Infectious Disease and Microbiology - Traveler’s diarrhea

Basics

Description

Traveler’s diarrhea is the most frequent illness encountered by people traveling internationally. It usually represents an acute gastrointestinal infection acquired after ingestion of food or water contaminated by fecal organisms. The likelihood of developing illness depends heavily on the travel destination, local sanitation, food preparation and storage practices, and the traveler’s own dietary and hygiene habits.

Most episodes are mild and resolve spontaneously. However, symptoms may significantly interfere with travel plans, and substantial fluid loss can occasionally produce clinically important dehydration.

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Epidemiology

Incidence

Approximately 20–50% of international travelers may develop diarrhea during travel. Men and women appear to have similar attack rates, but the overall risk varies considerably according to destination.

Historically, the highest-risk regions have included Latin America, Africa, much of Asia, and the Middle East, where attack rates may exceed 20% and sometimes 50%. Intermediate-risk areas have included parts of Southern Europe, Israel, and selected Caribbean islands. Lower-risk destinations generally include the United States, Canada, Northern Europe, Australia, New Zealand, Japan, and much of the Caribbean.

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Risk factors

Factors that increase the likelihood of traveler’s diarrhea include travel to regions with poor sanitation, failure to follow food and water precautions, immunocompromised status, inflammatory bowel disease, and reduced gastric acidity, particularly in people taking proton-pump inhibitors.

Students, backpackers, adventure travelers, and individuals with repeated previous episodes may also be at increased risk. Pregnancy may increase susceptibility because physiologic changes can alter gastric acidity and gastrointestinal function.

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Etiology

Most cases of traveler’s diarrhea are infectious, with bacteria responsible for the majority of episodes.

Bacterial causes

Bacteria account for roughly 80–90% of identified cases. The classic and important pathogen is enterotoxigenic Escherichia coli (ETEC). Enteroaggregative E. coli is also increasingly recognized.

Other bacterial causes include Campylobacter, nontyphoidal Salmonella, Shigella, Aeromonas, Plesiomonas shigelloides, and non-cholera Vibrio species.

Viral causes

Viruses account for a smaller proportion of disease. Important agents include norovirus and rotavirus.

Norovirus is particularly associated with outbreaks in cruise ships, camps, and other closed or semi-closed environments. Prominent vomiting is a useful clinical clue.

Parasitic causes

Protozoal infections become increasingly important in travelers with prolonged symptoms or long-duration travel. Important organisms include Giardia duodenalis, Entamoeba histolytica, Cryptosporidium, Cyclospora cayetanensis, Cystoisospora belli, and Balantidium coli.

Giardia is especially associated with contaminated food or water and wilderness exposure. E. histolytica may be acquired from contaminated food, water, or vegetables. Cryptosporidium can be transmitted through contaminated water or animal exposure, while Cyclospora is commonly linked to contaminated food or water.

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Incubation period

The incubation period can help suggest the likely category of pathogen.

Cause

Typical incubation

Bacterial infection

6–48 hours

Viral infection

6–48 hours

Protozoal infection

Usually 1–2 weeks

A rapid onset shortly after exposure favors a bacterial or viral cause, whereas delayed onset with persistent diarrhea should raise suspicion for protozoal infection.

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Clinical presentation

Classic traveler’s diarrhea

Traditionally, classic disease has been defined as three or more unformed stools within 24 hours together with at least one additional symptom such as nausea, vomiting, abdominal pain, cramps, fever, or blood in the stool.

Moderate disease

Moderate illness has traditionally included one or two loose stools accompanied by additional enteric symptoms, or multiple unformed stools with enough discomfort to interfere with usual activities.

Mild disease

Mild illness typically consists of only one or two loose stools with little or no associated systemic disturbance.

In contemporary practice, severity is increasingly judged by how much the illness interferes with planned activities, rather than by stool number alone.

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Clinical patterns according to cause

Bacterial diarrhea

Bacterial illness usually begins abruptly. Manifestations range from mild urgency, cramping, and watery stools to severe abdominal pain, fever, vomiting, and bloody diarrhea.

Without treatment, bacterial traveler’s diarrhea commonly lasts around 3–5 days.

Viral diarrhea

Viral gastroenteritis may closely resemble bacterial disease. Norovirus often produces prominent vomiting and usually resolves within approximately 2–3 days.

Protozoal diarrhea

Protozoal disease tends to develop more gradually and often produces fewer but persistent loose stools. Patients may have approximately two to five loose stools daily, with symptoms continuing for weeks or even months if untreated.

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Physical examination

Examination may reveal loose or watery stools, abdominal tenderness, and evidence of dehydration. Bloody stool occurs in a minority of cases and should increase concern for an invasive enteric pathogen.

Important signs of dehydration include tachycardia, orthostatic hypotension, dry mucous membranes, reduced urine output, poor skin turgor, and altered mental status in severe cases.

Young children, older adults, pregnant patients, and medically vulnerable individuals are particularly susceptible to complications from fluid loss.

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Diagnosis

Traveler’s diarrhea is usually diagnosed clinically from the combination of recent travel and compatible gastrointestinal symptoms. Routine laboratory testing is unnecessary in most uncomplicated, short-lived episodes.

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Diagnostic testing

Stool studies

Microbiologic stool testing should be considered when there is high fever, bloody diarrhea, severe illness, features of colitis, immunocompromise, failure of empiric treatment, or prolonged symptoms.

Stool culture is particularly appropriate in patients with fever and inflammatory or bloody diarrhea.

Persistent diarrhea

Diarrhea lasting longer than approximately 10–14 days should prompt evaluation for protozoal infection.

Important organisms include:

• Giardia duodenalis
• Entamoeba histolytica
• Cryptosporidium
• Cyclospora cayetanensis

A useful clinical rule is:

Traveler with diarrhea lasting more than 2 weeks → think protozoa.

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Differential diagnosis

Not every gastrointestinal illness that develops during travel is infectious traveler’s diarrhea. Other possibilities include food poisoning caused by preformed toxins, shellfish poisoning, scombroid poisoning, and ciguatera poisoning.

Depending on the clinical presentation, other infectious diarrheal illnesses, inflammatory bowel disease, and noninfectious gastrointestinal disorders may also need to be considered.

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General prevention

The major preventive goal is to avoid ingestion of fecally contaminated food and water.

Travelers should avoid unsafe tap water, including its use for brushing teeth when water quality is uncertain. Ice should be avoided unless made from purified water. Unpasteurized dairy products, raw or undercooked meat or seafood, unpeeled raw fruits, inadequately washed vegetables, raw leafy vegetables, and food from vendors with questionable hygiene should also be avoided.

A practical rule is:

Boil it, cook it, peel it—or leave it.

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Water safety

Boiling

Boiling remains one of the most dependable simple methods of making water microbiologically safer.

Chlorination and iodination

Chemical disinfection can reduce many infectious risks, but it is less reliable against organisms such as Cryptosporidium.

Bottled water

Commercial bottled water is generally considered safer when the original cap and seal remain intact.

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Hand hygiene

Travelers should wash their hands with soap and safe water whenever possible, especially before eating or handling food. When soap and water are unavailable, an alcohol-based hand sanitizer containing at least 60% alcohol can be used.

Good hand hygiene reduces both foodborne transmission and direct person-to-person spread.

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Chemoprophylaxis

Antibiotic prophylaxis

Although prophylactic antibiotics can decrease the frequency of traveler’s diarrhea, routine use is not recommended for most travelers because of adverse effects, alteration of normal intestinal flora, and increasing antimicrobial resistance.

Preventive antibiotics may occasionally be considered for selected high-risk individuals when even a brief diarrheal illness could have serious medical, occupational, or logistical consequences.

Historically used agents have included rifaximin and fluoroquinolones, but contemporary decisions should take current resistance patterns into account.

Bismuth subsalicylate

Bismuth subsalicylate can reduce the incidence of traveler’s diarrhea and is one of the better studied non-antibiotic preventive strategies.

A historically used regimen is two 262-mg tablets or 60 mL four times daily for up to about 3 weeks.

It should be avoided or used cautiously in patients taking anticoagulants or other salicylates and in those with contraindications to salicylate therapy. It may also interfere with doxycycline absorption.

Probiotics

Evidence supporting probiotics for prevention remains inconsistent. Preparations studied include Lactobacillus species and Saccharomyces boulardii.

They should not replace food, water, and hygiene precautions.

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Treatment

Rehydration is the priority

The most important treatment for traveler’s diarrhea is replacement of fluids and electrolytes.

Most infections are self-limited, and the greatest immediate danger—especially in vulnerable patients—is dehydration.

Oral rehydration solution (ORS) is particularly useful for infants, children, older adults, and patients with substantial fluid loss. Severe dehydration or inability to tolerate oral fluids may require intravenous therapy.

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Antibiotic treatment

Antibiotics can shorten the duration of moderate-to-severe bacterial disease but are unnecessary for every mild episode.

Choice of therapy depends on the travel destination, illness severity, presence of fever or dysentery, local resistance patterns, pregnancy status, age, and underlying medical conditions.

Azithromycin

Azithromycin is especially useful when there is febrile diarrhea, dysentery, or travel to regions with high rates of fluoroquinolone-resistant Campylobacter, particularly parts of South and Southeast Asia.

A commonly cited regimen is azithromycin 1 g orally as a single dose.

It is also an important option for children and pregnant patients when antimicrobial treatment is indicated.

Fluoroquinolones

Ciprofloxacin was historically a major treatment option. A classic regimen is ciprofloxacin 500 mg orally twice daily for 3 days.

However, fluoroquinolones are less universally useful today because resistance has increased, particularly among Campylobacter and some other enteric organisms. Safety concerns related to the drug class must also be considered.

Rifaximin

Rifaximin is a poorly absorbed antibiotic that may be used for afebrile, noninvasive, nondysenteric traveler’s diarrhea.

A commonly cited regimen is 200 mg orally twice daily for 3 days.

It should not be relied on when there is fever, bloody diarrhea, or concern for an invasive bacterial infection.

A useful distinction is:

Watery + afebrile → rifaximin may be appropriate.

Fever or blood → think invasive disease and choose another approach.

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Symptomatic therapy

Loperamide

Loperamide decreases intestinal motility and can provide rapid symptomatic relief, particularly when the traveler needs short-term control of diarrhea.

It may also be combined with an appropriate antibiotic in selected moderate-to-severe cases.

Loperamide should generally not be used alone when there is bloody diarrhea, high fever, or suspected invasive bacterial colitis. Extra caution is required in young children.

Bismuth subsalicylate

Bismuth subsalicylate may also reduce diarrhea and gastrointestinal discomfort. A traditional regimen is two 262-mg tablets or 60 mL up to four times daily.

It should be avoided when salicylates are contraindicated.

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Protozoal infections

Persistent post-travel diarrhea requires a different diagnostic and therapeutic approach from ordinary acute bacterial traveler’s diarrhea.

Giardiasis

Giardia should be suspected when persistent diarrhea is accompanied by bloating, flatulence, malabsorption, greasy or foul-smelling stools, or a history of contaminated water exposure.

A traditional treatment regimen is metronidazole 250 mg orally three times daily for 5 days.

Amebiasis

Invasive Entamoeba histolytica infection requires therapy against both invasive trophozoites and organisms remaining within the intestinal lumen.

A classic regimen is metronidazole 500–750 mg orally three times daily for 10 days, followed by a luminal agent such as paromomycin or iodoquinol.

A key principle is:

Metronidazole alone is not adequate treatment for invasive amebiasis. A luminal amebicide must follow.

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Pregnancy considerations

Pregnant travelers require careful attention to dehydration and medication safety.

Azithromycin may be used when antibiotic treatment is required. Fluoroquinolones are generally avoided when suitable alternatives are available. Bismuth subsalicylate is usually avoided, and the safety of rifaximin in pregnancy has not been sufficiently established for routine use.

Loperamide may sometimes be considered depending on the clinical circumstances. Medication choices should be individualized.

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Pediatric considerations

Infants and young children can become dehydrated quickly. The priority is oral rehydration and close monitoring.

Medical evaluation is especially important when a child has persistent vomiting, inability to drink, markedly reduced urine output, lethargy, high fever, bloody diarrhea, or other signs of significant dehydration.

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Diet during recovery

Normal feeding can usually be resumed early as tolerated. Prolonged fasting is unnecessary.

Temporary reduction of alcohol, coffee or caffeine, carbonated drinks, and dairy products may be helpful if these worsen symptoms.

The main priority remains adequate fluid, electrolyte, and nutritional intake.

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Prognosis

Most cases of traveler’s diarrhea resolve without lasting consequences.

Typical untreated durations are approximately:

• Viral illness: 2–3 days
• Bacterial illness: 3–5 days
• Protozoal illness: potentially weeks to months

The most important immediate threat is dehydration, especially in young children, older adults, pregnant patients, and people with significant underlying disease.

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Complications

Dehydration

This is the most important acute complication. Severe volume loss can cause electrolyte abnormalities, hypotension, acute kidney injury, and shock.

Reactive arthritis

Reactive arthritis can develop after infections caused by organisms such as Campylobacter, Salmonella, and Shigella.

Guillain–Barré syndrome

Campylobacter jejuni infection is a well-known infectious trigger for Guillain–Barré syndrome.

Postinfectious irritable bowel syndrome

Some patients develop persistent gastrointestinal symptoms even after the original infection has cleared. Manifestations may include abdominal discomfort, altered bowel frequency, diarrhea, constipation, and bloating.

This condition is known as postinfectious irritable bowel syndrome.

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High-yield approach to traveler’s diarrhea

Clinical pattern

Likely consideration

Acute watery diarrhea after travel

ETEC or another bacterial cause

Prominent vomiting during a cruise-ship or camp outbreak

Norovirus

Fever with bloody diarrhea

Invasive bacterial infection

South/Southeast Asia with inflammatory diarrhea

Resistant Campylobacter; azithromycin often useful

Diarrhea persisting >2 weeks

Protozoal infection

Persistent diarrhea with bloating or greasy stools

Giardia

Dysentery with appropriate exposure

E. histolytica

Weakness after Campylobacter infection

Guillain–Barré syndrome

Arthritis after bacterial diarrhea

Reactive arthritis

Chronic bowel symptoms after infection

Postinfectious IBS

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Exam essentials

Most common illness affecting international travelers:

→ Traveler’s diarrhea

Major route of acquisition:

→ Fecally contaminated food or water

Most cases are caused by:

→ Bacteria

Classic major pathogen:

→ Enterotoxigenic Escherichia coli (ETEC)

Prominent vomiting suggests:

→ Norovirus

Persistent or delayed diarrhea suggests:

→ Protozoal infection

Most important treatment:

→ Fluid and electrolyte replacement

Common antimotility drug:

→ Loperamide

Avoid loperamide alone when there is:

→ Bloody diarrhea or high fever

Rifaximin is best suited for:

→ Afebrile, noninvasive, nondysenteric diarrhea

Important fluoroquinolone resistance problem:

→ Campylobacter, especially in South and Southeast Asia

Useful antibiotic for dysentery or resistant Campylobacter:

→ Azithromycin

Treatment principle for invasive amebiasis:

→ Tissue-active therapy followed by a luminal amebicide

Diarrhea lasting >10–14 days:

→ Investigate for protozoa

Important Campylobacter complication:

→ Guillain–Barré syndrome

Important long-term complication after traveler’s diarrhea:

→ Postinfectious irritable bowel syndrome

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.

Ophthalmology — Metastatic Tumors to the Eye and Adnexa

Basics

Description

Intraocular metastasis is the most common malignant tumor involving the eye.

The choroid is the most common site, accounting for approximately 63% of ocular metastases because of its exceptionally rich vascular supply.

Other sites include:

• Orbit/adnexa: ~32%
• Iris and ciliary body: ~6%
• Retina
• Vitreous
• Optic disc/optic nerve
• Eyelid

An important diagnostic point is that ~25% of patients have no known malignancy when the ocular metastasis is discovered. Even after systemic investigation, the primary site remains unknown in approximately 10%.

Most common primary:

• Women → breast carcinoma
• Men → lung carcinoma

Epidemiology

The incidence of ocular metastasis is increasing, probably because patients with systemic malignancies are surviving longer.

The true incidence is difficult to determine because:

• Many lesions are asymptomatic.
• Patients may have advanced systemic disease.
• Small ocular metastases may remain undetected.

Reported figures include:

• Postmortem incidence: ~10%
• Uveal metastasis in systemic cancer: 2.3–9.2%
• Orbital metastasis in systemic cancer: 2–4.7%

Risk Factors

The major risk factor for uveal metastasis is widespread metastatic disease.

Approximately 70–90% of patients already have metastases elsewhere when ocular metastasis is diagnosed.

A particularly important risk factor is metastatic involvement of ≥2 other organs.

Median interval between diagnosis of the primary malignancy and ocular metastasis is approximately 12–55 months, depending on tumor type.

Pathophysiology

Ocular metastases usually spread hematogenously.

The choroid has one of the highest blood flows of any tissue in the body and therefore has an extremely high metastatic efficiency.

This explains why the choroid is much more commonly affected than the retina or other intraocular structures.

Common Primary Cancers

Approximate distribution:

Primary tumor

Approximate frequency

Breast

40–47%

Lung

14–30%

Melanoma

~5%

GI malignancy

~4%

Kidney

2–4%

Prostate

1–4%

Diagnosis

History

Many patients are asymptomatic.

When symptoms occur, the most common is:

Blurred vision

Uveal metastasis

Other symptoms include:

• Scotoma
• Pain
• Redness
• Photophobia

Orbital metastasis

Typical symptoms include:

• Diplopia
• Proptosis
• Pain
• Ptosis
• Visible or palpable mass

Choroidal Metastasis

The choroid is the classic and most common site of ocular metastasis.

Clinical Features

• Bilateral in 20–50%
• Multifocal in approximately 30%
• Usually located in the posterior choroid
• Frequently involves the macular region
• Typically cream-yellow or cream-colored
• Often associated with substantial subretinal fluid

Color Can Suggest the Primary

Orange choroidal metastasis may occur with:

• Renal cell carcinoma
• Thyroid carcinoma
• Bronchial carcinoid

Gray-brown metastasis may suggest:

• Metastatic melanoma

A “leopard-skin” appearance can occur from clumps of brown pigment.

Iris Metastasis

Typical appearance:

• Yellow-white nodule
• Single or multiple lesions

Associated findings may include:

• Anterior uveitis / iridocyclitis
• Hyphema
• Secondary glaucoma

Therefore, an unexplained unilateral anterior uveitis with an iris mass—particularly in a patient with malignancy—should raise suspicion for metastasis.

Ciliary Body Metastasis

Usually appears as a:

• Solitary
• Sessile or dome-shaped mass

Associated manifestations include:

• Cataract
• Iridocyclitis
• Hyphema

Ultrasound biomicroscopy (UBM) is particularly useful for evaluating these lesions.

Retinal Metastasis

Retinal metastases are uncommon.

They can resemble:

• Occlusive retinal vasculitis
• Retinal infiltrative disease

Vitreous tumor seeding may accompany retinal involvement.

Vitreous Metastasis

Tumor cells can infiltrate the vitreous and produce an appearance resembling:

Primary vitreoretinal lymphoma.

Optic Nerve Metastasis

May result from:

1. Juxtapapillary extension of a choroidal metastasis, or
2. Direct isolated optic nerve metastasis

Typical findings include:

• Unilateral optic disc elevation
• Significant visual loss

Orbital Metastasis

Orbital metastasis may produce a mass effect causing:

• Proptosis
• Globe displacement
• Pain
• Chemosis
• Eyelid swelling

Soft-tissue infiltration can cause:

• Ptosis
• Restricted extraocular movements
• Diplopia

Important Pearl — Enophthalmos

Unlike most orbital tumors, scirrhous metastatic carcinoma can cause enophthalmos rather than proptosis.

Classically associated with:

• Breast carcinoma
• Gastric carcinoma

Carcinoid Metastasis

Orbital metastasis can occasionally be the first manifestation of a carcinoid tumor.

A useful pattern:

• Small-intestinal carcinoid → orbit
• Bronchial carcinoid → choroid

Pediatric Orbital Metastases

Metastatic orbital tumors are uncommon in children.

Important primary tumors include:

• Neuroblastoma
• Wilms tumor
• Ewing sarcoma
• Rhabdomyosarcoma

Eyelid Metastasis

Presentation is variable and may include:

• Solitary nodule
• Multiple nodules
• Diffuse eyelid infiltration

Diagnostic Testing

Initial Approach

Diagnosis is often primarily clinical, especially in a patient with a known systemic malignancy and characteristic choroidal lesions.

However, brain/CNS imaging is important because ocular metastases may coexist with intracranial metastases.

Fluorescein Angiography

Choroidal metastases typically demonstrate:

• Early hypofluorescence
• Late hyperfluorescence/leakage

Ultrasonography

A-scan

Usually demonstrates:

Moderate-to-high internal reflectivity

This can help distinguish metastasis from melanoma, which generally has lower internal reflectivity.

B-scan

Typically demonstrates:

• Acoustic solidity
• Choroidal mass
• Associated subretinal fluid

A mushroom configuration is unusual but can occasionally occur.

Orbital Imaging

MRI

Preferred when detailed evaluation of:

• Orbital soft tissue
• Optic nerve
• Intracranial structures

is required.

CT

Especially useful for:

• Bone involvement
• Osteoblastic or destructive lesions

For example, prostate metastases may have prominent osseous involvement.

Biopsy

Definitive diagnosis can be obtained with:

• Fine-needle aspiration biopsy (FNAB)
• Open biopsy

Biopsy is particularly useful when:

• There is no known primary cancer.
• The lesion is atypical.
• The diagnosis will change systemic management.

Immunohistochemistry can help identify the tissue of origin.

Important Systemic Implication

Detection of ocular metastasis generally indicates:

Stage IV systemic malignancy.

The patient therefore requires oncologic evaluation for:

• Restaging
• Identification of additional metastatic sites
• Selection of systemic treatment

Differential Diagnosis

Choroidal Metastasis

Important mimickers include:

• Choroidal melanoma
• Choroidal nevus
• Choroidal hemangioma
• Choroidal osteoma
• Choroidal lymphoma
• Inflammatory choroidal lesions

Iris Metastasis

Consider:

• Amelanotic iris melanoma
• Iris nevus
• Inflammatory granuloma

Orbital/Eyelid Metastasis

Differential includes numerous:

• Benign orbital tumors
• Primary malignant orbital tumors
• Lymphoproliferative lesions
• Inflammatory orbital disease

Treatment

Treatment depends heavily on:

• Primary malignancy
• Extent of systemic disease
• Number and location of ocular lesions
• Visual potential
• Symptoms
• Expected survival

The overall goals are usually vision preservation and symptom control while treating systemic disease.

Uveal Metastasis

External Beam Radiotherapy

A traditional and effective treatment.

Typical dose:

20–50 Gy

Reported tumor response:

63–83%

Visual improvement:

27–89%

Possible complications include:

• Ocular surface disease
• Cataract
• Radiation retinopathy

Systemic Therapy

Systemic treatment may cause regression of ocular metastases.

Options depend on tumor biology and include:

• Chemotherapy
• Hormonal therapy
• Targeted therapy
• Immunotherapy

Systemic therapy is particularly important when widespread metastatic disease is present.

Plaque Radiotherapy

Useful particularly for:

• Solitary choroidal metastasis
• Localized disease requiring concentrated radiation
• Recurrence after external beam radiotherapy

It delivers a high radiation dose directly to the lesion while reducing exposure to surrounding tissues.

Proton Beam Therapy

Advantages include:

• Highly precise radiation delivery
• Reduced radiation scatter
• Potentially shorter treatment course

Other Local Treatments

Selected lesions may be treated with:

• Photodynamic therapy
• Transpupillary thermotherapy
• Laser photocoagulation

These are generally reserved for carefully selected localized tumors.

Enucleation

Rarely required.

Main indication:

Blind, painful eye, particularly from severe secondary glaucoma or extensive tumor involvement.

Orbital Metastasis

Treatment depends strongly on systemic prognosis.

External beam radiotherapy

Often the principal local treatment.

Typical dose:

20–40 Gy over approximately 2–4 weeks

Potential benefits:

• Tumor shrinkage
• Reduced proptosis
• Relief of pain
• Improved motility
• Preservation of vision

Complications include:

• Cataract
• Radiation retinopathy

Brain metastases may require concurrent intracranial radiation.

Systemic Therapy for Orbital Disease

Chemotherapy may be useful for chemosensitive tumors, particularly:

Small-cell lung carcinoma

Hormonal therapy can be useful for:

• Breast carcinoma
• Prostate carcinoma

Orbital Surgery

Surgical debulking is usually palliative rather than curative.

It may be performed to improve:

• Pain
• Severe proptosis
• Diplopia

Orbital exenteration is rarely indicated but may be considered for a severely disfiguring orbital tumor.

Eyelid Metastasis

Treatment depends on lesion number, size, location, systemic disease and prognosis.

Options include:

• Excisional biopsy for small solitary lesions
• External beam radiotherapy for multiple/recurrent lesions
• Systemic anticancer therapy for disseminated disease
• Palliative therapy in terminal disease

Unknown Primary Tumor

In a small proportion of patients, the primary tumor remains unknown despite systemic investigation.

These patients generally have a poor prognosis.

A systemic therapeutic trial may sometimes be considered after appropriate oncologic evaluation.

Follow-Up

Management requires coordinated multidisciplinary care involving:

• Ophthalmology/ocular oncology
• Medical oncology
• Radiation oncology
• Other specialists depending on the primary malignancy

Ophthalmic follow-up should monitor:

• Response of existing lesions
• Development of additional metastases
• Fellow-eye involvement
• Subretinal fluid
• Visual function
• Treatment-related complications

Prognosis

Historically, ocular metastasis indicates advanced systemic disease.

Reported median survival after diagnosis has been approximately:

6–9 months

However, prognosis varies considerably according to the primary malignancy, molecular subtype, treatment response, and extent of systemic disease.

Relatively more favorable survival is seen with:

• Breast carcinoma
• Carcinoid tumors

Key Clinical Pearls

• Choroid is the most common site of ocular metastasis.
• Breast cancer is the most common primary in women; lung cancer in men.
• Approximately 25% may have no known cancer when the ocular lesion is discovered.
• Choroidal metastases are classically cream-colored, posterior, and associated with subretinal fluid.
• They can be bilateral and multifocal, an important clue against primary choroidal melanoma.
• Orange metastasis → think renal cell, thyroid, or carcinoid.
• Gray-brown metastasis → consider metastatic melanoma.
• Iris metastasis can produce uveitis + hyphema + secondary glaucoma.
• Scirrhous breast carcinoma can cause orbital enophthalmos, rather than the more usual proptosis.
• On ultrasound, metastases generally have moderate-to-high internal reflectivity, whereas melanoma classically has lower reflectivity.
• Ocular metastasis generally signifies advanced systemic metastatic disease, so systemic restaging is essential.

Ophthalmology – Marfan Syndrome

Basics

Description

Marfan syndrome is an autosomal dominant connective tissue disorder that primarily affects the:

• Cardiovascular system
• Musculoskeletal system
• Eyes

It is most commonly caused by pathogenic variants in FBN1, the gene encoding fibrillin-1.

A major ophthalmic hallmark is ectopia lentis, and Marfan syndrome is one of the most important causes of nontraumatic lens dislocation.

Epidemiology

Marfan syndrome affects approximately 4–6 per 10,000 individuals.

It affects males and females equally.

Approximately 25% of cases arise from a new mutation without a prior family history.

Risk Factors

Important risk factors include:

• Family history of Marfan syndrome
• Known pathogenic FBN1 mutation

Because inheritance is autosomal dominant, an affected individual has approximately a 50% chance of transmitting the disorder with each pregnancy.

Genetics

Marfan syndrome is most commonly associated with mutations in:

• FBN1 on chromosome 15q21

Fibrillin-1 is an important component of extracellular matrix microfibrils.

The disorder has:

• High penetrance
• Marked variability in clinical severity

Some phenotypically related connective-tissue disorders involve abnormalities in the TGF-β signaling pathway.

Pathophysiology

Fibrillin is essential for normal microfibril formation and extracellular matrix integrity.

Within the eye, fibrillin is found in structures including:

• Ciliary zonules
• Lens capsule
• Schlemm canal region
• Sclera
• Choroid
• Bruch membrane
• Lamina cribrosa
• Corneal tissues

Abnormal fibrillin helps explain the tendency toward:

• Ectopia lentis
• Axial myopia
• Retinal detachment
• Glaucoma
• Corneal abnormalities

Commonly Associated Conditions

Cardiovascular

Cardiovascular involvement is a major determinant of morbidity and mortality.

Important manifestations include:

• Aortic root dilatation
• Aortic aneurysm
• Aortic dissection
• Mitral valve prolapse
• Mitral regurgitation

Musculoskeletal

Typical features include:

• Tall stature
• Long extremities
• Arachnodactyly
• Scoliosis or kyphoscoliosis
• Pectus excavatum or pectus carinatum
• Joint laxity or hypermobility

Pulmonary

Possible manifestations include:

• Apical pulmonary blebs
• Spontaneous pneumothorax

Neurologic

A characteristic association is:

• Dural ectasia

Diagnosis

Diagnosis is based on the overall clinical picture, family history, cardiovascular findings, ocular findings, and genetic evaluation when appropriate.

Modern diagnosis uses the revised Ghent criteria rather than relying on a single physical feature.

History

Important history includes:

• Family history of Marfan syndrome
• Sudden cardiovascular death in relatives
• Known aortic disease
• Previous retinal detachment
• Progressive myopia
• Lens instability
• Musculoskeletal abnormalities
• Pneumothorax
• Back or neurologic symptoms that may suggest dural ectasia

Ophthalmic Examination

A complete eye examination should include:

• Visual acuity
• Refraction
• Slit-lamp examination
• Pupil dilation
• Lens position
• IOP
• Dilated peripheral retinal examination

Ectopia Lentis

Ectopia lentis is one of the most characteristic ocular findings.

It occurs in a substantial proportion of patients.

The classic displacement is superotemporal, although displacement can occur in other directions.

The zonules are structurally weak because fibrillin is a major component of the suspensory apparatus of the lens.

Visual Effects of Ectopia Lentis

Lens displacement can cause:

• High astigmatism
• Myopia
• Irregular refractive error
• Monocular diplopia
• Reduced best-corrected vision
• Amblyopia in children

Severe displacement can eventually require surgery.

Iris and Pupil

Patients may have:

• Poor pupillary dilation
• Iris or ciliary muscle hypoplasia

Poor dilation may make both examination and intraocular surgery more difficult.

Refractive Error

Axial myopia is common.

Patients may develop significant refractive error even in the absence of severe lens displacement.

Cataract

Cataract may occur earlier than expected for age.

Nuclear sclerosis may develop earlier than in the general population.

Vitreous Changes

Vitreous abnormalities may include:

• Early central vitreous liquefaction
• Posterior vitreous degeneration

These changes may contribute to retinal complications.

Retinal Detachment

Marfan syndrome is associated with a significantly increased risk of rhegmatogenous retinal detachment.

Risk is increased by:

• Axial myopia
• Abnormal vitreous
• Lens instability
• Prior lens surgery

Retinal detachment may occur at a younger age than in the general population.

Bilateral involvement is an important concern.

Diagnostic Tests

Genetic Testing

Molecular testing for FBN1 can support the diagnosis.

However, diagnosis remains clinical and multidisciplinary because genetic findings must be interpreted in the context of phenotype and family history.

Cardiovascular Imaging

Regular cardiovascular surveillance is essential.

Important studies include:

• Echocardiography
• CT angiography when needed
• MR angiography when needed

The key parameter is often the size and rate of growth of the aortic root.

Ophthalmic Imaging

If the fundus cannot be visualized adequately, especially with severe lens displacement or poor pupillary dilation, B-scan ultrasonography may help evaluate for retinal detachment.

Differential Diagnosis

The differential diagnosis of ectopia lentis includes:

• Trauma
• Homocystinuria
• Weill-Marchesani syndrome
• Familial isolated ectopia lentis
• Ectopia lentis et pupillae
• Aniridia
• Buphthalmos
• Sulfite oxidase deficiency
• Molybdenum cofactor deficiency
• Other metabolic or connective-tissue disorders

Marfan Syndrome vs Homocystinuria

This is an important clinical distinction.

Marfan Syndrome

Lens displacement is classically:

• Superotemporal

Patients often have:

• Tall habitus
• Aortic root disease
• Joint laxity

Homocystinuria

Lens displacement may occur in various directions and is classically described as inferonasal.

Patients may additionally have:

• Developmental or intellectual impairment
• Osteoporosis
• Thromboembolic disease

Treatment

Management is multidisciplinary.

The major goals are:

• Prevent aortic complications
• Optimize vision
• Treat lens instability
• Detect retinal detachment early
• Manage associated systemic disease

Cardiovascular Medical Therapy

Medical therapy is directed toward reducing stress on the aortic wall.

Common approaches include:

• Beta-blockers
• Angiotensin receptor blockers

The exact regimen should be determined by cardiology according to current Marfan and aortopathy guidelines.

Ophthalmic Management

Refractive Correction

Mild-to-moderate ectopia lentis may be managed with:

• Spectacles
• Contact lenses

Children must be monitored carefully for amblyopia.

Amblyopia

In children, asymmetric refractive error or lens displacement can cause amblyopia.

Treatment may include:

• Full optical correction
• Patching
• Other standard amblyopia therapy

Early intervention is important.

Lens Surgery

Lens removal may be considered when there is:

• Severe lens displacement
• Inadequate visual correction
• Cataract
• Secondary glaucoma
• Progressive visual disability
• Lens-related complications

Surgery can be technically challenging because of weak zonules.

Surgical Approach

Modern surgical technique depends on:

• Age
• Degree of lens displacement
• Capsular support
• Retinal status
• Surgeon experience

Pars plana or limbal approaches may be considered depending on the anatomy.

Because retinal detachment risk is increased, careful preoperative and postoperative retinal assessment is important.

Retinal Detachment Treatment

Retinal detachment should be managed promptly by a vitreoretinal surgeon.

Possible procedures include:

• Scleral buckle
• Pars plana vitrectomy
• Combined buckle and vitrectomy

The choice depends on:

• Lens position
• Break configuration
• Extent of detachment
• Vitreous anatomy

The fellow eye should also be examined carefully because bilateral retinal disease is more common than in the general population.

Referral

Patients commonly require coordinated care involving:

• Cardiology
• Ophthalmology
• Retina specialist
• Medical genetics
• Orthopedics
• Pulmonology
• Neurosurgery when dural ectasia is significant

Pregnancy Considerations

Pregnancy increases cardiovascular stress and can increase the risk of aortic enlargement and dissection in women with Marfan syndrome.

Risk is especially important when significant aortic root enlargement is already present.

Management should involve a multidisciplinary team including:

• Cardiology
• Maternal-fetal medicine
• Cardiothoracic surgery when indicated
• Genetics

Serial aortic imaging during pregnancy may be required.

Delivery planning depends largely on:

• Aortic diameter
• Rate of aortic enlargement
• Prior aortic surgery
• Overall cardiovascular status

Because recommendations are highly dependent on current aortopathy guidelines, fixed historical diameter thresholds should not be used without specialist assessment.

Fetal Considerations

Because Marfan syndrome is autosomal dominant:

• Each pregnancy has approximately a 50% chance of inheritance

Severity is highly variable.

A mildly affected parent can have a more severely affected child.

Genetic counseling is strongly recommended.

Follow-Up

Long-term monitoring should include:

• Regular echocardiography or other aortic imaging
• Periodic ophthalmic examinations
• Refraction
• Lens position assessment
• IOP
• Dilated retinal examination

Follow-up frequency depends on disease severity.

Lifestyle

Patients are generally advised to avoid activities that produce extreme cardiovascular stress.

This may include:

• Heavy isometric exercise
• Very heavy weightlifting
• High-intensity contact sports in selected patients

Exercise recommendations should be individualized by cardiology.

Patient Education

Patients should understand the symptoms of retinal detachment:

• New flashes
• Sudden increase in floaters
• Curtain or shadow across the vision
• Sudden peripheral visual field loss

These symptoms require urgent retinal evaluation.

Patients should also understand warning symptoms of aortic emergencies, such as sudden severe chest, back, or abdominal pain, and seek emergency care immediately.

Prognosis

Modern cardiovascular surveillance and treatment have greatly improved life expectancy.

Visual prognosis depends on:

• Severity of ectopia lentis
• Degree of myopia
• Presence of amblyopia
• Cataract
• Glaucoma
• Retinal detachment

Many patients maintain good useful vision with appropriate ophthalmic management.

Complications

Major ocular complications include:

• Ectopia lentis
• High myopia
• Amblyopia
• Cataract
• Glaucoma
• Retinal detachment
• Permanent visual loss

Major systemic complications include:

• Aortic aneurysm
• Aortic dissection
• Valvular disease
• Pneumothorax
• Dural ectasia

Key Clinical Pearls

• Marfan syndrome is an autosomal dominant fibrillin-1 connective-tissue disorder.
• Ectopia lentis is a major ophthalmic hallmark and is classically superotemporal.
• Marfan syndrome is an important cause of nontraumatic ectopia lentis.
• Patients commonly have axial myopia and increased retinal detachment risk.
• Always examine the peripheral retina carefully, particularly before and after lens surgery.
• The most life-threatening manifestation is aortic root disease, so ophthalmic findings can provide an important clue to a systemic diagnosis requiring cardiology evaluation.

Ophthalmology: Macular Hole

BASICS

Description

A macular hole is a partial-thickness or full-thickness defect involving the retina at the center of the macula, particularly the fovea. Because the fovea is responsible for high-resolution central vision, macular holes can cause significant central visual disturbance.

EPIDEMIOLOGY

Incidence

The estimated annual incidence of macular hole is approximately 7.8–8.7 cases per 100,000 persons.

The highest incidence occurs during the seventh decade of life.

Prevalence

Reported prevalence ranges from approximately 0.02% to 0.8%.

Macular holes occur more frequently in women than in men and most commonly affect individuals older than 55 years of age.

RISK FACTORS

A history of recent ocular trauma is an important risk factor, particularly in younger patients or when the macular hole develops following blunt injury.

PATHOPHYSIOLOGY

The development of a macular hole is strongly associated with abnormal vitreoretinal traction at the fovea.

Persistent attachment of the posterior vitreous cortex to the central macula can exert tractional forces on the foveal tissue. Progressive traction may initially distort the normal foveal contour and eventually produce a partial- or full-thickness retinal defect.

ETIOLOGY

Most macular holes develop idiopathically, particularly in older adults.

Traumatic macular holes can also occur, usually following blunt ocular injury.

DIAGNOSIS

History

Patients commonly report blurred or reduced central vision, distortion of straight lines or objects (metamorphopsia), or a central area of missing vision (central scotoma) in one eye.

Symptoms may develop acutely or subacutely. Because the fellow eye may maintain good visual function, some patients do not recognize the visual deficit until the unaffected eye is accidentally covered.

A history of recent ocular trauma should be specifically sought, particularly when the presentation is atypical or occurs in a younger patient.

Physical Examination

Visual acuity varies according to the size and stage of the macular hole and may range from approximately 20/25 to 20/400.

Patients with a well-established full-thickness macular hole often have visual acuity around 20/200, although considerable variation occurs.

The diagnosis is primarily established by careful biomicroscopic examination of the macula, usually with a handheld indirect lens or a fundus contact lens.

Typical examination findings include:

• A dark, round or oval defect located at the center of the fovea
• A small surrounding neurosensory retinal detachment, which may appear as a fluid-filled cuff
• Small yellow-white deposits or dots at the level of the retinal pigment epithelium
• A possible pseudo-operculum suspended above the macular hole

Gass Biomicroscopic Classification

Macular holes may be classified according to the traditional Gass staging system.

Stage 1: Impending Macular Hole

The foveal depression is lost and a central yellow abnormality develops.

Stage 1A is characterized by a central yellow spot.

Stage 1B is characterized by formation of a yellow ring.

At this stage, a complete full-thickness retinal defect has not yet formed.

Stage 2

A small full-thickness macular hole, traditionally measuring less than approximately 400 microns, becomes visible within the fovea.

Stage 3

A larger full-thickness macular hole, traditionally greater than approximately 400 microns, is present without a complete posterior vitreous detachment.

Stage 4

A full-thickness macular hole is present in association with a posterior vitreous detachment.

Watzke-Allen Test

The Watzke-Allen test may be used clinically to help distinguish a full-thickness macular hole from a lamellar hole, pseudohole, or other macular abnormality.

During the test, a narrow slit-lamp beam is projected across the center of the macular lesion using a macular contact lens.

A patient with a full-thickness macular hole may describe the light beam as having a central break, interruption, narrowing, or compression.

DIAGNOSTIC TESTS AND INTERPRETATION

Laboratory Testing

Routine laboratory investigations are not indicated in the evaluation of an uncomplicated macular hole.

Imaging

Optical Coherence Tomography

Optical coherence tomography (OCT) is the principal imaging technique used to confirm the diagnosis and characterize the macular hole.

OCT provides high-resolution cross-sectional images of the retina and can demonstrate:

• A partial- or full-thickness defect involving the fovea
• The size and configuration of the macular hole
• Vitreomacular adhesion or vitreomacular traction
• Intraretinal cystic changes around the hole
• Elevation of the retinal edges
• A pseudo-operculum when present
• The relationship between the posterior vitreous and the macula

OCT is also valuable for surgical planning and for documenting anatomical closure following treatment.

Diagnostic Procedures

Laser Aiming Beam Test

A small laser aiming beam, traditionally approximately 50 microns in diameter, may be directed toward the center of the suspected lesion.

A patient with a full-thickness macular hole may be unable to perceive the light spot when it is positioned directly over the hole. Patients with other macular abnormalities may still be able to see the aiming beam.

This test is used much less frequently now because OCT provides more detailed and objective anatomical information.

Pathological Findings

Histopathologic examination is generally unnecessary because tissue specimens are not routinely obtained during the diagnosis or surgical treatment of a macular hole.

DIFFERENTIAL DIAGNOSIS

Conditions that may resemble a macular hole include:

• Epiretinal membrane with a macular pseudohole
• Lamellar macular hole
• Vitreomacular traction
• Cystoid macular edema
• Macular cyst
• Pigment epithelial detachment
• Central serous chorioretinopathy

Careful fundus examination and OCT imaging are particularly useful for differentiating these conditions from a true full-thickness macular hole.

TREATMENT

Medication

There is no conventional medication that directly closes an established full-thickness macular hole.

Management is therefore primarily based on observation in selected cases or vitreoretinal intervention when treatment is indicated.

ADDITIONAL TREATMENT

Issues for Referral

Patients with a suspected or confirmed full-thickness macular hole should be referred to a vitreoretinal specialist for assessment and discussion of management options.

Complementary and Alternative Therapies

No complementary or alternative therapy has an established role in the treatment of macular holes.

SURGERY AND OTHER PROCEDURES

Surgical repair is the standard treatment for most visually significant full-thickness macular holes.

The usual procedure is pars plana vitrectomy with intraocular gas tamponade.

During surgery, the vitreous is removed and traction on the macula is released. In many cases, the surgeon also performs internal limiting membrane (ILM) peeling around the fovea to improve the likelihood of anatomical hole closure.

A gas bubble is then placed inside the eye to provide temporary internal tamponade and facilitate approximation of the edges of the macular hole.

Surgery is generally not considered an immediate emergency. However, once intervention has been recommended, repair is commonly undertaken within a relatively short period because longer-standing holes may have a less favorable visual prognosis.

Postoperative positioning instructions depend on the characteristics of the hole, the gas used, and the surgeon’s technique. Some patients may be instructed to maintain a face-down position for a period after surgery.

Patients with their natural crystalline lens remain at increased risk of developing or accelerating cataract formation after vitrectomy and may subsequently require cataract extraction.

INPATIENT CONSIDERATIONS

Initial Stabilization

Macular hole treatment is generally managed on an outpatient basis.

Hospital admission is not ordinarily required for uncomplicated cases.

ONGOING CARE

Follow-Up Recommendations

Patients should be evaluated by a vitreoretinal surgeon to determine whether surgical treatment is appropriate.

Following surgery, ophthalmic examinations are commonly performed at intervals such as:

• The first postoperative day
• Approximately 1 week after surgery
• Approximately 2–3 weeks after surgery
• Approximately 6–12 weeks after surgery

The exact follow-up schedule varies according to surgical findings, intraocular pressure, the type of gas tamponade used, retinal status, and postoperative recovery.

OCT may be repeated to confirm anatomical closure of the hole and monitor restoration of the foveal architecture.

PATIENT EDUCATION

Patients should be informed that a macular hole can also develop in the fellow eye. Reported rates of fellow-eye involvement are approximately 5–20%, depending on the vitreomacular anatomy and duration of follow-up.

Patients should therefore monitor the vision in each eye separately and promptly report new central blurring, distortion, or a central blind spot in the opposite eye.

Following vitreoretinal surgery, patients should also be educated about symptoms that may indicate a retinal tear or retinal detachment, including:

• New flashes of light
• A sudden increase in floaters
• A curtain, shadow, or veil across the visual field
• Sudden deterioration in peripheral or central vision

These symptoms require urgent ophthalmologic evaluation.

Patients who receive an intraocular gas bubble must follow the surgeon’s specific postoperative precautions, including restrictions related to altitude and certain forms of anesthesia until the gas has completely resolved.

PROGNOSIS

Modern macular hole surgery has a high anatomical success rate, with hole closure achieved in more than 90% of appropriately selected cases.

Visual recovery varies between patients. Successful anatomical closure usually improves or stabilizes central vision, although the final visual acuity depends on factors such as the size of the hole, duration of symptoms, preoperative retinal changes, and restoration of the outer retinal layers.

Earlier treatment of suitable macular holes is generally associated with a better potential for visual improvement than treatment of longstanding disease.

COMPLICATIONS

Potential complications associated with macular hole and its surgical treatment include:

• Cataract formation or progression, particularly after vitrectomy in phakic patients
• Retinal tears
• Retinal detachment
• Persistent or recurrent macular hole
• Intraocular pressure abnormalities following surgery
• Rare macular hole-associated retinal detachment

Although anatomical closure is achieved in most surgically treated cases, the degree of postoperative visual improvement remains variable.

Ophthalmology: Macular Corneal Dystrophy

BASICS

Description

Macular corneal dystrophy, also known as Groenouw corneal dystrophy type II or Fehr spotted dystrophy, is a bilateral, progressive, noninflammatory corneal disorder inherited in an autosomal recessive pattern. It is characterized by numerous stromal opacities accompanied by diffuse haziness of the intervening corneal tissue.

Corneal clouding generally becomes apparent during childhood, most commonly between 3 and 9 years of age.

The corneal lesions appear as poorly demarcated, gray-white opacities that extend toward the peripheral cornea. Deposits may involve the full thickness of the corneal stroma. As the disorder advances, abnormalities may extend to Descemet’s membrane and the corneal endothelium, resulting in guttae-like excrescences and corneal edema. Centrally, the lesions are usually situated more superficially, whereas peripheral deposits tend to occur deeper within the posterior stroma.

When compared with other stromal corneal dystrophies, particularly granular and lattice corneal dystrophies, macular corneal dystrophy is less common and tends to impair vision at an earlier age. Central corneal thickness may also be reduced early in the course of the disease. Unlike granular and lattice dystrophies, clear areas are generally absent between the opacities, and the deposits characteristically extend into the peripheral cornea. Patients often require corneal transplantation earlier in life. Although graft replacement is required less frequently than in some other corneal dystrophies, recurrence of macular dystrophy within the transplanted cornea remains possible.

Common clinical complaints include gradually worsening vision, glare, photophobia, and recurrent corneal epithelial erosions. Visual impairment often becomes severe during the second or third decade of life.

EPIDEMIOLOGY

Incidence and Prevalence

Macular corneal dystrophy is considered an uncommon disorder. Reliable population-based incidence and prevalence figures have not been well established in the medical literature.

RISK FACTORS

Parental consanguinity increases the likelihood of the condition because of its autosomal recessive inheritance pattern.

GENETICS

Macular corneal dystrophy follows an autosomal recessive mode of inheritance.

The associated genetic locus is located on chromosome 16q22. Mutations involve the carbohydrate sulfotransferase 6 gene (CHST6).

PATHOPHYSIOLOGY

The corneal opacities result from the abnormal accumulation of glycosaminoglycans (GAGs), also referred to as mucopolysaccharides. These materials are deposited both intracellularly and extracellularly within the corneal stroma and may also involve Descemet’s membrane and endothelial cells.

In macular corneal dystrophy, glycosaminoglycan material accumulates within the endoplasmic reticulum of affected cells. This differs from systemic mucopolysaccharidoses, in which similar substances accumulate predominantly within lysosomal vacuoles.

Histochemical staining demonstrates the deposits using Alcian blue, Hale colloidal iron, metachromatic stains, and periodic acid-Schiff (PAS).

Electron microscopy demonstrates abnormal GAG-containing material within keratocytes and endothelial cells. Similar fibrillogranular deposits can also be identified within the extracellular stromal matrix.

ETIOLOGY

Macular corneal dystrophy develops as a result of an inherited defect affecting glycosaminoglycan metabolism. The disorder is autosomal recessive and produces progressive, bilateral, noninflammatory accumulation of abnormal material throughout the corneal stroma.

These mucopolysaccharide deposits are responsible for the characteristic corneal clouding that usually becomes evident between 3 and 9 years of age.

DIAGNOSIS

History

A typical history consists of progressive bilateral corneal clouding beginning in childhood. Because the disorder is inherited in an autosomal recessive manner, patients may report a family history of the disease or parental consanguinity.

Symptoms generally include gradually declining visual acuity, glare, photophobia, and episodes of recurrent corneal erosion. Significant visual impairment commonly develops by the second or third decade of life.

Physical Examination

A complete ophthalmic evaluation should be performed. This includes assessment of visual function, measurement of intraocular pressure, slit-lamp examination, and a dilated fundus examination whenever the posterior segment can be adequately visualized.

If dense corneal opacification prevents visualization of the posterior segment, B-scan ultrasonography may be performed to exclude significant vitreoretinal or other posterior segment abnormalities.

Ultrasound pachymetry can be used to assess central corneal thickness, while specular microscopy, when technically possible, can provide information regarding corneal endothelial cell density and morphology.

Slit-Lamp Findings

Typical slit-lamp findings include:

• Multiple gray-white stromal opacities with poorly defined margins
• Extension of the lesions into the peripheral cornea
• Diffuse haze involving the corneal tissue between individual deposits
• Absence of clear intervening stromal spaces
• Deposits occurring at different depths throughout the corneal stroma
• More superficial involvement centrally and deeper involvement toward the corneal periphery
• Extension to Descemet’s membrane and the endothelium in advanced cases
• Guttae-like endothelial changes and corneal edema in severe disease

DIAGNOSTIC TESTS AND INTERPRETATION

Laboratory Testing

An enzyme-linked immunosorbent assay (ELISA) may be used to measure circulating sulfated keratan sulfate when further biochemical characterization is required.

Follow-Up Investigations

Clinical monitoring may include repeated:

• Slit-lamp examinations
• Corneal pachymetry
• Specular microscopy

These investigations help document progression of stromal disease, corneal thickness, and endothelial involvement.

Pathological Findings

Microscopically, macular corneal dystrophy is characterized by intracellular and extracellular deposition of glycosaminoglycans within the corneal stroma. Abnormal material may also be found in Descemet’s membrane and endothelial cells.

Unlike the lysosomal storage seen in systemic mucopolysaccharidoses, intracellular deposits in macular corneal dystrophy are predominantly located within the endoplasmic reticulum.

The abnormal deposits stain positively with Alcian blue, Hale colloidal iron, metachromatic dyes, and PAS.

Electron microscopy reveals abnormal material within keratocytes and endothelial cells as well as fibrillogranular deposits within the extracellular matrix.

Immunohistochemical testing using antibodies directed against sulfated epitopes of antigenic keratan sulfate (AgKS) allows macular corneal dystrophy to be divided into three biochemical subtypes. Despite these laboratory differences, their clinical appearances are generally similar.

Type I

In Type I macular corneal dystrophy, AgKS is not detectable in either the corneal tissue or serum.

Type IA

In Type IA, keratocytes demonstrate AgKS reactivity, whereas the extracellular stromal matrix and serum remain nonreactive.

Type II

In Type II, AgKS can be demonstrated both within the cornea and in the serum.

DIFFERENTIAL DIAGNOSIS

Conditions that may resemble macular corneal dystrophy include:

• Granular corneal dystrophy
• Lattice corneal dystrophy
• Avellino corneal dystrophy
• Schnyder crystalline corneal dystrophy

The diffuse stromal haze, lack of clear spaces between deposits, peripheral extension, and autosomal recessive inheritance are useful features for distinguishing macular corneal dystrophy from several other stromal dystrophies.

TREATMENT

Medication

Medical therapy is primarily directed toward relieving symptoms and managing recurrent epithelial erosions rather than eliminating the underlying stromal deposits.

Artificial tears may be used to lubricate the ocular surface and reduce symptoms associated with recurrent corneal erosions.

Topical hypertonic saline 5% may also be prescribed. Drops can be administered several times during the day, with hypertonic ointment applied at bedtime when appropriate. Hypertonic therapy can help reduce epithelial and stromal edema in symptomatic patients.

ADDITIONAL TREATMENT

General Measures

Tinted contact lenses may help reduce photophobia and glare.

A temporary pressure patch may occasionally be used to promote healing of a corneal epithelial defect, although careful observation is required because patching may increase the risk of infection.

Therapeutic or bandage contact lenses can be useful for recurrent corneal erosions. When used for an epithelial defect, topical antibiotic prophylaxis is commonly provided to reduce the risk of microbial keratitis.

Both pressure patching and therapeutic contact lens wear carry a potential risk of corneal infection. Patients therefore require close follow-up until complete re-epithelialization has occurred.

Indications for Referral

Prompt ophthalmologic reassessment is appropriate when there is:

• Progressive or substantial deterioration in vision
• A persistent or nonhealing corneal epithelial defect

SURGERY AND OTHER PROCEDURES

Phototherapeutic Keratectomy

Phototherapeutic keratectomy (PTK) can be considered in patients with relatively early disease when the deposits are primarily confined to the anterior corneal stroma.

PTK may also be useful in selected patients with troublesome recurrent corneal erosions.

Because the disorder can involve deeper layers over time, PTK is generally less suitable for advanced stromal disease.

Keratoplasty

Corneal transplantation may be necessary when deeper stromal opacification produces substantial visual impairment.

Possible procedures include lamellar keratoplasty, deep anterior lamellar keratoplasty (DALK), and penetrating keratoplasty (PKP).

Deep Anterior Lamellar Keratoplasty

DALK may be considered when the disease involves the corneal stroma but Descemet’s membrane and the endothelium remain unaffected.

Because the patient’s own endothelium is retained, DALK avoids endothelial graft rejection and reduces some of the risks associated with full-thickness transplantation.

Penetrating Keratoplasty

Penetrating keratoplasty provides full-thickness replacement of the diseased cornea and may be required when macular dystrophy extends deeply or involves Descemet’s membrane or the endothelium.

Even after successful keratoplasty, deposits may gradually recur within the donor cornea.

INPATIENT AND DISCHARGE CONSIDERATIONS

Patients being treated for recurrent epithelial erosions should remain under close observation until the epithelial surface has completely healed.

Because pressure patches and therapeutic contact lenses can increase the likelihood of corneal infection, patients should be instructed to seek urgent care if symptoms suggestive of infection develop.

ONGOING CARE

Follow-Up Recommendations

Long-term ophthalmic follow-up is required to monitor the progression of corneal opacities, visual function, and the development of complications.

The frequency of follow-up depends on disease severity and current symptoms.

Patients with stable disease may generally be reassessed every 6 to 12 months.

Patients experiencing recurrent epithelial erosions may require examination approximately every 1 to 7 days until healing is complete.

Patients managed with a pressure patch should usually be reassessed within approximately 24 to 48 hours.

PATIENT EDUCATION

Patients should understand that macular corneal dystrophy is a progressive inherited disorder and that visual function may worsen with time.

They should seek immediate ophthalmic attention if they develop significant ocular pain, sudden reduction in vision, marked redness, purulent discharge, or severe photophobia, as these symptoms may indicate an epithelial complication or corneal infection.

When corneal opacification causes substantial visual impairment, surgical treatment such as PTK or corneal transplantation may eventually be necessary.

Patients should also be informed that recurrence of abnormal corneal deposits is possible even after apparently successful surgery.

PROGNOSIS

Macular corneal dystrophy usually progresses gradually throughout life. Patients commonly experience increasing loss of vision together with glare, photophobia, and recurrent corneal erosions.

Visual impairment may become severe by the second or third decade, although the rate of progression can vary among individuals.

COMPLICATIONS

Important complications include progressive loss of visual acuity, glare, photophobia, recurrent corneal epithelial erosions, corneal edema, and possible endothelial dysfunction in advanced disease.

Although PTK and corneal transplantation can provide substantial symptomatic and visual improvement, recurrence of macular dystrophic deposits can occur following either procedure.

Ophthalmology – Lyme Disease

Basics

Description

Lyme disease is a multisystem infectious disease caused by Borrelia burgdorferi, a spirochete transmitted by infected Ixodes ticks.

It may involve the:

• Skin
• Nervous system
• Heart
• Joints
• Eyes

Ocular involvement can occur at several stages and may affect almost any ocular structure.

Epidemiology

Lyme disease is one of the most common tick-borne diseases in temperate regions of the Northern Hemisphere.

It is especially important in endemic regions of:

• Northeastern United States
• Mid-Atlantic United States
• Upper Midwest
• Europe
• Parts of Asia

Cases occur most often during spring, summer, and early fall, corresponding to periods of tick activity.

Risk Factors

Important risk factors include:

• Residence in an endemic area
• Travel to an endemic area
• Outdoor exposure in wooded or grassy areas
• Tick bite
• Exposure to deer, rodents, and tick-infested environments

General Prevention

The most effective preventive strategy is avoidance of tick bites.

Measures include:

• Avoiding dense brush and tall grasses when possible
• Wearing long sleeves and long pants
• Wearing light-colored clothing to make ticks easier to identify
• Using appropriate tick repellents such as DEET
• Performing a thorough skin and scalp examination after outdoor activity
• Showering after returning indoors
• Checking children carefully for ticks
• Checking outdoor pets
• Removing attached ticks promptly

Etiology

Lyme disease is caused by Borrelia burgdorferi, a motile spirochete.

Transmission occurs through the bite of infected Ixodes ticks.

Small mammals, especially rodents, act as important reservoirs.

Humans are incidental hosts.

Person-to-person transmission does not occur through ordinary contact.

Pathophysiology

After entering through the skin, the organism can disseminate through tissues and the bloodstream.

Borrelia can evade host immunity through changes in its surface proteins and interaction with complement regulatory pathways.

The clinical manifestations result from:

• Direct infection
• Tissue invasion
• Host inflammatory response
• Immune-mediated injury

Ocular manifestations may therefore reflect either active infection or secondary immune inflammation.

Diagnosis

History

Important questions include:

• Recent tick bite
• Travel to or residence in an endemic area
• Outdoor exposure
• Previous erythema migrans rash
• Fever or flu-like symptoms
• Joint pain
• Cardiac symptoms
• Neurologic symptoms

Ocular symptoms may include:

• Blurred vision
• Eye pain
• Redness
• Diplopia
• Floaters
• Photophobia
• Progressive visual loss

Clinical Stages

Early Localized Disease

The classic early manifestation is erythema migrans.

This is usually:

• Expanding
• Erythematous
• Often greater than several centimeters
• Sometimes associated with central clearing

It may produce the classic bull’s-eye appearance, although many lesions do not have this exact morphology.

The rash is often neither painful nor itchy.

Associated symptoms may include:

• Fever
• Chills
• Fatigue
• Headache
• Myalgia
• Arthralgia
• Lymphadenopathy

Early Ocular Findings

Possible findings include:

• Conjunctivitis
• Periorbital edema

Early Disseminated Disease

Dissemination can occur over weeks to months.

Systemic manifestations may involve:

• Nervous system
• Heart
• Joints
• Skin

Neurologic Manifestations

These may include:

• Meningitis
• Cranial neuropathy
• Radiculopathy
• Facial nerve palsy
• Headache
• Photophobia

Cardiac Manifestations

These may include:

• Palpitations
• Arrhythmia
• Atrioventricular block

Ocular Manifestations

Lyme disease can produce a broad range of ophthalmic findings.

External and Anterior Segment

Possible manifestations include:

• Conjunctivitis
• Episcleritis
• Scleritis
• Keratitis
• Exposure keratopathy secondary to facial nerve palsy
• Anterior uveitis
• Granulomatous uveitis

Cranial Nerve Palsies

Lyme disease can involve cranial nerves, including:

• CN III
• CN IV
• CN VI
• CN VII

Patients may present with:

• Diplopia
• Ptosis
• Extraocular motility abnormalities
• Facial weakness

Facial nerve palsy may lead to lagophthalmos and exposure keratopathy.

Intermediate and Posterior Segment Disease

Reported manifestations include:

• Pars planitis
• Vitritis
• Choroiditis
• Retinitis
• Macular edema
• Retinal vascular occlusion
• Retinal vasculitis

These findings are less common than neurologic or anterior segment manifestations.

Optic Nerve Manifestations

Possible findings include:

• Optic neuritis
• Retrobulbar optic neuritis
• Optic disc edema
• Ischemic optic neuropathy
• Optic atrophy

Patients may develop:

• Reduced visual acuity
• Dyschromatopsia
• Relative afferent pupillary defect
• Visual field defects

Late Disease

Late manifestations can persist or recur over months to years.

Systemic disease may include:

• Arthritis
• Chronic neurologic manifestations
• Acrodermatitis chronica atrophicans in some geographic regions

Late ocular findings may include:

• Stromal keratitis
• Episcleritis
• Orbital myositis
• Chronic uveitis
• Rare severe visual pathway involvement

Physical Examination

A complete examination should include:

• General physical examination
• Neurologic examination
• Full ophthalmic examination

Ophthalmic assessment should include:

• Visual acuity
• Pupillary examination
• Ocular motility
• Cranial nerve testing
• Slit-lamp examination
• IOP
• Dilated fundus examination

Diagnostic Testing

Serology

Laboratory diagnosis is based on two-tier serologic testing in the appropriate clinical setting.

Modern testing generally begins with an antibody screening immunoassay followed by a confirmatory second assay according to current testing algorithms.

Interpretation depends heavily on:

• Timing of symptoms
• Clinical presentation
• Pretest probability

Early infection can be seronegative before antibodies develop.

Cerebrospinal Fluid

Lumbar puncture may be indicated when there is concern for:

• Meningitis
• Neuroborreliosis
• Significant neurologic manifestations

CSF evaluation may include:

• Cell count
• Protein
• Intrathecal antibody assessment when appropriate

Additional Testing

Depending on the differential diagnosis, testing may include:

• Syphilis serology
• Other infectious testing
• Neuroimaging
• OCT
• Fluorescein angiography

These are guided by the specific ocular manifestation.

Differential Diagnosis

For optic nerve edema, retinitis, or neuro-ophthalmic disease, important alternatives include:

• Syphilis
• Cat-scratch disease
• Toxoplasmosis
• Acute retinal necrosis
• Multiple sclerosis
• Other infectious or inflammatory uveitides

Treatment

Treatment depends on the stage of disease and whether neurologic involvement is present.

Early Lyme Disease

Oral antibiotics are typically used.

Common agents include:

• Doxycycline
• Amoxicillin
• Cefuroxime axetil

Selection depends on:

• Age
• Pregnancy status
• Allergies
• Clinical manifestation

Neuro-Ophthalmic or Neurologic Lyme Disease

Patients with meningitis, significant cranial neuropathy, or other neuroborreliosis may require more intensive antibiotic therapy.

Depending on the presentation, treatment may include:

• Oral doxycycline
• Intravenous ceftriaxone

The exact regimen should follow current infectious-disease guidelines.

Ocular Inflammation

Inflammatory ocular manifestations may require treatment in addition to antibiotics.

Examples include:

• Topical corticosteroids for anterior uveitis
• Cycloplegic agents for pain and synechiae prevention
• Systemic anti-inflammatory therapy in selected severe disease

Antimicrobial treatment of the underlying Lyme infection should not be omitted when active infection is suspected.

Tick Removal

An attached tick should be removed promptly with fine-tipped forceps.

Recommended technique:

• Grasp the tick close to the skin
• Pull upward steadily
• Avoid twisting
• Avoid crushing or squeezing the body
• Clean the bite site afterward

Prompt removal reduces the likelihood of transmission.

Follow-Up

Follow-up depends on the severity of ocular disease.

Patients with active uveitis, optic nerve disease, or significant neuro-ophthalmic manifestations require close monitoring.

Follow-up should assess:

• Visual acuity
• Pupillary function
• Ocular motility
• Degree of inflammation
• IOP
• Optic nerve appearance
• Retinal findings

Patient Education

Patients should be advised to:

• Use protective clothing outdoors
• Use tick repellent appropriately
• Perform skin checks
• Remove ticks promptly
• Seek evaluation for expanding rash or new neurologic symptoms
• Report new visual symptoms promptly

Prognosis

Most appropriately diagnosed and treated patients have a favorable outcome.

Prognosis depends on:

• Speed of diagnosis
• Severity of neurologic involvement
• Type of ocular involvement
• Presence of optic nerve or retinal damage

Some inflammatory manifestations may persist despite eradication of infection.

Complications

Ophthalmic complications can include:

• Chronic uveitis
• Keratitis
• Scleritis
• Cranial nerve palsy
• Optic neuropathy
• Retinal vasculitis
• Macular edema
• Permanent visual loss

Key Clinical Pearls

• Lyme disease is caused by Borrelia burgdorferi and transmitted by Ixodes ticks.
• The classic early manifestation is erythema migrans, but not every patient recalls a rash or tick bite.
• Ocular involvement is diverse and may include conjunctivitis, uveitis, cranial nerve palsies, keratitis, optic neuritis, and retinitis.
• Facial nerve palsy can produce lagophthalmos and exposure keratopathy.
• Diagnosis relies on clinical context plus appropriate serologic testing.
• In neuro-ophthalmic disease, consider neuroborreliosis and coordinate treatment with infectious disease or neurology.
• Always consider alternative diagnoses such as syphilis, cat-scratch disease, toxoplasmosis, and acute retinal necrosis when posterior segment or optic nerve findings are present.

Ophthalmology – Lowe Syndrome

Basics

Description

Lowe syndrome, also called oculocerebrorenal syndrome of Lowe, is a rare multisystem disorder affecting primarily the eyes, nervous system, and kidneys.

The classic clinical pattern includes congenital ocular abnormalities, neurologic dysfunction, and proximal renal tubular disease.

Epidemiology

Lowe syndrome is very rare.

It almost exclusively affects males because it is usually inherited in an X-linked recessive pattern.

Genetics

Lowe syndrome is caused by pathogenic variants in the OCRL gene on chromosome Xq24–26.

The OCRL protein is an inositol polyphosphate 5-phosphatase involved in phosphoinositide metabolism and intracellular membrane trafficking.

Approximately one-third of affected males may have a de novo mutation, meaning there is no previous family history.

Rare affected females have been described, usually because of unusual X-chromosome abnormalities or highly skewed X-inactivation.

Inheritance

Because the disease is X-linked recessive, a female carrier has, with each pregnancy:

• A 25% chance of having an affected son
• A 25% chance of having an unaffected son
• A 25% chance of having a carrier daughter
• A 25% chance of having a noncarrier daughter

Genetic counseling is therefore important for affected families.

Pathophysiology

Loss of normal OCRL function causes abnormal phosphoinositide metabolism.

This disrupts several cellular processes, including:

• Membrane trafficking
• Endocytosis
• Cytoskeletal organization
• Maintenance of tight and adherens junctions
• Protein transport

These abnormalities contribute to the ocular, neurologic, and renal manifestations.

Ocular Pathophysiology

Cataract

Congenital cataracts are thought to result from abnormal development and migration of lens epithelial cells.

The cataracts are usually:

• Bilateral
• Dense
• Present at birth

They may involve the posterior lens and can severely impair visual development if untreated.

Glaucoma

Infantile glaucoma is associated with goniodysgenesis, meaning abnormal development of the anterior chamber angle.

This can cause elevated intraocular pressure early in life.

Commonly Associated Ocular Conditions

Important ocular manifestations include:

• Congenital cataract
• Infantile glaucoma
• Conjunctival or corneal keloid-like lesions
• Late retinal dystrophy
• Amblyopia
• Reduced vision

Neurologic Manifestations

Neurologic abnormalities commonly include:

• Generalized hypotonia
• Reduced or absent deep tendon reflexes
• Poor suck reflex in infancy
• Developmental delay
• Intellectual disability
• Behavioral disturbances
• Seizures

Hypotonia can be pronounced during infancy.

Renal Manifestations

The characteristic renal abnormality is proximal renal tubular dysfunction, often resembling Fanconi syndrome.

Findings may include:

• Proteinuria
• Proximal renal tubular acidosis
• Phosphate wasting
• Aminoaciduria
• Hypercalciuria
• Potassium disturbances
• Progressive renal impairment

Renal disease contributes substantially to systemic morbidity.

Skeletal Complications

Renal phosphate loss can result in:

• Renal rickets
• Osteomalacia
• Pathologic fractures
• Growth failure

Hypercalciuria can cause:

• Nephrocalcinosis
• Nephrolithiasis

Other Associated Conditions

Additional systemic findings can include:

• Cryptorchidism
• Failure to thrive
• Characteristic facial appearance
• Recurrent respiratory or gastrointestinal infections

Diagnosis

History

Important clues include:

• Family history of an X-linked disorder
• Congenital or early visual impairment
• Cataract noted in infancy
• Signs of infantile glaucoma
• Failure to thrive
• Developmental delay
• Hypotonia
• Seizures
• Renal abnormalities

Ocular Symptoms

Infants with glaucoma may develop:

• Photophobia
• Excessive tearing
• Corneal clouding
• Enlarged globe or buphthalmos

Congenital cataract may cause poor fixation or reduced visual responsiveness.

Physical Examination

General Examination

Children may demonstrate:

• Hypotonia
• Poor growth
• Developmental delay
• Characteristic facies
• Prominent or elongated forehead
• Fair complexion

Height, weight, and head circumference should be tracked carefully.

Ophthalmic Examination

A full examination should evaluate for:

• Congenital cataract
• Corneal clarity
• Corneal diameter
• Intraocular pressure
• Anterior chamber angle abnormalities
• Optic nerve damage
• Conjunctival or corneal keloids
• Retinal disease

Examination under anesthesia may be required in infants or uncooperative young children.

Carrier Females

Female carriers may show characteristic lens abnormalities despite being otherwise clinically unaffected.

These may include:

• Multiple fine punctate lens opacities
• Radially distributed or wedge-shaped lens changes
• Posterior lens opacities in some cases

Careful slit-lamp examination of the mother may therefore provide a useful diagnostic clue.

Diagnostic Tests

Laboratory Studies

Important investigations include:

• Renal function tests
• Serum electrolytes
• Urinalysis
• Urinary amino acids
• Assessment of acid-base status

These help characterize the degree of proximal tubular dysfunction.

Genetic Testing

Molecular testing for an OCRL mutation confirms the diagnosis in most cases.

Genetic testing also assists with:

• Carrier identification
• Family counseling
• Prenatal counseling

Neuroimaging

Brain MRI may show:

• Mild ventriculomegaly
• Periventricular cystic changes
• Other white-matter abnormalities

These findings may remain relatively stable over time.

Ophthalmic Imaging

If the fundus cannot be visualized because of dense cataract, B-scan ultrasonography may be helpful.

Optic nerve photography can assist with long-term glaucoma monitoring.

Pathological Findings

Lens abnormalities may include:

• Small discoid cataracts
• Posterior lenticonus
• Abnormal fetal nuclear development
• Capsular abnormalities

Anterior chamber pathology may demonstrate:

• Immature angle structures
• Anterior displacement of rudimentary ciliary processes

Retinal abnormalities can include:

• Peripheral cystoid degeneration
• Retinal folds
• Vascular hyalinization
• Mild gliosis

Differential Diagnosis

Important differential diagnoses include:

• Congenital rubella
• Peroxisomal disorders
• Mitochondrial disorders
• Other congenital cataract syndromes
• Other disorders combining developmental delay and renal disease

The combination of congenital cataract + infantile glaucoma + proximal renal tubular dysfunction strongly supports Lowe syndrome.

Treatment

Treatment is multidisciplinary and directed at the individual manifestations.

Cataract Management

Congenital cataracts often require early cataract surgery to prevent profound deprivation amblyopia.

After surgery, visual rehabilitation may require:

• Aphakic spectacles
• Contact lenses
• Intraocular lens implantation in selected patients
• Amblyopia therapy

Timing depends on age, cataract density, and overall clinical status.

Glaucoma Management

Infantile glaucoma may require:

• Medical IOP-lowering treatment initially
• Surgical treatment when angle abnormalities are significant

Common initial surgical procedures include:

• Goniotomy
• Trabeculotomy

Long-term monitoring is essential because glaucoma can cause irreversible optic nerve injury.

Amblyopia

Amblyopia should be treated aggressively when present.

Management may include:

• Optical correction
• Patching
• Penalization
• Early visual rehabilitation

Visual development should be monitored closely.

Low-Vision Rehabilitation

Children with residual visual impairment may benefit from:

• Low-vision assessment
• Educational accommodations
• Magnification devices
• Developmental visual support

Renal Treatment

Renal management may include:

• Sodium bicarbonate
• Sodium or potassium citrate
• Phosphate replacement
• Vitamin D supplementation

Treatment is individualized according to the child’s biochemical abnormalities.

The goal is to maintain appropriate:

• Calcium
• Phosphate
• Acid-base balance
• Parathyroid hormone levels

Renal Failure

Progressive renal insufficiency can eventually require:

• Dialysis
• Renal transplantation

Management should be coordinated with pediatric nephrology.

Neurologic Treatment

Treatment may include:

• Antiseizure medications
• Developmental therapy
• Physical therapy
• Occupational therapy
• Speech therapy

Behavioral problems may require psychological or psychiatric management.

Referral

Patients typically require coordinated care involving:

• Pediatric ophthalmology
• Glaucoma specialist
• Medical genetics
• Nephrology
• Neurology
• Developmental pediatrics
• Physical therapy
• Occupational therapy
• Speech therapy
• Psychology or psychiatry

Surgical referral may also be needed for cryptorchidism.

Follow-Up

Regular ophthalmic follow-up is required for:

• Cataract management
• Glaucoma surveillance
• Optic nerve monitoring
• Amblyopia treatment
• Retinal dystrophy
• Visual development

Systemic monitoring should include:

• Renal function
• Growth
• Electrolytes
• Bone health
• Development
• Seizure control

Diet

Dietary recommendations are primarily determined by the degree of renal tubular dysfunction.

Patients may require individualized management of:

• Phosphate
• Sodium
• Potassium
• Calcium
• Fluid intake

A pediatric nephrologist or dietitian should guide these adjustments.

Patient Education

Families should understand that Lowe syndrome is a chronic multisystem genetic disorder requiring lifelong coordinated care.

Genetic counseling is particularly important for:

• Mothers
• Sisters
• Other potentially affected female relatives

Families should also be educated about:

• Seizures
• Renal complications
• Glaucoma symptoms
• Visual rehabilitation
• Developmental services

Prognosis

Prognosis varies according to the severity of renal, neurologic, and respiratory involvement.

Historically, life expectancy has been reduced, with major causes of mortality including:

• Progressive renal disease
• Respiratory complications
• Seizures
• Severe infections

Some patients survive well into adulthood with modern multidisciplinary care.

Visual Prognosis

Visual outcome depends primarily on:

• Timing of cataract treatment
• Severity and control of glaucoma
• Development of amblyopia
• Presence of retinal dystrophy

Early cataract and glaucoma treatment can produce meaningful visual benefit.

Later retinal dystrophy can limit long-term visual potential.

Complications

Major complications include:

• Congenital cataract
• Amblyopia
• Infantile glaucoma
• Optic nerve damage
• Retinal dystrophy
• Developmental delay
• Seizures
• Renal insufficiency
• Rickets and fractures
• Nephrocalcinosis
• Respiratory complications

Key clinical pearl: Lowe syndrome should be suspected in a male infant with bilateral congenital cataracts, infantile glaucoma, severe hypotonia/developmental delay, and proximal renal tubular dysfunction. Examination of the mother for characteristic punctate lens opacities can provide an additional clue to the X-linked carrier state.