Ophthalmology – Myopic Degeneration

Basics

Description

Myopic degeneration, also called pathologic myopia or degenerative myopia, refers to progressive structural changes of the posterior segment associated with excessive axial elongation.

It can cause mild to profound central visual loss through:

• Macular atrophy
• Chorioretinal degeneration
• Lacquer cracks
• Macular hemorrhage
• Myopic choroidal neovascularization (CNV)
• Posterior staphyloma
• Myopic traction maculopathy
• Retinal detachment

Unlike ordinary refractive myopia, pathologic myopia involves progressive degenerative changes of the sclera, choroid, RPE, Bruch membrane, and retina.

Classification of Myopia

Myopia has historically been divided into:

• Simple myopia
• Congenital myopia
• Degenerative/pathologic myopia

Simple and congenital myopia do not necessarily develop the characteristic posterior degenerative changes of pathologic myopia.

Epidemiology

Myopia commonly begins during:

• Childhood
• School years
• Adolescence

In patients who develop pathologic myopia, refractive error and axial length may continue increasing well beyond adolescence.

Degenerative macular changes can begin in:

• Young adulthood
• Middle age

and may progress throughout life.

Prevalence

The prevalence of myopia varies greatly according to:

• Age
• Ethnicity
• Geographic region
• Educational exposure
• Environmental factors

Pathologic myopia is considerably less common than simple myopia but represents an important cause of irreversible visual impairment worldwide.

Risk Factors

Major risk factors include:

• High axial myopia
• Long axial length
• Progressive myopia
• Posterior staphyloma
• Increasing age
• Existing lacquer cracks
• Patchy chorioretinal atrophy
• Previous myopic CNV in the fellow eye

Genetics

Myopia is genetically complex and generally multifactorial.

Both genetic and environmental factors contribute.

Pathologic myopia does not usually follow a simple single-gene inheritance pattern, although familial clustering is common and rare monogenic forms exist.

Pathophysiology

The fundamental process is progressive axial elongation of the globe, particularly at the posterior pole.

This produces mechanical stretching and thinning of multiple ocular layers.

Scleral Changes

The posterior sclera may become:

• Thin
• Ectatic
• Structurally weakened

Progressive posterior bulging can produce:

Posterior staphyloma

which is a hallmark of pathologic myopia.

Choroidal Changes

The choroid becomes markedly thinned.

Changes include:

• Attenuation of the choriocapillaris
• Reduction of choroidal melanocytes
• Increased visibility of large choroidal vessels
• Progressive choroidal atrophy

RPE Changes

The retinal pigment epithelium becomes:

• Stretched
• Thinned
• Irregular
• Atrophic

Loss of RPE and choroidal pigmentation contributes to the classic tessellated or tigroid fundus.

Bruch Membrane Changes

Bruch membrane may undergo:

• Thinning
• Splitting
• Mechanical rupture

Linear ruptures are known as:

Lacquer cracks

These are important because they indicate severe biomechanical stress and are associated with an increased risk of myopic CNV.

Etiology

The exact cause of the degenerative process is multifactorial.

A major mechanism is thought to be:

Progressive biomechanical stretching from excessive axial elongation

leading to thinning and disruption of:

• Sclera
• Choroid
• RPE
• Bruch membrane
• Retina

Commonly Associated Conditions

High myopia may also occur in association with:

• Prematurity
• Retinopathy of prematurity
• Connective-tissue disorders
• Certain inherited retinal disorders

Premature infants may develop substantial myopia even without retinopathy of prematurity.

Diagnosis

Diagnosis is based on:

• Refractive status
• Axial length
• Characteristic fundus changes
• Multimodal imaging

History

Patients may have:

• Longstanding high myopia
• Progressive refractive change
• Gradual reduction in central vision

A patient with high myopia who develops:

• Sudden visual loss
• New metamorphopsia
• New central scotoma

should be evaluated urgently for myopic CNV or macular hemorrhage.

Ophthalmic Features

Posterior Staphyloma

A posterior staphyloma is a localized outpouching of the posterior ocular wall.

It can contribute to:

• Progressive macular distortion
• Chorioretinal atrophy
• Myopic traction maculopathy
• Macular hole
• Retinal detachment

Optic Disc Changes

Typical findings include:

• Tilted optic disc
• Oval configuration
• Peripapillary atrophy
• Temporal myopic crescent
• Disc torsion

Glaucoma evaluation can be difficult in highly myopic eyes because of altered optic-disc anatomy.

Tessellated Fundus

Thinning of the RPE and choroid makes the underlying large choroidal vessels more visible.

This produces the classic:

Tessellated or tigroid fundus

appearance.

Chorioretinal Atrophy

Progressive atrophy can appear as sharply demarcated pale areas.

It may begin as:

• Diffuse chorioretinal atrophy
• Patchy atrophy

Over time, lesions may:

• Enlarge
• Coalesce
• Involve the fovea

Foveal atrophy can cause severe irreversible central visual loss.

Lacquer Cracks

Lacquer cracks are:

Linear breaks in Bruch membrane caused by mechanical stretching.

They appear as:

• Fine yellow-white lines
• Irregular linear lesions
• Occasionally stellate lesions

They are important markers of advanced pathologic myopia.

Macular Hemorrhage

Hemorrhage may occur when a lacquer crack develops.

A hemorrhage can occur:

• Without CNV
• After relatively minor trauma
• Spontaneously

Therefore, not every macular hemorrhage in a highly myopic eye represents CNV.

Choroidal Neovascularization

Myopic CNV is one of the most important vision-threatening complications.

Clinical findings may include:

• Subretinal hemorrhage
• Gray or dark subretinal lesion
• Subretinal fluid
• Intraretinal fluid
• RPE elevation
• Sudden metamorphopsia
• Central scotoma

Fuchs Spot

After myopic CNV regresses, it may leave a pigmented fibrotic macular scar known historically as a:

Fuchs spot

This can produce permanent central visual impairment.

Myopic Maculopathy

Modern descriptions of pathologic myopia often classify macular disease according to increasing severity of:

• Tessellation
• Diffuse chorioretinal atrophy
• Patchy atrophy
• Macular atrophy

Additional “plus” lesions include:

• Lacquer cracks
• Myopic CNV
• Fuchs spot

Myopic Traction Maculopathy

Highly myopic eyes are also prone to tractional complications, including:

• Epiretinal membrane
• Vitreomacular traction
• Foveoschisis
• Retinoschisis
• Foveal detachment
• Lamellar macular hole
• Full-thickness macular hole
• Macular hole retinal detachment

These complications are particularly common in eyes with posterior staphyloma.

Peripheral Retinal Changes

High myopia is associated with increased risk of:

• Lattice degeneration
• Retinal tears
• Peripheral retinal thinning
• Rhegmatogenous retinal detachment

A careful peripheral retinal examination is therefore important.

Diagnostic Testing

Optical Coherence Tomography

OCT is essential in evaluating pathologic myopia.

It can detect:

• Myopic CNV
• Subretinal fluid
• Intraretinal fluid
• Foveoschisis
• Retinoschisis
• Macular hole
• Tractional changes
• Atrophy
• Epiretinal membranes

Serial OCT is extremely useful for treatment monitoring.

Fluorescein Angiography

Fluorescein angiography can help distinguish:

• Myopic CNV
• Simple macular hemorrhage from lacquer crack
• Areas of chorioretinal atrophy

Active CNV typically demonstrates leakage.

OCT Angiography

OCT angiography can noninvasively demonstrate abnormal neovascular networks and may be useful for:

• Detecting CNV
• Monitoring vascular activity
• Follow-up after treatment

It should be interpreted alongside structural OCT and the clinical examination.

Fundus Photography

Useful for documenting:

• Atrophy
• Lacquer cracks
• Hemorrhage
• Pigmentation
• Progressive macular changes

Axial Length Measurement

Biometry may help document:

• Excessive axial length
• Progression of axial elongation

Differential Diagnosis

Conditions that may mimic or coexist with myopic macular changes include:

• Age-related macular degeneration
• Central serous chorioretinopathy
• Inflammatory CNV
• Ocular histoplasmosis-related CNV
• Angioid streaks
• Macular dystrophy
• Traumatic choroidal rupture

Treatment

There is no treatment that reverses the underlying structural elongation once pathologic changes are established.

Management is directed toward:

• Refractive correction
• Treatment of CNV
• Management of tractional complications
• Retinal detachment treatment
• Low-vision rehabilitation

Refractive Correction

Options include:

• Spectacles
• Contact lenses

Contact lenses can provide improved optical quality in very high myopia because they reduce:

• Image minification
• Peripheral distortion

Myopic CNV Treatment

Anti-VEGF Therapy

Intravitreal anti-VEGF therapy is the current first-line treatment for myopic CNV.

Agents may include:

• Ranibizumab
• Aflibercept
• Bevacizumab

Treatment often requires fewer injections than neovascular age-related macular degeneration, although follow-up remains essential.

Historical Treatments for CNV

Older approaches included:

• Thermal laser photocoagulation
• Photodynamic therapy

These are now much less commonly used because anti-VEGF therapy generally provides better outcomes with less collateral retinal damage.

Laser treatment is particularly problematic near the fovea because scars may enlarge over time in highly myopic eyes.

Myopic Traction Maculopathy Treatment

Surgery may be considered for progressive or visually significant:

• Foveoschisis
• Macular hole
• Foveal detachment
• Vitreomacular traction
• Macular hole retinal detachment

Options may include:

• Pars plana vitrectomy
• Internal limiting membrane techniques
• Gas tamponade
• Macular buckle in selected complex cases

Management should be individualized by a vitreoretinal specialist.

Retinal Detachment

Retinal detachment may require:

• Pars plana vitrectomy
• Scleral buckle
• Pneumatic retinopexy in selected cases
• Combined procedures

Highly myopic eyes may present additional surgical challenges because of:

• Thin sclera
• Posterior staphyloma
• Long axial length
• Macular hole-associated detachment

Low-Vision Support

Patients with irreversible macular damage may benefit from:

• Magnification devices
• Electronic visual aids
• High-contrast reading material
• Lighting optimization
• Low-vision rehabilitation

Follow-Up

Patients with pathologic myopia require regular ophthalmic surveillance.

Follow-up should assess:

• Visual acuity
• Refraction
• Macula
• Optic disc
• Peripheral retina
• CNV activity
• Progressive atrophy
• Tractional macular changes

Patient Education

Patients at risk of CNV should monitor each eye separately.

They should seek prompt review for:

• New metamorphopsia
• New central blur
• New central scotoma
• Sudden reduction in vision

An Amsler grid can be used for home monitoring.

Retinal Detachment Education

Patients should also be educated about symptoms of retinal tear or detachment:

• Sudden increase in floaters
• Flashing lights
• Curtain or shadow in the visual field
• Sudden peripheral field loss

These symptoms require urgent ophthalmic assessment.

Prognosis

Visual prognosis depends on:

• Degree of posterior staphyloma
• Extent of macular atrophy
• Development of CNV
• Tractional macular disease
• Retinal detachment

Patients with progressive staphyloma and increasing macular atrophy have a guarded long-term prognosis.

The risk of vision loss generally increases with age.

Complications

Major complications include:

• Myopic CNV
• Macular hemorrhage
• Fuchs spot
• Chorioretinal atrophy
• Macular atrophy
• Myopic foveoschisis
• Macular hole
• Macular hole retinal detachment
• Rhegmatogenous retinal detachment
• Epiretinal membrane
• Glaucoma
• Progressive irreversible central visual loss

Ophthalmology Pearls

• Pathologic myopia is more than refractive error—it is a structural degenerative disease of the posterior eye.
• Progressive axial elongation causes thinning of the sclera, choroid, RPE, Bruch membrane, and retina.
• Posterior staphyloma is a hallmark of advanced disease.
• Lacquer cracks are breaks in Bruch membrane and increase the risk of myopic CNV.
• Sudden metamorphopsia or central vision loss in a highly myopic patient should raise immediate concern for CNV.
• A macular hemorrhage in high myopia can occur from a lacquer crack without CNV.
• Anti-VEGF therapy is first-line treatment for myopic CNV.
• OCT is essential for detecting both neovascular and tractional complications.
• High myopia increases the risk of retinal tears and retinal detachment, so the peripheral retina must also be examined carefully.
• Long-term surveillance is important because macular atrophy and other degenerative changes may continue to progress throughout life.

Ophthalmology – Myelinated Nerve Fibers

Basics

Description

Myelinated retinal nerve fibers, also called medullated nerve fibers, are congenital areas of abnormal myelination of the retinal nerve fiber layer.

They appear ophthalmoscopically as:

• White, opaque, striated patches
• Usually adjacent to the superior or inferior margins of the optic disc
• Lesions with feathery or frayed borders that follow the orientation of normal retinal nerve fibers
• Partial obscuration of retinal vessels passing beneath the myelinated layer

Occasionally:

• Islands or slits of normal retina are visible within the lesion
• The myelination is discontinuous from the optic disc
• Rare acquired cases have been described after infancy or in adulthood, with trauma reported in some of these cases

Epidemiology

Myelinated nerve fibers occur in approximately:

1% of the general population

They are usually discovered incidentally during routine fundus examination.

Genetics

Most cases are sporadic.

Rare familial cases with an autosomal dominant inheritance pattern have been reported.

Myelinated nerve fibers have also been described in association with certain syndromes, including:

• Gorlin syndrome
• Rare inherited vitreoretinal dystrophy syndromes with extensive bilateral retinal nerve fiber myelination

One reported autosomal dominant vitreoretinopathy includes:

• Extensive bilateral retinal nerve fiber myelination
• Severe myopia
• Congenitally reduced vision
• Vitreous degeneration
• Retinal dystrophy
• Night blindness
• Reduced electroretinographic responses
• Limb abnormalities

Pathophysiology

Normally, retinal ganglion cell axons become myelinated posterior to the lamina cribrosa.

Myelination is produced by oligodendrocytes.

During normal fetal development:

• Myelination progresses anteriorly from the lateral geniculate region
• It normally stops at the lamina cribrosa
• Oligodendrocytes usually do not enter the retina

In myelinated nerve fibers, oligodendrocytes extend beyond the lamina cribrosa into the retinal nerve fiber layer.

Proposed Mechanisms

Possible developmental explanations include:

• Abnormality or defect in the lamina cribrosa
• Delayed formation of the lamina cribrosa
• Relatively large scleral canal with fewer axons, permitting oligodendrocytes to migrate anteriorly
• Abnormal persistence of access for oligodendrocytes into the retina

Etiology

The condition is usually congenital.

It represents retinal ganglion cell axons that have abnormally acquired a myelin sheath anterior to the lamina cribrosa.

Rare acquired cases have been described, particularly after:

• Ocular trauma
• Other optic nerve or retinal abnormalities

Commonly Associated Conditions

Myelinated nerve fibers may be associated with:

• High myopia
• Amblyopia
• Strabismus
• Tilted disc syndrome
• Anterior segment dysgenesis
• Rare craniofacial abnormalities

A classic association is the triad of:

• Extensive unilateral myelinated retinal nerve fibers
• High myopia
• Amblyopia

Gorlin Syndrome Association

Rarely, myelinated nerve fibers have been described with Gorlin syndrome, which may include:

• Multiple basal cell carcinomas or nevi
• Jaw cysts
• Skeletal abnormalities
• Increased risk of medulloblastoma in childhood

This association is uncommon.

Neurofibromatosis Type 2

A possible association with neurofibromatosis type 2 has been reported, although this remains debated.

Diagnosis

Diagnosis is usually made clinically on fundus examination.

History

Most patients are asymptomatic.

Possible historical findings include:

• Reduced vision in one eye
• Strabismus
• High myopia
• Amblyopia
• Rare history of trauma in acquired cases

Physical Examination

A complete ophthalmic examination should include:

• Visual acuity
• Cycloplegic refraction when appropriate
• Pupillary examination
• Ocular alignment
• Dilated fundus examination

Special attention should be paid to:

• Degree of myopia
• Presence of anisometropia
• Amblyopia
• Strabismus
• Extent of myelination

Fundus Appearance

Typical findings include:

• Bright white or gray-white patches
• Striated appearance
• Feathery borders
• Distribution along the retinal nerve fiber layer
• Frequently extending from the optic disc
• Retinal vessels partially hidden by the superficial myelinated fibers

Approximately a minority of cases may show lesions that are not directly contiguous with the optic disc.

Optical Coherence Tomography

OCT can be helpful.

It may demonstrate:

• Thickened retinal nerve fiber layer
• Increased reflectivity in the region of myelination
• Shadowing of deeper retinal structures

OCT can also help evaluate associated optic nerve or macular abnormalities.

Neuroimaging

Routine neuroimaging is generally not required for isolated myelinated retinal nerve fibers.

Imaging may be considered if:

• A systemic syndrome is suspected
• Neurologic abnormalities are present
• Gorlin syndrome is suspected
• The appearance is atypical

Differential Diagnosis

Important differential diagnoses include:

• Cotton-wool spots
• Hard exudates
• Retinal gliosis
• Chorioretinal scars
• Tilted disc syndrome
• Other congenital white retinal lesions

Myelinated Nerve Fibers vs Cotton-Wool Spots

Myelinated fibers:

• Follow the nerve fiber layer
• Have feathery, striated margins
• Are usually stable over time
• Commonly arise adjacent to the optic disc

Cotton-wool spots:

• Represent retinal ischemia
• Are acquired
• Usually resolve over weeks
• Are associated with vascular or systemic disease

Treatment

There is no treatment for the myelination itself.

Management is directed toward associated visual problems.

Refractive Correction

Significant refractive error should be corrected as early as possible.

This is particularly important in children with:

• High myopia
• Anisometropia
• Astigmatism

Amblyopia Therapy

Amblyopia should be treated when present.

Treatment may include:

• Full optical correction
• Patching
• Penalization

Historically, amblyopia associated with extensive myelinated nerve fibers and high myopia was believed to respond poorly.

However, some patients can achieve meaningful improvement with appropriately timed amblyopia therapy.

Strabismus

Strabismus should be managed according to:

• Visual potential
• Angle of deviation
• Binocular function
• Cosmetic considerations

Surgery may be considered when indicated.

Referral

Referral may be appropriate to:

• Pediatric ophthalmology for amblyopia or strabismus
• Medical genetics if a syndromic association is suspected
• Dermatology if findings suggest Gorlin syndrome

Ongoing Care

Follow-Up

Follow-up is usually determined by associated problems rather than the myelinated fibers themselves.

Children should be monitored for:

• Refractive change
• Amblyopia
• Strabismus
• Visual development

Patient Education

Patients and families should understand that:

• Myelinated nerve fibers are usually benign
• The retinal appearance itself generally does not require treatment
• Vision problems are usually due to associated:
• Myopia
• Anisometropia
• Amblyopia
• Strabismus

Early treatment of amblyopia is important.

Prognosis

The retinal myelination itself is generally stable and benign.

Visual prognosis depends mainly on associated:

• High myopia
• Amblyopia
• Strabismus
• Other ocular abnormalities

Some patients with substantial myelination and severe anisometropic myopia may have limited visual potential.

Regression or Disappearance

Rarely, previously visible myelinated nerve fibers have been reported to diminish or disappear after severe damage to retinal ganglion cell axons or the optic nerve.

Reported settings include:

• Optic atrophy
• Glaucoma
• Central retinal artery occlusion
• Optic neuritis
• Compressive optic neuropathy

Loss of the white myelinated appearance in these settings reflects axonal loss rather than improvement.

Complications

Potential associated complications include:

• Amblyopia
• High myopia
• Anisometropia
• Strabismus
• Reduced visual acuity

Ophthalmology Pearls

• Myelinated retinal nerve fibers appear as white, feathery, striated patches following the retinal nerve fiber layer.
• They commonly arise adjacent to the optic disc and can partially obscure retinal vessels.
• The condition is usually congenital and benign.
• Think of the classic association: myelinated nerve fibers + high myopia + amblyopia.
• The lesion itself requires no treatment.
• In children, the priority is early detection and treatment of refractive error and amblyopia.
• OCT may show a thick, highly reflective retinal nerve fiber layer with posterior shadowing.
• Do not confuse stable congenital myelination with acquired cotton-wool spots.
• Rare disappearance of myelination can occur after severe optic nerve or retinal ganglion cell injury.

Ophthalmology – Myasthenia Gravis

Basics

Description

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by painless, fluctuating, fatigable skeletal-muscle weakness.

The most commonly affected muscles are the extraocular and eyelid muscles, so ophthalmic manifestations are frequently the first sign of disease.

Typical manifestations include:

• Ptosis
• Diplopia
• Variable ophthalmoplegia
• Orbicularis weakness
• Bulbar weakness
• Limb weakness
• Respiratory muscle weakness in severe disease

A characteristic feature is that weakness:

• Worsens with repeated or prolonged muscle use
• Often worsens later in the day
• Improves after rest
• Can vary considerably from one examination to another

Sensation and pupillary function remain normal.

⸻

Clinical Forms

Ocular Myasthenia Gravis

In ocular MG, weakness remains limited to:

• Eyelids
• Extraocular muscles

Patients typically develop:

• Ptosis
• Diplopia
• Variable ocular misalignment

⸻

Generalized Myasthenia Gravis

Generalized disease can involve:

• Ocular muscles
• Bulbar muscles
• Facial muscles
• Neck muscles
• Limb muscles
• Respiratory muscles

Ocular manifestations often precede generalized disease.

⸻

Serologic Forms

MG can also be categorized according to circulating antibodies.

AChR-Antibody Positive MG

Antibodies are directed against the acetylcholine receptor (AChR) on the postsynaptic membrane.

This is the most common form.

MuSK-Antibody Positive MG

Antibodies are directed against muscle-specific receptor tyrosine kinase (MuSK).

These patients are more likely to have prominent:

• Bulbar weakness
• Facial weakness
• Neck weakness
• Respiratory involvement

Pure ocular presentations are uncommon.

Seronegative MG

Some patients have no detectable conventional AChR or MuSK antibodies despite a compatible clinical syndrome.

Additional antibodies such as LRP4 may be detectable in a subset.

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Epidemiology

MG may occur at any age.

A broadly bimodal pattern is recognized.

Earlier-Onset Disease

Usually affects younger adults and is more common in women.

Later-Onset Disease

Usually affects older adults and has a greater male predominance.

The prevalence has increased over time, probably because of:

• Better recognition
• Improved diagnostic testing
• Greater survival

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Risk Factors and Exacerbating Factors

Factors that can worsen myasthenic weakness include:

• Infection
• Fever
• Emotional or physical stress
• Heat
• Sleep deprivation
• Pregnancy
• Menstruation
• Thyroid dysfunction
• Certain medications

Patients should be reviewed carefully for drugs capable of worsening neuromuscular transmission.

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Genetics

MG is not usually inherited in a simple Mendelian fashion.

However:

• Autoimmune susceptibility may cluster in families.
• Relatives of affected individuals have an increased risk of autoimmune disease and MG.
• Congenital myasthenic syndromes are distinct inherited disorders and should not be confused with autoimmune MG.

⸻

Neonatal Myasthenia

Approximately a minority of infants born to mothers with autoimmune MG may develop transient neonatal myasthenia due to transplacental passage of maternal antibodies.

Symptoms may include:

• Poor suck
• Weak cry
• Generalized hypotonia
• Respiratory weakness

The condition usually resolves as maternal antibodies disappear.

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General Prevention

There is no proven method to prevent autoimmune MG.

However, exacerbations may sometimes be reduced by:

• Prompt treatment of infection
• Avoidance of medications known to impair neuromuscular transmission
• Maintaining appropriate vaccinations
• Careful perioperative planning
• Appropriate management during pregnancy

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Drugs That May Worsen MG

Important medications that can exacerbate weakness include selected:

• Aminoglycoside antibiotics
• Fluoroquinolones
• Macrolides
• Magnesium
• Neuromuscular blocking agents
• Beta-blockers
• Some antiarrhythmics

Penicillamine can induce an MG-like autoimmune syndrome.

Medication risks are not absolute in every patient, but potentially aggravating agents should be used carefully.

⸻

Pathophysiology

Normal neuromuscular transmission depends on acetylcholine released from the presynaptic nerve terminal binding to acetylcholine receptors on the postsynaptic muscle membrane.

In autoimmune MG, antibodies interfere with this process.

⸻

AChR Antibodies

Anti-AChR antibodies cause:

• Functional blockade of acetylcholine receptors
• Receptor internalization and degradation
• Complement-mediated postsynaptic membrane injury

This causes simplification of the postsynaptic folds and reduces the safety margin of neuromuscular transmission.

With repetitive stimulation, transmission increasingly fails, producing fatigable weakness.

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MuSK Antibodies

MuSK is important in organizing and maintaining acetylcholine receptors at the neuromuscular junction.

MuSK autoantibodies disrupt receptor clustering and neuromuscular transmission.

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Thymus and Myasthenia Gravis

The thymus plays an important role, particularly in AChR-antibody positive MG.

Abnormalities include:

• Thymic lymphoid hyperplasia
• Germinal-center formation
• Thymoma

Approximately 10–15% of MG patients have a thymoma.

Conversely, a significant proportion of patients with thymoma develop MG.

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Associated Conditions

MG is associated with other autoimmune disorders, particularly:

• Autoimmune thyroid disease
• Rheumatoid disease
• Systemic lupus erythematosus
• Pernicious anemia

Thyroid disease is especially relevant in patients with ocular symptoms because thyroid eye disease can mimic ocular MG.

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Diagnosis

History

Typical complaints include:

• Drooping eyelid
• Intermittent diplopia
• Worsening symptoms late in the day
• Increasing symptoms after reading or prolonged visual effort
• Difficulty chewing
• Difficulty swallowing
• Nasal or weak voice
• Choking during meals
• Liquids regurgitating through the nose
• Limb weakness
• Neck weakness

Respiratory weakness can occur and represents a potentially life-threatening complication.

Sensory symptoms are not characteristic of MG.

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Ophthalmic Examination

Ptosis

Ptosis may be:

• Unilateral
• Bilateral
• Asymmetric
• Alternating
• Highly variable

Fatigability may be demonstrated by asking the patient to maintain prolonged upgaze.

The eyelid may gradually descend.

⸻

Cogan Lid Twitch

After sustained downgaze, the patient rapidly returns the eyes to primary gaze.

The upper lid may:

1. Overshoot upward
2. Briefly retract
3. Then fall into ptosis

This is called Cogan’s lid twitch and supports the diagnosis of ocular MG.

⸻

Frontalis Compensation

Patients may compensate for ptosis by:

• Raising the eyebrows
• Contracting the frontalis
• Adopting a chin-up posture

⸻

Ice-Pack Test

Cooling improves neuromuscular transmission.

For ptosis:

• Ice is placed over the closed eyelid for several minutes.
• Improvement in ptosis supports MG.

An improvement of approximately 2 mm or more is generally considered strongly suggestive in the appropriate clinical context.

The test is particularly useful because it is:

• Rapid
• Noninvasive
• Inexpensive

⸻

Ocular Motility Findings

MG can mimic almost any ocular motility disorder.

Findings may include:

• Variable ophthalmoparesis
• Changing patterns of strabismus
• Horizontal diplopia
• Vertical diplopia
• Oblique diplopia
• Isolated-appearing muscle weakness
• Apparent cranial nerve palsies

A major clue is variability.

⸻

Pseudo-Internuclear Ophthalmoplegia

Medial rectus weakness can produce an apparent internuclear ophthalmoplegia-like pattern.

Unlike a true brainstem INO:

• The lesion is at the neuromuscular junction rather than the MLF.
• Other variable muscle weakness may be present.
• Ptosis frequently supports MG.
• Pupils remain normal.

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Pupils

The pupils are not affected in myasthenia gravis.

Pupillary abnormalities should suggest another diagnosis.

This is an important examination pearl.

⸻

Orbicularis Oculi Weakness

The examiner may be able to open the patient’s forcibly closed eyelids relatively easily.

A peek sign may occur:

• The patient initially closes the eyes completely.
• The eyelids then slowly separate because of orbicularis weakness.

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Other Examination Findings

Generalized MG may produce weakness of:

• Facial muscles
• Jaw closure
• Palatal muscles
• Tongue
• Neck flexors
• Proximal limb muscles

Deep tendon reflexes and sensation are generally preserved.

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Diagnostic Tests

Acetylcholine Receptor Antibodies

Testing commonly includes:

• AChR-binding antibodies
• AChR-blocking antibodies
• AChR-modulating antibodies

Binding antibody testing is usually the initial test.

Sensitivity is substantially higher in generalized MG than in purely ocular MG.

A positive result is highly supportive of the diagnosis.

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MuSK Antibodies

MuSK antibody testing is particularly useful when:

• Generalized MG is suspected
• AChR antibodies are negative
• Bulbar or respiratory weakness is prominent

MuSK-positive disease is uncommon in isolated ocular MG.

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Additional Antibody Testing

In appropriate seronegative patients, additional testing may include antibodies against:

• LRP4
• Other neuromuscular-junction targets

Availability varies.

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Thyroid Testing

Because autoimmune thyroid disease can coexist with MG and thyroid eye disease can mimic ocular MG, testing may include:

• TSH
• Free T4
• Thyroid antibodies when indicated

⸻

Imaging

Chest CT or MRI

Patients with confirmed MG should generally be evaluated for thymoma using imaging of the anterior mediastinum.

CT is commonly used.

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Neurophysiologic Testing

Repetitive Nerve Stimulation

Repetitive nerve stimulation may demonstrate a decremental response.

It is more useful in generalized disease than isolated ocular disease.

⸻

Single-Fiber EMG

Single-fiber electromyography is highly sensitive for abnormal neuromuscular transmission.

It may be especially useful when:

• Antibody testing is negative
• Clinical suspicion remains high

It is sensitive but not completely specific for MG.

⸻

Edrophonium Testing

Historically, intravenous edrophonium (Tensilon) was used to demonstrate transient improvement of ptosis or ophthalmoplegia.

Because of:

• Bradycardia
• Syncope
• Bronchospasm
• Other cholinergic adverse effects

and the availability of safer antibody and electrophysiologic testing, it is now rarely used.

⸻

Differential Diagnosis

Ocular MG Mimics

Important differential diagnoses include:

• Thyroid eye disease
• Cranial nerve III palsy
• Cranial nerve IV palsy
• Cranial nerve VI palsy
• Internuclear ophthalmoplegia
• Chronic progressive external ophthalmoplegia
• Mitochondrial myopathy
• Myotonic dystrophy
• Fisher syndrome
• Orbital disease
• Decompensated strabismus

⸻

Generalized MG Mimics

Consider:

• Lambert–Eaton myasthenic syndrome
• Botulism
• Amyotrophic lateral sclerosis
• Motor neuropathies
• Inflammatory myopathies
• Congenital myasthenic syndromes

⸻

Myasthenia vs Lambert–Eaton Syndrome

MG typically causes:

• Ocular and bulbar weakness
• Worsening with repetitive activity
• Normal or preserved reflexes

Lambert–Eaton syndrome more commonly causes:

• Proximal limb weakness
• Autonomic symptoms
• Reduced reflexes
• Strength that may transiently improve with activity

⸻

Treatment

Treatment depends on:

• Ocular versus generalized disease
• Degree of functional impairment
• Antibody status
• Bulbar or respiratory involvement
• Presence of thymoma
• Patient age
• Associated illnesses

⸻

Medication

Acetylcholinesterase Inhibitors

Pyridostigmine

Pyridostigmine (Mestinon) is the principal symptomatic treatment.

It increases the amount of acetylcholine available at the neuromuscular junction.

It may improve:

• Ptosis
• General muscle strength
• Bulbar symptoms

Its effect on ophthalmoplegia can be less reliable.

Common cholinergic adverse effects include:

• Abdominal cramping
• Diarrhea
• Excessive salivation
• Sweating
• Lacrimation

Dose is individualized according to response and adverse effects.

⸻

Corticosteroids

Corticosteroids may be used when symptomatic treatment is inadequate.

They are particularly useful for:

• Persistent ptosis
• Ophthalmoplegia
• Generalized disease

Prednisone is commonly used.

Treatment usually requires:

• Gradual titration
• Close monitoring
• Slow tapering once disease is controlled

Higher initial doses can occasionally transiently worsen weakness, so treatment strategy should be individualized by a clinician experienced in MG.

⸻

Steroid-Sparing Immunotherapy

When prolonged immunosuppression is required, options may include:

• Azathioprine
• Mycophenolate mofetil
• Tacrolimus
• Cyclosporine
• Methotrexate in selected cases

Monitoring depends on the medication and may include:

• CBC
• Liver function
• Renal function

⸻

Biologic and Targeted Therapy

For selected generalized or refractory MG, modern therapies can include targeted immunologic agents directed against:

• B cells
• Complement
• Neonatal Fc receptor pathways

These are generally managed by neuromuscular specialists.

⸻

Ophthalmic Symptomatic Treatment

Diplopia

Temporary measures include:

• Occlusion of one eye
• Translucent tape over one spectacle lens
• Eye patch

Prisms can help when deviation becomes sufficiently stable, but MG-related ocular misalignment is often too variable for prism correction to remain effective.

⸻

Ptosis

Mechanical ptosis crutches are occasionally used but are often poorly tolerated.

Definitive eyelid surgery should generally be avoided until:

• Disease is stable
• The degree of ptosis has remained consistent
• Medical treatment has been optimized

⸻

Thymectomy

Thymoma

A thymoma generally requires surgical management, usually with:

• Thymectomy
• Additional oncologic treatment when indicated

⸻

MG Without Thymoma

Thymectomy can benefit selected patients with generalized AChR-antibody positive MG, particularly younger adults.

It can reduce:

• Disease severity
• Steroid requirements
• Exacerbations

Its role in purely ocular MG is much less established.

⸻

Myasthenic Crisis

Alert

Difficulty breathing or swallowing in a patient with MG is a medical emergency.

A myasthenic crisis is severe worsening resulting in:

• Respiratory insufficiency
• Bulbar failure
• Inability to protect the airway

Patients may require:

• Intensive care
• Respiratory monitoring
• Mechanical ventilation

⸻

Acute Immunomodulatory Treatment

For severe exacerbations or myasthenic crisis:

• Intravenous immunoglobulin (IVIG)
• Plasma exchange

can produce relatively rapid improvement.

These are also used before surgery or during severe deterioration in selected patients.

⸻

Cholinergic Crisis

Excessive acetylcholinesterase inhibitor use can rarely produce excessive cholinergic activity.

Features may include:

• Weakness
• Salivation
• Diarrhea
• Sweating
• Miosis
• Bradycardia

It should be distinguished from worsening MG.

⸻

In-Patient Considerations

Admission may be required for:

• Myasthenic crisis
• Significant dysphagia
• Respiratory weakness
• Severe infection
• Rapidly progressive generalized weakness
• Plasma exchange
• IVIG

Respiratory parameters should be monitored carefully in patients with generalized deterioration.

⸻

Anesthetic Considerations

Patients with MG may be extremely sensitive to neuromuscular blocking medications.

Anesthesiologists must be informed of the diagnosis before surgery.

Perioperative medication management requires individualized planning.

⸻

Issues for Referral

Patients with confirmed or strongly suspected MG should be managed jointly with a:

Neurologist or neuromuscular specialist

because:

• Ocular disease can generalize
• Respiratory complications can occur
• Immunosuppressive therapy requires monitoring
• Thymic evaluation may be necessary

Neuro-ophthalmology referral is useful for complex ocular presentations.

⸻

Ongoing Care

Follow-Up

Patients should be monitored for:

• Change in ptosis
• Ocular motility
• Diplopia
• Development of bulbar symptoms
• Limb weakness
• Breathing difficulty
• Medication adverse effects

Patients initially presenting with ocular disease should be asked specifically about emerging systemic symptoms.

⸻

Prognosis

The course is variable.

Many patients initially present with ocular symptoms.

When ocular MG generalizes, this most commonly occurs during the first few years after onset, especially early in the disease course.

With modern therapy:

• Most patients achieve substantial disease control.
• Permanent remission without treatment is uncommon.
• Mortality is low when respiratory crises are rapidly recognized and appropriately managed.

⸻

Complications

The most important complication is:

Myasthenic Crisis

This is a neurologic emergency characterized by severe respiratory and/or bulbar weakness.

Management may require:

• ICU admission
• Airway support
• Mechanical ventilation
• IVIG
• Plasma exchange
• Treatment of precipitating infection or other trigger

Other complications arise from:

• Aspiration
• Infection
• Long-term corticosteroid treatment
• Chronic immunosuppression
• Thymoma

⸻

Ophthalmology Pearls

• Fluctuating ptosis + variable diplopia + normal pupils = think myasthenia gravis.
• MG can imitate almost any pattern of ocular motor palsy.
• Ocular findings may change during the same examination.
• Sustained upgaze can bring out fatigable ptosis.
• Cogan lid twitch is a useful bedside clue.
• The ice-pack test is a simple, useful test for myasthenic ptosis.
• Pupils are spared—pupillary involvement points away from MG.
• Medial rectus weakness can mimic an INO, producing a pseudo-INO.
• Orbicularis weakness and the peek sign are helpful supportive findings.
• AChR antibodies are less sensitive in isolated ocular MG than in generalized MG.
• Single-fiber EMG can help when antibody studies are negative.
• Evaluate confirmed MG for thymoma.
• New dysphagia, choking, weak cough, or dyspnea may represent impending myasthenic crisis and requires urgent assessment.

Ophthalmology – Multifocal Choroiditis / Punctate Inner Choroiditis

Basics

Description

Multifocal choroiditis (MFC) and punctate inner choroiditis (PIC) are inflammatory disorders affecting the choroid and outer retina.

Multifocal choroiditis with panuveitis is characterized by:

• Multiple active choroidal or chorioretinal lesions
• Vitreitis
• Frequently anterior uveitis
• Recurrent episodes of intraocular inflammation
• Risk of choroidal neovascularization and permanent chorioretinal scarring

Punctate inner choroiditis is closely related but typically:

• Occurs in young myopic women
• Produces small inflammatory lesions predominantly in the posterior pole
• Has little or no anterior chamber inflammation or vitreitis
• Frequently causes photopsias and central/paracentral scotomas

A related severe phenotype is diffuse subretinal fibrosis (DSF), in which inflammatory lesions coalesce and produce extensive subretinal fibrosis.

Etiology

The exact cause of MFC and PIC remains unknown.

They are believed to represent immune-mediated inflammatory chorioretinal disorders.

Possible mechanisms include:

• Abnormal autoimmune response against ocular antigens
• Molecular mimicry after exposure to an infectious or viral antigen
• Genetic susceptibility combined with an environmental trigger

MFC, PIC, and diffuse subretinal fibrosis may represent different manifestations along a common inflammatory disease spectrum.

Epidemiology

Multifocal Choroiditis

Typically affects:

• Young to middle-aged adults
• Women more often than men
• Commonly patients in the third to fourth decades of life

Punctate Inner Choroiditis

Classically occurs in:

• Young women
• Frequently myopic patients
• Otherwise healthy individuals

Both disorders may be bilateral, although disease activity may be markedly asymmetric.

History

Patients with MFC are usually otherwise healthy.

Some report a preceding:

• Viral-like illness
• Upper respiratory infection
• Nonspecific systemic prodrome

Common ocular complaints include:

• Blurred or decreased vision
• Floaters
• Photopsias
• Scotomas
• Peripheral visual field loss
• Metamorphopsia
• Distorted central vision

Symptoms may develop gradually.

Although patients may notice symptoms in only one eye initially, bilateral involvement is common.

Punctate Inner Choroiditis Symptoms

Patients with PIC commonly report:

• Photopsias
• Central or paracentral scotomas
• Metamorphopsia
• Blurred central vision

Because PIC often lacks significant anterior chamber or vitreous inflammation, the eye may appear externally quiet.

Physical Examination

Multifocal Choroiditis

Typical examination findings include:

• Vitreitis in most patients
• Anterior chamber inflammation in approximately half of cases
• Multiple yellow-white choroidal or chorioretinal lesions
• Pigmented borders around older lesions
• Chorioretinal scars in healed disease

The lesions:

• Are usually approximately 50–300 μm
• May occur throughout the posterior pole and peripheral fundus
• Represent focal inflammatory involvement of the choroid and outer retina

Older lesions often become:

• Punched-out
• Atrophic
• Pigmented

Punctate Inner Choroiditis

PIC lesions are generally:

• Small
• Yellow-white
• Located at the posterior pole
• Often at the level of the inner choroid/RPE/outer retina

Unlike classic MFC:

• Vitreitis is typically absent or minimal
• Anterior uveitis is generally absent

This distinction is clinically useful.

Diffuse Subretinal Fibrosis

In severe disease, multiple inflammatory lesions may coalesce, producing:

• Broad zones of subretinal fibrosis
• Macular distortion
• Extensive photoreceptor and RPE damage
• Severe irreversible visual loss

This phenotype is referred to as diffuse subretinal fibrosis syndrome.

Diagnostic Tests & Interpretation

Laboratory Evaluation

There is no specific laboratory test that confirms MFC or PIC.

Testing is primarily directed at excluding infectious and systemic inflammatory mimickers.

Depending on history, examination, and geographic exposure, investigations may include:

• Syphilis serology
• Tuberculosis testing
• Sarcoidosis evaluation
• Toxoplasmosis testing
• Lyme disease testing when epidemiologically appropriate

Before initiating systemic immunosuppression, baseline investigations commonly include:

• Complete blood count
• Liver function tests
• Renal function tests
• Screening for latent infection according to the proposed immunomodulatory agent

Imaging

Fundus Photography

Color and red-free fundus photography are useful for:

• Baseline documentation
• Assessing lesion distribution
• Comparing active versus healed lesions
• Monitoring progression or recurrence
• Documenting scar formation

Fluorescein Angiography

Fluorescein angiography (FA) is useful for identifying:

• Clinically inapparent lesions
• Active inflammatory lesions
• Choroidal neovascularization
• Cystoid macular edema
• Vascular leakage

Active lesions

Typically demonstrate:

• Early hypofluorescence from blockage
• Progressive hyperfluorescence or staining in later phases

Inactive lesions

May demonstrate:

• Window defects from RPE atrophy
• Late staining
• Persistent hypofluorescence if choriocapillaris loss is severe

Optical Coherence Tomography

OCT is essential for evaluating the macula.

It can demonstrate:

• Disruption of the outer retinal layers
• Photoreceptor loss
• RPE changes
• Subretinal fluid
• Intraretinal fluid
• Cystoid macular edema
• Choroidal neovascular membrane
• Fibrotic scar formation

Serial OCT is extremely useful for monitoring:

• Disease activity
• Treatment response
• Development of CNV
• Resolution of macular edema

OCT in PIC

Modern spectral-domain OCT may demonstrate focal abnormalities involving:

• RPE
• Ellipsoid zone
• Outer nuclear layer
• Choroid

Active lesions may protrude through or disrupt the RPE and outer retina before evolving into atrophic scars.

Indocyanine Green Angiography

Indocyanine green angiography may demonstrate more extensive choroidal involvement than is clinically visible.

It can show:

• Multiple hypofluorescent choroidal spots
• Areas of occult inflammatory activity

It may be particularly useful when the clinical diagnosis is uncertain.

Fundus Autofluorescence

Fundus autofluorescence can assist in demonstrating:

• Active RPE stress
• Areas of RPE loss
• Subclinical lesions
• Progression of chorioretinal atrophy

Hyperautofluorescent borders may indicate active or stressed RPE, whereas established atrophy generally becomes hypoautofluorescent.

Visual Field Testing

Visual field testing may show:

• Paracentral scotomas
• Peripheral field defects
• Enlarged blind spot

Visual field defects do not always correspond directly to currently active choroidal lesions.

Follow-Up During Active Disease

During active inflammation, patients may require examination every:

1–4 weeks

depending on:

• Severity
• Macular involvement
• Degree of vitreous inflammation
• Presence of CNV
• Treatment being used

Choroidal Neovascularization

One of the most important complications of both MFC and PIC is:

Choroidal neovascularization (CNV)

It may develop:

• Beneath the macula
• Adjacent to active inflammatory lesions
• In old scars
• In the peripapillary region
• Even after active inflammation has subsided

Patients should be educated to recognize:

• New metamorphopsia
• New central scotoma
• Sudden reduction in central vision

Amsler Grid

Home Amsler grid monitoring may help identify:

• New distortion
• New central scotoma
• Blurring
• Possible development of CNV

Any new change warrants prompt examination.

Differential Diagnosis

Important differential diagnoses include:

• Ocular syphilis
• Tuberculosis
• Toxoplasmosis
• Presumed ocular histoplasmosis syndrome
• Sarcoidosis
• Central serous chorioretinopathy
• Age-related macular degeneration
• Choroidal neovascularization from other causes
• Ocular trauma
• Acute posterior multifocal placoid pigment epitheliopathy
• Multiple evanescent white dot syndrome
• Birdshot chorioretinopathy
• Vogt–Koyanagi–Harada disease
• Intraocular lymphoma in atypical cases

Treatment

Treatment is determined by:

• Degree of active inflammation
• Laterality
• Macular involvement
• Presence of CNV
• Recurrence frequency
• Degree of structural damage

Medication

First Line

For significant posterior inflammation, topical corticosteroids alone are generally inadequate.

Treatment may include:

• Systemic corticosteroids
• Periocular corticosteroid injection
• Intravitreal corticosteroid therapy in selected cases

Topical corticosteroids may still be useful when there is significant anterior uveitis.

Important Precaution

Infectious causes must be excluded before starting corticosteroids or systemic immunosuppressive therapy.

Immunosuppression of an undiagnosed infectious posterior uveitis may result in severe disease progression.

Systemic Corticosteroids

Oral corticosteroids may be useful for:

• Bilateral disease
• Severe posterior inflammation
• Vision-threatening macular involvement
• Extensive active lesions

Long-term systemic corticosteroid therapy should generally be avoided when a steroid-sparing treatment strategy is appropriate.

Second-Line Therapy

Systemic immunomodulatory therapy may be indicated when:

• Disease is recurrent
• Inflammation is chronic
• Corticosteroid dependence develops
• Disease is bilateral and vision-threatening
• Corticosteroid toxicity is problematic

Potential steroid-sparing agents include, depending on the patient:

• Methotrexate
• Mycophenolate mofetil
• Azathioprine
• Cyclosporine
• Tacrolimus
• Selected biologic agents in refractory disease

These treatments require appropriate systemic monitoring.

Pregnancy Considerations

Many immunomodulatory drugs may:

• Be teratogenic
• Affect fetal development
• Require discontinuation before conception

Treatment in pregnancy should therefore be coordinated with:

• Uveitis specialist
• Obstetrician
• Rheumatologist or other prescribing specialist

Choroidal Neovascularization Treatment

Modern treatment for inflammatory CNV generally centers on:

Intravitreal anti-VEGF therapy

Examples include:

• Bevacizumab
• Ranibizumab
• Aflibercept

Treatment of underlying inflammatory activity may also be necessary.

Historically used treatments include:

• Photodynamic therapy
• Thermal laser photocoagulation in selected extrafoveal lesions

These are used much less commonly than anti-VEGF therapy for macular CNV.

Cystoid Macular Edema

CME may respond to:

• Periocular corticosteroid
• Intravitreal corticosteroid
• Systemic anti-inflammatory therapy

Anti-VEGF treatment may occasionally be used depending on the mechanism and associated pathology.

Issues for Referral

Because posterior uveitis has numerous infectious and inflammatory mimickers and can cause permanent vision loss, patients should generally be managed by or referred to a:

Uveitis specialist

Additional referral may be needed to:

• Retina specialist for CNV, macular edema, or structural complications
• Rheumatology for systemic immunomodulatory therapy
• Infectious disease when an infectious cause is suspected

Surgery / Other Procedures

Cataract Surgery

Chronic inflammation and corticosteroid treatment may cause cataract.

Cataract surgery can be considered when:

• Cataract is visually significant
• Inflammation has been well controlled
• The eye has been appropriately quiet before surgery

Perioperative anti-inflammatory therapy is often required.

Steroid Implants

Sustained-release intraocular corticosteroid implants may be considered in selected cases of:

• Chronic posterior uveitis
• Recurrent disease
• Inadequate response to other therapy

Potential complications include:

• Cataract
• Ocular hypertension
• Glaucoma

Vitrectomy

Pars plana vitrectomy may be considered for:

• Visually significant vitreous opacities
• Diagnostic uncertainty
• Suspected intraocular lymphoma or infection
• Selected structural complications

Diagnostic vitreous sampling may be particularly important in atypical presentations.

Ongoing Care

Long-term follow-up is important because disease may recur after prolonged periods of inactivity.

Monitoring should include:

• Visual acuity
• Slit-lamp examination
• Vitreous inflammation
• Dilated fundus examination
• OCT
• Assessment for CNV
• Intraocular pressure
• Cataract development

Patient Education

Patients should be advised to seek prompt review for:

• New photopsias
• New floaters
• New scotoma
• Metamorphopsia
• Sudden or progressive central visual loss

Home Amsler grid monitoring can be useful.

Prognosis

MFC and PIC often follow a chronic or relapsing course lasting months to years.

Visual prognosis depends primarily on:

• Macular involvement
• Recurrent inflammation
• Development of CNV
• Cystoid macular edema
• Photoreceptor loss
• Extent of chorioretinal scarring
• Diffuse subretinal fibrosis

Patients without foveal involvement may maintain good central vision.

Repeated macular inflammation, CNV, or extensive fibrosis can result in severe permanent visual impairment.

Complications

Important complications include:

• Choroidal neovascularization
• Cystoid macular edema
• Subretinal fibrosis
• Chorioretinal atrophy
• Photoreceptor loss
• Cataract
• Ocular hypertension
• Glaucoma
• Steroid-related complications
• Permanent central visual loss

CNV may occur even when there is no clinically active inflammation, making long-term surveillance essential.

Ophthalmology Pearls

• MFC = multifocal choroidal lesions + vitreitis ± anterior uveitis.
• PIC = young myopic women + posterior pole punctate lesions + little or no vitreitis.
• The two disorders likely belong to a related inflammatory spectrum.
• CNV is one of the most important causes of visual loss and may develop even after inflammation appears inactive.
• OCT is indispensable for distinguishing inflammatory damage from treatable complications such as CNV, CME, or subretinal fluid.
• Before immunosuppression, exclude important infectious mimickers—particularly syphilis and tuberculosis.
• Anti-VEGF therapy is the main contemporary treatment for inflammatory CNV.
• Recurrent disease can lead to extensive subretinal fibrosis and irreversible visual loss.
• Long-term, often lifelong ophthalmic surveillance is appropriate because recurrence and CNV can occur after apparently quiet intervals.

Ophthalmology – Morning Glory Syndrome

Basics

Description

Morning glory syndrome, also called morning glory disc anomaly (MGDA), is a rare congenital malformation characterized by a distinctive funnel-shaped excavation of the optic disc and surrounding posterior fundus.

Its name comes from the resemblance of the anomalous optic nerve head to a morning glory flower.

MGDA is usually:

• Unilateral
• Congenital
• Associated with reduced vision
• Occasionally associated with serious neurologic, cerebrovascular, craniofacial, pituitary, and retinal abnormalities

Because of these systemic associations, recognition of MGDA should prompt evaluation beyond the eye.

Epidemiology

Incidence

MGDA is very rare.

An estimated incidence of approximately:

1 per 1,000,000 live births

has been reported.

Pathophysiology

MGDA is thought to result from abnormal development of the optic nerve and surrounding posterior sclera during embryogenesis.

Typical developmental abnormalities include:

• Funnel-shaped excavation of the optic nerve head
• Abnormal surrounding scleral and peripapillary tissue
• Persistent glial tissue centrally
• Abnormal retinal vascular emergence

A characteristic central glial tuft often remains over the optic disc.

Some authors have proposed that the anomaly represents a form of mesenchymal or mesodermal dysgenesis.

Myocontractile tissue has occasionally been identified histologically, and rare contractile movements of the anomalous disc region have been described clinically.

Commonly Associated Conditions

Retinal Detachment

Retinal detachment occurs in a substantial proportion of patients, historically reported in approximately one-third.

The mechanism is variable and incompletely understood.

Proposed mechanisms include:

• Peripapillary retinal breaks
• Retinoschisis-like communications
• Abnormal communication between:
• The subarachnoid space
• The anomalous optic nerve
• The subretinal space
• Vitreoretinal traction

Detachment may be:

• Localized to the macula
• Shallow and chronic
• Bullous
• Total

Rare spontaneous resolution has been reported.

Cerebrovascular Abnormalities

MGDA has important associations with abnormalities of the intracranial circulation.

These may include:

• Internal carotid artery stenosis
• Carotid hypoplasia
• Carotid aplasia
• Abnormal Circle of Willis
• Cerebral arterial stenosis

These abnormalities may predispose to:

• Stroke
• Transient ischemic events
• Seizures

Moyamoya Disease

MGDA is associated with moyamoya arteriopathy.

Moyamoya is characterized by:

• Progressive stenosis of major intracranial arteries
• Development of abnormal collateral vessels
• Increased risk of:
• Cerebral ischemia
• Infarction
• Intracranial hemorrhage

The abnormal collateral network produces the classic angiographic appearance described as a “puff of smoke.”

Because of this association, cerebral vascular imaging is an important component of evaluation in MGDA.

Midline Cranial Abnormalities

MGDA may occur with congenital midline abnormalities such as:

• Basal encephalocele
• Absent or abnormal septum pellucidum
• Corpus callosal abnormalities
• Pituitary abnormalities
• Other midline craniofacial defects

Pituitary Dysfunction

Pituitary abnormalities can be:

• Structural
• Functional
• Both

Possible manifestations include:

• Growth hormone deficiency
• Growth retardation
• Hypothyroidism
• Other pituitary hormone deficiencies

Children with MGDA should therefore have growth and endocrine development assessed carefully.

Other Associations

Less commonly reported associations include:

• Retinal arteriovenous malformations
• Renal abnormalities
• Papillorenal-spectrum disorders
• Persistent fetal vasculature
• Craniofacial abnormalities

Scattered reports have also linked MGDA with other neurodevelopmental syndromes.

Diagnosis

Diagnosis is primarily based on the characteristic funduscopic appearance of the optic nerve head.

History

Patients may present with:

• Poor vision
• Strabismus
• Failed vision screening
• Leukocoria
• Abnormal pupillary reflex
• Acute visual decline

Acute visual decline should raise concern for:

Retinal detachment

Systemic History

Ask about manifestations suggesting associated neurologic or endocrine disease.

Possible Pituitary Dysfunction

• Poor growth
• Short stature
• Delayed development
• Symptoms of hypothyroidism

Possible Cerebrovascular Disease

• Seizures
• Transient weakness
• Stroke-like episodes
• Developmental regression
• Headaches
• Syncope

Physical Examination

Visual Acuity

Visual acuity is highly variable.

It may range from:

• Nearly normal vision
• Mild visual impairment
• Severe visual impairment
• No light perception

Visual potential depends on:

• Degree of optic nerve malformation
• Macular involvement
• Presence of retinal detachment
• Refractive error
• Amblyopia

Refraction

Myopia is common.

Significant refractive error should be corrected promptly, particularly in children.

Strabismus

Strabismus is common because of unilateral visual impairment.

Most commonly:

• Esotropia
• Exotropia

may occur depending on visual function and age.

Pupillary Examination

A unilateral case may show a:

Relative afferent pupillary defect

if optic nerve dysfunction is sufficiently asymmetric.

Color Vision

Color discrimination may be reduced in the affected eye.

Characteristic Fundus Appearance

The classic features of morning glory disc anomaly include:

• Large optic disc
• Funnel-shaped excavation of the optic nerve head and surrounding posterior sclera
• Central white glial tuft
• Radial arrangement of retinal vessels
• Vessels emerging abnormally from the peripheral edge of the excavation
• Peripapillary pigmentary disturbance
• Circumferential annular ring of pigmented chorioretinal tissue

The vessels may be:

• Numerous
• Narrow
• Radially oriented

and often lack the normal central emergence pattern.

Laterality

MGDA is usually:

Unilateral

Bilateral disease is uncommon.

Retinal Examination

Carefully inspect for:

• Shallow retinal detachment
• Macular detachment
• Retinoschisis
• Peripheral retinal abnormalities

Detachment can occasionally be subtle.

Systemic Examination

Children should have:

• Height measurement
• Weight measurement
• Growth chart assessment
• Complete neurologic assessment
• Developmental assessment

Diagnostic Tests

Laboratory Evaluation

Because of the association with pituitary dysfunction, selected endocrine testing may include:

• TSH
• Free T4
• Growth hormone axis testing
• IGF-1
• Additional pituitary hormones as clinically indicated

Endocrine testing should be guided by clinical findings and pediatric/endocrinology evaluation.

Renal Evaluation

When clinically indicated:

• Serum electrolytes
• Creatinine
• Basic metabolic panel
• Urinalysis

may be obtained.

Routine renal investigations are not necessary in every patient unless the phenotype suggests a syndromic association.

Neuroimaging

A patient with MGDA should be considered for brain and cerebrovascular imaging because of the potentially serious associated abnormalities.

In children, preferred evaluation often includes:

• MRI brain
• MRA head and neck

These avoid ionizing radiation.

Imaging should carefully evaluate:

• Internal carotid arteries
• Circle of Willis
• Intracranial arterial circulation
• Midline brain structures
• Pituitary gland
• Skull base

CT / CTA

CT or CTA may be considered when:

• MRI is unavailable
• Bony anatomy needs detailed assessment
• Basal encephalocele is suspected
• Rapid vascular imaging is clinically necessary

Fundus Photography

Fundus photography is useful for:

• Baseline documentation
• Long-term comparison
• Recording optic disc morphology
• Monitoring associated retinal changes

Optical Coherence Tomography

OCT is especially useful for evaluating:

• Peripapillary architecture
• Macular anatomy
• Intraretinal splitting
• Retinoschisis-like changes
• Subretinal fluid
• Retinal detachment

OCT may help demonstrate a potential communication between abnormal peripapillary structures and the subretinal space.

Fluorescein Angiography

Fluorescein angiography may help evaluate:

• Abnormal retinal vascular anatomy
• Retinal perfusion
• Associated vascular malformations
• Areas of leakage

It is not always required for diagnosis.

Differential Diagnosis

Important differential diagnoses include:

• Optic disc coloboma
• Peripapillary staphyloma
• Posterior staphyloma
• Optic nerve coloboma
• Microphthalmia with cyst
• Congenital optic nerve excavation

Morning Glory Disc vs Optic Disc Coloboma

MGDA typically shows:

• Central glial tuft
• Radial retinal vessels
• Annular peripapillary pigmentation
• Funnel-shaped excavation

Optic disc coloboma more often shows:

• Inferior excavation
• Sharply demarcated congenital defect
• Association with other colobomatous abnormalities

Treatment

There is no treatment that can correct the congenital optic nerve anomaly itself.

Management focuses on:

• Maximizing useful vision
• Treating amblyopia
• Correcting refractive error
• Managing retinal detachment
• Detecting systemic associations
• Protecting the better eye

Refractive Correction

Correct significant:

• Myopia
• Astigmatism
• Anisometropia

as early as possible in children.

Amblyopia Therapy

Amblyopia treatment may be appropriate when useful visual potential exists.

Options include:

• Full optical correction
• Patching of the better eye
• Penalization in selected cases

However, treatment should be pursued cautiously, because the affected eye may have limited structural visual potential.

Excessive occlusion of the better eye should be avoided.

Retinal Detachment Treatment

Retinal detachment associated with MGDA is often difficult to manage.

Treatment may include:

• Pars plana vitrectomy
• Removal of vitreoretinal traction
• Internal drainage when appropriate
• Laser photocoagulation
• Long-acting gas tamponade
• Silicone oil in selected complex cases

The optimal technique depends on:

• Retinal configuration
• Presence of retinal breaks
• Macular involvement
• Vitreous traction
• Patient age

Medical Treatment

There is no specific ophthalmic medication for MGDA itself.

Systemic therapy depends on associated abnormalities.

Examples include:

• Hormonal replacement for pituitary deficiencies
• Antithrombotic or cerebrovascular management as directed by neurology/neurosurgery

Issues for Referral

Pediatric Ophthalmology

Recommended for:

• Refraction
• Amblyopia management
• Strabismus assessment
• Long-term visual development monitoring

Retina Specialist

Indicated when there is:

• Retinal detachment
• Retinoschisis
• Subretinal fluid
• Sudden visual decline

Neurology

Neurologic evaluation is appropriate because of the association with:

• Seizures
• Stroke
• Cerebral arterial abnormalities
• Moyamoya disease

Neurosurgery / Neurovascular Specialist

Referral is important if imaging demonstrates:

• Moyamoya arteriopathy
• Severe carotid stenosis
• Intracranial arterial abnormalities
• Basal encephalocele

Endocrinology

Endocrine referral is appropriate for:

• Growth retardation
• Abnormal pituitary imaging
• Growth hormone deficiency
• Hypothyroidism
• Other pituitary hormone abnormalities

Additional Therapy

Monocular Precautions

When one eye has poor vision, the better eye should be protected.

Recommend:

Polycarbonate protective spectacles

especially for:

• Children
• Sports
• Occupational activities
• Any activity with potential eye trauma

Ongoing Care

Follow-Up Recommendations

Children with MGDA generally require regular lifelong ophthalmic surveillance.

At minimum:

• Annual ophthalmic examination

More frequent follow-up is appropriate when there is:

• Amblyopia
• Significant refractive error
• Strabismus
• Retinal detachment
• Progressive retinal changes

Patient Monitoring

Parents should monitor for:

• Sudden reduction in vision
• New strabismus
• Behavioral evidence of visual loss
• New visual field complaints
• Metamorphopsia
• Micropsia

Neurologic symptoms should also prompt urgent medical assessment.

Retinal Detachment Warning Symptoms

Patients and families should be educated about:

• New flashes
• New floaters
• Curtain or shadow in vision
• Sudden visual loss

In MGDA, a shallow macular detachment may produce more subtle symptoms such as:

• Metamorphopsia
• Micropsia
• Blurred central vision

Prognosis

Visual prognosis is highly variable but is often limited because of the underlying optic nerve malformation.

Vision depends on:

• Degree of optic nerve dysplasia
• Macular involvement
• Refractive error
• Amblyopia
• Retinal detachment

Patients presenting with relatively good stable vision and no retinal detachment may retain useful vision long term.

Complications

Important complications include:

• Retinal detachment
• Retinoschisis
• Amblyopia
• Strabismus
• Severe visual impairment
• Cerebral ischemia or stroke from associated vascular abnormalities
• Seizures
• Pituitary hormone deficiency

Ophthalmology Pearls

• Morning glory disc anomaly = funnel-shaped congenital optic disc excavation with a central glial tuft and radially arranged retinal vessels.
• It is usually unilateral.
• Always think beyond the eye: MGDA can be associated with carotid abnormalities, moyamoya disease, basal encephalocele, and pituitary dysfunction.
• MRI/MRA of the brain and cerebral circulation should be strongly considered, particularly in children.
• Approximately one-third of patients have historically been reported to develop retinal detachment.
• Acute deterioration in vision in a patient with MGDA should prompt urgent evaluation for retinal detachment.
• A child with poor unilateral vision requires careful refractive and amblyopia management, but aggressive patching may be inappropriate when structural visual potential is severely limited.
• Protect the better eye with polycarbonate spectacles when visual function is markedly asymmetric.

Ophthalmology – Moebius Syndrome

Basics

Description

Moebius syndrome is a congenital, usually nonprogressive disorder characterized primarily by:

• Unilateral or bilateral facial weakness
• Impaired ocular abduction
• Variable involvement of other cranial nerves
• Possible craniofacial and limb anomalies

The disorder is considered part of the spectrum of congenital cranial dysinnervation disorders (CCDDs).

Epidemiology

Incidence

Approximately 0.0002–0.002% of live births.

Prevalence

Estimated historical figures include:

• About 2,000 affected individuals worldwide
• About 800 affected individuals in the United States

Because the syndrome is rare and variably expressed, its true prevalence is uncertain.

Risk Factors

Possible risk factors include:

• Family history of Moebius syndrome
• Family history of another congenital cranial dysinnervation disorder
• In-utero exposure to certain proposed teratogens or vascular-disruptive events

Reported associations include:

• Maternal hyperthermia
• Chorionic villus sampling
• Electric shock
• Benzodiazepine abuse
• Alcohol
• Cocaine
• Thalidomide
• Misoprostol

Not every exposed pregnancy develops Moebius syndrome, and many cases occur without an identifiable exposure.

Genetics

Most cases are sporadic, but several inheritance patterns have been reported:

• Autosomal dominant
• Autosomal recessive
• X-linked recessive

Expression and penetrance may vary.

Reported loci have included:

• MBS1: 13q12.2–q13
• Proposed MBS2: 3q21–q22
• Proposed MBS3: 10q21.3–q22.1

Multiple chromosomal abnormalities have also been associated with a Moebius-like phenotype.

General Prevention

There is no specific preventive treatment.

General measures include:

• Avoidance of known or suspected teratogens during pregnancy
• Genetic counseling when there is:
• A family history
• A syndromic phenotype
• A known chromosomal abnormality

Pathophysiology

The exact mechanism is incompletely understood.

Moebius syndrome is thought to result from abnormal development of the rhombencephalon/brainstem, affecting predominantly:

• Cranial motor nuclei
• Cranial nerve axons
• Their long central pathways

Developmental disruption is thought to occur very early in embryogenesis, approximately during the 3rd to 5th weeks of gestation.

The classic neurologic involvement affects:

• CN VI — abducens nerve
• CN VII — facial nerve

Other cranial nerves may also be involved.

Etiology

Possible etiologies include:

• Genetic or inherited developmental abnormalities
• Chromosomal abnormalities
• Teratogenic exposure
• Embryonic vascular disruption

In many patients, no single cause is identified.

Commonly Associated Conditions

Cranial Nerve Abnormalities

Other cranial nerve abnormalities may occur.

CN XII Involvement

Hypoglossal nerve involvement may cause:

• Tongue hypoplasia
• Abnormal lateral tongue grooves or crenulations

Craniofacial Abnormalities

Reported features include:

• Epicanthal folds
• Flat nasal bridge
• Micrognathia
• High-arched palate
• External ear abnormalities
• Dental abnormalities
• Hypertelorism

Limb Abnormalities

Extremity malformations are common and may include:

• Syndactyly
• Brachydactyly
• Limb reduction defects
• Clubfoot
• Arthrogryposis

Feeding and Swallowing Problems

These are common and may result from:

• Cranial nerve dysfunction
• Poor oral motor coordination
• Weak facial musculature
• Tongue dysfunction

Other Ocular Motility Disorders

Duane retraction syndrome may coexist.

Poland Syndrome

Some patients have associated Poland syndrome, characterized by:

• Hypoplasia or absence of the pectoral muscle
• Ipsilateral upper-limb abnormalities

Rare Associations

Reported uncommon associations include:

• Congenital heart defects
• Dextrocardia
• Arthrogryposis multiplex congenita
• Urinary tract abnormalities
• Anosmia
• Hypogonadotropic hypogonadism

Diagnosis

Diagnosis is primarily clinical.

The classic combination is:

• Congenital facial weakness
• Congenital limitation of ocular abduction

Other cranial nerve, limb, and craniofacial abnormalities support the diagnosis.

History

Important points include:

• Family history
• Maternal medication or drug exposure
• Possible teratogenic exposure during pregnancy
• Feeding difficulties
• Swallowing difficulties
• Speech delay
• Abnormal facial movement since birth
• Eye movement abnormalities since birth
• Exposure symptoms such as:
• Tearing
• Irritation
• Redness
• Photophobia

Physical Examination

Ocular Examination

A complete ophthalmic examination should include:

• Visual acuity
• Refraction
• Pupils
• Ocular motility
• Alignment
• Anterior segment examination
• Corneal surface assessment
• Fundus examination

Ocular Motility

The most characteristic abnormality is limited abduction due to CN VI dysfunction.

Patients may have:

• Bilateral abduction limitation
• Unilateral abduction limitation
• Esotropia
• Variable primary-position alignment

Some patients may be approximately orthophoric in primary gaze despite significant abduction limitation.

Facial Weakness

CN VII dysfunction may cause:

• Reduced facial expression
• Inability to smile normally
• Weak orbicularis oculi
• Poor eyelid closure
• Lagophthalmos

The characteristic “mask-like” facial appearance is due to congenital facial nerve weakness rather than lack of emotional expression.

Ocular Surface Examination

Because orbicularis weakness may impair blinking and closure, evaluate carefully for:

• Lagophthalmos
• Exposure keratopathy
• Superficial punctate keratitis
• Corneal epithelial defects
• Corneal ulceration

Visual Function

Assess for:

• Refractive error
• Strabismic amblyopia
• Anisometropic amblyopia
• Reduced visual acuity from corneal exposure

Children require particular attention because amblyopia can become permanent.

External Examination

Look for:

• Facial asymmetry
• Mask-like facial appearance
• Micrognathia
• Ear abnormalities
• Dental abnormalities
• Palatal abnormalities
• Limb defects

Systemic Examination

Patients should be evaluated for:

• Limb abnormalities
• Feeding dysfunction
• Swallowing dysfunction
• Speech abnormalities
• Hearing problems
• Respiratory compromise
• Developmental concerns

Diagnostic Tests

Laboratory Testing

Routine laboratory testing is generally unnecessary.

When the phenotype is atypical or no clear environmental cause is identified, consider:

• Chromosomal microarray
• Karyotype in selected patients
• Targeted genetic testing when another congenital cranial dysinnervation disorder is suspected

There is no single universally diagnostic genetic test for classic Moebius syndrome.

Imaging

Routine imaging is not always necessary.

MRI Brain and Brainstem

MRI may be performed to assess:

• Brainstem anatomy
• Cranial nerve nuclei
• Cranial nerve pathways
• Associated central nervous system abnormalities

Imaging findings may be normal despite clinically definite disease.

Special Considerations

If the history of congenital disease is uncertain and ophthalmoplegia is progressive rather than static, consider alternative diagnoses such as:

• Mitochondrial disorders
• Chronic progressive external ophthalmoplegia
• Kearns–Sayre syndrome

A progressive course is not typical of Moebius syndrome.

Differential Diagnosis

Important differential diagnoses include:

• Isolated CN VI palsy
• Congenital esotropia with pseudo-abduction deficit
• Duane retraction syndrome
• Other congenital cranial dysinnervation disorders
• Hanhart syndrome
• Hypoglossia-hypodactyly syndrome
• Oromandibular limb hypogenesis syndromes
• Chronic progressive external ophthalmoplegia
• Mitochondrial disorders
• Thyroid eye disease
• Brainstem lesions

Internuclear ophthalmoplegia is fundamentally different because it is a central supranuclear/internuclear disorder rather than a congenital bilateral abduction deficit.

Treatment

There is no medication that corrects the underlying congenital cranial dysinnervation.

Management focuses on:

• Protecting the cornea
• Treating strabismus
• Preventing amblyopia
• Supporting feeding, speech, and development
• Correcting associated craniofacial or limb abnormalities when appropriate

Ocular Surface Treatment

Lubrication

For ocular surface dryness or exposure:

• Preservative-free artificial tears
• Lubricating gel
• Ophthalmic ointment at bedtime

Eyelid Protection

If lagophthalmos is significant:

• Tape eyelids closed at night
• Use moisture chambers when appropriate
• Increase lubrication

Bandage Contact Lens

A bandage contact lens may be considered for severe exposure-related epithelial disease.

Close monitoring is essential because contact lenses can increase the risk of infectious keratitis.

Amblyopia Treatment

Treat amblyopia when present using:

• Full refractive correction
• Patching of the better eye
• Penalization when appropriate

Early childhood treatment is especially important.

Strabismus Management

Strabismus surgery may be considered when clinically significant esotropia or another alignment abnormality is present.

Goals include:

• Improving primary-position alignment
• Improving binocular function where possible
• Improving abnormal head posture
• Cosmetic improvement

Because the underlying disorder is dysinnervational, normal abduction usually cannot be restored completely.

Exposure Keratopathy Surgery

Tarsorrhaphy

Temporary or permanent tarsorrhaphy may be needed for severe:

• Lagophthalmos
• Exposure keratopathy
• Recurrent epithelial breakdown
• Corneal ulceration

Multidisciplinary Management

Moebius syndrome frequently requires care from multiple specialties.

Possible referrals include:

• Pediatric ophthalmology
• Strabismus specialist
• Oculoplastic specialist
• Clinical genetics
• Pediatrics
• Neurology
• ENT
• Dentistry
• Orthopedics
• Plastic/craniofacial surgery
• Speech-language pathology
• Occupational therapy
• Physical therapy
• Nutrition
• Psychology or neuropsychology

Feeding and Swallowing

Feeding difficulties may require:

• Feeding therapy
• Occupational therapy
• Speech-language pathology
• Nutritional support

Severe bulbar dysfunction may rarely necessitate more intensive airway or feeding support.

Speech

Facial, lingual, and palatal weakness can cause dysarthria.

Speech therapy may improve:

• Articulation
• Oral motor control
• Communication strategies

Complementary and Alternative Therapy

No complementary treatment has been proven to reverse the underlying neurologic abnormalities.

Ongoing Care

Follow-Up Recommendations

Follow-up frequency depends on ocular complications.

Patients with exposure keratopathy may require frequent review.

Children require ongoing surveillance for:

• Refractive error
• Amblyopia
• Strabismus
• Corneal exposure

Patient Monitoring

Monitor:

• Visual acuity
• Refraction
• Ocular alignment
• Corneal integrity
• Lid closure
• Amblyopia treatment response
• School performance
• Feeding and speech development
• Overall developmental progress

Diet

There is no specific Moebius syndrome diet.

Dietary modifications may be needed when swallowing or chewing difficulties are present.

A nutritionist or feeding team may help determine:

• Food consistency
• Caloric requirements
• Aspiration precautions

Patient and Family Education

Families should understand that:

• Moebius syndrome is congenital
• It is generally nonprogressive
• Facial immobility does not indicate lack of emotion or cognitive impairment
• Corneal protection is important
• Amblyopia treatment must be performed early
• Multidisciplinary support may substantially improve function

Genetic counseling should be offered when appropriate.

The Moebius Syndrome Foundation can provide patient and family support.

Prognosis

Moebius syndrome is generally a nonprogressive congenital condition.

With appropriate supportive care:

• Life expectancy is usually normal
• Vision can remain good if:
• Exposure keratopathy is prevented
• Amblyopia is treated
• Significant strabismus is managed

Functional outcome depends largely on the extent of associated cranial nerve and systemic abnormalities.

Complications

Important ophthalmic complications include:

• Exposure keratopathy
• Corneal epithelial breakdown
• Corneal ulceration
• Corneal scarring
• Rare corneal perforation
• Amblyopia
• Strabismus-related visual dysfunction

Other important complications may include:

• Feeding difficulty
• Aspiration
• Speech impairment
• Dental problems
• Psychosocial difficulties related to facial immobility

Ophthalmology Pearls

• The classic Moebius phenotype combines CN VI and CN VII dysfunction.
• Think abduction deficit + congenital facial weakness.
• The ocular motility disorder is developmental and typically nonprogressive.
• Facial weakness can cause lagophthalmos and exposure keratopathy, making corneal protection a major ophthalmic priority.
• Strabismus and refractive error can produce amblyopia, so early pediatric ophthalmic surveillance is important.
• Progressive ophthalmoplegia should prompt reconsideration of the diagnosis and investigation for mitochondrial or acquired neurologic disease.
• A child with Moebius syndrome may appear expressionless, but facial immobility should not be interpreted as impaired emotion or intelligence.

Infectious Disease and Microbiology - Typhus

Basics

Description

Typhus refers to a group of rickettsial infections characterized primarily by acute fever, headache, systemic illness, and often a rash.

The major forms are:

• Epidemic typhus — classic or louse-borne typhus
• Murine typhus — endemic or flea-borne typhus
• Scrub typhus — mite-borne infection
• Brill-Zinsser disease — recrudescence of previous epidemic typhus

Although these illnesses share several clinical features, they differ in their causative organisms, vectors, reservoirs, geographic distribution, and severity.

⸻

Etiology

Typhus infections are caused by small, obligate intracellular bacteria.

Important organisms include:

• Rickettsia prowazekii → epidemic typhus
• Rickettsia typhi → murine typhus
• Orientia tsutsugamushi → scrub typhus
• Reactivation of R. prowazekii → Brill-Zinsser disease

⸻

Vectors and Reservoirs

Epidemic Typhus

Organism: Rickettsia prowazekii

Vector:

→ Human body louse

Major reservoir:

→ Humans

Flying squirrels may also serve as a reservoir in some regions.

Transmission occurs when infected lice defecate while feeding. Scratching contaminates the bite site with infected louse feces.

⸻

Murine Typhus

Organism: Rickettsia typhi

Vector:

→ Fleas

Traditional reservoirs include:

• Rats
• Other rodents

In some regions, transmission cycles involving:

• Cats
• Opossums
• Their fleas

also contribute.

⸻

Scrub Typhus

Organism: Orientia tsutsugamushi

Vector:

→ Larval trombiculid mites, also called chiggers

Reservoir:

→ Rodents and mites

Unlike flea- and louse-associated typhus, the mite directly inoculates the organism during feeding.

⸻

Epidemiology

Typhus historically caused devastating epidemics during periods of:

• War
• Famine
• Population displacement
• Overcrowding
• Poor sanitation

Epidemic typhus was especially important during major conflicts in Europe during the twentieth century.

Improved hygiene, delousing, and public-health measures have dramatically reduced its incidence in many developed countries.

⸻

Geographic Distribution

Epidemic Typhus

Persists mainly in regions with poverty, crowding, and body-louse infestation, including parts of:

• Africa
• South America
• Asia

⸻

Murine Typhus

Has a broad worldwide distribution.

It is particularly associated with warm regions and remains endemic in selected areas of the:

• Southern United States
• Gulf Coast
• Mediterranean region
• Tropical and subtropical areas

⸻

Scrub Typhus

Traditionally occurs within the so-called tsutsugamushi triangle, encompassing much of:

• South Asia
• Southeast Asia
• East Asia
• Western Pacific
• Northern Australia

However, scrub-typhus-like infections have increasingly been recognized outside the traditional geographic range.

⸻

Brill-Zinsser Disease

Brill-Zinsser disease is a recrudescence of previous epidemic typhus caused by latent R. prowazekii infection.

It may occur:

Years or even decades after the original illness

The recurrent illness is usually milder than primary epidemic typhus.

Patients with Brill-Zinsser disease can become a source of infection for body lice and theoretically contribute to renewed outbreaks in crowded populations.

⸻

Risk Factors

Important risk factors include:

• Poor sanitation
• Overcrowding
• Homelessness
• War
• Famine
• Refugee or displaced-person settings
• Prison populations
• Body-louse infestation
• Flea exposure
• Rodent exposure
• Exposure to scrub vegetation in mite-endemic regions

A careful travel and environmental exposure history is extremely important.

⸻

General Prevention

Prevention depends largely on controlling the relevant vector and reservoir.

Important measures include:

• Improved personal hygiene
• Adequate sanitation
• Delousing
• Washing or heat-treating contaminated clothing and bedding
• Flea control
• Rodent control
• Avoidance of mite-infested vegetation
• Protective clothing
• Appropriate insect repellents

Routine vaccines are not generally available for modern civilian use.

Antibiotic chemoprophylaxis is generally not routinely recommended for ordinary travelers.

⸻

Pathophysiology

After inoculation, rickettsiae multiply locally and then disseminate hematogenously.

The primary target is the:

Vascular endothelial cell

Infection and destruction of endothelial cells produce widespread:

• Vasculitis
• Increased vascular permeability
• Tissue edema
• Microvascular thrombosis
• Reduced organ perfusion

This explains many of the systemic manifestations, including:

• Rash
• Hypotension
• Neurologic dysfunction
• Pulmonary edema
• Renal injury
• Hepatic abnormalities

Severe disease may therefore resemble a systemic vasculitic or septic illness.

⸻

Incubation Period

Typical incubation periods are approximately:

Epidemic typhus

→ About 1–2 weeks

Murine typhus

→ Approximately 1–2 weeks

Scrub typhus

→ Approximately 6–21 days

Symptoms usually begin abruptly.

⸻

Clinical Presentation

Common manifestations across the typhus group include:

• Sudden fever
• Chills
• Severe headache
• Myalgias
• Malaise
• Nausea
• Vomiting
• Anorexia
• Dry cough
• Altered mental status in severe disease

Some patients may develop:

• Tinnitus
• Transient hearing impairment
• Delirium
• Encephalopathy

The presence and pattern of rash vary among the individual diseases.

⸻

Epidemic Typhus

Epidemic typhus is generally the most severe form.

Typical features include:

• Abrupt high fever
• Severe frontal headache
• Marked myalgias
• Profound malaise
• Delirium or altered consciousness in severe cases
• Rash developing several days after fever begins

⸻

Rash in Epidemic Typhus

The rash classically begins around the:

• Upper trunk
• Axillary regions

It then spreads centrifugally to the extremities.

Initially it may be:

• Macular
• Blanching

and later may become:

• Petechial
• Confluent

Classically, the rash tends to spare the face, palms, and soles.

There is usually no eschar.

⸻

Murine Typhus

Murine typhus is usually milder than epidemic typhus.

Symptoms include:

• Fever
• Headache
• Myalgias
• Malaise
• Nausea
• Cough
• Abdominal symptoms

A rash occurs in only a proportion of patients.

⸻

Rash in Murine Typhus

The rash often appears several days after fever begins.

It is usually:

• Macular
• Maculopapular

and commonly involves:

• Trunk
• Extremities

Petechiae are less common than in severe epidemic typhus.

There is usually no eschar.

⸻

Scrub Typhus

Scrub typhus frequently causes:

• Fever
• Severe headache
• Myalgias
• Lymphadenopathy
• Rash
• Respiratory symptoms

A particularly important clue is the presence of an:

Eschar

⸻

Eschar in Scrub Typhus

At the mite inoculation site, a lesion may evolve from:

• Papule
• Vesicle
• Ulcer

into a characteristic:

Black necrotic eschar

The eschar may be painless and can occur in hidden areas such as:

• Axilla
• Groin
• Inframammary region
• Genital region

Therefore, a careful skin examination is important.

An eschar is highly suggestive of scrub typhus when present, but its absence does not exclude the diagnosis.

⸻

Other Findings in Scrub Typhus

Possible findings include:

• Regional lymphadenopathy
• Generalized lymphadenopathy
• Splenomegaly
• Conjunctival injection
• Maculopapular rash

Severe cases can progress to:

• Shock
• Encephalitis
• Acute respiratory distress syndrome
• Renal failure
• Multiorgan dysfunction

⸻

Brill-Zinsser Disease

Brill-Zinsser disease generally resembles a mild episode of epidemic typhus.

Manifestations may include:

• Fever
• Headache
• Myalgias
• Mild rash
• Malaise

The illness is usually substantially less severe than the original infection.

⸻

Diagnosis

Typhus should be suspected in a patient with:

Acute fever + severe headache ± rash + relevant vector or geographic exposure

Important exposure questions include:

• Body lice?
• Fleas?
• Rodents?
• Homelessness or crowded living?
• Refugee camp exposure?
• Scrub vegetation?
• Travel to endemic regions?

Treatment should not be delayed while awaiting confirmatory testing if clinical suspicion is high.

⸻

Routine Laboratory Findings

Common abnormalities include:

• Mild thrombocytopenia
• Normal or mildly reduced leukocyte count
• Anemia in some patients
• Elevated liver enzymes
• Hyponatremia
• Hypoalbuminemia

More severe disease may cause:

• Azotemia
• Coagulopathy
• Renal impairment
• Marked electrolyte abnormalities

These findings are supportive but nonspecific.

⸻

Serologic Testing

Serology is commonly used for laboratory confirmation.

The most useful modern method is typically:

Indirect immunofluorescence assay (IFA)

A diagnosis is best supported by:

A fourfold rise in antibody titer between acute and convalescent specimens

An important limitation is that antibodies may not become detectable until several days or even more than a week after illness begins.

Therefore:

Early negative serology does not exclude typhus.

⸻

Weil-Felix Test

The Weil-Felix test is an old serologic test based on cross-reacting antibodies to certain Proteus antigens.

It has historically been used in settings where better testing is unavailable.

However, it has poor:

• Sensitivity
• Specificity

Therefore, it should not be relied upon when modern molecular or serologic diagnostics are available.

⸻

PCR

PCR-based testing can detect rickettsial DNA.

It may be useful early in the disease, particularly before antibodies develop.

Samples may include:

• Blood
• Eschar material
• Tissue

For scrub typhus, PCR of an eschar can be particularly useful.

⸻

Imaging

Imaging is dictated by the organ system involved.

Possible studies include:

Chest radiograph

May reveal:

• Interstitial infiltrates
• Pneumonitis
• Pulmonary edema

Echocardiography

May be indicated when myocarditis or endocarditis is suspected.

Neuroimaging

May be needed for severe encephalopathy, seizures, or focal neurologic signs.

⸻

Pathology

The characteristic pathologic process is:

Small-vessel vasculitis caused by endothelial infection

This may lead to:

• Endothelial swelling
• Perivascular inflammation
• Thrombosis
• Leakage of blood and plasma into tissues

These changes account for the characteristic rash and multiorgan complications.

⸻

Differential Diagnosis

Important differential diagnoses include:

• Rocky Mountain spotted fever
• Ehrlichiosis
• Anaplasmosis
• Meningococcemia
• Bacterial meningitis
• Typhoid fever
• Leptospirosis
• Dengue
• Malaria
• Secondary syphilis
• Measles
• Rubella
• Infectious mononucleosis
• Other viral febrile illnesses

In scrub typhus, additional considerations include other causes of:

Fever + eschar

such as:

• Anthrax
• Tularemia
• Spotted-fever rickettsioses

⸻

Treatment

The most important principle is:

Start treatment promptly when typhus is clinically suspected.

Waiting for serologic confirmation can increase the risk of complications.

⸻

First-Line Therapy

Doxycycline

Doxycycline is the drug of choice for most typhus-group infections.

A typical adult regimen is:

Doxycycline 100 mg orally or intravenously every 12 hours

Treatment is generally continued until:

• The patient has been afebrile for at least 48 hours

and usually for a minimum total course appropriate to the clinical syndrome.

Clinical improvement is often rapid.

⸻

Response to Therapy

One of the characteristic features of rickettsial infections is rapid defervescence after appropriate doxycycline treatment.

Most patients improve within approximately:

24–72 hours

Failure to improve should prompt reconsideration of:

• Diagnosis
• Drug absorption
• Resistance, especially in selected scrub-typhus regions
• Complications

⸻

Chloramphenicol

Chloramphenicol has historically been an alternative treatment.

However, its role is now limited because of:

• Bone marrow toxicity
• Aplastic anemia risk
• Availability of safer alternatives

It may still be considered in selected circumstances when doxycycline cannot be used.

⸻

Azithromycin

Azithromycin is an important alternative for scrub typhus, particularly in:

• Pregnancy
• Patients unable to take doxycycline
• Areas where reduced doxycycline responsiveness is suspected

⸻

Fluoroquinolones

Fluoroquinolones have been studied in rickettsial infections, but they are generally not preferred over doxycycline.

They should not be considered universal first-line therapy for typhus.

⸻

Pregnancy

The choice of antibiotic in pregnancy should be individualized.

For scrub typhus, azithromycin is commonly used.

Management should account for:

• Disease severity
• Organ involvement
• Local recommendations
• Maternal and fetal risks

⸻

Supportive Treatment

Patients with severe disease may require:

• Intravenous fluids
• Electrolyte correction
• Oxygen
• Mechanical ventilation
• Vasopressors
• Renal replacement therapy
• Nutritional support

Care must be taken because widespread endothelial injury can result in both:

• Intravascular volume depletion
• Tissue edema

⸻

Vector Control in Epidemic Typhus

For patients with suspected louse-borne typhus, treatment must include delousing.

Measures include:

• Bathing
• Changing clothing
• Heat treatment or laundering of clothes and bedding
• Appropriate pediculicides when indicated

Without vector control, transmission can continue.

⸻

Admission Criteria

Hospitalization should be considered for:

• Severe systemic illness
• Hypotension
• Altered mental status
• Seizures
• Respiratory compromise
• Renal failure
• Significant hepatic dysfunction
• Inability to tolerate oral therapy

Severe epidemic or scrub typhus may require ICU-level care.

⸻

Prognosis

The prognosis depends strongly on:

• Type of typhus
• Age
• Comorbidities
• Delay before treatment
• Presence of organ failure

Prompt doxycycline therapy dramatically improves outcomes.

⸻

Epidemic Typhus Prognosis

Epidemic typhus is the most dangerous form.

Untreated disease can have substantial mortality, particularly among:

• Older adults
• Malnourished patients
• Severely ill patients

With appropriate antimicrobial treatment, mortality decreases markedly.

⸻

Murine Typhus Prognosis

Murine typhus is generally a milder disease.

Most patients recover completely with treatment.

Severe complications can occur but are much less common.

⸻

Scrub Typhus Prognosis

Severity varies considerably.

Untreated scrub typhus may lead to:

• ARDS
• Encephalitis
• Shock
• Renal failure
• Myocarditis
• Multiorgan failure

Early therapy greatly reduces mortality.

⸻

Complications

Potential complications across the typhus group include:

• Cardiovascular collapse
• Myocarditis
• Endocarditis
• Acute kidney injury
• Hepatitis
• Hepatic failure
• Pneumonitis
• Pulmonary edema
• Acute respiratory distress syndrome
• Gastrointestinal bleeding
• Encephalitis
• Seizures
• Delirium
• Coma
• Secondary bacterial infections

Severe endothelial injury may result in widespread multiorgan dysfunction.

⸻

High-Yield Comparison

Epidemic typhus

→ Rickettsia prowazekii

→ Body louse

→ Humans

→ Severe disease

→ Rash starts on trunk and spreads outward

→ Usually spares face, palms, and soles

→ No eschar

Murine typhus

→ Rickettsia typhi

→ Fleas

→ Rodents/opossums and other mammalian hosts

→ Generally milder

→ Rash may be absent

→ No eschar

Scrub typhus

→ Orientia tsutsugamushi

→ Chigger/larval mite

→ Rodents and mites

→ Asia-Pacific predominance

→ Characteristic eschar may occur

→ Generalized lymphadenopathy may occur

Brill-Zinsser disease

→ Reactivation of R. prowazekii

→ Years after epidemic typhus

→ Usually milder than primary disease

⸻

High-Yield Clinical Approach

Fever + headache + rash + body lice

→ Think epidemic typhus

Fever + flea/rodent exposure + mild maculopapular rash

→ Think murine typhus

Fever + travel in Asia + black eschar

→ Think scrub typhus

Previous epidemic typhus years ago + recurrent febrile illness

→ Think Brill-Zinsser disease

Early serology negative but clinical suspicion strong

→ Do not exclude typhus

Suspected typhus

→ Start doxycycline promptly

Rapid improvement after doxycycline

→ Supports a rickettsial diagnosis

⸻

Exam Essentials

Typhus organisms:

→ Obligate intracellular bacteria

Main pathologic target:

→ Vascular endothelial cells

Major mechanism of injury:

→ Systemic vasculitis and increased vascular permeability

Epidemic typhus organism:

→ Rickettsia prowazekii

Epidemic typhus vector:

→ Body louse

Murine typhus organism:

→ Rickettsia typhi

Murine typhus vector:

→ Flea

Scrub typhus organism:

→ Orientia tsutsugamushi

Scrub typhus vector:

→ Chigger/larval mite

Classic scrub-typhus clue:

→ Black eschar

Brill-Zinsser disease:

→ Reactivation of previous epidemic typhus

Preferred diagnostic serology:

→ Indirect immunofluorescence assay

Best confirmation:

→ Fourfold rise in paired antibody titers

Old, poorly specific test:

→ Weil-Felix reaction

Drug of choice:

→ Doxycycline

Expected response to therapy:

→ Defervescence usually within 1–3 days

Most severe form:

→ Epidemic typhus

Major complications:

→ Encephalitis, ARDS, renal failure, shock, myocarditis, multiorgan dysfunction

Ophthalmology – Migraine & Cluster Headache

Basics

Description

Migraine headache is a chronic, recurrent, episodic primary headache disorder caused by dysfunction of neural pain-processing pathways rather than an underlying intracranial or systemic disease. It may occur with or without aura and is commonly associated with nausea, vomiting, photophobia, and phonophobia.

Cluster headache is a primary trigeminal autonomic cephalalgia characterized by recurrent, short-lived attacks of excruciating unilateral orbital, supraorbital, or temporal pain associated with ipsilateral cranial autonomic manifestations. Attacks characteristically occur in temporal clusters separated by pain-free periods.

Migraine Without Aura – Diagnostic Features

Typical diagnostic criteria include:

• At least 5 attacks
• Individual attacks lasting approximately 4–72 hours
• Headache has at least 2 of:
• Unilateral location
• Pulsating or throbbing quality
• Moderate-to-severe intensity
• Aggravation by routine physical activity or avoidance of activity
• During the headache, at least 1 of:
• Nausea and/or vomiting
• Photophobia and phonophobia
• Not better explained by another disorder

Cluster Headache – Diagnostic Features

Typical features include:

• At least 5 attacks
• Severe or very severe unilateral:
• Orbital
• Supraorbital
• Temporal pain
• Attack duration approximately 15–180 minutes
• Frequency ranging from every other day to several attacks per day

At least one ipsilateral autonomic feature commonly accompanies the pain:

• Conjunctival injection
• Lacrimation
• Nasal congestion
• Rhinorrhea
• Eyelid edema
• Forehead or facial sweating
• Ptosis
• Miosis

Patients may instead or additionally demonstrate prominent:

• Restlessness
• Agitation

Cluster headache has characteristic:

• Circadian periodicity
• Circannual periodicity
• Repeated attacks during a cluster period

Initial Assessment

The first questions are whether the headache is:

1. Primary or secondary
2. New-onset or chronic/recurrent

A typical longstanding migraine with a normal neurologic examination generally does not require extensive investigation.

A first, unusual, rapidly progressive, or neurologically complicated headache requires evaluation for secondary causes.

Red Flags

Urgent evaluation should be considered with:

• Sudden or thunderclap onset
• Maximum severity immediately at onset
• New focal neurologic deficit
• Progressive headache pattern
• Fever or systemic illness
• New headache at older age
• Major change from the patient’s usual headache pattern
• Known malignancy
• Significant immunocompromise
• Headache precipitated by:
• Exertion
• Sexual activity
• Valsalva
• Position change
• Papilledema
• Persistent visual field defect
• Altered consciousness

Epidemiology

Migraine

Migraine is much more common in women.

Typical epidemiologic features include:

• Female-to-male predominance approximately 3:1
• Lifetime prevalence substantially higher in women
• Overall population prevalence roughly 12–15%

Cluster Headache

Cluster headache is much less common than migraine.

Historically it has shown a strong male predominance, although the sex difference is less marked in more contemporary series.

Risk Factors

Family History

A family history of migraine substantially increases the likelihood of developing migraine.

Genetics

Most migraine is polygenic and multifactorial.

Rare monogenic migraine syndromes include familial hemiplegic migraine, in which mutations affecting neuronal ion transport and neurotransmission have been identified.

General Prevention

Prevention begins with identifying and minimizing individual triggers.

Potential migraine triggers include:

• Sleep deprivation
• Excessive sleep
• Irregular sleep schedule
• Stress
• Missed meals
• Dehydration
• Excessive caffeine
• Caffeine withdrawal
• Alcohol
• Hormonal changes
• Certain foods in susceptible patients

A headache diary can help establish individual patterns.

Pathophysiology

Migraine is no longer considered simply a vascular headache.

Important mechanisms include:

• Activation of central pain-sensitive cranial pathways
• Trigeminovascular activation
• Release of neuropeptides such as CGRP
• Central pain sensitization
• Altered serotonergic neurotransmission
• Hypothalamic and brainstem network involvement

Migraine Aura

Aura is strongly associated with cortical spreading depolarization, a slowly propagating wave of neuronal and glial activity followed by temporary suppression of cortical function.

Cluster Headache

Cluster headache involves:

• Trigeminal nociceptive activation
• Parasympathetic cranial autonomic activation
• Hypothalamic mechanisms

Hypothalamic involvement helps explain the striking circadian and circannual pattern.

Etiology

Migraine is generally hereditary and multifactorial.

Multiple genetic and environmental influences contribute.

The exact inheritance pattern for common migraine is not defined.

Commonly Associated Conditions

Migraine has associations with:

• Depression
• Anxiety
• Panic disorder
• Epilepsy
• Asthma
• Other chronic pain syndromes
• Sleep disorders

Diagnosis

History

The history is the most important component of diagnosis.

Assess:

• Inciting event
• Age at onset
• New versus chronic/recurrent headache
• Location
• Quality
• Duration
• Severity
• Frequency
• Time course
• Associated symptoms
• Triggers
• Aggravating factors
• Relieving factors
• Positional relationship
• Valsalva relationship
• Exertional relationship
• Neurologic symptoms
• Visual symptoms
• Previous treatments
• Medication overuse

Time–Intensity Relationship

Subarachnoid Hemorrhage

Classically:

Sudden thunderclap headache with maximal intensity at or very near onset.

Cluster Headache

Typically:

• Reaches severe intensity rapidly
• Often peaks within minutes
• Remains severe for a relatively short period
• Resolves much faster than a typical migraine

Migraine

Typically:

• Builds over minutes to hours
• Persists for hours
• May last up to several days

Migraine-Associated Features

Ask specifically about:

• Aura
• Nausea
• Vomiting
• Photophobia
• Phonophobia

Visual Aura

Migraine aura commonly produces positive visual phenomena.

Typical symptoms include:

• Scintillating scotoma
• Zigzag lines
• Fortification spectra
• Flashing lights
• Shimmering areas
• Expanding visual disturbance

Symptoms usually:

• Develop gradually
• Spread across the visual field
• Resolve completely

A persistent visual field deficit or a fixed homonymous defect should prompt investigation for a structural or vascular cerebral lesion.

Cluster Headache History

Typical cluster headache produces:

• Excruciating unilateral periorbital pain
• Rapid crescendo
• Ipsilateral autonomic symptoms
• Marked agitation or restlessness

During an active cluster period, alcohol can precipitate an attack in many patients.

Additional Symptoms Suggesting Secondary Headache

Ask about:

• Transient visual obscurations
• Vertigo
• Meningismus
• Fever
• Purulent nasal discharge
• Myalgias
• Cognitive dysfunction
• Amenorrhea
• Galactorrhea
• Scalp tenderness
• Jaw claudication
• Focal neurologic symptoms

Also obtain history of:

• Cancer
• Aneurysm
• Immunocompromise
• Recent trauma
• Vascular disease
• New medications

Physical Examination

Perform a complete neurologic examination.

Important components include:

• Mental status
• Cranial nerves
• Motor function
• Sensation
• Reflexes
• Coordination
• Gait

Ophthalmic Examination

Evaluate:

• Visual acuity
• Pupillary responses
• Relative afferent pupillary defect
• Ocular motility
• Alignment
• Visual fields
• Anterior segment
• Intraocular pressure when indicated
• Fundus
• Optic nerve

Between migraine attacks, the neurologic and ophthalmic examinations are generally normal.

Diagnostic Testing

Laboratory Tests

Routine laboratory testing is unnecessary in a classic primary migraine presentation.

Testing should be tailored to the suspected secondary diagnosis.

Possible investigations include:

• CBC
• Platelet count
• Metabolic profile
• ESR
• CRP

Patients Older Than 50

In a patient over 50 with new headache, particularly with:

• Scalp tenderness
• Jaw claudication
• Constitutional symptoms
• Polymyalgia symptoms
• Transient or permanent visual disturbance

consider giant cell arteritis and obtain inflammatory markers urgently.

Additional Laboratory Testing

Selected investigations depending on the clinical picture may include:

• ANA
• Anti-dsDNA
• Thyroid studies
• Arterial blood gases
• Sleep study for suspected obstructive sleep apnea

Testing should be guided by the history rather than ordered indiscriminately.

Imaging

Nonurgent New Headache

When imaging is indicated in a nonemergent setting:

MRI brain is generally preferred because of its superior soft-tissue sensitivity.

Acute Severe or Thunderclap Headache

Initial evaluation commonly includes:

Urgent noncontrast head CT

Further vascular imaging may be required depending on the suspected cause.

MR Venography

MRV is useful when considering:

• Cerebral venous sinus thrombosis
• Idiopathic intracranial hypertension

CTA and MRA

Vascular imaging can be used to evaluate:

• Intracranial aneurysm
• Arteriovenous malformation
• Cervical or intracranial arterial dissection

Lumbar Puncture

Lumbar puncture may be required when:

• Meningitis is suspected
• Intracranial pressure disorders are suspected
• Subarachnoid hemorrhage remains clinically suspected despite nondiagnostic initial imaging

The exact sequence of CT, vascular imaging, and LP depends on timing and clinical circumstances.

Additional Diagnostic Procedures

Visual Aura

Formal visual field testing can help determine whether a persistent defect is:

• Homonymous
• Monocular
• Compatible with retinal/optic nerve disease

A fixed homonymous defect raises concern for retrochiasmal cerebral pathology.

Headache Disability Assessment

Validated instruments may include:

• MIDAS
• HIT-6

These can help quantify functional burden and monitor treatment response.

Differential Diagnosis

Other Primary Headaches

Differentiate migraine from:

• Tension-type headache
• Cluster headache
• Other trigeminal autonomic cephalalgias

A large proportion of self-described “sinus headaches” are actually migraine.

Secondary Headache Causes

Important secondary diagnoses include:

Vascular

• Subarachnoid hemorrhage
• Intracerebral hemorrhage
• Ischemic stroke
• Cervical artery dissection
• Cerebral venous sinus thrombosis
• Intracranial aneurysm
• Arteriovenous malformation

Neoplastic

• Primary brain tumor
• Metastatic disease
• Lymphoproliferative disease

Other

• Meningitis
• Encephalitis
• Idiopathic intracranial hypertension
• Chiari malformation
• Hypertensive emergency
• Giant cell arteritis
• Cranial neuralgia
• Tolosa–Hunt syndrome
• Infectious sinusitis
• Acute angle-closure glaucoma
• Hypercapnia
• Obstructive sleep apnea

Treatment of Migraine

First-Line Acute Treatment

Acute or abortive treatment is preferably administered early in the headache phase.

For mild-to-moderate attacks, options include:

• Acetaminophen
• Aspirin
• Ibuprofen
• Naproxen

An antiemetic may be added when nausea or vomiting is prominent.

Antiemetics

Useful agents include:

• Metoclopramide
• Prochlorperazine

These may:

• Reduce nausea
• Improve gastric motility
• Improve absorption of oral medication
• Have independent antimigraine effects in some patients

Triptans

Triptans are selective 5-HT1B/1D receptor agonists.

Choice should be individualized according to:

• Route of administration
• Speed of onset
• Duration
• Recurrence tendency
• Side-effect profile
• Previous response

They are generally most effective when used early after the headache begins.

Examples include:

• Sumatriptan
• Rizatriptan
• Zolmitriptan
• Eletriptan
• Naratriptan
• Almotriptan
• Frovatriptan

Triptan Precautions

Avoid or use cautiously in patients with significant:

• Ischemic coronary disease
• Previous myocardial infarction
• Certain cerebrovascular diseases
• Poorly controlled hypertension

Older teaching discouraged triptans in hemiplegic migraine and migraine with brainstem aura; management of these unusual disorders should be individualized by a headache specialist.

Medication Interaction Alert

Do not use a triptan and an ergot derivative within 24 hours of one another because of excessive vasoconstrictive risk.

Certain triptans also interact with monoamine oxidase inhibitors (MAOIs) and require drug-specific avoidance periods.

Concurrent SSRI/SNRI and triptan use has historically raised concern for serotonin syndrome; clinically significant serotonin toxicity appears uncommon, but patients should still be educated about symptoms.

Ergot Derivatives

Dihydroergotamine may be used in selected severe or refractory migraine attacks.

Routes include:

• Intravenous
• Intranasal

Antiemetic pretreatment is often required.

Its use is limited by:

• Vasoconstrictive effects
• Drug interactions
• Cardiovascular contraindications
• Availability of newer migraine-specific agents

Second-Line / Refractory Acute Therapy

In monitored emergency or inpatient settings, selected refractory attacks may be treated with agents such as:

• IV antiemetics
• IV NSAIDs
• IV dihydroergotamine
• IV valproate in selected patients
• IV fluids when dehydrated

Corticosteroids are sometimes used to reduce recurrence in prolonged migraine but are not routine first-line therapy.

Opioids

Opioids should generally be avoided or strongly limited because they can contribute to:

• Medication-overuse headache
• Chronification
• Dependence
• Poor long-term migraine control

Migraine Preventive Therapy

Preventive therapy should be considered when attacks are:

• Frequent
• Prolonged
• Severe
• Disabling
• Poorly responsive to acute therapy
• Associated with contraindications to acute drugs
• Causing excessive acute-medication use

Goals are to reduce:

• Frequency
• Severity
• Duration
• Disability
• Need for rescue medication

Preventive medications are titrated gradually according to clinical response and tolerability.

Traditional Preventive Medications

Options include:

Beta-Blockers

For example:

• Propranolol
• Metoprolol

Antiepileptic Medications

Especially:

• Topiramate
• Valproate

Other anticonvulsants generally have less consistent evidence.

Antidepressants

Examples include:

• Amitriptyline
• Venlafaxine

Calcium-Channel Blockers

Certain agents may be used in selected migraine subtypes or particular geographic practice settings.

Modern Migraine Prevention

Modern preventive options also include:

• CGRP monoclonal antibodies
• Oral CGRP receptor antagonists used preventively
• OnabotulinumtoxinA for chronic migraine

OnabotulinumtoxinA is particularly useful in appropriately selected patients with chronic migraine, rather than occasional episodic migraine.

Cluster Headache – Acute Treatment

Because attacks are brief and extremely severe, therapy must act rapidly.

High-Flow Oxygen

A major first-line treatment is:

100% oxygen through a non-rebreather mask

High flow rates are typically used for approximately 15–20 minutes or until the attack subsides.

Sumatriptan

A highly effective acute treatment is:

Subcutaneous sumatriptan

Intranasal triptans may also be used when injections are unsuitable.

Other Acute Cluster Treatments

Selected alternatives include:

• Intranasal triptans
• Intranasal lidocaine in some patients
• Dihydroergotamine in selected circumstances

Cluster Headache Preventive Therapy

Verapamil

Verapamil is a principal first-line preventive medication for cluster headache.

Dose is titrated according to response.

Because it can produce:

• Bradycardia
• PR prolongation
• Heart block

ECG monitoring is important during dose escalation.

Corticosteroids

A short course of corticosteroids may provide transitional or bridging therapy while a longer-term preventive treatment becomes effective.

They are not generally intended for prolonged prophylaxis.

Lithium

Lithium may be particularly useful in:

• Chronic cluster headache
• Refractory cases

Monitoring includes:

• Serum lithium concentration
• Renal function
• Thyroid function
• Electrolytes

Pediatric Considerations

Migraine occurs in children and adolescents.

Important measures include:

• Regular sleep
• Adequate hydration
• Regular meals
• Avoiding excessive caffeine
• Limiting medication overuse
• Age-appropriate acute therapy

Emergency therapy may include antiemetics plus analgesics when indicated.

Preventive therapy is individualized according to:

• Frequency
• Disability
• School impact
• Comorbidities

Pregnancy Considerations

Nonpharmacologic approaches are emphasized whenever possible.

Acetaminophen is commonly used for acute attacks.

Medication choice requires individual risk-benefit assessment because several migraine drugs are undesirable or contraindicated during pregnancy.

Important points include:

• Avoid indiscriminate NSAID use, especially later in pregnancy.
• Valproate should generally be avoided in pregnancy because of major fetal risks.
• Ergot derivatives are contraindicated.
• Preventive therapy requires specialist guidance.

A new, severe, or altered headache during pregnancy should not automatically be attributed to migraine. Consider:

• Preeclampsia/eclampsia
• Cerebral venous thrombosis
• Reversible cerebral vasoconstriction syndrome
• Pituitary disease
• Intracranial hemorrhage

Additional Treatment

General Measures

Management should be individualized according to:

• Attack characteristics
• Frequency
• Severity
• Disability
• Associated symptoms
• Comorbidities

Associated conditions should also be addressed, including:

• Obesity
• Anxiety
• Depression
• Sleep disorders

Issues for Referral

Neurology or headache-specialist referral is appropriate for:

• Chronic migraine
• Frequent disabling headaches
• Status migrainosus
• Medication-overuse headache
• Complex aura
• Hemiplegic migraine
• Migraine with brainstem symptoms
• Unclear diagnosis
• Failure of standard prophylaxis
• Recurrent emergency visits
• Need for advanced preventive therapy

Additional Therapies

Nonpharmacologic strategies may include:

• Cognitive behavioral therapy
• Relaxation training
• Biofeedback
• Regular aerobic exercise
• Consistent sleep
• Stress management

Supplements with some evidence in migraine prevention include:

• Magnesium
• Riboflavin
• Coenzyme Q10
• Melatonin in selected patients

Evidence and optimal dosing vary.

Complementary and Alternative Therapies

Acupuncture

May provide benefit for some patients with migraine prevention.

Butterbur

Older literature suggested benefit, but butterbur is generally not favored because of concerns about hepatotoxic pyrrolizidine alkaloids and product purity.

Feverfew

Evidence is inconsistent.

Hyperbaric Oxygen

Hyperbaric oxygen is not routine migraine therapy.

This should not be confused with high-flow normobaric oxygen, which is an established acute treatment for cluster headache.

Procedures

OnabotulinumtoxinA

Effective for appropriately selected patients with chronic migraine.

Occipital Nerve Procedures

Occipital nerve block or neuromodulation may be considered in highly selected refractory headache syndromes.

Occipital nerve stimulation is generally reserved for severe treatment-resistant disease.

In-Patient Considerations

Admission Criteria

Admission may be necessary for:

• Intractable headache
• Status migrainosus
• Severe dehydration
• Recurrent vomiting
• Need for monitored intravenous treatment
• Medication-withdrawal protocols
• Uncertain secondary headache requiring further workup

IV Fluids

IV isotonic fluids may be given when:

• Oral intake is inadequate
• Significant vomiting has caused dehydration

Routine IV hydration is not itself a specific migraine treatment in a normally hydrated patient.

Nursing

Routine monitoring is appropriate, with additional observations determined by:

• Medication administered
• Cardiovascular status
• Neurologic status
• Secondary headache concern

Discharge Criteria

Discharge is appropriate when:

• Dangerous secondary causes have been excluded when necessary
• Headache has substantially improved
• Oral hydration is adequate
• Neurologic status is stable
• A safe outpatient treatment plan is established

Ongoing Care

Follow-Up Recommendations

Follow-up depends on response to treatment.

Care may be coordinated through:

• Primary care
• Neurology
• Headache specialist

Patient Monitoring

After an emergency visit or major medication change, earlier reassessment may be appropriate, often within approximately:

1–2 weeks

Poorly controlled headaches may require follow-up every:

2–4 weeks

until a stable regimen is achieved.

Once stable, visits can become less frequent.

Diet and Lifestyle

Patients should be encouraged to:

• Eat regular meals
• Maintain adequate hydration
• Avoid excessive caffeine
• Avoid large fluctuations in caffeine intake
• Identify genuine food triggers rather than imposing unnecessary dietary restriction
• Maintain a balanced diet

Skipping meals is a common migraine precipitant.

Patient Education

Patients should understand:

• Their headache diagnosis
• Expected course
• Individual triggers
• Appropriate use of acute medications
• Preventive medication goals
• Potential adverse effects
• Importance of lifestyle regularity
• Risks of medication overuse
• When to seek urgent medical attention

Medication-Overuse Headache

Frequent use of acute medication can itself produce or perpetuate chronic headache.

Common culprits include:

• Combination analgesics
• Opioids
• Triptans
• Ergot derivatives
• Frequent simple analgesic use

Recognition and withdrawal of the overused medication are essential parts of management.

Prognosis

The long-term course of migraine is variable and multifactorial.

Many patients experience:

• Fluctuating frequency over time
• Periods of remission
• Improvement with appropriate preventive therapy
• Changes in pattern with age and hormonal status

Cluster headache likewise varies, with some patients having episodic cluster periods separated by prolonged remissions and others developing chronic disease.

Complications

Important complications include:

• Chronic migraine
• Chronic daily headache
• Medication-overuse headache
• Status migrainosus
• Disability affecting work or school
• Anxiety and depression
• Excessive emergency-care use
• Adverse effects from medications

Rare neurologic complications related to migraine include persistent aura and migrainous infarction.

Ophthalmology Pearls

• Migraine aura usually consists of positive visual phenomena that develop gradually and resolve completely.
• Migraine visual aura is usually binocular/homonymous, even when the patient describes it as affecting “one eye.”
• A true episode of monocular transient visual loss should prompt consideration of retinal or optic nerve ischemia rather than automatically being labeled migraine.
• A fixed homonymous visual field defect requires investigation for a retrochiasmal lesion.
• Cluster headache commonly causes ipsilateral lacrimation and conjunctival injection.
• Cluster headache can produce a transient partial Horner syndrome with ptosis and miosis.
• Headache plus a painful red eye requires exclusion of acute angle-closure glaucoma.
• Headache plus papilledema suggests raised intracranial pressure and requires investigation.
• In a patient older than 50 with a new headache and visual symptoms, always consider giant cell arteritis.
• A first or “worst-ever” thunderclap headache should be treated as a potential vascular emergency rather than presumed to be migraine.

Ophthalmology – Microphthalmia

Basics

Description

Microphthalmia is a congenital developmental disorder in which one or both eyes are abnormally small, involving reduced axial length and/or corneal diameter.

It may occur:

• Unilaterally or bilaterally
• In isolation
• With other ocular malformations
• As part of a systemic genetic syndrome

Associated visual function ranges from near normal to profoundly impaired.

Epidemiology

Microphthalmia occurs in approximately:

1–2 per 10,000 newborns

Severity and associated abnormalities vary widely.

Risk Factors

Important associations include:

• Ocular coloboma
• Congenital cataract
• Persistent fetal vasculature
• Intrauterine infection, especially rubella
• Chromosomal abnormalities
• Congenital syndromes
• Teratogenic exposure

Potential teratogens include:

• Ionizing radiation
• Alcohol
• Isotretinoin

Genetics

Microphthalmia is genetically heterogeneous.

Genes associated with isolated ocular microphthalmia include:

• SOX2
• OTX2
• PAX6
• FOXE3
• GDF6
• SIX6
• RAX
• MAF
• CRYAA
• CRYBA4

Syndromic forms may involve genes such as:

• CHD7 – CHARGE syndrome
• HESX1 – septo-optic dysplasia
• SOX2 – syndromic microphthalmia
• BMP4
• STRA6
• HCCS – microphthalmia with linear skin defects
• BCOR – oculofaciocardiodental syndrome

Inheritance may be:

• Autosomal dominant
• Autosomal recessive
• X-linked dominant
• X-linked recessive

Some cases are sporadic.

Importantly, unilateral microphthalmia can still have a genetic cause.

General Prevention

Potential preventive measures include:

• Genetic counseling
• Prenatal genetic testing when a familial mutation is known
• Prevention of maternal infections
• Avoidance of known teratogens during pregnancy

Severe microphthalmia may sometimes be detected by prenatal ultrasound, including in the late first trimester.

Pathophysiology

Microphthalmia results from incomplete ocular development during embryogenesis.

Developmental gene abnormalities can disrupt:

• Optic vesicle formation
• Optic cup development
• Closure of the embryonic fissure
• Growth of the globe
• Formation of the anterior and posterior segments

Because many involved genes are transcription factors, abnormalities can affect multiple downstream developmental pathways.

Etiology

Causes include:

• Genetic mutations
• Chromosomal abnormalities
• Intrauterine infections
• Teratogenic exposure
• Ocular coloboma
• Persistent fetal vasculature
• Rare primary aphakia
• Idiopathic developmental abnormalities

Bilateral disease is particularly suggestive of a genetic or syndromic etiology.

Commonly Associated Ocular Conditions

Microphthalmia may be associated with:

• Ocular coloboma
• Congenital cataract
• Persistent fetal vasculature
• Anterior segment dysgenesis
• Optic nerve hypoplasia
• Retinal dysplasia
• Congenital retinal detachment
• Strabismus
• Nystagmus
• Refractive error
• Glaucoma

Anterior chamber depth is often normal in microphthalmia but is characteristically shallow in nanophthalmos.

Systemic Associations

Systemic abnormalities vary according to the underlying syndrome.

Possible associated findings include:

• Developmental delay
• Neurologic abnormalities
• Craniofacial malformations
• Cardiac disease
• Skeletal anomalies
• Endocrine abnormalities
• Hearing impairment

The presence of developmental delay or multiple congenital abnormalities increases suspicion for a syndromic or chromosomal disorder.

Diagnosis

History

Important questions include:

• Family history of small eyes, coloboma, congenital cataract, or blindness
• Maternal infections during pregnancy
• Medication or teratogen exposure
• Other congenital anomalies
• Developmental delay
• Previous ocular surgery

Physical Examination

A complete ocular examination should assess:

• Globe size
• Corneal diameter
• Axial appearance
• Palpebral fissure size
• Orbital and periocular development
• Anterior chamber depth
• Lens
• Iris
• Retina
• Optic nerve

Particular attention should be paid to the inferonasal peripheral fundus, where a coloboma is commonly found.

Visual Function

Assess:

• Fixation behavior
• Visual acuity
• Preferential looking in infants when appropriate
• Refractive error
• Amblyopia

Visual acuity can vary widely depending on associated structural abnormalities.

Refractive Error

Patients may have:

• High hyperopia
• High myopia
• Astigmatism

Refraction should be performed carefully because correct optical treatment may significantly improve visual development.

Strabismus and Nystagmus

Both are common, especially when there is:

• Asymmetric visual input
• Bilateral poor vision
• Optic nerve abnormalities
• Retinal dysplasia

Laboratory Evaluation

No routine laboratory tests are required in isolated microphthalmia without systemic abnormalities.

Consider:

• Chromosomal analysis if multiple congenital anomalies are present
• Targeted molecular genetic testing
• Syndrome-specific testing

Genetic evaluation is particularly appropriate when:

• Disease is bilateral
• There is developmental delay
• There are systemic malformations
• There is a positive family history

Imaging

A-Scan Ultrasonography

Useful for measuring:

• Axial length

This helps confirm reduced globe size.

B-Scan Ultrasonography

Useful when the fundus cannot be visualized.

It can evaluate:

• Retina
• Optic nerve
• Retinal detachment
• Persistent fetal vasculature
• Presence or absence of the lens

Ultrasound Biomicroscopy

UBM may help evaluate:

• Anterior segment anatomy
• Scleral thickness
• Ciliary body anatomy
• Shallow anterior chamber

Neuroimaging

Consider MRI when there is:

• Bilateral optic nerve abnormality
• Developmental delay
• Neurologic findings
• Suspected syndromic disease

Orbital Imaging

CT or MRI may be useful in severe cases to assess:

• Orbital size
• Bony development
• Associated craniofacial abnormalities

Differential Diagnosis

Important differential diagnoses include:

• Anophthalmia
• Nanophthalmia
• Microcornea without microphthalmia
• Phthisis bulbi

Anophthalmia

No identifiable globe is present clinically or on imaging.

Nanophthalmia

The eye is globally small but structurally relatively complete and often has:

• Very short axial length
• Marked hyperopia
• Thick sclera
• Shallow anterior chamber
• Increased angle-closure risk

Phthisis

Represents acquired shrinkage of a previously developed eye following:

• Trauma
• Infection
• Severe inflammation
• Surgery

Treatment

There is no medication that can enlarge or normalize the congenitally small globe.

Management focuses on:

• Maximizing vision
• Preventing amblyopia
• Treating associated ocular disease
• Supporting normal orbital and facial development

Amblyopia Treatment

Amblyopia therapy should be initiated when appropriate.

Treatment may include:

• Full refractive correction
• Patching
• Penalization

This is particularly important in asymmetric or unilateral disease.

Optical Rehabilitation

Options include:

• Spectacles
• Contact lenses
• Low-vision devices

In a mildly microphthalmic but poorly functioning eye, a plus spectacle lens can sometimes enlarge the cosmetic appearance of the eye.

Orbital Growth and Cosmetic Rehabilitation

A severely microphthalmic eye may not adequately stimulate normal orbital growth.

In a nonfunctional eye, treatment may include:

• Conformer
• Scleral shell
• Progressive prosthetic expansion

These help encourage growth of:

• Eyelids
• Conjunctival socket
• Orbit
• Periocular tissues

Severe cases may require expandable orbital implants or tissue expanders coordinated with craniofacial or oculoplastic specialists.

Early intervention is especially important during the first years of life.

Cataract Surgery

Congenital cataract may require surgery when visually significant.

Visual prognosis depends heavily on associated retinal and optic nerve abnormalities.

Glaucoma Management

Glaucoma may occur particularly with:

• Aphakia
• Persistent fetal vasculature
• Anterior segment dysgenesis

Management may include:

• Medical therapy
• Laser treatment
• Surgery

Patients at risk require long-term IOP monitoring.

Shallow Anterior Chamber

In nanophthalmic-type anatomy with a very shallow anterior chamber, management requires special caution.

Miotics such as pilocarpine can worsen anterior displacement and angle crowding in some situations.

Treatment should be directed by a glaucoma/anterior-segment specialist.

Retinal Detachment

Colobomatous eyes have an increased risk of retinal detachment.

Retinal surgery may be considered for acquired rhegmatogenous detachment.

However, surgery is generally not beneficial for:

• Congenital retinal nonattachment
• Severe retinal dysplasia
• Some congenital tractional detachments

Strabismus Surgery

Strabismus surgery may be considered for:

• Functional alignment
• Abnormal head posture
• Cosmetic improvement

The visual potential of each eye should be taken into account.

Referral

Appropriate referrals may include:

• Pediatric ophthalmology
• Ocular genetics
• Medical genetics
• Retina specialist
• Glaucoma specialist
• Low-vision services
• Oculoplastic/craniofacial surgery
• Developmental pediatrics

Follow-Up

Follow-up depends on associated abnormalities.

Children require monitoring for:

• Amblyopia
• Refractive error
• Cataract
• Glaucoma
• Retinal detachment
• Strabismus
• Orbital growth

Patients with coloboma or glaucoma risk may require examinations approximately every 6 months, depending on severity.

Patient Monitoring

Monitor:

• Visual development
• School performance
• Developmental milestones
• Orbital and periocular growth
• Cosmetic concerns
• Psychosocial impact

Orbital growth is particularly important during the first 5 years of life.

Patient Education

Families should receive counseling regarding:

• Visual potential
• Possibility of associated systemic disease
• Genetic implications
• Importance of amblyopia treatment
• Retinal detachment symptoms
• Long-term glaucoma monitoring
• Low-vision resources

Genetic counseling is especially useful in bilateral or familial cases.

Prognosis

Visual prognosis is highly variable.

Better prognosis is generally seen when microphthalmia is mild and the:

• Retina
• Optic nerve
• Lens
• Macula

are relatively normal.

Poor visual prognosis is associated with:

• Primary aphakia
• Severe retinal dysplasia
• Congenital retinal detachment/nonattachment
• Severe optic nerve abnormalities

Complications

Important complications include:

• Amblyopia
• Strabismus
• Nystagmus
• Refractive error
• Cataract
• Glaucoma
• Retinal detachment, especially with coloboma
• Poor orbital development
• Cosmetic asymmetry
• Low vision

Key Clinical Pearls

• Microphthalmia = congenitally small eye involving reduced globe size, often including reduced axial length.
• It can be unilateral or bilateral and may be isolated or syndromic.
• Always search carefully for an inferonasal ocular coloboma.
• Bilateral microphthalmia strongly raises suspicion for a genetic or syndromic cause.
• A-scan measures axial length; B-scan evaluates posterior anatomy when there is no fundus view.
• Distinguish microphthalmia from nanophthalmia, anophthalmia, and phthisis.
• Visual prognosis depends much more on associated retinal, optic nerve, and lens abnormalities than on globe size alone.
• Early treatment of refractive error and amblyopia is essential.
• In a severely small nonfunctional eye, conformers or scleral shells can promote orbital and periocular growth.
• Coloboma increases the risk of retinal detachment, while aphakia/PFV/anterior segment dysgenesis increase the risk of glaucoma.

Ophthalmology – MEWDS (Multiple Evanescent White Dot Syndrome)

Basics

Description

Multiple Evanescent White Dot Syndrome (MEWDS) is an acute, idiopathic inflammatory white-dot syndrome involving primarily the outer retina and retinal pigment epithelium (RPE).

Typical features include:

• Sudden unilateral visual disturbance
• Multiple small white dots at the posterior pole
• Photopsias
• Enlarged blind spot or central/paracentral scotoma
• Characteristic foveal granularity
• Spontaneous recovery over several weeks
• Rare recurrence

It is usually self-limited.

Epidemiology

MEWDS typically affects:

• Young adults
• Most commonly patients in the 2nd to 5th decades
• Women in about 90% of cases

The disease is usually unilateral, although rare bilateral or asynchronous cases can occur.

Risk Factors

Approximately 50% of patients report a preceding viral-like illness.

A possible association with HLA-B51 has been described.

Pathophysiology

The exact mechanism is not fully understood.

Although historically considered primarily a choroidal inflammatory disorder, modern imaging suggests that the main abnormalities involve the:

• Photoreceptor outer segments
• Ellipsoid zone
• RPE–outer retinal complex

The disease is thought to represent an inflammatory or immune-mediated response.

Etiology

The cause is unknown.

Proposed mechanisms include:

• Viral trigger
• Postviral immune response
• Genetic susceptibility combined with an environmental trigger

Commonly Associated Conditions

MEWDS has clinical overlap with:

Acute Idiopathic Blind Spot Enlargement Syndrome (AIBSES/AIBES).

Some authors consider MEWDS and other white-dot syndromes to represent related disorders along a disease spectrum.

Diagnosis

History

Typical presentation is:

• Sudden decrease in central vision in one eye

Patients may also report:

• Photopsias
• Central or paracentral scotoma
• Enlarged blind spot
• Mild dyschromatopsia
• Recent viral illness

Rarely, the disorder may affect both eyes.

Physical Examination

Common findings include:

• Mild myopia
• Mild relative afferent pupillary defect in some patients
• Mild vitreous inflammation
• Optic disc edema
• Multiple small, poorly defined white lesions in the posterior pole
• Lesions located at the level of the outer retina/RPE
• Orange or granular appearance of the fovea

Classic Finding

Foveal granularity is one of the most characteristic clinical signs of MEWDS.

Fluorescein Angiography

Fluorescein angiography classically shows:

• Early punctate hyperfluorescence
• Late staining
• Lesions arranged in a wreath-like pattern

High-Yield Pearl

MEWDS → wreath-like hyperfluorescence on fluorescein angiography.

Optical Coherence Tomography

OCT commonly demonstrates transient disruption of:

• Ellipsoid zone
• Photoreceptor outer segments
• Interdigitation zone

These abnormalities generally improve as the patient recovers.

Indocyanine Green Angiography

ICG is usually not necessary to establish the diagnosis.

When performed, it typically shows:

• Multiple hypofluorescent spots

The number of lesions on ICG is often greater than the number visible clinically or on fluorescein angiography.

Electroretinography

ERG may show transient abnormalities.

Electrophysiologic changes generally improve during recovery.

Laboratory Testing

Routine laboratory testing is usually unnecessary in a typical case.

MEWDS is primarily diagnosed clinically with the assistance of multimodal retinal imaging.

Additional testing should be considered if the presentation is atypical.

Differential Diagnosis

Important differential diagnoses include:

• Acute idiopathic blind spot enlargement syndrome
• Acute posterior multifocal placoid pigment epitheliopathy
• Acute macular neuroretinopathy
• Multifocal choroiditis
• Birdshot chorioretinopathy
• Other white-dot syndromes

In older patients, particularly those over 50 with unusual or persistent findings, consider:

• Primary vitreoretinal lymphoma

Treatment

Observation

Observation is the usual treatment.

Most patients do not require medication because the condition is:

• Self-limited
• Mild to moderately vision-threatening
• Associated with spontaneous recovery

Symptoms usually improve within:

Several weeks to 1–2 months.

Referral

Referral to a retina or uveitis specialist should be considered if:

• Diagnosis is uncertain
• Disease is bilateral
• Findings are atypical
• Vision does not improve
• Symptoms recur
• Choroidal neovascularization is suspected

Follow-Up

Patients can usually be followed approximately:

• Monthly until symptoms and retinal findings resolve
• Thereafter as needed

Follow-up should assess:

• Visual acuity
• Visual symptoms
• Fundus appearance
• OCT abnormalities
• Optic disc changes

Prognosis

The prognosis is excellent.

Most patients recover to:

• 20/40 or better
• Frequently their previous baseline vision

Recovery usually occurs within several weeks.

Recurrence is rare.

Some patients may have subtle persistent symptoms despite good central visual acuity, particularly:

• Photopsias
• Enlarged blind spot

Complications

Complications are uncommon.

A rare complication is:

• Choroidal neovascularization

Key Clinical Pearls

• MEWDS typically affects young women.
• Usually presents with acute unilateral photopsias and mildly reduced vision.
• About 50% have a preceding viral-like illness.
• Multiple small white dots are found at the posterior pole.
• Foveal granularity is highly characteristic.
• Fluorescein angiography shows wreath-like punctate hyperfluorescence.
• OCT shows transient outer retinal/ellipsoid-zone disruption.
• ICG reveals more hypofluorescent lesions than are visible clinically.
• Enlarged blind spot is common.
• Treatment is usually observation only.
• Recovery typically occurs within 1–2 months.
• Recurrence and choroidal neovascularization are rare.