerve pathway

This remains an active research field and is not currently achievable in routine clinical glaucoma care.

IOP Reduction as Indirect Neuroprotection

Although conventional glaucoma medications are not usually classified as neuroprotectants, reducing IOP protects RGCs by reducing the primary mechanical and physiologic stress on the optic nerve.

Established treatments include:

• Prostaglandin analogs
• Beta-blockers
• Alpha agonists
• Carbonic anhydrase inhibitors
• Rho kinase inhibitors
• Laser trabeculoplasty
• Incisional glaucoma surgery
• Minimally invasive glaucoma procedures in selected patients

From a practical standpoint:

Effective IOP lowering remains the most important proven form of RGC preservation.

Systemic Factors Relevant to RGC Protection

Neuroprotection may also involve optimizing systemic contributors to optic nerve stress.

Important considerations include:

• Avoiding severe nocturnal hypotension
• Treating significant sleep apnea
• Controlling diabetes
• Controlling vascular risk factors
• Avoiding smoking
• Maintaining general cardiovascular health

These measures may be particularly relevant in patients with normal-tension glaucoma, although they do not substitute for IOP control.

Follow-Up

Patients with glaucoma should be monitored longitudinally with:

• IOP measurement
• Gonioscopy when appropriate
• Optic disc examination
• OCT RNFL
• Macular ganglion cell analysis
• Standard automated perimetry

Progression should be assessed using both:

Structural + functional information

When Glaucoma Progresses Despite “Normal” IOP

If progression continues despite apparently controlled pressure:

• Confirm true progression.
• Review medication adherence.
• Look for IOP fluctuations or peaks.
• Reassess target IOP.
• Consider lowering the target further.
• Evaluate corneal thickness and other measurement issues.
• Review systemic hypotension.
• Consider sleep apnea or vascular dysregulation.
• Exclude nonglaucomatous optic neuropathy when findings are atypical.

The response should generally be to optimize proven glaucoma management rather than substitute an unproven neuroprotective supplement.

Clinical Challenges in Neuroprotection Research

Demonstrating neuroprotection is difficult because:

• Glaucoma progresses slowly.
• Visual fields are variable.
• Structural and functional changes may not occur simultaneously.
• IOP itself affects progression and confounds study results.
• Very long trials may be required.
• RGC death occurs at different rates among patients.

A true clinical trial must separate:

IOP-lowering benefit from independent neuronal protection.

Prognosis

The concept of neuroprotection is scientifically compelling and remains a major area of glaucoma research.

However, current evidence supports:

Aggressive control of IOP as the cornerstone of preventing glaucomatous visual loss.

Future therapies may combine:

• IOP lowering
• Neuroprotection
• Mitochondrial support
• Neuroinflammation modulation
• Axonal regeneration

Ophthalmology Pearls

• Glaucoma is a retinal ganglion cell neurodegenerative disease, not simply a disease of high IOP.
• IOP remains the only major modifiable risk factor with unequivocal clinical evidence for reducing glaucoma progression.
• Proposed non-IOP mechanisms include excitotoxicity, mitochondrial dysfunction, oxidative stress, neuroinflammation, impaired axonal transport, and loss of neurotrophic support.
• Memantine showed promise experimentally but failed to establish meaningful neuroprotection in phase III glaucoma trials.
• Brimonidine has experimental neuroprotective properties, but independent clinical neuroprotection remains unproven.
• Betaxolol, Ginkgo biloba, vitamin E, CoQ10, citicoline, neurotrophins, and other agents remain unproven or investigational for direct glaucoma neuroprotection.
• Nicotinamide is a promising modern research target, particularly through mitochondrial and NAD-related mechanisms, but is not established standard therapy.
• OCT and visual field testing remain the main methods for monitoring glaucomatous structural and functional progression.
• Progression despite apparently controlled IOP usually warrants a lower target IOP and reassessment of other risk factors, not replacement of proven therapy with an experimental neuroprotectant.
• At present, the most reliable way to protect retinal ganglion cells clinically is still effective and sustained reduction of intraocular pressure.

Ophthalmology – Neurofibromatosis

Basics

Description

Neurofibromatosis refers to inherited tumor-predisposition syndromes affecting the:

• Nervous system
• Skin
• Eyes
• Bones
• Soft tissues

The two historically recognized major forms are:

• Neurofibromatosis type 1 (NF1) – formerly von Recklinghausen disease
• NF2-related schwannomatosis – historically called neurofibromatosis type 2 or central neurofibromatosis

NF1 and NF2 are genetically and clinically distinct disorders.

Neurofibromatosis Type 1

NF1 is the much more common form.

Important ophthalmic manifestations include:

• Lisch nodules
• Optic pathway glioma
• Choroidal abnormalities
• Plexiform neurofibroma involving the eyelid/orbit
• Proptosis
• Strabismus
• Sphenoid wing dysplasia

NF2-Related Schwannomatosis

NF2-related schwannomatosis is characterized predominantly by tumors of the central and peripheral nervous systems.

The hallmark is:

Bilateral vestibular schwannomas

Important ocular manifestations include:

• Early-onset cataract
• Epiretinal membrane
• Retinal hamartoma
• Optic nerve sheath meningioma
• Strabismus or cranial nerve palsies from intracranial tumors

Epidemiology

NF1

Occurs in approximately:

1 in 3,000–3,500 individuals

NF2-Related Schwannomatosis

Much rarer, traditionally estimated at approximately:

1 in 25,000–60,000

Both sexes are affected approximately equally.

Genetics

Both NF1 and NF2-related schwannomatosis are inherited in an:

Autosomal dominant pattern

However, many patients have a new pathogenic variant without an affected parent.

NF1 Gene

The NF1 gene is located on:

Chromosome 17q11.2

It encodes:

Neurofibromin

Neurofibromin acts as a tumor suppressor and negatively regulates RAS signaling.

NF2 Gene

The NF2 gene is located on:

Chromosome 22q12

It encodes:

Merlin, also called schwannomin.

Merlin functions as a tumor-suppressor protein involved in cellular growth regulation.

Penetrance and Expression

NF1 has:

• Very high penetrance
• Markedly variable expression

Thus, members of the same family may have very different disease severity.

Mosaic forms can also occur.

Genetic Counseling

Because inheritance is autosomal dominant, an affected individual generally has a:

50% chance of transmitting the pathogenic variant to each child.

Genetic counseling is appropriate for:

• Affected patients
• Parents
• Families planning pregnancy

Prenatal and preimplantation genetic testing may be possible when the familial pathogenic variant is known.

Pathophysiology

Both neurofibromin and merlin act as tumor suppressors.

Loss of normal tumor-suppressor function predisposes to development of:

• Schwannomas
• Neurofibromas
• Gliomas
• Meningiomas
• Other benign and malignant tumors

Neurofibromatosis Type 1 – Diagnostic Features

Modern diagnostic criteria for NF1 incorporate clinical findings and molecular testing.

In a patient without an affected parent, the diagnosis generally requires at least 2 characteristic features.

Important features include:

• Six or more café-au-lait macules
• Axillary or inguinal freckling
• Two or more neurofibromas or one plexiform neurofibroma
• Optic pathway glioma
• Two or more Lisch nodules
• Characteristic choroidal abnormalities
• Characteristic osseous lesion
• Pathogenic heterozygous NF1 variant

Café-au-Lait Macules

Typical café-au-lait macules are:

• Flat
• Hyperpigmented
• Well-defined

Diagnostic size thresholds are approximately:

• >5 mm before puberty
• >15 mm after puberty

Six or more are characteristic of NF1.

Axillary and Inguinal Freckling

Freckling in skin-fold areas is highly characteristic.

Common sites include:

• Axilla
• Groin
• Inframammary folds

Neurofibromas

Patients may develop:

• Cutaneous neurofibromas
• Subcutaneous neurofibromas
• Plexiform neurofibromas

A plexiform neurofibroma is particularly characteristic of NF1.

Ophthalmic Manifestations of NF1

Lisch Nodules

Lisch nodules are benign melanocytic hamartomas of the iris.

They appear as:

• Small
• Dome-shaped
• Pigmented iris nodules

They are best detected by:

Slit-lamp examination

Lisch nodules:

• Usually do not affect vision
• Become increasingly common with age
• Are highly characteristic of NF1

Choroidal Abnormalities

Near-infrared fundus imaging may reveal multiple bright choroidal nodules.

These abnormalities are now included among recognized diagnostic features of NF1.

They usually:

• Do not reduce vision
• Are difficult to see on ordinary ophthalmoscopy
• Are readily visible with near-infrared imaging

Optic Pathway Glioma

Optic pathway glioma (OPG) is one of the most important ophthalmic complications of NF1.

It is usually a:

Low-grade pilocytic astrocytoma

and may involve:

• Optic nerve
• Optic chiasm
• Optic tract
• Hypothalamic region

Epidemiology of Optic Pathway Glioma

Radiographic optic pathway gliomas occur in approximately:

15–20% of children with NF1

However, many remain asymptomatic and never require treatment.

Most clinically significant tumors present during childhood.

Clinical Features of Optic Pathway Glioma

Possible manifestations include:

• Reduced visual acuity
• Color vision loss
• Relative afferent pupillary defect
• Optic disc pallor
• Optic disc swelling
• Proptosis
• Strabismus
• Visual field loss
• Nystagmus

Chiasmal or hypothalamic tumors may be associated with:

• Precocious puberty
• Endocrine abnormalities

Plexiform Neurofibroma of the Eyelid

Plexiform neurofibromas commonly involve the:

• Upper eyelid
• Orbit
• Temporal region

Possible findings include:

• Thickened eyelid
• S-shaped upper lid
• Ptosis
• Facial asymmetry
• Proptosis
• Strabismus

These lesions can become extensive and difficult to excise completely.

Sphenoid Wing Dysplasia

Sphenoid wing dysplasia may lead to:

• Enlargement of the orbit
• Pulsatile proptosis
• Facial asymmetry

The temporal lobe may herniate toward the orbit when the sphenoid wing is markedly deficient.

Glaucoma in NF1

Glaucoma may occur, particularly in eyes with:

• Ipsilateral eyelid plexiform neurofibroma
• Orbital involvement
• Anterior segment developmental abnormalities

Congenital or early-onset glaucoma should therefore be considered in affected children.

Other Manifestations of NF1

Neurologic manifestations may include:

• Seizures
• Learning difficulties
• Attention problems
• Gliomas
• Spinal tumors
• Chiari malformation
• Vascular abnormalities

Skeletal Manifestations

Possible findings include:

• Scoliosis
• Long-bone dysplasia
• Tibial bowing
• Pseudarthrosis
• Sphenoid wing dysplasia
• Reduced bone mineral density

Vascular Disease

NF1 can cause vascular abnormalities such as:

• Renal artery stenosis
• Cerebral vasculopathy
• Aneurysms
• Moyamoya arteriopathy

Moyamoya Disease

NF1 is associated with moyamoya arteriopathy, a progressive stenotic disorder affecting intracranial arteries around the Circle of Willis.

Children may present with:

• Transient ischemic attacks
• Stroke
• Seizures
• Weakness

Adults may also develop intracranial hemorrhage.

Hypertension

Hypertension in NF1 may result from:

• Essential hypertension
• Renal artery stenosis
• Pheochromocytoma

Blood pressure should therefore be monitored regularly.

Pheochromocytoma

Symptoms may include:

• Episodic headache
• Palpitations
• Sweating
• Hypertension

Evaluation may include plasma or urinary metanephrines when clinically indicated.

Malignant Peripheral Nerve Sheath Tumor

Patients with NF1 have an increased risk of malignant peripheral nerve sheath tumor (MPNST).

Warning symptoms include:

• Rapid tumor enlargement
• Persistent or increasing pain
• Hardening of a previously soft neurofibroma
• Neurologic deficit

These require urgent evaluation.

NF2-Related Schwannomatosis

The defining tumor predisposition differs substantially from NF1.

Typical tumors include:

• Vestibular schwannomas
• Other cranial nerve schwannomas
• Spinal schwannomas
• Meningiomas
• Ependymomas

Vestibular Schwannomas

The classic hallmark is:

Bilateral vestibular schwannomas

Symptoms include:

• Progressive hearing loss
• Tinnitus
• Imbalance
• Vertigo

Presentation often occurs in adolescence or early adulthood.

Other Cranial Nerve Tumors

Schwannomas may involve other cranial nerves, including:

• CN III
• CN V
• CN VII

These can produce:

• Diplopia
• Ptosis
• Facial sensory abnormalities
• Facial weakness

Ophthalmic Manifestations of NF2

Important ocular abnormalities include:

• Early-onset cataract
• Epiretinal membrane
• Combined hamartoma of retina and RPE
• Retinal abnormalities
• Optic nerve sheath meningioma
• Strabismus
• Cranial nerve palsies

Cataract in NF2

A characteristic finding is a:

Juvenile posterior subcapsular or cortical cataract

Cataract may precede neurologic symptoms and can therefore provide an early clue to the diagnosis.

Epiretinal Membrane

Epiretinal membranes may occur at an unusually young age.

They may cause:

• Metamorphopsia
• Reduced visual acuity
• Macular distortion

Combined Hamartoma of Retina and RPE

This lesion may appear as:

• Elevated gray retinal lesion
• Retinal distortion
• Vascular tortuosity
• Epiretinal fibrosis

It can reduce vision if the macula is involved.

Optic Nerve Sheath Meningioma

NF2 predisposes to meningiomas, including those around the optic nerve.

Possible manifestations include:

• Progressive visual loss
• Optic atrophy
• Optociliary shunt vessels
• Proptosis

Diagnosis

History in NF1

Ask about:

• Café-au-lait lesions
• Skin tumors
• Family history
• Bone abnormalities
• Learning difficulties
• Visual decline
• Proptosis
• Precocious puberty
• Headaches
• Hypertension

History in NF2

Ask about:

• Hearing loss
• Tinnitus
• Balance problems
• Family history
• Diplopia
• Progressive visual loss
• Early cataract
• Neurologic deficits

Ophthalmic Examination

For NF1, examine:

• Visual acuity
• Pupils
• Color vision
• Ocular motility
• Optic discs
• Iris by slit lamp
• Eyelids and orbit
• Fundus

Near-infrared imaging may identify choroidal abnormalities.

Ophthalmic Examination in NF2

Evaluate for:

• Cataract
• Epiretinal membrane
• Retinal hamartoma
• Optic nerve abnormalities
• Strabismus
• Cranial nerve palsies

Genetic Testing

Molecular testing may include:

• NF1 gene sequencing and deletion/duplication analysis
• NF2 gene testing
• Mosaicism assessment when appropriate

Genetic testing is especially useful when:

• Clinical findings are incomplete
• Atypical phenotype is present
• Family planning is being considered

Imaging in NF1

MRI may be indicated when there are:

• Visual abnormalities suggesting optic pathway glioma
• Proptosis
• Neurologic symptoms
• Precocious puberty
• Suspected intracranial or spinal tumor

Routine screening MRI solely to look for an asymptomatic optic pathway glioma is generally not required when reliable ophthalmic surveillance is possible.

MRI Findings in NF1

Possible findings include:

• Optic pathway glioma
• Other low-grade gliomas
• T2-hyperintense focal areas historically called unidentified bright objects

These focal signal abnormalities are particularly common in children.

Imaging in NF2

MRI is central to surveillance because of the high tumor burden.

Serial MRI may assess:

• Vestibular schwannomas
• Meningiomas
• Spinal tumors
• Other cranial nerve schwannomas

Volumetric MRI can be useful for monitoring tumor growth.

Hearing Evaluation in NF2

Assessment may include:

• Pure-tone audiometry
• Speech discrimination testing
• Auditory brainstem response testing

Hearing surveillance is an essential part of management.

Differential Diagnosis of NF1

Important alternatives include:

• Legius syndrome
• McCune-Albright syndrome
• Constitutional café-au-lait pigmentation
• Other RASopathies
• Segmental/mosaic NF1

Legius Syndrome

Legius syndrome is caused by pathogenic variants in:

SPRED1

It can produce:

• Café-au-lait spots
• Axillary or inguinal freckling

but typically lacks:

• Neurofibromas
• Lisch nodules
• Optic pathway gliomas

This is an important differential in young children with pigmentary findings alone.

Differential Diagnosis of NF2

Consider:

• Other forms of schwannomatosis
• Sporadic vestibular schwannoma
• Multiple meningioma syndromes
• Other hereditary tumor-predisposition syndromes

Treatment of NF1

Treatment is individualized according to the complication.

There is no single therapy for NF1 itself.

Optic Pathway Glioma – Observation

Many NF1-associated optic pathway gliomas:

• Grow slowly
• Remain asymptomatic
• Do not require treatment

Treatment is generally based more on:

Documented visual deterioration

than on MRI appearance alone.

Optic Pathway Glioma – Treatment

Treatment is considered when there is:

• Progressive visual loss
• Significant tumor progression with functional impact
• Other clinically important progression

Systemic chemotherapy has traditionally included regimens such as:

• Carboplatin
• Vincristine

Modern targeted treatment, including MEK inhibition, may be considered in selected progressive NF1-associated tumors under specialist care.

Radiation in NF1

Radiotherapy is generally avoided when possible, particularly in children with NF1, because of increased risks of:

• Secondary tumors
• Radiation-induced vasculopathy
• Moyamoya-type vascular disease

Plexiform Neurofibroma

Management may include:

• Observation
• Surgical resection
• Targeted systemic treatment for symptomatic, inoperable lesions

The MEK inhibitor selumetinib is used for selected children with symptomatic, unresectable NF1-associated plexiform neurofibromas.

Treatment of NF2-Related Schwannomatosis

Management may include:

• Observation with serial MRI
• Microsurgery
• Stereotactic radiation in selected patients
• Systemic targeted therapy

Treatment aims to preserve:

• Hearing
• Facial nerve function
• Neurologic function
• Vision

Bevacizumab in NF2

Bevacizumab can be useful in selected patients with progressive vestibular schwannomas, particularly when hearing is deteriorating.

Potential benefits include:

• Tumor shrinkage
• Hearing improvement or stabilization

Treatment requires specialist systemic monitoring.

Cataract Treatment

Visually significant cataract is treated with:

• Cataract extraction
• Intraocular lens implantation when appropriate

Epiretinal Membrane

Observation is appropriate when mild.

Vitrectomy with membrane peeling may be considered when there is significant:

• Visual loss
• Metamorphopsia
• Macular distortion

Multidisciplinary Care

Patients may require involvement of:

• Ophthalmology
• Neuro-ophthalmology
• Neurology
• Neurosurgery
• Neuro-oncology
• Genetics
• ENT/audiology
• Orthopedics
• Dermatology
• Endocrinology
• Cardiology or vascular specialists

Ongoing Ophthalmic Surveillance in NF1

Children require regular ophthalmic examinations, particularly during the years when optic pathway glioma is most likely to become symptomatic.

Monitoring should include:

• Age-appropriate visual acuity
• Pupils
• Color vision when possible
• Ocular alignment
• Optic nerve examination
• Eyelid/orbital assessment

Blood Pressure Monitoring

Patients with NF1 should undergo regular blood pressure assessment because hypertension may indicate:

• Renal artery stenosis
• Pheochromocytoma
• Other vascular disease

Pregnancy Considerations

During pregnancy, women with NF1 may experience:

• Enlargement of existing neurofibromas
• Development of additional neurofibromas

Pregnancy planning should include:

• Genetic counseling
• Assessment of significant tumor burden
• Blood pressure monitoring

Patient Education

Patients and families should seek evaluation for:

• New visual loss
• New strabismus
• Proptosis
• Persistent headache
• New neurologic deficit
• Rapidly enlarging painful neurofibroma
• Hearing loss
• Tinnitus
• Balance problems

Prognosis

NF1

Many patients have relatively mild disease and normal or near-normal life expectancy.

Morbidity depends on complications such as:

• Malignant peripheral nerve sheath tumor
• Severe vascular disease
• CNS tumors
• Large plexiform neurofibromas

NF2-Related Schwannomatosis

NF2 generally causes greater neurologic morbidity because patients frequently develop multiple:

• Schwannomas
• Meningiomas
• Spinal tumors

Modern surveillance, surgery, hearing rehabilitation, and targeted therapy have substantially improved management.

Complications

NF1

Important complications include:

• Visual loss from optic pathway glioma
• Amblyopia
• Glaucoma
• Proptosis
• Skeletal deformity
• Seizures
• Moyamoya disease
• Hypertension
• Malignant peripheral nerve sheath tumor

NF2

Important complications include:

• Hearing loss
• Tinnitus
• Balance dysfunction
• Cranial nerve palsies
• Spinal cord compression
• Visual loss
• Cataract
• Retinal or epiretinal abnormalities

Ophthalmology Pearls

• NF1 = café-au-lait spots + axillary/inguinal freckling + neurofibromas + Lisch nodules + optic pathway glioma.
• Lisch nodules are benign iris hamartomas and usually do not affect vision.
• Choroidal abnormalities detectable by near-infrared imaging are now recognized diagnostic features of NF1.
• The most important vision-threatening lesion in children with NF1 is the optic pathway glioma.
• Most NF1-associated optic pathway gliomas do not require treatment unless visual function deteriorates.
• Plexiform neurofibroma involving the upper eyelid can cause the characteristic S-shaped eyelid deformity.
• NF1 is associated with moyamoya disease, renal artery stenosis, and pheochromocytoma.
• NF2-related schwannomatosis = bilateral vestibular schwannomas until proven otherwise.
• Early cataract, epiretinal membrane, or retinal hamartoma in a young patient may provide an ophthalmic clue to NF2.
• Radiation is generally used cautiously in NF1 because of increased risks of secondary tumors and vasculopathy.
• Both NF1 and NF2 require lifelong multidisciplinary surveillance.

Ophthalmology – Neovascular Glaucoma

Basics

Description

Neovascular glaucoma (NVG) is a severe secondary glaucoma caused by retinal ischemia–driven neovascularization of the iris and anterior chamber angle.

The disease progresses from:

• Iris neovascularization (rubeosis iridis)
• Angle neovascularization
• Formation of a fibrovascular membrane
• Contraction of this membrane
• Progressive peripheral anterior synechiae
• Secondary angle closure
• Markedly elevated intraocular pressure

NVG is often painful and potentially blinding.

Older synonyms include:

• Rubeotic glaucoma
• Hemorrhagic glaucoma
• Congestive glaucoma
• Thrombotic glaucoma

Major Causes

The most important causes are:

• Proliferative diabetic retinopathy
• Ischemic central retinal vein occlusion
• Ocular ischemic syndrome from carotid occlusive disease

Any condition causing sufficiently severe retinal ischemia may produce NVG.

Epidemiology

NVG is relatively uncommon but represents one of the most severe forms of secondary glaucoma.

It occurs predominantly in:

• Older adults
• Patients with diabetes
• Patients with retinal vascular disease
• Patients with severe systemic atherosclerotic disease

The risk is especially high in eyes with:

• Proliferative diabetic retinopathy
• Ischemic CRVO

Risk Factors

Major risk factors include:

• Severe retinal ischemia
• Proliferative diabetic retinopathy
• Ischemic CRVO
• Carotid occlusive disease
• Poorly controlled diabetes
• Hypertension
• Atherosclerosis

Historically, diabetic eyes undergoing extensive intraocular surgery were recognized as being at particularly high risk when severe untreated retinal ischemia was present.

Pathophysiology

The fundamental mechanism is:

Retinal ischemia → angiogenic factor release → anterior segment neovascularization → fibrovascular contraction → angle closure glaucoma

VEGF

Hypoxic retina produces angiogenic mediators, particularly:

Vascular endothelial growth factor (VEGF)

VEGF diffuses through the vitreous and aqueous humor and stimulates formation of abnormal vessels on the:

• Iris
• Pupillary margin
• Anterior chamber angle

Early Stage

Initially, new vessels appear:

• At the pupillary border
• On the anterior iris surface
• Within the anterior chamber angle

At this stage, the angle may still be anatomically open.

IOP may be:

• Normal
• Mildly elevated
• Significantly elevated

Early disease can sometimes be reversed if the underlying ischemic stimulus is treated promptly.

Fibrovascular Membrane Formation

Neovascular tissue is accompanied by fibrovascular proliferation.

This membrane grows across the:

• Iris
• Trabecular meshwork
• Anterior chamber angle

Contraction eventually pulls the peripheral iris anteriorly.

Late Stage

Progressive contraction leads to:

• Peripheral anterior synechiae
• Progressive angle closure
• Severe reduction of aqueous outflow
• Markedly elevated IOP

Once extensive synechial closure develops, regression of vessels alone does not reopen the angle.

Therefore, glaucoma treatment becomes much more difficult.

Etiology

Important causes of retinal ischemia associated with NVG include:

• Central retinal vein occlusion
• Proliferative diabetic retinopathy
• Ocular ischemic syndrome
• Central retinal artery occlusion
• Branch retinal vein occlusion
• Chronic retinal detachment
• Radiation retinopathy
• Sickle cell retinopathy
• Coats disease
• Eales disease
• Retinopathy of prematurity
• Severe chronic ocular inflammation
• Uveitis-glaucoma-hyphema syndrome
• Intraocular tumors
• Carotid-cavernous fistula
• Giant cell arteritis
• Takayasu arteritis
• Anterior segment ischemia
• Severe ocular trauma

Intraocular Tumors

Rarely, rubeosis may develop secondary to:

• Retinoblastoma in children
• Choroidal melanoma
• Other intraocular tumors

When the fundus cannot be visualized, an occult intraocular tumor must be considered before performing destructive glaucoma procedures.

Associated Systemic Conditions

Common systemic associations include:

• Diabetes mellitus
• Hypertension
• Hyperlipidemia
• Atherosclerotic cardiovascular disease
• Carotid artery disease

Clinical Stages

NVG can be considered in three broad stages.

Stage 1 – Rubeosis Iridis

Features:

• Fine iris neovascularization
• Usually begins at the pupillary margin
• Angle may remain open
• IOP may still be normal

This is the ideal stage for intervention.

Stage 2 – Open-Angle NVG

Features include:

• Neovascularization of the angle
• Fibrovascular membrane over the trabecular meshwork
• Increasing IOP
• Angle still partly open

This stage may still respond to rapid retinal ischemia treatment and IOP-lowering therapy.

Stage 3 – Synechial Angle Closure

Features include:

• Extensive peripheral anterior synechiae
• Closed angle
• Very high IOP
• Pain
• Corneal edema
• Marked visual loss

At this stage, glaucoma surgery is frequently required.

Diagnosis

History

Typical symptoms include:

• Painful red eye
• Ocular pressure sensation
• Headache
• Photophobia
• Decreased vision
• Halos around lights

Some patients may initially be asymptomatic when only iris neovascularization is present.

External and Anterior Segment Examination

Possible findings include:

• Conjunctival injection
• Ciliary flush
• Corneal edema
• Shallow or normal anterior chamber depending on stage
• Anterior chamber cells and flare
• Hyphema

Rubeosis Iridis

The earliest iris finding is often:

Fine abnormal vessels at the pupillary margin

These vessels:

• Are irregular
• Cross normal iris architecture
• Extend onto the anterior iris surface

They should not be confused with normal radial iris vessels.

Gonioscopy

Gonioscopy is essential.

Look for:

• Fine neovascular vessels crossing the scleral spur
• Neovascularization of the trabecular meshwork
• Peripheral anterior synechiae
• Extent of angle closure

Angle neovascularization can precede obvious iris neovascularization.

Hyphema

Fragile new vessels may bleed spontaneously, causing:

• Microhyphema
• Gross hyphema

Hyphema can further increase IOP.

Intraocular Pressure

IOP can be:

• Normal in very early rubeosis
• Moderately elevated in open-angle disease
• Extremely elevated after synechial angle closure

Posterior Segment Examination

A dilated retinal examination should identify the ischemic cause.

Central Retinal Vein Occlusion

Features suggesting CRVO include:

• Dilated tortuous retinal veins
• Widespread retinal hemorrhages
• Cotton-wool spots
• Disc edema
• Macular edema

Extensive ischemia greatly increases NVG risk.

Proliferative Diabetic Retinopathy

Look for:

• Neovascularization of the disc
• Neovascularization elsewhere
• Preretinal hemorrhage
• Vitreous hemorrhage
• Extensive capillary nonperfusion

Ocular Ischemic Syndrome

Possible findings include:

• Midperipheral dot-blot hemorrhages
• Narrow retinal arteries
• Dilated but often not markedly tortuous veins
• Delayed retinal arterial filling
• Iris neovascularization
• Ocular pain

Severe carotid stenosis should be investigated.

Central Retinal Artery Occlusion

Look for:

• Retinal whitening
• Cherry-red spot
• Attenuated retinal arteries

NVG is less common after CRAO than after ischemic CRVO but can occur when widespread ocular ischemia persists.

Diagnostic Testing

Fluorescein Angiography

Fluorescein angiography can identify:

• Areas of retinal capillary nonperfusion
• Retinal neovascularization
• Leakage
• Severity of ischemia

It can be particularly useful in:

• CRVO
• Diabetic retinopathy
• Ocular ischemic syndrome

OCT

OCT may be useful for evaluating:

• Macular edema
• Diabetic macular disease
• Retinal structural damage

It does not replace fluorescein angiography for assessing widespread retinal perfusion.

B-Scan Ultrasonography

B-scan is useful when the fundus cannot be seen because of:

• Dense cataract
• Vitreous hemorrhage
• Corneal opacity

It can help identify:

• Retinal detachment
• Intraocular tumor
• Other posterior segment abnormalities

Carotid Evaluation

When ocular ischemic syndrome or arterial occlusive disease is suspected, evaluation may include:

• Carotid duplex ultrasonography
• CT angiography
• MR angiography

Systemic vascular referral may be necessary.

Laboratory Evaluation

Laboratory testing depends on the underlying cause.

Possible tests include:

• Fasting glucose
• HbA1c
• Lipid profile
• Blood pressure assessment

In selected patients:

• ESR
• CRP
• Platelet count

may be appropriate when giant cell arteritis is suspected.

Younger patients with unusual retinal vascular occlusion may require targeted evaluation for:

• Hypercoagulable states
• Hyperviscosity disorders
• Systemic inflammatory disease

Follow-Up After CRVO

Eyes with CRVO require close surveillance for:

• Iris neovascularization
• Angle neovascularization
• Conversion to a more ischemic phenotype

The highest risk period is within the first several months.

Monthly anterior segment examination and gonioscopy during the early high-risk period is often appropriate, especially in ischemic or indeterminate CRVO.

Differential Diagnosis

Important differential diagnoses include:

• Uveitic glaucoma
• Fuchs uveitis syndrome
• Primary angle-closure glaucoma
• Posner-Schlossman syndrome
• Traumatic glaucoma
• Ghost-cell glaucoma
• Hemolytic glaucoma

The presence of iris or angle neovascularization strongly supports NVG.

Treatment Principles

Treatment has two simultaneous goals:

1. Eliminate the retinal ischemic stimulus
2. Lower intraocular pressure and control pain

Treating IOP alone without treating retinal ischemia usually fails.

Panretinal Photocoagulation

Panretinal photocoagulation (PRP) is the definitive treatment for retinal ischemia when sufficient retina can be visualized.

PRP reduces the ischemic retinal tissue producing VEGF.

It can cause regression of:

• Iris neovascularization
• Angle neovascularization

and helps reduce recurrent neovascularization.

Anti-VEGF Therapy

Intravitreal anti-VEGF treatment produces rapid regression of anterior segment neovascularization.

Common agents include:

• Bevacizumab
• Ranibizumab
• Aflibercept

Role of Anti-VEGF

Anti-VEGF therapy:

• Acts rapidly
• Reduces iris neovascularization
• Reduces angle neovascularization
• Reduces bleeding
• May facilitate subsequent glaucoma surgery

However:

Anti-VEGF therapy is temporary and does not replace PRP when retinal ischemia is present and treatable.

The ischemic retina continues to produce VEGF once the drug effect disappears.

PRP + Anti-VEGF

A common modern strategy is:

Anti-VEGF for rapid vessel regression + PRP for durable treatment of the ischemic drive

This combination is particularly valuable when there is:

• Florid rubeosis
• Hyphema
• Very active neovascularization

When PRP Cannot Initially Be Performed

PRP may be impossible because of:

• Dense vitreous hemorrhage
• Cataract
• Corneal edema
• Poor pupillary dilation

Options may include:

• Anti-VEGF as temporary control
• Pars plana vitrectomy
• Endolaser PRP during vitrectomy

depending on the underlying condition.

Medical IOP Treatment

Aqueous suppressants are preferred.

Useful medications include:

• Beta-blockers
• Alpha-2 agonists such as brimonidine
• Topical carbonic anhydrase inhibitors
• Oral acetazolamide when appropriate

Prostaglandin Analogs

Prostaglandin analogs may sometimes be used if additional IOP reduction is needed.

However, they may be less effective in severely inflamed or extensively closed angles and are generally not the central therapy.

Pilocarpine

Pilocarpine should generally be avoided.

Reasons include:

• Poor efficacy in a synechially closed angle
• Increased inflammation
• Potential worsening of ocular discomfort

Cycloplegics

Atropine or another cycloplegic may be useful to:

• Reduce ciliary spasm
• Improve pain
• Stabilize the blood-aqueous barrier

Topical Corticosteroids

Topical corticosteroids can help control:

• Anterior segment inflammation
• Pain
• Ciliary congestion

They do not treat the underlying retinal ischemia.

Hyperosmotic Therapy

For very high IOP in selected acute situations:

• Oral glycerol
• IV mannitol

may be considered, depending on systemic health.

These are short-term measures.

Glaucoma Surgery

If extensive angle closure has occurred and IOP remains uncontrolled, surgery is often necessary.

Glaucoma Drainage Device

A tube shunt is commonly favored in established NVG.

Examples include:

• Ahmed valve
• Baerveldt implant

Advantages include better performance than conventional filtration surgery in many eyes with:

• Active neovascularization
• Previous surgery
• Conjunctival scarring
• High risk of filtration failure

Trabeculectomy

Trabeculectomy with an antimetabolite such as mitomycin-C may be considered in carefully selected eyes.

Success is better when:

• Neovascular activity has been suppressed
• PRP has been completed
• The eye is relatively quiet

Failure rates are higher than in uncomplicated primary glaucoma because of aggressive scarring and inflammation.

Cyclodestructive Procedures

Transscleral cyclophotocoagulation can reduce aqueous production.

It is particularly useful in eyes with:

• Poor visual potential
• Severe pain
• Refractory IOP
• Poor candidacy for incisional surgery

Modern techniques include:

• Continuous-wave diode CPC
• Micropulse CPC in selected cases

Endocyclophotocoagulation

Endoscopic cyclophotocoagulation may be performed intraocularly in selected surgical situations but is less commonly used as primary therapy for severe NVG.

Painful Blind Eye

When visual potential is absent, management prioritizes comfort.

Options include:

• Cycloplegic drops
• Topical corticosteroids
• IOP-lowering therapy
• Cyclodestructive procedures

In a persistently painful blind eye despite treatment, definitive procedures such as:

• Enucleation
• Evisceration

may occasionally be considered.

Tumor-Associated NVG

If rubeosis is caused by an intraocular tumor, treatment is directed toward the tumor.

Possible treatments include:

• Radiation
• Tumor-directed therapy
• Enucleation in selected cases

Destructive glaucoma procedures should not be undertaken until an occult tumor has been excluded when the posterior segment cannot be visualized.

Systemic Disease Management

Control of systemic disease is essential.

This includes:

• Optimizing diabetes
• Treating hypertension
• Managing dyslipidemia
• Evaluating significant carotid disease
• Addressing systemic vascular risk

Referral

Patients with suspected NVG generally require urgent involvement of:

• Glaucoma specialist
• Retina specialist

Additional referral may include:

• Internal medicine
• Endocrinology
• Neurology
• Vascular surgery
• Stroke service

depending on the underlying cause.

Follow-Up

Follow-up is generally frequent until:

• Neovascularization regresses
• IOP stabilizes
• PRP is completed
• Underlying retinal disease is controlled

Monitoring includes:

• Visual acuity
• IOP
• Iris examination
• Gonioscopy
• Fundus examination
• Retinal imaging

Patient Education

Patients should understand that NVG is usually the consequence of severe retinal or ocular ischemia.

Important preventive measures include:

• Good diabetic control
• Blood pressure control
• Lipid management
• Smoking cessation
• Regular retinal examinations
• Timely treatment of proliferative diabetic retinopathy

Patients with retinal vascular occlusion require reliable follow-up even if the eye initially feels comfortable.

Prognosis

The prognosis is guarded.

Outcome depends on:

• Underlying retinal disease
• Severity of retinal ischemia
• Stage at diagnosis
• Amount of synechial angle closure
• Baseline visual function
• Response to PRP
• Ability to control IOP

Treatment during the early rubeotic stage offers a much better chance of avoiding severe glaucoma.

Complications

Potential complications include:

• Severe chronic ocular pain
• Hyphema
• Corneal edema
• Permanent optic nerve damage
• Complete visual loss
• Choroidal effusion
• Suprachoroidal hemorrhage
• Recurrent glaucoma after surgery
• Phthisis bulbi
• Loss of the eye

Ophthalmology Pearls

• Neovascular glaucoma = retinal ischemia → VEGF → rubeosis → fibrovascular membrane → peripheral anterior synechiae → angle closure.
• The three major causes are PDR, ischemic CRVO, and ocular ischemic syndrome.
• Rubeosis usually begins at the pupillary margin.
• Gonioscopy may reveal angle neovascularization before obvious iris vessels.
• Anti-VEGF causes rapid but temporary regression of neovascularization.
• PRP treats the underlying ischemic drive and is essential whenever feasible.
• Once extensive synechial closure has developed, vessel regression does not reopen the angle.
• Aqueous suppressants are preferred for IOP control; pilocarpine should generally be avoided.
• Established uncontrolled NVG frequently requires a glaucoma drainage device.
• A painful blind eye may eventually require cyclodestruction or definitive comfort surgery.
• After ischemic CRVO, careful surveillance during the first several months is crucial because anterior segment neovascularization can develop rapidly.

Ophthalmology – Neonatal Conjunctivitis

Basics

Description

Neonatal conjunctivitis (ophthalmia neonatorum) is conjunctival inflammation occurring during the first 4 weeks of life.

It may be:

• Infectious
• Chemical/toxic
• Iatrogenic

Because some causes—particularly gonococcal and herpes simplex infection—can rapidly threaten the cornea, vision, or life, neonatal conjunctivitis requires prompt etiologic assessment.

Major Causes

Important infectious causes include:

• Neisseria gonorrhoeae
• Chlamydia trachomatis
• Herpes simplex virus (HSV)
• Staphylococcus aureus, including MRSA
• Streptococcus pneumoniae
• Gram-negative enteric organisms
• Other bacterial pathogens

Noninfectious causes include:

• Chemical conjunctivitis
• Toxic reaction to topical medications

Epidemiology

The incidence varies markedly according to:

• Maternal infection prevalence
• Quality of prenatal care
• STI screening programs
• Availability of neonatal prophylaxis

Gonococcal ophthalmia has become uncommon in countries with effective maternal screening and neonatal prophylaxis but remains a major preventable cause of severe ocular morbidity in some settings.

Risk Factors

Important risk factors include:

• Maternal sexually transmitted infection
• Inadequate prenatal care
• Premature rupture of membranes
• Prolonged rupture of membranes
• Low birth weight
• Prematurity
• Failure to receive indicated ocular prophylaxis
• Contaminated ophthalmic instruments
• Respiratory support devices
• Poor infection-control practices

Irritating topical substances or inappropriate traditional remedies may also cause conjunctival inflammation or secondary infection.

Genetics

There is no recognized genetic contribution to ordinary neonatal conjunctivitis.

Prevention

The most important preventive measure is appropriate prenatal screening and treatment of maternal infection, especially:

• Gonorrhea
• Chlamydia
• Syphilis
• HIV
• Genital herpes when clinically relevant

Strict hygiene and sterile technique should be used in neonatal care.

Ocular Prophylaxis

Where recommended by local public-health policy, neonatal ocular prophylaxis is directed primarily against gonococcal ophthalmia.

In the United States, the CDC recommends a single application of erythromycin 0.5% ophthalmic ointment to both eyes at birth. This prophylaxis does not reliably prevent chlamydial conjunctivitis, so prenatal maternal screening remains essential. 

Pathophysiology

Neonatal conjunctivitis usually results from inoculation of the conjunctiva through:

• Passage through an infected birth canal
• Ascending infection after ruptured membranes
• Postnatal contact
• Contaminated equipment or caregivers

Neonates have relatively immature immune defenses, which can allow rapid progression of infection.

Timing of Presentation

The timing of onset can provide an important diagnostic clue.

Chemical Conjunctivitis

Usually:

• Within the first 24 hours

Gonococcal Conjunctivitis

Usually:

• Approximately 2–5 days after birth

Chlamydial Conjunctivitis

Usually:

• Approximately 5–14 days after birth

Herpes Simplex Conjunctivitis

Often develops:

• During the first 1–2 weeks of life

There is overlap, so timing alone must not determine treatment.

Gonococcal Ophthalmia Neonatorum

Neisseria gonorrhoeae is the most immediately vision-threatening bacterial cause.

Typical findings include:

• Rapid onset
• Marked eyelid edema
• Severe conjunctival injection
• Chemosis
• Copious hyperpurulent discharge

The organism can penetrate intact corneal epithelium.

Gonococcal Corneal Disease

Serious complications include:

• Keratitis
• Corneal ulceration
• Corneal melting
• Corneal perforation
• Endophthalmitis
• Permanent blindness

Therefore, suspected gonococcal conjunctivitis is an ophthalmic and pediatric emergency.

Chlamydial Conjunctivitis

Chlamydia trachomatis is another major cause of neonatal conjunctivitis.

Typical manifestations include:

• Mucopurulent discharge
• Eyelid edema
• Conjunctival hyperemia
• Chemosis

Because newborns lack mature conjunctival lymphoid tissue, the classic follicular response seen in adults may be absent.

Chlamydial Systemic Association

Neonatal chlamydial conjunctivitis may be associated with:

• Nasopharyngeal infection
• Genital infection
• Rectal colonization
• Chlamydial pneumonitis

Therefore, topical therapy alone is inadequate.

Herpes Simplex Virus

Neonatal HSV infection may involve:

• Conjunctiva
• Cornea
• Skin
• Mouth
• Central nervous system
• Multiple visceral organs

Ocular HSV should always raise concern for systemic neonatal herpes.

HSV Ocular Findings

Possible findings include:

• Watery or mucoid discharge
• Conjunctivitis
• Vesicular eyelid or skin lesions
• Dendritic epithelial keratitis
• Geographic epithelial ulcer
• Stromal keratitis

Absence of skin vesicles does not exclude neonatal herpes.

Chemical Conjunctivitis

Chemical conjunctivitis may follow exposure to irritating prophylactic or topical agents.

Typical features include:

• Conjunctival injection
• Chemosis
• Mucous discharge

It is generally:

• Early in onset
• Bilateral
• Self-limited

History

Maternal and Birth History

Ask about:

• Quality of prenatal care
• Maternal gonorrhea or chlamydia
• Genital herpes
• Other sexually transmitted infections
• Maternal genital discharge
• Partner STI history
• Premature rupture of membranes
• Duration of membrane rupture
• Mode of delivery
• Perinatal antibiotic treatment

Infant History

Ask about:

• Age at symptom onset
• Low birth weight
• Prematurity
• Fever
• Poor feeding
• Lethargy
• Respiratory symptoms
• Skin vesicles
• Ocular prophylaxis received
• Intensive-care procedures
• Respiratory support
• Previous eye examination or instrumentation

Physical Examination

A complete systemic and ophthalmic examination is required.

Assess:

• General appearance
• Temperature
• Feeding
• Respiratory status
• Skin
• Oral cavity
• Neurologic status

Eyelid Findings

Look for:

• Edema
• Erythema
• Vesicles
• Skin erosions
• Preseptal cellulitis

Marked tense lid edema with copious purulent discharge raises particular concern for gonococcus.

Conjunctiva

Assess for:

• Injection
• Chemosis
• Membranes or pseudomembranes
• Character of discharge

Important Pearl

Discharge without significant conjunctival injection should raise suspicion for congenital nasolacrimal duct obstruction rather than primary conjunctivitis.

Character of Discharge

Gonococcal

Typically:

Profuse, thick, hyperpurulent discharge

Chlamydial

Typically:

• Mucopurulent discharge

HSV

May produce:

• Watery
• Serous
• Mucoid discharge

The discharge pattern alone is not sufficiently reliable to establish the diagnosis.

Corneal Examination

The cornea must be examined carefully in every neonate with significant conjunctivitis.

Look for:

• Epithelial defect
• Infiltrate
• Ulcer
• Corneal thinning
• Perforation

Gonococcal Cornea

Possible findings include:

• Peripheral or central ulcer
• Rapid stromal thinning
• Perforation

Urgent corneal specialist involvement may be required.

HSV Cornea

Possible findings include:

• Dendritic epithelial lesion
• Geographic epithelial defect
• Stromal infiltrate

Topical corticosteroids should not be started empirically in suspected epithelial HSV disease.

Diagnostic Testing

Significant neonatal conjunctivitis should undergo microbiologic investigation rather than being treated empirically with topical drops alone.

Gram Stain

An urgent conjunctival Gram stain is particularly useful when gonorrhea is suspected.

Classic finding:

Intracellular gram-negative diplococci

A suspicious clinical presentation warrants immediate systemic treatment without waiting for final culture results.

Bacterial Culture

Conjunctival specimens should be obtained for:

• Gram stain
• Culture
• Antimicrobial susceptibility testing

Appropriate media must be used when gonococcus is suspected.

Chlamydial Testing

Conjunctival samples should contain epithelial cells, not simply surface discharge.

Testing may include:

• Culture
• Direct fluorescent antibody testing
• Validated nucleic-acid amplification testing depending on local laboratory capability

A neonate evaluated for chlamydial ophthalmia should also be evaluated for gonorrhea. 

HSV Testing

When HSV is suspected, testing may include:

• HSV PCR from ocular or mucosal specimens
• Surface cultures/PCR
• Blood PCR
• CSF evaluation when indicated

Evaluation should be coordinated urgently with pediatrics or pediatric infectious disease.

Additional STI Evaluation

When neonatal gonorrhea or chlamydia is identified, maternal infection and other perinatal infections must be considered.

Depending on the clinical situation, evaluation may include:

• Syphilis
• HIV
• Other sexually transmitted infections

The mother and her sexual partner(s) require evaluation and treatment.

Lumbar Puncture

Lumbar puncture should be considered when:

• HSV infection is suspected
• Meningitis is suspected
• The infant is systemically unwell
• Disseminated infection is possible

Neuroimaging

Brain MRI or other imaging may be indicated when there is concern for:

• HSV encephalitis
• Neurologic abnormalities
• Intracranial complications

Orbital imaging may be required if:

• Orbital cellulitis is suspected
• There is proptosis
• Ocular motility is impaired
• Significant periocular swelling is present

Differential Diagnosis

Important differential diagnoses include:

• Congenital nasolacrimal duct obstruction
• Dacryocystitis
• Neonatal blepharitis
• Blepharoconjunctivitis
• Congenital glaucoma
• Keratitis
• Corneal foreign body or trauma
• Uveitis secondary to congenital infection
• Rare infiltrative ocular disorders

Important Differential – Nasolacrimal Duct Obstruction

NLDO usually causes:

• Epiphora
• Mucous discharge
• Matted lashes

but typically:

Little or no conjunctival injection

Important Differential – Congenital Glaucoma

Congenital glaucoma typically presents with:

• Epiphora
• Photophobia
• Blepharospasm
• Corneal enlargement
• Corneal haze

This requires urgent ophthalmologic assessment.

Treatment

Treatment depends on the organism.

Because neonatal infection can progress rapidly, significant conjunctivitis should be managed jointly with:

• Ophthalmology
• Pediatrics
• Pediatric infectious disease when appropriate

Gonococcal Conjunctivitis

Emergency Treatment

Current CDC therapy for uncomplicated gonococcal ophthalmia neonatorum is:

Ceftriaxone 25–50 mg/kg IV or IM once, maximum 250 mg.

Cefotaxime can be used in neonates in whom ceftriaxone is unsuitable, such as certain situations involving hyperbilirubinemia or IV calcium exposure. Systemic treatment—not topical therapy alone—is essential. 

The infant should also be assessed for disseminated gonococcal infection, including:

• Sepsis
• Arthritis
• Meningitis

Ocular Irrigation in Gonococcal Disease

Frequent sterile saline irrigation may be useful to remove large amounts of purulent material.

This is adjunctive and never substitutes for systemic antibiotics.

Chlamydial Conjunctivitis

Systemic therapy is mandatory because infection can also involve the respiratory and nasopharyngeal tracts.

The CDC recommended regimen is:

Erythromycin base or ethylsuccinate 50 mg/kg/day orally in 4 divided doses for 14 days. 

A short-course azithromycin regimen may be used in selected circumstances, although evidence in neonates is more limited. 

Chlamydia – Important Medication Warning

Oral erythromycin and azithromycin in infants younger than approximately 6 weeks have been associated with:

Infantile hypertrophic pyloric stenosis

Parents should be advised to monitor for:

• Forceful vomiting
• Feeding intolerance
• Progressive vomiting

despite the need to treat the infection appropriately. 

Topical Therapy in Chlamydia

Topical antibiotics alone are inadequate because chlamydia is not limited to the conjunctiva.

When appropriate systemic therapy is given, routine topical treatment is generally unnecessary. 

Herpes Simplex Virus

Neonatal HSV requires urgent systemic acyclovir.

Standard systemic therapy is:

Acyclovir 20 mg/kg IV every 8 hours

with duration depending on disease extent:

• Approximately 14 days for disease limited to skin, eyes, and mouth
• 21 days for CNS or disseminated disease 

Ocular HSV should also be managed with a pediatric ophthalmologist, with topical antiviral treatment when indicated.

HSV and Steroids

Topical corticosteroids should not be used empirically in neonatal epithelial HSV keratitis.

Any steroid treatment for HSV-associated stromal disease requires specialist supervision and concurrent antiviral coverage.

Other Bacterial Conjunctivitis

Treatment should be guided by:

• Gram stain
• Culture
• Sensitivities
• Clinical severity

Coverage should reflect local resistance patterns, including MRSA where appropriate.

Systemically ill neonates require systemic evaluation and treatment.

Chemical Conjunctivitis

Management consists primarily of:

• Discontinuing the offending agent
• Gentle ocular cleansing or irrigation
• Supportive care

Most cases are self-limited.

Persistent or worsening inflammation should prompt reconsideration of an infectious cause.

Corneal Involvement

Urgent corneal or pediatric ophthalmology consultation is required for:

• Corneal ulcer
• Stromal infiltrate
• Progressive thinning
• Impending perforation
• Actual perforation
• Persistent HSV keratitis

Hospital Admission

Admission should be strongly considered for neonates with:

• Suspected gonococcal disease
• Suspected neonatal HSV
• Severe purulent conjunctivitis
• Corneal involvement
• Dacryocystitis with systemic illness
• Preseptal or orbital cellulitis
• Fever or sepsis
• Poor feeding
• Neurologic symptoms

A systemically ill neonate should be managed as a medical emergency.

Infection-Control Precautions

Appropriate contact and infection-control precautions should be used according to the suspected organism and hospital protocol.

Maternal and Partner Management

If gonorrhea or chlamydia is identified:

• The mother requires evaluation and treatment.
• Sexual partner(s) require evaluation and treatment.
• Other STIs should be considered.

This reduces maternal complications and future transmission.

Follow-Up

Close follow-up is required until:

• Discharge resolves
• Conjunctival inflammation clears
• Corneal integrity is confirmed
• Systemic infection has been excluded or treated

Chlamydial disease requires follow-up because treatment failure can occur.

Long-Term Ophthalmic Follow-Up

If corneal scarring develops, the infant should be monitored for:

• Refractive error
• Irregular astigmatism
• Anisometropia
• Deprivation amblyopia

Early amblyopia management may be essential.

Patient Education

Parents should understand that neonatal conjunctivitis can occasionally represent a serious systemic infection.

Urgent reassessment is needed for:

• Increased eyelid swelling
• Copious purulent discharge
• Corneal clouding
• Poor feeding
• Fever
• Lethargy
• Skin vesicles
• Seizures
• Respiratory symptoms

Unsterile traditional remedies, including substances such as urine, should not be placed into the infant’s eyes.

Prognosis

Uncomplicated Disease

Prognosis is generally:

Excellent

when the cause is identified and treated promptly.

Corneal Scarring

Visual prognosis becomes variable because of:

• Optical distortion
• Anisometropia
• Amblyopia

Gonococcal Corneal Perforation

Prognosis can be poor because of:

• Dense corneal scarring
• Endophthalmitis
• Structural ocular damage
• Severe amblyopia

Complications

Important complications include:

• Corneal ulceration
• Corneal perforation
• Corneal scarring
• Keratitis
• Endophthalmitis
• Amblyopia
• Preseptal cellulitis
• Orbital cellulitis
• Sepsis
• Chlamydial pneumonitis
• HSV encephalitis
• Disseminated neonatal HSV

Ophthalmology Pearls

• Neonatal conjunctivitis = conjunctivitis during the first 4 weeks of life.
• Timing is helpful: chemical first day, gonococcus approximately 2–5 days, chlamydia approximately 5–14 days, HSV commonly during the first 1–2 weeks.
• Copious hyperpurulent discharge = gonococcus until proven otherwise.
• Gonococcus can invade an intact cornea and rapidly cause ulceration and perforation.
• Chlamydial conjunctivitis requires systemic therapy because of associated nasopharyngeal and pulmonary infection.
• Neonatal HSV requires systemic IV acyclovir, even when ocular disease appears localized.
• Dendritic keratitis in a neonate should immediately raise concern for HSV.
• Discharge with little or no conjunctival injection favors nasolacrimal duct obstruction.
• Epiphora with photophobia, blepharospasm, and corneal haze suggests congenital glaucoma rather than simple conjunctivitis.
• Any systemically unwell neonate with conjunctivitis requires urgent pediatric evaluation.

Ophthalmology – Nasolacrimal Duct Obstruction in Children

Basics

Description

Congenital nasolacrimal duct obstruction (CNLDO) is the most common congenital abnormality of the lacrimal drainage system.

The nasolacrimal duct normally carries tears from the:

• Lacrimal sac
• Through the nasolacrimal duct
• Into the inferior meatus beneath the inferior turbinate

Congenital obstruction most commonly results from persistence of a thin membranous blockage at the distal duct near the:

Valve of Hasner

Typical manifestations are:

• Epiphora
• Increased tear lake
• Mucous or mucopurulent discharge
• Crusting of the eyelashes

Most cases resolve spontaneously during infancy.

⸻

Epidemiology

Congenital NLDO is common.

Reported incidence is approximately:

6–20% of neonates

It is the most common congenital lacrimal drainage abnormality.

Approximately 90% of affected infants improve spontaneously by about 1 year of age.

⸻

Risk Factors

Most cases occur in otherwise healthy children.

Risk may be increased in children with:

• Craniofacial malformations
• Down syndrome
• Oculonasal developmental abnormalities
• Cornelia de Lange syndrome
• Johanson-Blizzard syndrome
• Other syndromes involving craniofacial development

These patients may have more complex lacrimal drainage abnormalities in addition to simple distal NLDO.

⸻

Genetics

No single causative genetic abnormality is responsible for most isolated cases.

However:

• Familial clustering has been reported.
• When NLDO occurs as part of a genetic syndrome, inheritance follows the pattern of that syndrome.
• Expression of the lacrimal anomaly may vary among affected family members.

⸻

Pathophysiology

The nasolacrimal drainage system develops from a cord of surface ectoderm between the:

• Maxillary process
• Lateral nasal process

The epithelial cord later canalizes.

Failure of complete distal canalization produces a membranous obstruction, most commonly at the:

Valve of Hasner

This prevents normal drainage of tears into the nose.

⸻

Etiology

The exact reason why distal canalization fails in individual infants is usually unknown.

Most cases are:

• Sporadic
• Congenital
• Isolated

⸻

Commonly Associated Conditions

Associated conditions include:

• Down syndrome
• Craniofacial abnormalities
• Preauricular sinus
• Syndromes with oculofacial malformations

However, the majority of children with CNLDO have no systemic abnormality.

⸻

Diagnosis

Diagnosis is usually clinical.

The typical infant presents with:

• Persistent tearing
• Mucous discharge
• Matted eyelashes
• Little or no conjunctival injection

⸻

History

Parents commonly report:

• Constant or intermittent epiphora
• Mucous or mucopurulent discharge
• Eyelashes sticking together
• Symptoms worse on awakening
• Increased discharge during upper respiratory infections
• Increased tearing outdoors or in windy conditions

Symptoms may not be obvious immediately after birth because tear production is relatively low in the early neonatal period.

⸻

Physical Examination

Typical findings include:

• Wet eyelid margin
• Matted eyelashes
• Increased tear lake
• Mucous discharge
• Minimal conjunctival redness

⸻

Lacrimal Sac Compression

Gentle pressure over the lacrimal sac may cause:

• Mucous reflux
• Mucopurulent reflux
• Purulent material through the puncta

This strongly supports distal lacrimal drainage obstruction.

⸻

Skin Changes

Longstanding overflow of tears may produce:

• Irritation
• Erythema
• Excoriation
• Chronic dermatitis of the lower eyelid and cheek

⸻

Important Examination Point

A complete examination of the:

• Eyelids
• Puncta
• Conjunctiva
• Cornea

should be performed to exclude other causes of tearing.

⸻

Diagnostic Testing

Laboratory Testing

Routine laboratory testing is unnecessary.

If frank infection is present, cultures may occasionally be useful.

⸻

Fluorescein Dye Disappearance Test

This is a simple and useful test for lacrimal drainage.

A drop of fluorescein is placed in the conjunctival sac.

After approximately 5 minutes:

• Normal drainage → little fluorescein remains
• Obstruction → persistent pooling of fluorescein

Comparison between the two eyes is particularly helpful in unilateral disease.

⸻

Nasal Fluorescein Recovery

If fluorescein reaches the nasal cavity, this supports a patent drainage pathway.

Historically, fluorescein may be detected with:

• A cotton-tipped applicator beneath the inferior turbinate

This is not routinely necessary in straightforward cases.

⸻

Imaging

Most children do not require imaging.

Consider CT or other imaging when there is:

• Craniofacial abnormality
• Facial trauma
• Atypical presentation
• Suspected mass
• Complex lacrimal anatomy

⸻

Differential Diagnosis

Important differential diagnoses include:

• Dacryocele
• Congenital entropion
• Congenital ectropion
• Epiblepharon
• Trichiasis
• Infectious conjunctivitis
• Keratitis
• Uveitis
• Corneal foreign body
• Punctal agenesis or stenosis
• Canalicular abnormalities
• Lacrimal fistula
• Congenital glaucoma

⸻

Important Differential – Congenital Glaucoma

An infant with tearing should always be assessed for congenital glaucoma.

Features that favor glaucoma include:

• Photophobia
• Blepharospasm
• Corneal haze
• Enlarged corneal diameter
• Buphthalmos

These are not typical features of uncomplicated NLDO.

⸻

Dacryocele

A dacryocele results from obstruction both:

• Distally at the nasolacrimal duct
• Proximally near the common canaliculus

It typically appears as a:

• Bluish
• Cystic
• Medial canthal swelling

A dacryocele may extend into the nose and cause respiratory difficulty in neonates, particularly if bilateral.

⸻

Dacryocystitis

If an infant develops:

• Painful swelling
• Erythema
• Tenderness over the lacrimal sac
• Fever
• Purulent discharge

suspect:

Acute dacryocystitis

This requires urgent treatment.

⸻

Treatment

First-Line – Lacrimal Sac Massage

The usual initial treatment is:

Crigler lacrimal sac massage

The goal is to increase hydrostatic pressure within the lacrimal sac and help rupture the distal membranous obstruction.

⸻

Massage Technique

The caregiver places a finger over the lacrimal sac region just below the medial canthus.

Then:

• Apply firm pressure inward toward the lacrimal sac
• Sweep downward along the side of the nose

This compresses the lacrimal sac and increases pressure toward the distal obstruction.

Massage is commonly performed:

Several times per day

Parents should be shown the technique directly.

⸻

Observation

Because spontaneous resolution is very common, observation with massage is appropriate for most infants during the first year of life.

⸻

Antibiotics

Antibiotics are not routinely required for uncomplicated CNLDO.

They may be used when there is:

• Significant mucopurulent discharge
• Secondary bacterial conjunctivitis
• Dacryocystitis

Topical antibiotics may help control discharge, but they:

Do not open the obstruction itself.

⸻

Referral

Referral to pediatric ophthalmology is appropriate when:

• Symptoms persist near or beyond 12 months
• Symptoms are severe
• Copious discharge persists
• There is recurrent infection
• Diagnosis is uncertain
• Craniofacial anomalies are present
• Massage fails to improve symptoms
• Dacryocystitis or cellulitis is suspected

Urgent referral is required for:

• Acute dacryocystitis
• Preseptal cellulitis
• Orbital cellulitis
• Infected dacryocele

⸻

Surgical Treatment

When symptoms persist despite conservative management, intervention may be required.

⸻

Probing

Nasolacrimal duct probing is the traditional first-line procedure for persistent congenital NLDO.

A probe is passed through:

• Punctum
• Canaliculus
• Lacrimal sac
• Nasolacrimal duct

to mechanically open the distal obstruction.

Success rates are generally high, especially in younger children with uncomplicated disease.

⸻

Timing of Probing

Probing is commonly considered when:

• Obstruction persists beyond approximately 1 year
• Symptoms are troublesome
• There is recurrent infection

Earlier probing may be appropriate for:

• Severe disease
• Dacryocele
• Recurrent dacryocystitis
• Significant persistent discharge

Practice varies regarding office probing versus probing under general anesthesia.

⸻

Balloon Catheter Dilation

Balloon dacryoplasty may be considered in:

• Persistent obstruction
• Older children
• Failed initial probing
• More complex stenosis

A balloon catheter is used to dilate the nasolacrimal duct.

⸻

Silicone Intubation

Nasolacrimal intubation may be performed with:

• Monocanalicular tube
• Bicanalicular tube

The tube is left in place temporarily to maintain duct patency.

It is often used when:

• Initial probing fails
• The child is older
• There is complex obstruction
• Repeat procedures are required

⸻

Tube-Related Issues

Potential problems include:

• Premature extrusion
• Corneal irritation
• Granuloma
• Need for later removal

Some children require sedation or anesthesia for tube removal.

⸻

Dacryocystorhinostomy

Dacryocystorhinostomy (DCR) is rarely required in children.

It is generally reserved for:

• Multiple failed probing/intubation procedures
• Complex congenital obstruction
• Severe structural abnormalities

⸻

In-Patient Considerations

Most children are treated as outpatients.

Hospital admission may be required for:

• Acute dacryocystitis with systemic illness
• Preseptal cellulitis
• Orbital cellulitis
• Need for intravenous antibiotics

⸻

Follow-Up

Children undergoing conservative treatment should be monitored until symptoms resolve.

Follow-up is especially important if there is:

• Persistent discharge
• Significant tearing
• Recurrent infection
• Skin breakdown

After complete resolution, routine follow-up specifically for NLDO is generally unnecessary.

⸻

Patient Monitoring

Parents should monitor for:

• Increasing redness
• Medial canthal swelling
• Fever
• Purulent discharge
• Rapid eyelid swelling
• Reduced visual behavior

These may suggest infection or another diagnosis.

⸻

Patient Education

Parents should understand that:

• CNLDO is common.
• Most cases resolve spontaneously.
• Massage is often sufficient.
• Antibiotic drops do not cure the obstruction.
• Surgery, when needed, is usually highly successful.

⸻

Prognosis

The prognosis is excellent.

Most cases resolve:

• Spontaneously
• With lacrimal sac massage
• Or after a simple probing procedure

Children with significant craniofacial abnormalities may have:

• More complex obstruction
• Lower success rates
• Greater likelihood of requiring repeat procedures

⸻

Complications

Potential complications include:

• Persistent epiphora
• Chronic mucopurulent discharge
• Dacryocystitis
• Preseptal cellulitis
• Orbital cellulitis
• Chronic skin irritation

Procedural complications are uncommon but may include:

• Mild epistaxis
• Corneal abrasion
• Creation of a false passage
• Tube extrusion
• Granuloma formation

⸻

Ophthalmology Pearls

• Congenital NLDO is the most common lacrimal drainage abnormality in children.
• The usual obstruction is a persistent membrane at the Valve of Hasner.
• Classic presentation: tearing + mucous discharge + matted lashes + little conjunctival injection.
• Approximately 90% resolve spontaneously by about 1 year of age.
• Crigler massage is first-line treatment.
• Antibiotics are reserved for secondary infection; they do not correct the obstruction.
• Persistent symptoms beyond infancy may require probing.
• Failed probing may be followed by balloon dilation or silicone intubation.
• DCR is rarely required in children.
• A tearing infant with photophobia, blepharospasm, or corneal haze should be evaluated urgently for congenital glaucoma.
• Medial canthal swelling with erythema or fever suggests dacryocystitis or infected dacryocele and warrants urgent ophthalmic assessment.

Ophthalmology – Nasolacrimal Duct Obstruction

Basics

Description

Nasolacrimal duct obstruction (NLDO) is blockage of the lacrimal drainage pathway, preventing normal passage of tears from the lacrimal sac into the nasal cavity beneath the inferior turbinate.

It may cause:

• Epiphora
• Blurred vision from excessive tearing
• Mucous or purulent discharge
• Recurrent dacryocystitis

NLDO may be:

• Congenital
• Acquired

Acquired NLDO in adults can be divided into:

• Primary acquired nasolacrimal duct obstruction
• Secondary acquired nasolacrimal duct obstruction

Epidemiology

Acquired NLDO is more common in women.

A reported incidence is approximately:

20 per 100,000 persons

Female predominance is approximately:

3:1

One proposed explanation is that women may have a relatively narrower bony nasolacrimal canal.

Risk Factors

Important risk factors include:

• Chronic topical ophthalmic medications
• Long-term glaucoma drops
• Previous facial trauma
• Previous nasal or sinus surgery
• Recurrent dacryocystitis
• Recurrent conjunctivitis
• Systemic chemotherapy
• Previous radiation therapy

Chemotherapeutic agents associated with lacrimal drainage obstruction include:

• 5-fluorouracil
• Taxanes such as docetaxel

General Prevention

Many cases cannot be prevented.

Potential preventive measures include:

• Protective eyewear during high-risk activities to reduce facial trauma
• Appropriate management of chronic ocular surface inflammation
• Minimizing unnecessary long-term exposure to irritating topical medications
• Punctal occlusion techniques when appropriate to reduce systemic and nasolacrimal exposure to chronic eye drops

Pathophysiology

Primary Acquired NLDO

Primary acquired NLDO is thought to result from a chronic:

Fibro-inflammatory narrowing and scarring of the nasolacrimal duct

without a clearly identifiable initiating cause.

This progressive fibrosis eventually obstructs tear drainage.

Secondary Acquired NLDO

Secondary NLDO has an identifiable cause.

Major categories include:

• Infectious
• Inflammatory
• Neoplastic
• Traumatic
• Mechanical
• Iatrogenic

Infectious Causes

Reported infectious causes include:

• Bacterial infections
• Viral infections
• Fungal infections
• Parasitic infections

Chronic infection can promote:

• Mucosal inflammation
• Fibrosis
• Ductal obstruction

Inflammatory Causes

Associated inflammatory disorders include:

• Sarcoidosis
• Granulomatosis with polyangiitis
• Ocular cicatricial pemphigoid
• Scleroderma
• Chronic herpetic disease
• Radiation-related inflammation

Chronic topical medications may also induce cicatricial changes.

Neoplastic Causes

Tumors of the lacrimal sac or nasolacrimal drainage system are uncommon but important because they can masquerade as routine NLDO.

Reported tumors include:

• Squamous papilloma
• Squamous cell carcinoma
• Transitional-type carcinomas
• Adenocarcinoma
• Lymphoid tumors
• Melanoma
• Metastatic lesions

Trauma and Iatrogenic Causes

Obstruction may occur following:

• Facial fractures
• Canalicular laceration
• Previous probing
• Lacrimal surgery
• Nasal surgery
• Sinus surgery

Mechanical Causes

Mechanical obstruction may result from:

• Foreign body
• Dacryolith
• Canalicular concretions
• Mucous casts

Commonly Associated Conditions

Conditions associated with acquired NLDO include:

• Sarcoidosis
• Granulomatosis with polyangiitis
• Ocular cicatricial pemphigoid
• Scleroderma
• Herpetic conjunctivitis or keratitis
• Previous chemotherapy
• Previous radiation
• Chronic glaucoma therapy

Diagnosis

Diagnosis is based primarily on:

• History
• Eyelid and lacrimal examination
• Probing and irrigation
• Selected imaging when an atypical or secondary cause is suspected

History

The most common complaint is:

Persistent tearing

Usually the tearing is:

• Unilateral
• Constant or intermittent
• Worse outdoors or in cold/windy conditions

Patients may also complain of:

• Blurred vision
• Difficulty reading
• Difficulty driving
• Tears running down the cheek
• Mucous discharge
• Recurrent painful swelling near the medial canthus

Epiphora can have a substantial effect on daily activities and quality of life.

Physical Examination

A complete examination should first exclude other causes of tearing.

Assess:

• Eyelid position
• Punctal position
• Punctal stenosis
• Lash position
• Blink function
• Lacrimal pump function
• Conjunctiva
• Cornea
• Tear film
• Anterior chamber

Tear Meniscus

An elevated tear meniscus or increased tear lake supports impaired drainage.

A tear lake greater than approximately:

2 mm

may suggest significant outflow obstruction.

Lacrimal Sac Examination

Palpate the lacrimal sac region.

Pressure over the lacrimal sac may produce:

• Clear reflux
• Mucous reflux
• Mucopurulent material
• Purulent discharge

Reflux through the puncta supports obstruction distal to the canalicular system.

Important Tumor Warning Sign

A firm mass above the medial canthal tendon is particularly concerning for a lacrimal sac neoplasm.

Other warning features include:

• Bloody tears
• Bloody reflux
• Persistent unilateral symptoms
• Palpable firm mass
• Failure of standard treatment

These findings warrant imaging and specialist evaluation.

Nasal Examination

The nasal cavity should be assessed for:

• Septal deviation
• Inferior turbinate abnormalities
• Nasal masses
• Chronic inflammation
• Postsurgical changes
• Structural narrowing

ENT evaluation may be helpful in selected patients.

Diagnostic Testing

Laboratory Tests

Routine laboratory testing does not diagnose NLDO.

If purulent discharge is present, consider:

• Gram stain
• Bacterial culture
• Sensitivity testing

This is especially useful in:

• Recurrent infection
• Severe dacryocystitis
• Unusual organisms
• Treatment failure

Probing and Irrigation

Lacrimal probing and irrigation are among the most useful office tests.

They help determine:

• Whether the canaliculi are patent
• Whether obstruction is partial or complete
• Approximate level of obstruction

Interpretation of Irrigation

Fluid reaches the nose or throat

Suggests:

• Patent drainage system
• Possibly partial obstruction if flow is delayed or requires pressure

Reflux through the opposite punctum

Suggests obstruction distal to the common canaliculus or nasolacrimal duct.

Reflux through the same punctum

May suggest canalicular obstruction.

Jones Dye Tests

Jones I Test

A functional drainage test.

Fluorescein is placed in the conjunctival sac and recovery in the nose suggests functional drainage.

Jones II Test

Used when Jones I is negative.

It helps distinguish:

• Functional delay
• Partial anatomic obstruction

These tests are now used less commonly than direct irrigation and modern imaging.

Schirmer Testing

Schirmer testing measures tear production.

It may help determine whether tearing results from:

• Excessive tear production
• Reflex tearing
• Drainage failure

It does not directly diagnose NLDO.

Imaging

Routine imaging is not necessary in straightforward primary acquired NLDO.

CT or MRI

Imaging is indicated when there is concern for:

• Lacrimal sac tumor
• Nasal or sinus mass
• Orbital involvement
• Trauma
• Atypical obstruction
• Bloody tears
• Palpable mass
• Recurrent disease after surgery

CT is particularly useful for:

• Bone
• Sinuses
• Trauma

MRI is useful for:

• Soft tissue
• Suspected neoplasm
• Infiltrative disease

Dacryocystography

Dacryocystography can outline the anatomy of the lacrimal drainage system and localize obstruction.

It is now usually reserved for:

• Complex cases
• Recurrent obstruction
• Surgical planning

Dacryoscintigraphy

Dacryoscintigraphy using technetium can assess the functional transit of tears through the lacrimal system.

It is rarely required.

Pathology

Histopathology in primary acquired NLDO typically shows:

• Chronic inflammation
• Fibrosis
• Mucosal thickening

When obstruction is secondary to systemic disease, pathology may reveal the cause.

Examples include:

• Granulomatous inflammation in sarcoidosis
• Vasculitic inflammation
• Neoplastic cells

Differential Diagnosis

Not all tearing is caused by NLDO.

Important differential diagnoses include:

• Dry eye disease with reflex tearing
• Blepharitis
• Conjunctivitis
• Trichiasis
• Corneal foreign body
• Corneal abrasion
• Entropion
• Ectropion
• Punctal stenosis
• Canalicular obstruction
• Lacrimal pump dysfunction
• Acute angle-closure glaucoma
• Lacrimal sac tumor

Dry Eye and Reflex Tearing

Dry eye may paradoxically produce excessive tearing because ocular surface irritation stimulates reflex lacrimation.

Signs of ocular surface disease should therefore be sought before diagnosing NLDO.

Treatment

Definitive treatment of symptomatic complete acquired NLDO is usually surgical.

Medical therapy is mainly used to treat:

• Infection
• Inflammation
• Associated ocular surface disease

Dacryocystitis

Stagnant tears within an obstructed system can become infected, producing:

Acute dacryocystitis

Clinical features include:

• Pain
• Erythema
• Tender swelling below the medial canthus
• Purulent discharge
• Fever in more severe cases

Antibiotic Therapy

Acute dacryocystitis usually requires:

• Systemic antibiotics

Antibiotic selection should reflect:

• Severity
• Local microbial patterns
• Culture results when available
• Patient comorbidities

Severe infection may require intravenous antibiotics.

Actinomyces

Chronic canalicular infection caused by Actinomyces should be considered when there are:

• Recurrent unilateral discharge
• Canalicular swelling
• Concretions or dacryoliths

Definitive treatment usually requires removal of the concretions rather than antibiotics alone.

Dacryocystorhinostomy

DCR

Dacryocystorhinostomy (DCR) is the standard definitive treatment for symptomatic acquired distal NLDO.

The procedure creates a new drainage pathway between:

• Lacrimal sac
• Nasal cavity

bypassing the obstructed nasolacrimal duct.

External DCR

An external skin incision is used to access the lacrimal sac.

Advantages include:

• Excellent visualization
• High success rate
• Ability to obtain lacrimal sac tissue for pathology

Disadvantages include:

• Small external scar
• More disruption of medial canthal tissues

Endoscopic DCR

Performed through the nasal cavity.

Advantages include:

• No external scar
• Direct visualization of intranasal pathology
• Preservation of medial canthal structures