Ophthalmology – Hypotony

Basics

Description

Ocular hypotony refers to abnormally low intraocular pressure (IOP). A commonly used statistical definition is an IOP below approximately 6–6.5 mmHg.

However, the clinically important concept is clinically significant hypotony, in which the pressure is low enough to produce structural changes in the eye or reduced vision.

Transient hypotony is relatively common after glaucoma surgery, procedures involving the pars plana, and ocular trauma. Chronic hypotony is less common but may produce serious complications such as hypotony maculopathy, choroidal detachment, corneal decompensation, and eventually phthisis bulbi.

Epidemiology

Transient postoperative hypotony is relatively common following trabeculectomy and other glaucoma operations, particularly when antifibrotic agents such as mitomycin-C are used.

It may also occur after vitreoretinal surgery, trauma, inflammatory ocular disease, or procedures that reduce aqueous production.

Hypotony following uncomplicated cataract surgery is uncommon.

Chronic hypotony severe enough to produce phthisis is relatively rare and generally occurs in eyes with substantial underlying damage.

Risk Factors

Risk factors include:

• Young age
• Male sex
• Myopia
• Low scleral rigidity
• Uveitis
• Previous glaucoma surgery
• Use of potent antifibrotic agents
• Ocular trauma
• Cyclodialysis
• Ciliary body dysfunction

Highly myopic eyes may be particularly susceptible to hypotony maculopathy because their sclera is more deformable.

General Prevention

Prevention is particularly important after glaucoma surgery.

During trabeculectomy, excessive filtration can be reduced by:

• Limiting the concentration and duration of antimetabolite exposure
• Using adequate scleral-flap sutures
• Employing releasable or adjustable sutures where appropriate
• Avoiding excessive filtration in high-risk eyes

With glaucoma drainage devices, flow may be reduced by using a valved implant or temporarily ligating a nonvalved tube.

Leaving the anterior chamber formed with viscoelastic at the end of surgery can also decrease immediate postoperative chamber shallowing.

Prompt control of postoperative inflammation helps prevent ciliary body shutdown and persistent hypotony.

Pathophysiology

Hypotony occurs when aqueous humor production is insufficient relative to aqueous outflow.

The problem can therefore result from either:

1. Excessive outflow, or
2. Reduced aqueous production.

Excessive Aqueous Outflow

Excessive outflow occurs with conditions such as:

• Wound leak
• Overfiltering trabeculectomy bleb
• Excessive drainage through a tube shunt
• Cyclodialysis cleft
• Occult scleral or corneal perforation

A cyclodialysis cleft creates an abnormal communication between the anterior chamber and the suprachoroidal space, allowing aqueous to bypass the normal outflow pathways.

Reduced Aqueous Production

Aqueous production decreases when the ciliary body is dysfunctional.

Causes include:

• Uveitis or iridocyclitis
• Ciliary body detachment
• Traction on the ciliary body
• Ocular ischemia
• Retinal detachment
• Cyclodestructive procedures
• Severe trauma
• Pharmacologic aqueous suppression

Inflammation increases permeability of the blood-aqueous barrier and can directly suppress ciliary body function.

Choroidal Effusion Cycle

At very low IOP, conventional aqueous outflow decreases because IOP approaches or falls below episcleral venous pressure.

Uveoscleral flow then becomes relatively more important.

Fluid may accumulate in the suprachoroidal space, producing choroidal effusion.

Anterior choroidal detachment can rotate the ciliary body forward and further impair aqueous production, creating a self-perpetuating cycle:

Hypotony → choroidal detachment → ciliary body dysfunction → more hypotony.

Etiology

Unilateral Hypotony

Common unilateral causes include:

• Postoperative wound leak
• Overfiltering bleb
• Tube-shunt overdrainage
• Cyclodialysis cleft
• Uveitis
• Ocular trauma
• Retinal detachment
• Ocular ischemia
• Scleral perforation
• Ciliary body destruction
• Excessive aqueous suppressant medication

Bilateral Hypotony

Bilateral hypotony is much less common.

Possible causes include:

• Severe dehydration
• Systemic acidosis
• Uremia
• Poorly controlled metabolic disease
• Hyperosmotic therapy
• Certain neuromuscular disorders such as myotonic dystrophy

Commonly Associated Conditions

A particularly important association is ocular trauma with occult globe-wall injury or cyclodialysis.

Hypotony also commonly occurs in association with:

• Uveitis
• Glaucoma surgery
• Retinal detachment
• Ciliary body damage
• Choroidal effusion
• Suprachoroidal hemorrhage

Diagnosis

History

Ask specifically about:

• Recent ocular surgery
• Glaucoma surgery
• Use of mitomycin-C or other antifibrotic agents
• Recent trauma
• Ocular inflammation
• Previous retinal surgery
• Glaucoma medications
• Symptoms suggestive of retinal detachment

Patients may complain of:

• Blurred vision
• Distorted vision
• Deep ocular aching
• Photophobia
• Reduced vision after surgery

Pain is particularly concerning when associated with choroidal hemorrhage, which may cause severe ocular pain.

Physical Examination

The examination should include visual acuity, IOP, slit-lamp examination, anterior chamber depth, fundus examination, and evaluation for wound leakage.

Important findings include:

• Low IOP
• Positive Seidel test
• Large or excessively elevated filtering bleb
• Shallow or flat anterior chamber
• Corneal folds
• Corneal edema
• Peripheral anterior synechiae
• Anterior chamber inflammation
• Cyclodialysis cleft
• Choroidal detachment
• Retinal folds
• Optic disc edema
• Retinal detachment

Seidel Test

A positive Seidel test demonstrates aqueous leakage through a corneal, limbal, or conjunctival wound.

Fluorescein is placed over the suspected leakage site. Clear aqueous diluting the fluorescein produces a visible streaming pattern.

A positive Seidel test after ocular surgery strongly suggests a wound or bleb leak.

Shallow Anterior Chamber

Hypotony may cause the anterior chamber to become shallow because the globe loses internal support.

A very shallow or flat chamber increases the risk of:

• Iris-cornea touch
• Lens-cornea touch
• Peripheral anterior synechiae
• Corneal endothelial damage
• Cataract formation

A flat chamber therefore requires prompt attention.

Ciliochoroidal Detachment

Low IOP can lead to accumulation of fluid in the suprachoroidal space.

Choroidal detachments may be:

• Serous
• Hemorrhagic

Serous detachments are often smooth and dome shaped.

Large detachments may approach or touch centrally and are sometimes referred to as kissing choroidals.

Hypotony Maculopathy

Hypotony maculopathy is one of the most important causes of visual loss in chronic hypotony.

Reduced pressure allows inward collapse and deformation of the posterior scleral wall.

This produces:

• Chorioretinal folds
• Macular striae
• Retinal vascular tortuosity
• Optic disc swelling
• Distortion of the foveal architecture

Patients may complain of reduced or distorted central vision.

Young, myopic patients are particularly susceptible because of greater scleral elasticity.

Diagnostic Tests and Interpretation

Laboratory Testing

Hypotony is usually diagnosed primarily through history and examination, rather than laboratory testing.

When recurrent or unexplained uveitis is present, systemic inflammatory evaluation may be indicated.

In bilateral hypotony, laboratory tests may include:

• Blood glucose
• BUN
• Creatinine
• Electrolytes
• Assessment of hydration and acid-base status

B-Scan Ultrasonography

B-scan ultrasonography is particularly useful when the fundus cannot be adequately visualized.

It can identify:

• Choroidal detachment
• Suprachoroidal hemorrhage
• Retinal detachment
• Vitreous abnormalities

Ultrasound Biomicroscopy

UBM is especially useful for evaluating the anterior segment and ciliary body.

It may demonstrate:

• Cyclodialysis cleft
• Ciliary body detachment
• Anterior choroidal effusion
• Abnormal ciliary body position

Anterior Segment OCT

Anterior-segment OCT can help evaluate:

• Anterior chamber depth
• Wound architecture
• Bleb anatomy
• Selected cyclodialysis clefts

Macular OCT

Posterior-segment OCT is very useful in suspected hypotony maculopathy.

It may show:

• Chorioretinal folds
• Macular thickening
• Intraretinal fluid
• Cystoid changes
• Distortion of retinal layers

Subtle folds may be much easier to recognize on OCT than by ophthalmoscopy alone.

Fluorescein Angiography

Fluorescein angiography may demonstrate characteristic alternating linear areas of hyperfluorescence and hypofluorescence associated with chorioretinal folds.

It is rarely essential but can help in subtle cases.

Pathological Findings

Chronic hypotony may cause changes involving multiple ocular structures.

These include:

• Corneal folds and decompensation
• Accelerated cataract formation
• Choroidal effusion
• Choroidal folds
• Retinal pigment epithelial disturbance
• Cystoid macular edema
• Optic disc swelling
• Progressive structural collapse of the globe in severe cases

Differential Diagnosis

Important differential diagnoses include:

• Idiopathic chorioretinal folds
• Choroidal detachment from another cause
• Postoperative endophthalmitis
• Posterior scleritis
• Uveitis
• Hyphema
• Corneoscleral laceration
• Rhegmatogenous retinal detachment
• Tractional retinal detachment
• Postoperative retinal detachment

Treatment

Treatment is directed primarily at the underlying cause of the low pressure.

The goal is not simply to increase IOP numerically, but to restore enough pressure and ocular anatomy to prevent structural and visual damage.

Medication

Corticosteroids

When hypotony results from ciliary body inflammation, corticosteroids may restore aqueous production by suppressing inflammation.

Depending on severity, treatment may include:

• Topical corticosteroids
• Periocular corticosteroids
• Systemic corticosteroids
• Other immunosuppressive therapy for chronic uveitis

Cycloplegics

Atropine or other cycloplegic agents can be useful.

Cycloplegia:

• Relaxes the ciliary muscle
• Deepens the anterior chamber
• Reduces iris-cornea contact
• Helps stabilize the blood-aqueous barrier
• Reduces discomfort from ciliary spasm

Viscoelastic Injection

Injection of ophthalmic viscoelastic into the anterior chamber can temporarily:

• Reform a shallow or flat chamber
• Increase IOP
• Protect the corneal endothelium
• Separate the iris and lens from the cornea

This is generally a temporizing measure, and the underlying cause must still be corrected.

General Measures

Patients should avoid:

• Heavy lifting
• Bending
• Straining
• Vigorous exercise
• Direct pressure on the eye

These precautions are particularly important when choroidal detachments are present because sudden changes in pressure may increase the risk of suprachoroidal hemorrhage.

An eye shield may be useful, especially during sleep.

Good hydration should be maintained unless medically contraindicated.

Treatment of Wound or Bleb Leak

Small leaks with a well-formed anterior chamber may sometimes be managed conservatively.

Options include:

• Reduced manipulation
• Protective measures
• Large-diameter bandage contact lens
• Modification of topical medications

A persistent focal leak may occasionally be sealed with tissue adhesive.

Large leaks associated with marked hypotony or a shallow chamber usually require surgical repair.

Overfiltering Trabeculectomy

When excessive filtration is responsible, management may include:

• Adjustment or placement of scleral-flap sutures
• Compression sutures
• Bleb revision
• Conjunctival advancement
• Autograft or patch graft when tissue is markedly thin

Persistent hypotony with maculopathy generally warrants more aggressive correction.

Tube-Shunt Overdrainage

When a tube shunt causes excessive drainage, options include:

• Temporary tube ligation
• Intraluminal stenting
• Tube revision

The objective is to reduce outflow while preserving long-term glaucoma control.

Cyclodialysis Cleft

Small cyclodialysis clefts may occasionally close spontaneously, especially with cycloplegic therapy.

Persistent clefts can be treated with:

• Laser photocoagulation
• Cryotherapy
• Transscleral treatment
• Direct surgical cyclopexy

Definitive closure reconnects the ciliary body to the scleral spur and reduces abnormal uveoscleral outflow.

Choroidal Detachment

Small serous choroidal detachments often improve when the underlying hypotony is corrected.

Management may include:

• Cycloplegia
• Corticosteroids
• Correction of wound leak or overfiltration

Surgical drainage is considered when detachments are:

• Large
• Persistent
• Associated with a flat anterior chamber
• Kissing centrally
• Accompanied by severe pain or hemorrhage
• Preventing recovery of ocular anatomy

Flat Anterior Chamber

A flat chamber associated with iris or lens-cornea touch can rapidly damage the corneal endothelium.

Prompt management may include:

• Cycloplegia
• Viscoelastic chamber reformation
• Correction of wound leak
• Tightening of the filtration site
• Drainage of significant choroidal effusion when necessary

Chronic Uveitic Hypotony

Chronic inflammatory hypotony can be particularly difficult to treat.

Aggressive anti-inflammatory therapy is essential.

When a cyclitic membrane is pulling on the ciliary body, surgical removal of the membrane may restore ciliary body anatomy and aqueous production.

Selected refractory eyes may benefit from:

• Pars plana vitrectomy
• Membrane removal
• Silicone oil tamponade

Inpatient Considerations

Most cases can be treated as an outpatient.

Hospitalization may become appropriate if severe associated disease is present, such as:

• Major ocular trauma
• Suprachoroidal hemorrhage
• Severe postoperative complications
• Systemic disease requiring inpatient management

Follow-Up

Follow-up frequency depends on severity.

Patients with:

• Wound leakage
• Flat or markedly shallow anterior chamber
• Large choroidal detachments
• Rapid visual decline

may need examination every few days or more frequently until stable.

Patients wearing a therapeutic bandage contact lens require monitoring for infectious keratitis and are commonly given prophylactic topical antibiotic coverage.

Patient Monitoring

Monitoring should include:

• Visual acuity
• IOP
• Anterior chamber depth
• Seidel testing
• Corneal condition
• Choroidal detachment
• Macular anatomy on OCT
• Optic nerve appearance

Visual recovery may lag behind normalization of IOP because macular folds and retinal distortion can take time to resolve.

Diet and Hydration

Patients should maintain adequate oral hydration unless restricted for another medical reason.

Avoidance of constipation and Valsalva may also be useful in patients with severe hypotony and choroidal detachment.

Patient Education

Patients should understand that low eye pressure is not always harmless.

They should be warned to report:

• Increasing pain
• Sudden decrease in vision
• New distortion
• Increasing redness
• New flashes or floaters

Patients should also understand that restoration of normal IOP does not always produce immediate visual recovery.

Prognosis

The prognosis depends primarily on:

• Cause
• Duration
• Severity
• Presence of hypotony maculopathy
• Associated retinal or choroidal disease
• Speed of correction

Transient postoperative hypotony often resolves without permanent damage.

Chronic hypotony can produce progressive structural changes and irreversible visual loss.

Earlier correction of hypotony maculopathy generally provides a better chance of restoring macular anatomy and vision.

Complications

Potential complications include:

• Hypotony maculopathy
• Chorioretinal folds
• Corneal edema and decompensation
• Peripheral anterior synechiae
• Cataract
• Cystoid macular edema
• Choroidal detachment
• Retinal detachment
• Suprachoroidal hemorrhage
• Optic disc edema
• Permanent visual loss

Severe persistent hypotony may ultimately result in pre-phthisis or phthisis bulbi, with progressive shrinkage and loss of function of the eye.

Ophthalmology – Hyphema

Basics

Description

Hyphema is the presence of blood within the anterior chamber of the eye. The blood may appear as suspended red blood cells, a layered collection, or a clot.

Most cases follow ocular trauma, but hyphema may also occur after intraocular surgery, laser procedures, neovascularization, tumors, inflammation, or bleeding disorders.

Because a hyphema can be associated with other serious ocular injuries, the first priority is always to exclude open-globe injury and intraocular foreign body.

General Prevention

Prevention centers on the use of appropriate protective eyewear, especially during sports, occupational activities, and situations involving high-velocity objects.

Polycarbonate protective lenses are particularly useful for patients at increased risk of recurrent ocular trauma.

Pathophysiology

Hyphema results from bleeding from anterior-segment structures.

In traumatic cases, the mechanism commonly involves tearing of vessels in the:

• Iris
• Ciliary body
• Anterior chamber angle

Associated injuries may include:

• Iris sphincter tears
• Iridodialysis
• Cyclodialysis
• Angle recession

Blood then accumulates within the aqueous-filled anterior chamber.

Red blood cells can obstruct the trabecular meshwork and produce elevated intraocular pressure.

Etiology

The most common cause is blunt ocular trauma.

Other causes include:

• Penetrating trauma
• Intraocular surgery
• Laser procedures
• Iris or angle neovascularization
• Intraocular tumors
• Uveitis
• Coagulopathy
• Anticoagulant or antiplatelet therapy
• Hemoglobinopathies such as sickle cell disease

Commonly Associated Conditions

Hyphema may be associated with:

• Open-globe injury
• Lens dislocation
• Traumatic cataract
• Angle recession
• Iridodialysis
• Cyclodialysis
• Vitreous hemorrhage
• Retinal tears or detachment
• Choroidal rupture
• Traumatic optic neuropathy
• Coagulopathies
• Intraocular neoplasms
• Neovascular glaucoma

Diagnosis

History

When trauma is suspected, obtain a careful description of the mechanism.

Important details include:

• Type of object
• Size and shape
• Velocity
• Direction of impact
• Exact site of impact
• Use of protective eyewear
• Time since injury

A high-velocity projectile raises concern for an intraocular foreign body, while blunt trauma from a fist or ball may produce extensive angle and iris injury despite an intact globe.

Ask specifically about:

• Anticoagulant or antiplatelet medication
• Bleeding disorders
• Sickle cell disease or trait
• Previous ocular surgery
• Previous trauma
• Prior glaucoma

Physical Examination

The initial examination should first determine whether the globe is intact.

If open globe is suspected, avoid unnecessary manipulation or pressure on the eye.

When safe, establish baseline:

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

On slit-lamp examination, blood may appear:

• Suspended diffusely in the anterior chamber
• Layered inferiorly
• Clotted
• As a nearly total or total hyphema

Grading

A practical clinical grading system is based on the proportion of the anterior chamber filled with blood.

Microhyphema: circulating red blood cells without a visible layered collection.

Grade I: less than one-third of the anterior chamber filled.

Grade II: one-third to one-half filled.

Grade III: more than one-half but less than total.

Grade IV: total hyphema.

A completely dark or black total hyphema may indicate prolonged blood stasis and is sometimes called an eight-ball hyphema.

Diagnostic Tests and Interpretation

Visual Acuity

Visual acuity should be documented at presentation and during follow-up.

Reduction in vision may result from the blood itself, corneal edema, lens injury, retinal injury, or optic nerve damage.

Intraocular Pressure

IOP must be monitored carefully.

Pressure can rise when red blood cells, inflammatory debris, or clotted blood obstruct the trabecular meshwork.

Pressure elevation may occur immediately or several days after the initial injury.

Measurement of Hyphema

The height or proportion of layered blood should be documented at each visit.

Serial measurement allows assessment of:

• Resolution
• Enlargement
• Rebleeding

Laboratory Testing

Laboratory investigations depend on the clinical situation.

Consider:

• CBC
• Platelet count
• Coagulation studies
• Hemoglobin electrophoresis when appropriate

Patients at risk for sickle cell disease or sickle cell trait require particular attention because even modest IOP elevation may be more dangerous to the optic nerve and certain pressure-lowering medications may promote sickling.

Imaging

CT

If orbital fracture or intraocular foreign body is suspected, CT of the orbits is generally the preferred initial imaging study.

MRI should not be performed until a metallic intraocular foreign body has been excluded.

Ultrasound

B-scan ultrasonography can evaluate the posterior segment when the fundus cannot be visualized.

However, it should be used with extreme caution or deferred if an open globe is suspected.

Ultrasound Biomicroscopy

UBM may be useful later to evaluate:

• Angle anatomy
• Cyclodialysis
• Ciliary body abnormalities
• Lens position

Differential Diagnosis

The main diagnostic task is usually to determine the cause and associated injuries rather than to distinguish hyphema from many mimics.

Conditions that may resemble or accompany hyphema include:

• Anterior chamber inflammatory cells
• Pigment dispersion
• Hypopyon
• Iris neovascularization
• Intraocular tumor
• Uveitis-glaucoma-hyphema syndrome

Treatment

Management aims to:

• Protect the eye
• Prevent rebleeding
• Control inflammation
• Control intraocular pressure
• Prevent corneal blood staining
• Detect associated ocular injuries

General Measures

The patient should wear a rigid protective eye shield.

The head should be elevated, generally about 30–45 degrees, including during sleep, so that blood settles inferiorly and the visual axis remains relatively clear.

Activity should be restricted.

Avoid:

• Heavy lifting
• Bending
• Strenuous exercise
• Contact sports
• Activities associated with Valsalva

A pressure patch should generally be avoided because the patient should be able to detect changes in vision and because pressure on a traumatized globe is undesirable.

Pain and Nausea Control

Acetaminophen is usually preferred for pain.

Avoid aspirin and NSAIDs when possible because of their antiplatelet effects and potential to increase rebleeding.

Nausea and vomiting should be treated promptly with antiemetics because vomiting increases venous pressure and may promote rebleeding.

Stool softeners may be useful if straining is anticipated.

Topical Corticosteroids

Topical corticosteroids such as prednisolone acetate 1% are often used to reduce traumatic anterior chamber inflammation.

Frequency depends on the severity of inflammation.

If a significant corneal epithelial defect or abrasion is present, corticosteroid use should be individualized because steroids can delay epithelial healing and increase infection risk.

Cycloplegic Therapy

Cycloplegic agents reduce ciliary spasm, pain, and iris movement.

Common options include:

• Atropine
• Homatropine
• Cyclopentolate

Cycloplegia may also reduce the risk of posterior synechiae when significant inflammation is present.

Intraocular Pressure Elevation

IOP management depends on:

• Magnitude of pressure elevation
• Duration
• Optic nerve status
• Presence of sickle cell disease or trait

Beta-Blockers

Topical beta-blockers are commonly used as first-line pressure-lowering agents when not systemically contraindicated.

Alpha-2 Agonists

Agents such as brimonidine may be used selectively, with attention to age and systemic side effects.

Carbonic Anhydrase Inhibitors

Topical or systemic carbonic anhydrase inhibitors may be useful in many patients.

However, particular caution is required in sickle cell disease or trait, because systemic acidosis and changes in aqueous chemistry may worsen sickling.

Prostaglandin Analogs

These are often avoided in the acute inflammatory phase because of concern for exacerbating inflammation.

Sickle Cell Disease and Trait

Sickle cell patients deserve special consideration.

Sickling of red blood cells within the relatively hypoxic and acidic anterior chamber can obstruct aqueous outflow and produce marked IOP elevation.

Optic nerve and retinal ischemia may occur at pressures that would be better tolerated by other patients.

Therefore:

• Lower IOP thresholds for intervention may be appropriate.
• Carbonic anhydrase inhibitors and hyperosmotic agents require careful selection.
• Hematology consultation may be helpful.
• Surgical evacuation may be considered earlier.

Rebleeding

One of the most important complications is secondary hemorrhage, typically occurring several days after the original injury as the initial clot retracts and damaged vessels reopen.

Rebleeding can produce:

• Larger hyphema
• Higher IOP
• Greater risk of corneal blood staining
• Worse visual outcome

Close follow-up during the first several days is therefore important.

Antifibrinolytic Therapy

Agents such as aminocaproic acid were historically used to reduce rebleeding.

They are used much less commonly today because of side effects and limited routine benefit, but may occasionally be considered in selected high-risk patients.

Corneal Blood Staining

Corneal blood staining is a serious complication in which hemoglobin and iron products from lysed red blood cells enter the corneal stroma.

Risk is increased by:

• Large or total hyphema
• Prolonged hyphema
• Elevated intraocular pressure
• Corneal endothelial dysfunction

Early staining may appear yellowish.

Persistent blood staining can take months or longer to clear and may permanently affect vision.

Surgery

Anterior chamber washout may be required when medical management is insufficient.

Potential indications include:

• Persistently uncontrolled IOP
• Total or near-total hyphema that does not clear
• Corneal blood staining or high risk of staining
• Persistent large hyphema
• Earlier intervention in selected patients with sickle cell disease or trait

The exact threshold depends on the patient’s age, IOP, optic nerve status, size and duration of the hyphema, and systemic risk factors.

Anterior Chamber Washout

Surgical evacuation is performed carefully using irrigation and aspiration techniques.

The goal is to remove blood while minimizing:

• Iris trauma
• Lens injury
• Further disruption of clot
• Rebleeding

Inpatient Considerations

Most uncomplicated hyphemas can be managed as outpatients if the patient can comply with restrictions and return promptly for follow-up.

Admission may be considered for:

• Poor compliance
• Children in whom activity restriction is difficult
• Severe hyphema
• Uncontrolled IOP
• Rebleeding
• Sickle cell disease
• Monocular patients
• Associated major ocular injuries

Initial Stabilization

The initial priorities are:

1. Exclude open globe and intraocular foreign body.
2. Document visual acuity and pupillary function.
3. Measure IOP only if globe integrity is secure.
4. Perform slit-lamp examination.
5. Examine the retina when safely possible.
6. Protect the eye with a shield.
7. Treat significant pressure elevation and inflammation.

Follow-Up

Patients require close observation until the hyphema resolves and IOP remains stable.

Early follow-up is especially important because the risk of rebleeding and pressure elevation is greatest during the first several days.

The examination should monitor:

• Visual acuity
• Hyphema size
• IOP
• Corneal clarity
• Rebleeding
• Anterior chamber inflammation

Gonioscopy

After the acute injury has resolved, gonioscopy should be performed to evaluate for angle recession.

Gonioscopy is generally delayed until the eye is stable so that manipulation does not provoke rebleeding.

Angle-Recession Glaucoma

Blunt trauma can split the ciliary body face and widen the anterior chamber angle.

This angle recession can predispose to glaucoma months, years, or even decades later.

Therefore, patients with significant traumatic hyphema require long-term IOP surveillance.

Patient Education

Patients should be instructed to:

• Keep the protective shield in place as directed
• Sleep with the head elevated
• Avoid strenuous activity
• Avoid aspirin and NSAIDs unless medically essential
• Take prescribed drops exactly as directed
• Return immediately for increased pain or decreased vision

Patients should understand that apparent improvement does not eliminate the risk of delayed rebleeding or pressure elevation.

Prognosis

Most uncomplicated traumatic hyphemas resolve with good visual recovery.

Prognosis depends largely on the presence of associated injuries rather than on the hyphema alone.

Poorer outcomes are associated with:

• Open-globe injury
• Retinal damage
• Optic nerve injury
• Recurrent bleeding
• Persistent elevated IOP
• Corneal blood staining
• Severe angle recession

Complications

Important complications include:

• Rebleeding
• Elevated intraocular pressure
• Secondary glaucoma
• Angle-recession glaucoma
• Peripheral anterior synechiae
• Posterior synechiae
• Corneal blood staining
• Optic nerve damage
• Amblyopia in children
• Permanent visual loss from associated ocular trauma

The most important long-term issue after a traumatic hyphema is the possibility of delayed angle-recession glaucoma, which is why periodic lifelong ophthalmic surveillance may be appropriate after significant injury.

TRACHOMA

BASICS

Description

• Trachoma is a chronic follicular conjunctivitis caused by Chlamydia trachomatis.
• Repeated ocular infection, particularly during childhood, produces chronic inflammation and progressive conjunctival scarring that can ultimately cause entropion, trichiasis, corneal damage, and blindness.
• In non-endemic areas, genital strains of C. trachomatis may be transmitted from the genital tract to the eye, producing inclusion conjunctivitis.
• Active infection is predominantly a disease of young children, whereas the consequences of repeated infection—scarring, trichiasis, and blindness—are mainly seen in adults.

EPIDEMIOLOGY

• Trachoma is associated particularly with poor, remote, rural communities where there is inadequate sanitation and limited access to clean water.
• Historically, hyperendemic regions have included parts of Africa, Asia, Central and South America, Australia, and the Middle East.
• Transmission occurs from the ocular and nasal secretions of infected individuals through:
• Hands and close personal contact
• Shared towels or other fomites
• Eye-seeking flies
• Transmission is particularly intense among young children and their caregivers.
• Boys and girls are affected approximately equally during childhood.
• In adulthood, women may be affected 2–6 times more frequently, largely because of repeated exposure while caring for infected children.
• Trachoma has historically affected tens of millions of people and is an important infectious cause of preventable blindness.

RISK FACTORS

The major risk factor is residence in a trachoma-endemic community.

Important environmental and social risk factors include:

• Overcrowding
• Poor facial and personal hygiene
• Limited availability of clean water
• Inadequate sanitation
• High density of flies
• Poor disposal of human and animal feces
• Close proximity to livestock
• Dry, dusty environments
• Recurrent bacterial or viral conjunctivitis
• Repeated exposure to infected children

Ocular infection with genital C. trachomatis strains is particularly associated with sexually active adolescents and young adults and produces inclusion conjunctivitis.

GENERAL PREVENTION

Prevention depends heavily on reducing transmission within affected communities.

Important measures include:

• Daily facial washing, particularly in children
• Improved personal hygiene
• Reliable access to clean water
• Proper latrine use
• Appropriate disposal of human and animal feces
• Refuse disposal
• Reduction of fly populations
• Health education
• Reduction of overcrowding where possible

Community health workers and school teachers can reinforce these measures in endemic areas.

PATHOPHYSIOLOGY

C. trachomatis has a predilection for conjunctival epithelial cells.

Repeated infections cause recurrent conjunctival inflammation. Over many years:

Repeated infection → chronic conjunctivitis → conjunctival fibrosis → eyelid deformity → entropion → trichiasis → corneal trauma → ulceration/scarring → blindness

Entropion

The eyelid turns inward.

Trichiasis

The eyelashes turn inward and repeatedly rub against the cornea.

Continued mechanical trauma produces:

• Corneal epithelial abrasion
• Ulceration
• Inflammation
• Superficial vascularization
• Corneal pannus
• Corneal haze
• Scarring
• Permanent visual impairment or blindness

ETIOLOGY

The causative organism is Chlamydia trachomatis, an obligate intracellular bacterium.

Serovars

• A, B, Ba, C → endemic trachoma
• D–K → genital chlamydial infection and inclusion conjunctivitis

A useful distinction is:

A–C = trachoma

D–K = genital/inclusion conjunctivitis

DIAGNOSIS

History

Endemic trachoma and inclusion conjunctivitis may initially present as mild conjunctivitis.

Many patients are asymptomatic. Others may develop:

• Ocular irritation
• Conjunctival inflammation
• Mucopurulent discharge
• Dry eyes
• Eyelid abnormalities
• Foreign-body sensation from trichiasis
• Progressive visual impairment

Longstanding trachoma may produce ocular dryness secondary to damage to the lacrimal ducts and lacrimal gland.

In adults, important historical clues include:

• Current or previous residence in an endemic area
• Recurrent conjunctivitis
• Progressive eyelid changes
• Inward-growing eyelashes
• Visual complaints

Neonatal chlamydial conjunctivitis

Neonatal disease tends to have a more acute onset and can produce profuse mucopurulent discharge.

PHYSICAL EXAMINATION

In endemic areas, trachoma is principally a clinical diagnosis.

The upper eyelid should be everted, and the upper tarsal conjunctiva and cornea carefully examined under adequate illumination and magnification.

Active disease

Children characteristically develop follicles on the upper tarsal conjunctiva.

These follicles represent focal collections of inflammatory tissue.

Chronic cicatricial disease

Repeated inflammation leads to conjunctival fibrosis and scarring.

Important classic findings include:

Arlt’s line

A horizontal line of conjunctival scarring along the superior palpebral/tarsal conjunctiva.

Herbert’s pits

Small limbal depressions produced by healed trachomatous follicles.

Corneal pannus

Superficial corneal inflammation accompanied by leukocytic infiltration and neovascularization.

Progression may therefore be:

Follicles → conjunctival scarring → Arlt’s line → entropion/trichiasis → pannus → corneal opacity → blindness

INCLUSION CONJUNCTIVITIS

Inclusion conjunctivitis caused by genital strains of C. trachomatis may produce:

• Conjunctivitis
• Follicular inflammation
• Discrete corneal infiltrates
• Punctate epithelial erosions
• Mild superficial corneal vascularization

A considerable proportion of affected adults have a concomitant genital chlamydial infection, even though many have no genital symptoms.

Therefore, affected patients and their sexual partners should be evaluated and systemically treated when indicated.

Failure to treat sexual partners increases the risk of reinfection and recurrent ocular disease.

DIAGNOSTIC TESTS AND INTERPRETATION

Trachoma is commonly diagnosed clinically in endemic regions, but laboratory testing can demonstrate C. trachomatis.

Diagnostic methods include:

• Giemsa-stained conjunctival smears
• Immunofluorescent staining
• Cell culture
• DNA-based testing
• Nucleic-acid amplification techniques

Detection of the organism provides definitive evidence of infection.

DIFFERENTIAL DIAGNOSIS

Other causes of conjunctivitis should be considered, including:

• Viral conjunctivitis
• Other bacterial conjunctivitis
• Parasitic infection
• Fungal infection

Important causes of neonatal conjunctivitis include:

• Chlamydia trachomatis
• Neisseria gonorrhoeae
• Haemophilus influenzae
• Streptococcus pneumoniae
• Herpes simplex virus

TREATMENT

First Line

Azithromycin

The source describes:

Azithromycin 20 mg/kg orally as a single dose

as the treatment of choice for active trachoma.

Systemic treatment is particularly useful because it treats both ocular infection and infection at extraocular sites.

Neonatal Chlamydial Conjunctivitis

Neonates require systemic antimicrobial therapy, rather than topical treatment alone.

This is important because concomitant nasopharyngeal chlamydial infection is common and untreated infection may subsequently produce chlamydial pneumonia.

Alternative Therapy

Topical tetracycline

The source describes:

Tetracycline ophthalmic ointment 1% twice daily for at least 6 weeks

or intermittent courses for 5 consecutive days each month for 6 months.

Other systemic alternatives

The source also lists:

• Doxycycline 100 mg PO twice daily for 21 days
• Tetracycline 250 mg PO four times daily for 14 days

Tetracyclines should be avoided when contraindicated, including in young children.

COMMUNITY TREATMENT

Individual therapy alone is insufficient in highly endemic communities because patients are repeatedly exposed to infected household and community contacts.

Mass antibiotic administration has therefore been used to reduce the community reservoir of infection.

The source describes community-wide treatment when active disease is sufficiently prevalent among children, followed by repeated treatment and subsequent reassessment.

WHO SAFE STRATEGY

The central public-health approach to trachoma control is easily remembered as SAFE:

S — Surgery

Surgery for trachomatous trichiasis/in-turned eyelids.

A — Antibiotics

Antimicrobial therapy, particularly oral azithromycin, to eliminate active C. trachomatis infection.

F — Facial cleanliness

Regular face washing, especially in young children, to reduce ocular and nasal secretions and transmission.

E — Environmental improvement

Measures include:

• Improved access to safe water
• Better sanitation
• Proper disposal of human and animal feces
• Latrine use
• Fly control
• Improved environmental hygiene

Thus:

SAFE = Surgery + Antibiotics + Facial cleanliness + Environmental improvement

SURGERY / OTHER PROCEDURES

Antibiotics eradicate active infection but cannot reverse established cicatricial eyelid deformity.

Patients with trichiasis therefore require corrective surgery.

Bilamellar tarsal rotation

Bilamellar tarsal rotation is an important surgical procedure for trachomatous trichiasis.

The operation redirects the eyelashes away from the cornea, reducing continuing corneal trauma and helping preserve vision.

Access to surgery may be limited in endemic regions because of:

• Lack of patient awareness
• Limited availability of trained personnel
• Cost
• Transportation difficulties
• Insufficient healthcare resources

ONGOING CARE

Follow-Up Recommendations

Patients require monitoring for:

• Recurrent active infection
• Persistent or recurrent trichiasis
• Progressive conjunctival scarring
• Corneal ulceration
• Corneal opacity
• Visual deterioration

Old trachoma may occasionally relapse, including after inappropriate use of topical corticosteroids.

PATIENT MONITORING

In communities undergoing mass antibiotic treatment, children should be reassessed clinically after completion of the community treatment program.

The source describes reassessment after approximately 3 years.

When prevalence has fallen sufficiently, management may transition from mass community treatment toward treatment of affected individuals and their household contacts.

PATIENT EDUCATION

Community education should emphasize:

• Regular facial washing
• Keeping children’s faces clean
• Fly control
• Adequate use of available water
• Latrine use
• Proper waste disposal
• Reducing exposure to animal and human feces
• Environmental sanitation

Patients with trichiasis should be educated about the benefits of corrective eyelid surgery before irreversible corneal damage occurs.

GENITAL INFECTION AND PARTNER MANAGEMENT

A substantial proportion of adults with chlamydial inclusion conjunctivitis have simultaneous genital chlamydial infection.

Importantly, many have no genital symptoms.

Patients with inclusion conjunctivitis should therefore undergo appropriate evaluation for genital infection.

Their sexual partners should also be evaluated and treated when indicated.

This is important because failure to treat the partner creates a reservoir for reinfection.

Untreated partner → reinfection → recurrent inclusion conjunctivitis

PROGNOSIS

The prognosis is generally good when infection is recognized and treated early.

The major determinant of long-term visual outcome is the cumulative burden of repeated infection and inflammation.

Repeated episodes progressively increase the risk of:

Scarring → entropion → trichiasis → corneal injury → irreversible blindness

Thus, preventing reinfection is as important as treating an individual episode.

COMPLICATIONS

The most important complications result from chronic cicatricial disease.

1. Entropion and trichiasis

Conjunctival scarring causes the eyelid to turn inward, bringing the eyelashes into contact with the cornea.

2. Corneal ulceration

Continuous eyelash abrasion damages the corneal epithelium and can produce corneal ulceration.

3. Corneal scarring and vascularization

Repeated trauma and inflammation cause:

• Corneal pannus
• Neovascularization
• Corneal opacity
• Permanent scarring

These changes can culminate in severe visual impairment or blindness.

4. Persistent inclusion conjunctivitis

Untreated inclusion conjunctivitis can persist for prolonged periods—from weeks to much longer periods.

5. Conjunctival scarring

Chronic inclusion conjunctivitis can itself produce conjunctival scarring. The source particularly associates scarring with prolonged inappropriate treatment using topical glucocorticoids.

6. Recurrent ocular infection

Recurrent inclusion conjunctivitis is especially likely when the patient’s sexual partner remains untreated.

Therefore, treatment must address both the ocular disease and the underlying genital reservoir when present.

HIGH-YIELD SUMMARY

Organism: Chlamydia trachomatis

Trachoma serovars: A, B, Ba, C

Inclusion conjunctivitis/genital serovars: D–K

Main reservoir in endemic communities: infected young children

Transmission: hands + fomites/towels + flies + ocular/nasal secretions

Characteristic active lesion: upper tarsal conjunctival follicles

Arlt’s line: linear conjunctival scar

Herbert’s pits: healed limbal follicles

Pannus: superficial corneal inflammation + neovascularization

Major mechanism of blindness:

Repeated infection → scarring → entropion → trichiasis → corneal ulceration/scarring → blindness

Treatment of active trachoma: oral azithromycin

Established trichiasis: surgery

Public-health strategy: SAFE

Surgery

Antibiotics

Facial cleanliness

Environmental improvement

Adult inclusion conjunctivitis: always think of concomitant genital chlamydia and an untreated sexual partner as a source of reinfection.

Infectious Disease and Microbiology – Toxoplasmosis

Toxoplasmosis is an infection caused by the intracellular protozoan Toxoplasma gondii. Infection is usually asymptomatic in immunocompetent people, but severe disease can occur in immunocompromised patients and in fetuses infected transplacentally during pregnancy. Symptomatic disease ranges from a mild, self-limited mononucleosis-like illness to disseminated infection involving the central nervous system, eyes, lymph nodes, skeletal or cardiac muscle, lungs, and liver.

Epidemiology

The frequency of previous exposure to T. gondii varies greatly according to geography, age, dietary practices, and environmental conditions. Seroprevalence generally increases with age.

Among people with HIV, the greatest risk of clinically significant toxoplasmosis occurs when the CD4 T-cell count falls below 100 cells/mm³, especially in patients who are seropositive and are not receiving effective antiretroviral therapy or prophylaxis.

Congenital toxoplasmosis occurs when maternal infection is transmitted across the placenta. The probability of fetal transmission generally increases as pregnancy progresses, while infection acquired earlier in pregnancy tends to cause more severe fetal disease.

Women who were infected before pregnancy and have established immunity are generally at very low risk of transmitting infection during a subsequent pregnancy unless they become severely immunocompromised.

Risk factors

Important risk factors include eating raw or undercooked meat containing tissue cysts, consuming contaminated fruits or vegetables, and exposure to soil or material contaminated with cat feces.

Cats are the definitive hosts of T. gondii and excrete environmentally resistant oocysts in their feces.

Immunosuppression is a major risk factor for reactivation, particularly advanced HIV infection, hematologic malignancy, solid-organ or hematopoietic transplantation, prolonged high-dose corticosteroid use, and treatment with other immunosuppressive agents.

Seronegative transplant recipients who receive organs from seropositive donors may acquire primary toxoplasmosis from the transplanted organ.

Prevention

People with HIV should be tested for T. gondii IgG antibodies after HIV diagnosis to determine whether they are at risk of reactivation.

Seropositive patients with CD4 counts below 100 cells/mm³ generally require primary prophylaxis.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred preventive regimen and also provides protection against Pneumocystis jirovecii pneumonia.

Alternative prophylactic options include combinations containing dapsone plus pyrimethamine and leucovorin, or atovaquone in selected patients.

Primary prophylaxis can generally be discontinued after sustained immune recovery with effective antiretroviral therapy.

High-risk transplant recipients may also receive TMP-SMX prophylaxis.

Pregnant patients who are seronegative should avoid raw or undercooked meat and unpasteurized products, wash fruits and vegetables thoroughly, wash their hands after handling raw meat or soil, and use gloves during gardening.

Cat litter should ideally be changed by another person during pregnancy. If this is not possible, gloves and careful hand hygiene should be used.

Pathophysiology

T. gondii has both sexual and asexual phases in its life cycle.

The sexual phase occurs in cats, where oocysts are produced in the intestinal tract and subsequently excreted in feces.

After oocysts sporulate in the environment, they become infectious and may remain viable for prolonged periods.

Humans and other intermediate hosts acquire infection by ingesting sporulated oocysts or tissue cysts.

After ingestion, parasites transform into rapidly replicating tachyzoites, which disseminate through the body and can infect numerous organs.

As host immunity develops, organisms persist in tissues as slowly replicating bradyzoites contained within tissue cysts, particularly in the brain, retina, skeletal muscle, and myocardium.

When cellular immunity becomes profoundly impaired, dormant tissue cysts may reactivate and produce severe disease.

Etiology

Toxoplasma gondii is an obligate intracellular protozoan.

Cats are the definitive hosts, while humans and many other mammals and birds serve as intermediate hosts.

Human infection commonly occurs through ingestion of undercooked meat containing tissue cysts, ingestion of environmentally contaminated food or water, transplacental transmission, or less commonly transplantation or transfusion.

Toxoplasmosis in immunocompetent patients

Approximately 80–90% of newly infected immunocompetent people are asymptomatic.

When symptoms occur, the most common presentation is lymphadenopathy, especially involving the cervical lymph nodes.

Patients may also experience fever, malaise, myalgias, arthralgias, sore throat, night sweats, headache, or a maculopapular rash.

The illness usually resembles infectious mononucleosis and is generally self-limited.

Rare manifestations include myocarditis, pericarditis, polymyositis, hepatitis, encephalitis, or other organ involvement.

Ocular toxoplasmosis

Toxoplasmosis is an important cause of chorioretinitis.

Many cases of ocular disease represent reactivation of congenital infection later in childhood or adulthood.

Patients may present with blurred vision, scotomas, ocular pain, photophobia, or excessive tearing.

Ophthalmologic examination typically shows yellow-white retinal lesions with surrounding inflammation, which may later develop sharply defined borders and areas of pigmentation or scarring.

Recurrences are relatively common and may progressively impair vision.

Toxoplasmosis in immunocompromised patients

In patients with advanced immunosuppression, toxoplasmosis most commonly involves the central nervous system.

CNS disease usually results from reactivation of latent infection rather than newly acquired disease.

Symptoms typically develop over days to weeks and include headache, fever, confusion, seizures, focal weakness or numbness, speech difficulty, imbalance, visual-field defects, and altered mental status.

Patients may also develop meningismus or cranial nerve abnormalities.

Extracerebral disease is less common but may involve the lungs, eyes, heart, gastrointestinal tract, liver, skin, or multiple organs simultaneously.

Pulmonary toxoplasmosis

Toxoplasmic pneumonitis may cause fever, progressive dyspnea, dry cough, and hypoxemia.

Pulmonary disease can resemble Pneumocystis jirovecii pneumonia, bacterial pneumonia, or other opportunistic pulmonary infections.

Congenital toxoplasmosis

Congenital infection has a highly variable presentation.

Some infected infants are asymptomatic at birth but develop complications months or years later.

Premature infants are more likely to present with severe neurologic or ocular disease, whereas full-term infants may initially have milder findings such as hepatosplenomegaly or lymphadenopathy.

Important manifestations include chorioretinitis, hydrocephalus, intracranial calcifications, seizures, developmental impairment, and hearing or visual abnormalities.

Physical examination

Patients with CNS toxoplasmosis may demonstrate focal motor or sensory deficits, cranial nerve abnormalities, visual-field defects, cerebellar signs, altered mental status, or meningismus.

In immunocompetent patients, lymph nodes are usually discrete, non-tender, non-suppurative, and less than approximately 3 cm in diameter.

Hepatomegaly may occasionally occur.

Patients with ocular disease require a detailed ophthalmologic examination because retinal lesions may be multiple and vision-threatening.

Diagnosis

Diagnosis is based on the combination of clinical presentation, immune status, serologic findings, and imaging, with direct demonstration of the organism in tissue providing definitive confirmation.

Serology

T. gondii-specific IgG and IgM antibodies are commonly used in the initial evaluation.

IgG generally indicates previous exposure, while IgM may suggest recent infection, although interpretation can be complicated by prolonged persistence or false-positive results.

In immunocompromised patients, antibody responses may be weak or absent, so negative serology does not completely exclude disease.

For an HIV-positive patient with typical brain lesions, however, a negative IgG makes reactivated toxoplasmosis substantially less likely.

PCR and direct detection

PCR may detect T. gondii DNA in CSF, amniotic fluid, blood, bronchoalveolar lavage fluid, or tissue specimens.

PCR can be particularly useful in congenital infection and selected immunocompromised patients, although sensitivity varies with specimen type and disease burden.

Tachyzoites may occasionally be identified directly in body fluids or tissues using cytologic stains or immunofluorescence.

Cerebrospinal fluid

CSF findings in CNS toxoplasmosis are usually nonspecific.

Patients may have mild lymphocytic pleocytosis and elevated protein, but CSF can also be nearly normal.

Neuroimaging

Brain MRI is more sensitive than CT and is preferred when CNS toxoplasmosis is suspected.

Typical findings are multiple ring-enhancing lesions surrounded by edema, commonly involving the basal ganglia, thalamus, corticomedullary junction, or other deep structures.

Although multiple lesions are characteristic, a solitary lesion can occur.

MRI findings must be interpreted in the clinical context because similar abnormalities may occur with primary CNS lymphoma, bacterial abscess, tuberculosis, fungal infection, or other opportunistic diseases.

Diagnosis of congenital disease

Prenatal diagnosis may use PCR of amniotic fluid, together with maternal serologic testing and fetal ultrasonography.

Fetal imaging may demonstrate ventriculomegaly, intracranial calcifications, hydrocephalus, or other abnormalities in severe cases.

Newborn evaluation includes serology, neurologic examination, ophthalmologic assessment, and appropriate imaging.

Brain biopsy

In patients with advanced HIV and typical CNS lesions, empiric treatment is commonly started before brain biopsy.

Biopsy should be considered when lesions are atypical, the patient deteriorates rapidly, or there is no convincing clinical or radiographic improvement after an appropriate therapeutic trial.

Histopathology may demonstrate tachyzoites and tissue cysts.

Differential diagnosis

In immunocompetent patients with lymphadenopathy, the differential diagnosis includes Epstein-Barr virus infection, cytomegalovirus infection, acute HIV infection, lymphoma, and other causes of lymphadenopathy.

In immunocompromised patients with focal CNS lesions, important alternatives include primary CNS lymphoma, cryptococcosis, tuberculosis or nontuberculous mycobacterial disease, bacterial brain abscess, fungal infection, and progressive multifocal leukoencephalopathy.

Ocular disease must be differentiated from other infectious and inflammatory causes of retinitis and chorioretinitis.

Treatment

Most asymptomatic immunocompetent patients do not require specific antiparasitic therapy.

Treatment is indicated for severe or persistent disease, ocular involvement threatening vision, CNS disease, pulmonary or disseminated infection, congenital infection, and disease occurring in immunocompromised patients.

First-line therapy

Traditional first-line treatment for severe toxoplasmosis consists of pyrimethamine plus sulfadiazine plus leucovorin (folinic acid).

Pyrimethamine inhibits folate metabolism in the parasite but can also cause significant bone marrow toxicity.

For this reason, leucovorin must always be administered with pyrimethamine to reduce hematologic toxicity.

Acute treatment of CNS toxoplasmosis typically continues for at least six weeks, with longer therapy when disease is extensive or response is incomplete.

Alternative therapy

TMP-SMX is an effective alternative regimen and is commonly used in many clinical settings.

Other alternatives include pyrimethamine plus clindamycin with leucovorin, or selected regimens incorporating atovaquone.

Choice of therapy depends on disease severity, drug tolerance, allergies, interactions, pregnancy status, and immune function.

Empiric treatment of CNS disease

In a patient with advanced HIV infection, positive Toxoplasma IgG, and typical ring-enhancing brain lesions, an empiric therapeutic trial is reasonable.

Clinical improvement is often evident within approximately one to two weeks.

Failure to improve should prompt reconsideration of the diagnosis and often brain biopsy or additional diagnostic testing.

Treatment during pregnancy

Management of acute maternal toxoplasmosis depends on gestational age and whether fetal infection has been demonstrated.

Spiramycin has historically been used to reduce fetal transmission when maternal infection is diagnosed but fetal infection has not been confirmed.

When fetal infection is established, regimens containing pyrimethamine, sulfadiazine, and leucovorin may be used later in pregnancy under specialist supervision.

Because treatment recommendations in pregnancy are highly specialized, management should involve maternal-fetal medicine and infectious-disease specialists.

Congenital toxoplasmosis

Infants with congenital toxoplasmosis require prolonged antiparasitic therapy, generally using combinations of pyrimethamine, sulfadiazine, and leucovorin.

Close ophthalmologic, neurologic, auditory, developmental, and laboratory follow-up is essential.

Corticosteroids

Corticosteroids are not routinely required.

They may be considered in selected patients with severe CNS mass effect or impending herniation, or in ocular toxoplasmosis with vision-threatening inflammation.

Steroids should only be used together with appropriate antiparasitic therapy because immunosuppression without treatment can worsen infection.

Secondary prophylaxis

Patients with HIV who recover from CNS toxoplasmosis require chronic maintenance therapy to prevent relapse.

Maintenance commonly uses lower-dose combinations of the same active agents used during induction.

Secondary prophylaxis can generally be discontinued after sustained immune reconstitution on antiretroviral therapy, typically when the CD4 count has remained above 200 cells/mm³ for an adequate period and the patient is clinically stable.

Monitoring

Patients receiving pyrimethamine require regular complete blood counts because bone marrow suppression can occur.

Sulfadiazine may cause rash, gastrointestinal intolerance, hepatitis, leukopenia, renal injury, or crystalluria, so renal function and other laboratory parameters should be monitored.

Patients with CNS disease should undergo repeated neurologic examinations and follow-up imaging to document improvement.

Newborns with congenital disease require repeated ophthalmologic examinations because ocular lesions may emerge or recur long after birth.

Prognosis

Most immunocompetent patients recover completely without treatment.

Patients with HIV-associated CNS toxoplasmosis usually improve substantially when therapy is started promptly and immune function is restored with effective antiretroviral treatment.

A lack of improvement after approximately 7–14 days of appropriate therapy should prompt reconsideration of the diagnosis.

Congenital disease has a variable prognosis depending on the timing and severity of fetal infection.

Ocular toxoplasmosis may relapse and can produce cumulative retinal damage.

Complications

Ocular toxoplasmosis may cause permanent central vision loss, retinal scarring, strabismus, or nystagmus.

CNS disease can cause seizures, persistent focal neurologic deficits, altered cognition, cerebral edema, and death when untreated.

Congenital infection may result in chorioretinitis, hydrocephalus, intracranial calcification, developmental impairment, seizures, and long-term visual or neurologic disability.

Disseminated toxoplasmosis in severely immunocompromised patients may lead to respiratory failure, myocarditis, hepatitis, multiorgan failure, and death.

High-Yield Pattern

Advanced HIV + CD4 <100 + multiple ring-enhancing brain lesions → strongly consider cerebral toxoplasmosis

Basal ganglia lesions + positive Toxoplasma IgG + focal neurologic deficits → classic CNS toxoplasmosis pattern

First-line severe disease → pyrimethamine + sulfadiazine + leucovorin

Leucovorin must accompany pyrimethamine to reduce bone marrow toxicity

No improvement after 1–2 weeks of appropriate empiric CNS therapy → reconsider diagnosis and evaluate for brain biopsy

Pregnancy → risk of fetal transmission rises with gestational age, but earlier fetal infection is generally more severe

Prevention → thoroughly cook meat, wash produce, avoid contaminated soil or cat feces, and provide prophylaxis to high-risk immunocompromised patients

Infectious Disease and Microbiology – Toxic shock syndrome

Toxic shock syndrome (TSS) is a severe toxin-mediated illness caused mainly by Staphylococcus aureus or Streptococcus pyogenes. It typically presents with abrupt fever, hypotension, diffuse erythematous rash, and rapidly progressive multiorgan dysfunction. Gastrointestinal symptoms, severe myalgias, mucosal hyperemia, renal or hepatic dysfunction, thrombocytopenia, and altered mental status may occur, while desquamation of the palms and soles often develops during convalescence.

Epidemiology

Staphylococcal TSS is uncommon, with an estimated incidence of roughly 1–3 cases per 100,000 people, whereas streptococcal TSS is also rare but generally carries a higher mortality.

Approximately half of staphylococcal TSS cases have historically occurred in menstruating women using tampons, although nonmenstrual disease occurs in people of all ages and sexes.

Streptococcal TSS most often accompanies invasive soft-tissue infection, particularly necrotizing fasciitis, myonecrosis, or severe cellulitis.

Risk factors

Important risk factors for staphylococcal TSS include tampon use, barrier contraceptive devices, postpartum infection, septic abortion, gynecologic procedures, surgical wounds, burns, nasal packing, skin infections, bacteremia, and musculoskeletal infections.

Risk factors for streptococcal TSS include minor trauma, open wounds, surgery, varicella, invasive group A streptococcal infection, and close contact with a person who has invasive streptococcal disease.

Pathophysiology

TSS is caused by bacterial toxins that act as superantigens.

These toxins bypass conventional antigen processing and directly activate large populations of T lymphocytes, producing massive release of inflammatory cytokines such as tumor necrosis factor, interleukin-1, and interleukin-6.

The resulting cytokine surge causes high fever, profound vasodilation, capillary leakage, hypotension, shock, and tissue injury.

In menstrual staphylococcal TSS, tampons can provide a local environment that promotes colonization and toxin production by S. aureus.

Etiology

Most cases of staphylococcal TSS are associated with S. aureus strains producing toxic shock syndrome toxin-1 (TSST-1).

Other staphylococcal enterotoxins can occasionally produce a similar syndrome.

For disease to develop, the patient generally must be colonized or infected with a toxigenic strain and lack sufficient neutralizing antibodies against its toxin.

Streptococcal TSS is caused by invasive Streptococcus pyogenes infection, with production of streptococcal pyrogenic exotoxins and other virulence factors.

Clinical presentation

TSS develops rapidly over hours to a few days.

Patients usually present with high fever, hypotension, diffuse erythematous rash, vomiting, diarrhea, severe myalgia, weakness, and signs of multiorgan involvement.

Shock can progress rapidly and may require substantial fluid resuscitation and vasopressor support.

Staphylococcal toxic shock syndrome

The classic presentation includes a temperature of at least approximately 38.9°C, diffuse macular erythroderma, and hypotension.

At least several organ systems are usually involved.

Gastrointestinal manifestations commonly include vomiting and diarrhea at the onset of illness.

Muscle involvement is characterized by severe myalgia or elevated creatine kinase.

Mucosal involvement can produce conjunctival, oral, pharyngeal, or vaginal hyperemia.

Renal involvement may present with elevated creatinine or pyuria, while hepatic involvement causes elevated bilirubin or aminotransferases.

Thrombocytopenia is common.

Neurologic manifestations may include confusion or disorientation without focal neurologic signs.

A diffuse “sunburn-like” rash is characteristic, followed approximately one to two weeks later by desquamation, particularly of the palms and soles.

An obvious focus of infection is often absent in staphylococcal TSS.

Streptococcal toxic shock syndrome

Streptococcal TSS is usually associated with a clear invasive focus such as necrotizing fasciitis, myositis, cellulitis, or another deep soft-tissue infection.

Diagnosis is supported by identification of group A streptococcus from a sterile or clinically relevant site together with hypotension and evidence of multiorgan dysfunction.

Organ involvement may include acute kidney injury, coagulopathy or DIC, hepatic injury, acute respiratory distress syndrome, generalized erythematous rash, and soft-tissue necrosis.

Bacteremia occurs much more frequently in streptococcal TSS than in staphylococcal TSS.

Physical examination

The most prominent finding in staphylococcal TSS is often a diffuse erythematous macular rash.

Desquamation is a delayed finding and usually does not help with the earliest diagnosis.

In menstruating patients with possible TSS, a gynecologic examination is important, and any tampon or vaginal foreign body should be removed immediately.

Patients with streptococcal TSS should be carefully examined for a source of invasive infection, including painful swollen soft tissues, bullae, skin discoloration, crepitus, rapidly spreading erythema, or pain out of proportion to visible findings.

Laboratory findings

Laboratory abnormalities reflect systemic inflammation and multiorgan injury.

Common findings include leukocytosis or leukopenia with a left shift, thrombocytopenia, azotemia, elevated creatine kinase, hypoalbuminemia, hypocalcemia, hypophosphatemia, pyuria, elevated liver enzymes, and metabolic abnormalities associated with shock.

Blood cultures should be obtained in all suspected cases to evaluate for bacteremia and alternative causes such as meningococcemia or gram-negative sepsis.

Blood cultures are often negative in staphylococcal TSS but are positive in a substantial proportion of streptococcal TSS cases.

Cultures should also be obtained from any suspected wound, soft-tissue infection, vaginal source, surgical site, or other focus.

Differential diagnosis

Important alternatives include meningococcemia, severe gram-negative sepsis, Rocky Mountain spotted fever, leptospirosis, measles, Kawasaki disease, heat stroke, severe drug reactions, and other causes of distributive shock with rash.

Necrotizing soft-tissue infection must be considered particularly when the patient has severe focal pain, rapidly progressive swelling, tissue necrosis, or crepitus.

Initial treatment

TSS is a medical emergency requiring immediate resuscitation, broad antimicrobial therapy, and urgent source control.

Treatment should not be delayed while waiting for definitive culture results.

Staphylococcal TSS treatment

Empiric treatment should cover MRSA and suppress toxin production.

A typical initial regimen includes vancomycin plus clindamycin.

Clindamycin is especially valuable because it suppresses bacterial protein synthesis and therefore decreases toxin production.

If cultures identify methicillin-susceptible S. aureus, therapy can be narrowed to an antistaphylococcal β-lactam such as nafcillin or oxacillin, while continuing clindamycin during the acute toxin-mediated phase.

Linezolid is another potential toxin-suppressing anti-MRSA agent in selected cases.

Streptococcal TSS treatment

The preferred regimen is high-dose intravenous penicillin G plus clindamycin.

Penicillin provides potent bactericidal activity against group A streptococcus, while clindamycin reduces toxin synthesis and remains active even when bacterial burden is high.

Antimicrobial treatment is subsequently adjusted according to microbiology, clinical response, and the extent of associated infection.

Source control

Source control is essential and should occur as early as possible.

Any tampon, vaginal device, nasal packing, infected catheter, or other foreign material should be removed.

Abscesses should be drained.

Patients with necrotizing fasciitis or myonecrosis require immediate surgical exploration and aggressive debridement, often with repeated operations.

Delay in surgical treatment of invasive streptococcal infection significantly worsens outcome.

Hemodynamic support

Most patients require admission to the intensive care unit.

Large-volume isotonic intravenous fluid resuscitation is frequently necessary because profound capillary leakage and vasodilation can cause severe intravascular depletion.

If hypotension persists despite fluids, vasopressors are required.

Respiratory support, including mechanical ventilation, may be necessary in patients with ARDS or severe shock.

Intravenous immunoglobulin

IVIG may be considered in severe streptococcal TSS, particularly when shock or invasive soft-tissue disease is refractory to standard therapy.

Its proposed benefit comes from neutralization of circulating exotoxins and superantigens.

Evidence is less certain for staphylococcal TSS, although IVIG may occasionally be considered in exceptionally severe cases.

Routine corticosteroid treatment is not established for TSS.

In-patient considerations

Patients with suspected TSS should be treated in the ICU because deterioration can occur rapidly.

Continuous monitoring of blood pressure, urine output, oxygenation, renal function, hepatic function, platelet count, coagulation parameters, and metabolic status is required.

Discharge is appropriate only after the patient is afebrile, hemodynamically stable without vasopressors, clinically improving, and no longer requires intensive supportive therapy.

Follow-up

Patients recovering from staphylococcal TSS may benefit from evaluation for S. aureus colonization.

In selected patients with persistent nasal carriage, intranasal mupirocin and other decolonization measures may be considered.

Staphylococcal TSS can recur, particularly when the patient remains colonized with a toxin-producing strain and does not develop protective antibodies.

Women who have experienced menstrual TSS should generally avoid tampons and certain intravaginal barrier contraceptive devices, particularly if the risk of recurrence remains high.

Household contacts of patients with invasive streptococcal TSS do not routinely require prophylaxis, although prophylaxis may be considered for particularly vulnerable close contacts such as older adults or those with significant immunocompromise.

Prognosis

Staphylococcal TSS generally has a lower mortality than streptococcal TSS when recognized and treated promptly.

Most deaths occur early and are related to refractory shock and multiorgan failure.

Streptococcal TSS has a substantially worse prognosis because it is often accompanied by bacteremia and destructive invasive soft-tissue infection.

Complications

TSS can cause profound shock with secondary injury to virtually every organ system.

Major complications include acute respiratory distress syndrome, acute kidney injury, disseminated intravascular coagulation, hepatic dysfunction, encephalopathy, myocardial dysfunction, ischemic injury, and multiorgan failure.

Severe invasive streptococcal disease can additionally result in extensive tissue necrosis, limb loss, and death.

High-Yield Pattern

Fever + diffuse sunburn-like rash + hypotension + multiorgan dysfunction → suspect toxic shock syndrome

Menstruating patient using tampon + shock + erythroderma → strongly consider staphylococcal TSS

Severe soft-tissue pain + hypotension + organ failure → suspect streptococcal TSS and necrotizing infection

Staphylococcal TSS → vancomycin + clindamycin initially

Streptococcal TSS → penicillin G + clindamycin

Any TSS → immediate source control + aggressive fluids + vasopressors when needed

Necrotizing soft-tissue infection → urgent surgical exploration and debridement

Click here to start customizing

Infectious Disease and Microbiology – Thrombophlebitis

Suppurative, or septic, thrombophlebitis is an infectious inflammation of a vein accompanied by thrombus formation and bacteremia. It may involve superficial veins, central veins including pelvic veins, intracranial venous structures, or the portal venous system.

Septic thrombophlebitis occasionally complicates central venous catheter-associated bloodstream infection, including infections related to peripherally inserted central catheters (PICC lines).

Epidemiology

Superficial suppurative thrombophlebitis is an important healthcare-associated infection and is usually related to skin and soft-tissue infection or an indwelling intravenous catheter.

Risk increases when peripheral intravenous catheters remain in place for prolonged periods, particularly for three days or longer.

Lower-extremity intravenous catheters are associated with a greater risk than upper-extremity cannulation.

Patients with extensive burns are particularly vulnerable, followed by those with malignancy or receiving systemic corticosteroids.

Septic pelvic thrombophlebitis is uncommon but is primarily associated with pregnancy, cesarean delivery, gynecologic surgery, or septic abortion.

Pelvic septic thrombophlebitis generally develops approximately one to two weeks after delivery or pelvic surgery.

Risk factors

Important risk factors for septic pelvic thrombophlebitis include cesarean delivery, pregnancy, pelvic infection, induced abortion, pelvic surgery, uterine fibroids, malignancy, and hormonal stimulation.

For catheter-associated disease, prolonged venous cannulation, burns, immunosuppression, malignancy, and contamination of the catheter or infusion system increase the likelihood of infection.

Prevention

Avoiding unnecessary venous catheterization and using meticulous sterile technique are fundamental preventive measures.

When possible, lower-extremity peripheral cannulation should be avoided, particularly in patients at increased risk of bloodstream infection.

Catheter insertion sites should be managed using appropriate skin antisepsis and aseptic technique, and unnecessary intravascular catheters should be removed promptly.

Antimicrobial-impregnated central venous catheters may be considered in selected patients or units with persistently high catheter-related infection rates despite strict adherence to standard infection-control practices.

Maximal sterile barrier precautions during central venous catheter insertion remain an important component of prevention.

Pathophysiology

Septic thrombophlebitis develops when a venous thrombus becomes infected, creating a protected nidus in which microorganisms can persist despite the host immune response.

Microorganisms may reach the vein by migration from the skin along a catheter tract, contamination of intravenous fluids or catheter equipment, or hematogenous spread from another infected focus.

The infected thrombus can continuously release organisms into the bloodstream, resulting in persistent or recurrent bacteremia.

Septic pelvic thrombophlebitis

Pelvic thrombophlebitis commonly affects the ovarian veins or inferior vena cava.

Pregnancy and the postpartum state promote venous thrombosis through venous stasis and physiologic hypercoagulability.

Bacteria from vaginal or perineal flora may subsequently infect the thrombus.

Common organisms include Bacteroides species, streptococci, and Enterobacteriaceae such as Escherichia coli.

Portal vein septic thrombophlebitis

Infection and thrombosis of the portal venous system, sometimes called pylephlebitis, may develop secondary to intra-abdominal infection.

It can be associated with hepatic abscesses, although an obvious extrahepatic source is not always found.

Intracranial suppurative thrombophlebitis

Intracranial septic thrombophlebitis may involve cerebral veins or the major dural venous sinuses.

It may occur after infections involving the paranasal sinuses, middle ear, mastoid, facial skin, or oropharynx.

It can also complicate epidural abscess, subdural empyema, bacterial meningitis, or hematogenous dissemination from a distant infectious focus.

Cavernous sinus thrombosis

Septic cavernous sinus thrombosis most commonly develops after paranasal sinusitis or infections involving the face, nose, teeth, or oral cavity.

Staphylococcus aureus is the most important pathogen and is responsible for the majority of septic cavernous sinus thrombosis cases.

Other possible organisms include streptococci, pneumococci, gram-negative bacilli, and anaerobes such as Bacteroides.

In immunocompromised patients or in the appropriate clinical setting, invasive fungi including Aspergillus, Mucor, and Rhizopus should also be considered.

Etiology of superficial disease

The most commonly isolated pathogen in superficial suppurative thrombophlebitis is Staphylococcus aureus.

Other organisms include coagulase-negative staphylococci, Enterobacteriaceae, Pseudomonas aeruginosa, enterococci, and Candida species.

Anaerobic organisms are considerably less common in superficial catheter-associated infections.

Clinical presentation

Fever occurs in most patients with septic thrombophlebitis, although shaking chills or rigors may be absent.

Patients with infection of the large central thoracic veins often present primarily with bacteremia or sepsis and may have few or no local findings.

Persistent bloodstream infection despite appropriate antimicrobial therapy should raise suspicion for an infected intravascular thrombus.

Superficial thrombophlebitis

Superficial septic thrombophlebitis usually produces recognizable local findings.

The affected vein may demonstrate erythema, warmth, tenderness, induration, and lymphangitic spread.

Local findings may be difficult to appreciate in patients with extensive burns or severely abnormal skin.

Pelvic septic thrombophlebitis

Patients commonly present with persistent high fever, chills, anorexia, nausea, vomiting, and lower abdominal or flank discomfort.

Pelvic thrombophlebitis should be considered when postpartum or postoperative fever persists despite apparently appropriate treatment for pelvic infection.

Intracranial thrombophlebitis

Clinical manifestations vary according to the affected venous structure and extent of intracranial involvement.

Patients may develop headache, seizures, focal neurologic deficits, altered consciousness, or manifestations of increased intracranial pressure.

Cavernous sinus thrombosis

Typical symptoms include fever, severe headache, and swelling around the eye.

Patients may also develop diplopia, photophobia, tearing, drowsiness, or changes in mental status.

Physical findings can include periorbital edema, chemosis, proptosis, ptosis, papilledema, and weakness of the extraocular muscles.

An early and particularly important neurologic sign is lateral gaze palsy, reflecting involvement of the abducens nerve.

Diagnosis

Diagnosis requires recognition of the combination of infection, venous thrombosis, and persistent bacteremia or local suppuration.

Blood cultures should be obtained before antimicrobial therapy whenever possible.

Superficial suppurative thrombophlebitis is frequently accompanied by bacteremia, making multiple blood cultures essential.

Routine laboratory studies may include a complete blood count, C-reactive protein, and erythrocyte sedimentation rate.

Persistent leukocytosis or inflammatory marker elevation can support the diagnosis but is nonspecific.

Imaging

Contrast-enhanced CT is particularly useful for detecting septic thrombosis of major central veins, pelvic veins, and the portal venous system.

CT can demonstrate venous filling defects, surrounding inflammatory changes, abscess formation, and extension of infection.

MRI, often combined with MR venography, is preferred when intracranial septic thrombophlebitis is suspected.

Venography can occasionally provide additional evidence of thrombosis in large thoracic central veins.

Catheter-associated infection

When an indwelling venous catheter is suspected as the source, the catheter should generally be removed promptly.

The catheter tip may be sent for microbiologic culture when clinically appropriate.

Persistent bacteremia after catheter removal increases concern for septic thrombosis, endocarditis, or another metastatic focus of infection.

Treatment of superficial septic thrombophlebitis

Prompt antimicrobial treatment is required because untreated disease may progress to sepsis, metastatic infection, or death.

Empiric therapy should cover S. aureus, including MRSA when appropriate.

Vancomycin is commonly used empirically when MRSA is a concern.

In burn patients, immunocompromised individuals, or patients at high risk for gram-negative infection, additional coverage against gram-negative bacilli including Pseudomonas aeruginosa may be necessary.

Antimicrobial treatment should subsequently be narrowed according to blood, catheter, or tissue culture results.

Surgical treatment

Most superficial infections respond to catheter removal and appropriate antimicrobial therapy.

Excision of the infected vein may be required if persistent bacteremia, suppuration, or sepsis continues despite adequate antibiotic therapy and source control.

Treatment of septic pelvic thrombophlebitis

Treatment requires broad-spectrum intravenous antibiotics directed against gram-negative organisms, streptococci, and anaerobes.

Appropriate regimens may include a broad-spectrum β-lactam/β-lactamase inhibitor, a carbapenem, or a cephalosporin combined with anaerobic coverage, depending on local resistance patterns and patient factors.

Anticoagulation with heparin has historically been used in some patients, but its role is not universal and should be individualized according to the clinical situation.

Treatment of intracranial septic thrombophlebitis

Intracranial disease requires urgent high-dose intravenous antimicrobial therapy covering staphylococci, streptococci, gram-negative organisms when appropriate, and anaerobes according to the suspected source.

Vancomycin should be included when MRSA is possible.

Treatment should also aggressively address the primary infectious focus, such as sinusitis, mastoiditis, dental infection, or intracranial abscess.

The role of anticoagulation in septic intracranial thrombophlebitis remains controversial and generally requires individualized assessment involving infectious disease, neurology, neurosurgery, and hematology expertise.

Follow-up

Patients with suppurative thrombophlebitis require close follow-up because relapse can occur if infected thrombus remains.

Repeat blood cultures are important to document clearance of bacteremia.

In selected severe cases, surveillance cultures after completion of therapy may be considered when recurrent bloodstream infection is a major concern.

Patients with unexplained bacteremia, particularly those with burns or recent intravenous catheterization, should have previous catheter sites and cannulated veins carefully examined.

Complications

The infected thrombus may serve as a source of continuous or intermittent bacteremia, leading to sepsis and septic shock.

Metastatic infection may produce pneumonia, septic pulmonary emboli, distant abscesses, or acute bacterial endocarditis.

Intracranial disease can produce cerebral infarction, seizures, meningitis, brain abscess, cranial nerve deficits, or increased intracranial pressure.

High-Yield Pattern

Peripheral IV site + erythema/tenderness + bacteremia → suspect superficial septic thrombophlebitis

Persistent bacteremia after catheter removal → consider septic central venous thrombosis

Postpartum fever despite antibiotics + pelvic or flank pain → consider septic pelvic thrombophlebitis

Sinus/facial infection + fever + proptosis/ophthalmoplegia → suspect septic cavernous sinus thrombosis

Diagnosis → blood cultures + contrast vascular imaging

Treatment → remove infected catheter/source + prolonged targeted IV antibiotics ± drainage or vein excision

Persistent infection despite therapy → search for endocarditis, abscess, or residual infected thrombus

Infectious Disease and Microbiology – Syphilis

Syphilis is a sexually transmitted infection caused by Treponema pallidum. The disease progresses through overlapping stages known as primary, secondary, latent, and tertiary syphilis, while neurosyphilis can occur at any stage.

Epidemiology

Syphilis occurs worldwide and remains an important sexually transmitted infection. Rates are particularly high in populations with increased sexual exposure risk, including people with multiple or anonymous partners.

Coinfection with HIV is relatively common because syphilis and HIV can facilitate the acquisition and transmission of one another.

Risk factors

Important risk factors include unprotected sexual activity, multiple sexual partners, anonymous sexual encounters, injection-drug use, and exchanging sex for money or drugs.

Prevention

Prevention is based on safer sexual practices, including appropriate use of barrier protection during vaginal, anal, and oral sexual contact.

Testing and treatment of infected individuals and their sexual partners are also essential for interrupting transmission.

Pathophysiology

Syphilis is transmitted primarily through direct contact with infectious mucocutaneous lesions, which are most commonly present during primary and secondary disease.

Transmission may occur through sexual contact, kissing, or direct contact with an infectious lesion.

After penetrating the skin or mucous membranes, T. pallidum enters the lymphatic system and bloodstream, allowing widespread dissemination throughout the body.

Vertical transmission across the placenta can cause congenital syphilis.

Transmission through blood products is possible but is now extremely uncommon.

Primary syphilis

Primary syphilis usually appears after an incubation period of approximately 2–4 weeks.

The characteristic lesion is a chancre, which begins as a small papule at the inoculation site and subsequently erodes into a firm, well-defined ulcer.

The classic chancre is painless, indurated, and nonpurulent.

It may occur on the external genitalia, anus, lips, oral cavity, breasts, fingers, or other sites exposed during transmission.

Regional lymphadenopathy may accompany the lesion.

Secondary syphilis

Secondary syphilis develops after systemic dissemination of the organism, usually several weeks after the primary lesion appears or resolves.

Patients may develop fever, malaise, headache, sore throat, weight loss, myalgias, and arthralgias.

A generalized rash occurs in most patients.

The eruption often begins as faint pink macules on the trunk and proximal extremities and later becomes more prominent and papular.

A particularly important clue is involvement of the palms and soles.

The rash is generally nonpruritic and may be macular, papular, maculopapular, or occasionally pustular.

Generalized painless lymphadenopathy is common.

Mucous patches may develop in the mouth and other mucosal surfaces.

Condylomata lata are broad, moist, flat or exophytic lesions occurring particularly in warm intertriginous or perianal regions. These lesions contain large numbers of organisms and are highly infectious.

Other manifestations may include patchy alopecia, loss of eyebrows or beard hair, hepatitis, arthritis, osteitis, periosteitis, gastrointestinal involvement, and immune-complex glomerulonephritis.

Latent syphilis

After secondary manifestations resolve, patients enter the latent stage, during which they have no clinical signs or symptoms but remain serologically positive.

Early latent disease refers to infection acquired relatively recently and carries a greater chance of relapse or transmission than late latent infection.

Late latent syphilis refers to infection of longer duration, during which sexual transmission becomes much less likely.

When the timing of infection cannot be established, the condition is classified as latent syphilis of unknown duration.

Tertiary syphilis

Tertiary disease may develop years or decades after untreated infection.

Cardiovascular manifestations include syphilitic aortitis, particularly involving the ascending aorta, which can lead to aortic aneurysm or aortic valve regurgitation.

Gummas are granulomatous destructive lesions that may involve the skin, bone, or internal organs.

Neurosyphilis

Neurosyphilis can occur during any stage of infection.

Early neurosyphilis commonly manifests as aseptic meningitis or meningovascular disease.

Patients may develop cranial nerve abnormalities, stroke-like syndromes, or spinal cord involvement.

Ocular syphilis can cause uveitis, interstitial keratitis, optic neuritis, retinal disease, or other visual abnormalities.

Otosyphilis can produce sensorineural hearing loss, tinnitus, vertigo, or disequilibrium.

Late neurologic manifestations include general paresis, characterized by progressive cognitive and behavioral deterioration, and tabes dorsalis, characterized by sensory ataxia, lightning-like pains, and impaired proprioception.

The classic Argyll Robertson pupil is small and fails to constrict normally to light but retains accommodation.

Diagnosis

Diagnosis generally requires a combination of clinical assessment and serologic testing.

Direct detection methods include dark-field microscopy, immunofluorescence, and molecular techniques such as PCR, where available.

Dark-field examination can identify T. pallidum from primary or secondary lesions but is generally unsuitable for oral lesions because nonpathogenic oral spirochetes can complicate interpretation.

Serologic testing

Serologic diagnosis usually combines a nontreponemal test with a treponemal test.

Common nontreponemal tests include RPR and VDRL.

Nontreponemal titers correlate approximately with disease activity and are therefore useful for monitoring treatment response.

False-positive nontreponemal tests can occur with pregnancy, autoimmune disease, intravenous drug use, older age, and certain infections.

Treponemal tests include assays such as FTA-ABS, TPPA, TPHA, and treponemal enzyme immunoassays.

Treponemal tests are more specific but usually remain positive for a prolonged period or for life, so their titers are not useful for assessing treatment response.

Many laboratories now use a reverse screening algorithm, beginning with a treponemal immunoassay followed by a quantitative nontreponemal test.

When the treponemal screening assay is reactive but the nontreponemal test is negative, an additional treponemal assay can help clarify whether the result represents previous treated infection, early infection, or a false-positive screening test.

Cerebrospinal fluid evaluation

Lumbar puncture may be indicated when patients have neurologic, ophthalmic, or otologic manifestations suggestive of neurosyphilis, or in selected cases of treatment failure or tertiary disease.

CSF findings may include lymphocytic pleocytosis, increased protein concentration, and a reactive CSF-VDRL.

A reactive CSF-VDRL is highly supportive of neurosyphilis, although a negative result does not completely exclude the diagnosis.

Differential diagnosis

Primary genital lesions may resemble genital herpes, chancroid, lymphogranuloma venereum, granuloma inguinale, traumatic ulcers, malignancy, or fixed drug eruptions.

Secondary syphilis can mimic many conditions, including acute HIV infection, viral exanthems, drug eruptions, erythema multiforme, scabies, fungal disease, and other systemic infections.

Because its clinical manifestations are extremely diverse, syphilis is often described as a “great imitator.”

Treatment of primary, secondary, and early latent syphilis

The traditional first-line treatment is benzathine penicillin G administered intramuscularly.

Patients with early disease generally require a single appropriately dosed injection, provided there is no evidence of neurosyphilis.

Late latent and tertiary syphilis

Late latent syphilis, syphilis of unknown duration, and tertiary syphilis without neurologic involvement generally require multiple weekly doses of benzathine penicillin G.

Neurosyphilis

Neurosyphilis requires high-dose intravenous aqueous crystalline penicillin G for an extended treatment course because adequate concentrations must be achieved in the cerebrospinal fluid.

An alternative regimen involving procaine penicillin plus probenecid may be used in selected circumstances.

Penicillin allergy

For certain nonpregnant patients with early syphilis who cannot receive penicillin, doxycycline may be used as an alternative.

Alternative regimens for late latent disease generally require a longer course than those used for early syphilis.

Macrolide therapy is unreliable because T. pallidum resistance and treatment failures have been documented.

Pregnancy

Penicillin is the only established effective treatment for syphilis during pregnancy and is essential for prevention and treatment of fetal infection.

Pregnant patients who report a penicillin allergy should generally undergo penicillin desensitization so that appropriate penicillin treatment can be administered.

Jarisch–Herxheimer reaction

A Jarisch–Herxheimer reaction may occur within the first 24 hours after starting treatment.

It is characterized by an acute onset of fever, chills, headache, myalgia, and transient worsening of symptoms caused by the inflammatory response to rapid destruction of spirochetes.

It occurs particularly often in early syphilis and should not be mistaken for penicillin allergy.

Follow-up

Sexual partners should be clinically evaluated and tested, and treated when indicated according to the timing and stage of exposure.

Partners with recent exposure to someone diagnosed with primary, secondary, or early latent syphilis may require presumptive treatment even when initial serologic testing is negative.

Treatment response is monitored using quantitative nontreponemal titers, such as RPR or VDRL.

An appropriate decline in nontreponemal titers over time supports successful therapy, whereas persistently high or increasing titers may indicate reinfection, inadequate treatment, or treatment failure.

Patients with late disease require longer-term serologic monitoring than patients with early syphilis.

Patients treated for neurosyphilis may require additional neurologic, ophthalmologic, or audiologic follow-up depending on their presenting manifestations.

Prognosis

Early diagnosis and appropriate treatment generally produce an excellent prognosis and prevent progression to late destructive disease.

Neurologic or cardiovascular damage that has already occurred in advanced syphilis may not completely reverse after antimicrobial treatment.

High-Yield Pattern

Painless indurated genital ulcer → primary syphilis

Diffuse nonpruritic rash involving palms and soles → secondary syphilis

Positive serology without symptoms → latent syphilis

Aortic disease, gummas, or late neurologic manifestations → tertiary syphilis

Neurologic, ocular, or auditory manifestations can occur at any stage → consider neurosyphilis

Diagnosis → treponemal + nontreponemal testing

Treatment → penicillin remains the cornerstone of therapy