01Approach to the Critical Patient/attcp57

Immediate priorities

›Neonatal stabilization requirements

›Airway and respiratory support

›Respiratory distress from pneumonitis or sepsis physiology

›Supplemental oxygen for SpO2 target >= 95%

›Intubation if respiratory failure present

›Circulatory status

›Hemodynamic instability from severe sepsis

›IV access and fluid resuscitation if indicated

›Neurologic emergency screen

›Seizure activity: benzodiazepine and phenobarbital as first-line

›Hydrocephalus with bulging fontanelle and sunsetting eyes

›Immediate neurosurgical consult if symptomatic hydrocephalus

›Critical alarm features

›Progressive hydrocephalus

›Rapidly increasing head circumference

›Bulging fontanelle

›Vomiting and irritability

›Severe thrombocytopenia with active bleeding

›Platelet count < 50 x10^9/L with petechiae or purpura

›Platelet transfusion if active hemorrhage

›CSF protein > 1000 mg/dL on LP

›Corticosteroids indicated: prednisone 1 mg/kg/day

›Indicates severe CNS involvement

Monitoring and targets

›Monitoring bundle for confirmed or suspected cases

›Neurologic monitoring

›Serial head circumference measurements

02History/hx56

Maternal exposure history

›Primary maternal infection markers

›Seroconversion during index pregnancy

›IgM positive with low IgG avidity confirms recent infection

›High avidity IgG argues against infection in prior 3-4 months

›Timing relative to gestational age

›First trimester: transmission ~10-15% but highest severity

›Second trimester: intermediate risk and severity

›Third trimester: transmission >60% but lower severity

›Prenatal treatment received

›Spiramycin if < 14-18 weeks and amniocentesis PCR negative

›Pyrimethamine-sulfadiazine-leucovorin if fetal infection confirmed

›Environmental and dietary exposures

›Raw or undercooked meat consumption

›Lamb, pork, venison highest risk

›Game meat handling

›Cat feces contact

›Litter box cleaning

›Gardening without gloves in contaminated soil

›Contaminated water or unwashed produce

›Travel to endemic regions: France, Brazil, parts of Africa

›Foodborne outbreak exposure

Neonatal presentation

›Symptomatic presentation features

›Classic triad when present

›Chorioretinitis

›Hydrocephalus

›Intracranial calcifications diffusely scattered

03Physical Exam/exam66

Vital signs and general appearance

›Neonatal vital sign assessment

›Temperature

›Fever suggests systemic infection

›Hypothermia may indicate severe sepsis

›Heart rate and blood pressure

›Tachycardia with hemolytic anemia or sepsis

›Hypotension in severe systemic disease

›General appearance

›Lethargy or irritability

›Poor feeding as systemic illness marker

Head and neurologic exam

›Head circumference and fontanelle

›Macrocephaly from hydrocephalus

›Serial measurement for trend

›Crossing percentiles upward on growth chart

›Microcephaly from severe early gestational infection

›Head circumference below 3rd percentile

›Associated with worse neurodevelopmental outcomes

›Anterior fontanelle tension

›Bulging indicates elevated intracranial pressure

›Sunken indicates dehydration

›Neurologic signs

›Sunsetting eyes

›Downward deviation of eyes with sclera visible above iris

›Sign of hydrocephalus with increased ICP

›Tone assessment

›Hypotonia with cortical involvement

04Differential Diagnosis/ddx47

TORCH infection differential

›Other congenital infections in the TORCH group

›Congenital CMV

›ICD-10 P35.1

›Most common congenital infection overall

›Periventricular calcifications (vs diffuse in toxoplasmosis)

›Sensorineural hearing loss prominent feature

›Congenital rubella

›ICD-10 P35.0

›Cataracts, cardiac defects (PDA), sensorineural hearing loss

›Blueberry muffin rash from dermal erythropoiesis

›Congenital syphilis

›ICD-10 A50.0

›Hepatosplenomegaly, snuffles, osteochondritis

›Positive RPR/VDRL in mother and infant

›Congenital HSV

›ICD-10 P35.2

›Vesicular skin lesions, encephalitis, DIC, liver failure

›Skin-eye-mouth form vs disseminated form vs CNS form

›Congenital Zika

›Severe microcephaly, arthrogryposis

›Subcortical calcifications, cortical malformations

›Congenital LCMV

›Hydrocephalus, chorioretinitis, periventricular calcifications

›Rodent exposure history in mother

Non-infectious mimics

›Structural and metabolic conditions

›Neonatal alloimmune thrombocytopenia

05Laboratory Tests/lt59

Serologic diagnosis

›Neonatal serology

›Toxoplasma IgM

›Positive in neonate indicates congenital infection (not passively transferred)

›Sensitivity approximately 75-90%

›IgM does not cross placenta

›Toxoplasma IgA

›Higher sensitivity than IgM for congenital infection

›Complement to IgM testing

›Produced by fetus independently

›Toxoplasma IgG

›Passively transferred maternal IgG confounds interpretation

›Declining IgG beyond 12 months suggests passive transfer only

›Persistent or rising IgG beyond 12 months confirms congenital infection

›IgG avidity testing (maternal)

›High avidity argues against infection in prior 3-4 months

›Low avidity consistent with recent primary infection

Hematologic and metabolic labs

›Complete blood count

›Thrombocytopenia

›Platelet count < 100 x10^9/L in significant disease

›Severe: < 50 x10^9/L with hemorrhagic risk

›Hemolytic anemia

›Hemoglobin and reticulocyte count

›Bilirubin elevation from hemolysis

›Weekly CBC during daily pyrimethamine dosing

›Monthly CBC when switched to thrice-weekly dosing

›Leukopenia and thrombocytopenia are pyrimethamine toxicity signs

06Diagnostic Tests/dt87

Scoring Systems

›Severity stratification framework

›Subclinical disease

›Normal exam at birth

›Identified only through serologic screening

›High risk of late sequelae (chorioretinitis, neurodevelopmental delay) without treatment

›Mild to moderate disease

›Isolated chorioretinitis without hydrocephalus

›Scattered calcifications without mass effect

›Mild hepatosplenomegaly or jaundice

›Severe disease

›Hydrocephalus with neurologic signs

›Extensive calcifications throughout parenchyma

›Microcephaly, seizures, generalized systemic involvement

›CSF protein > 1 g/L

›Prognostic scoring considerations

›National Collaborative Chicago-Based Congenital Toxoplasmosis Study findings

›12 months pyrimethamine-sulfadiazine resulted in normal cognitive, neurologic, and auditory outcomes in infants without substantial neurologic disease

›72% of infants with moderate-to-severe neurologic disease achieved normal cognitive outcomes with treatment

›Prenatal treatment effect

›RR 0.34 for infection risk with prenatal treatment

›RR 0.30 for clinical manifestations at birth

MRI

›Brain MRI indications

›Superior to CT for white matter and cortical assessment

›Periventricular white matter signal abnormalities

›Cortical dysplasia or porencephaly

›Calcification detection requires GRE or SWI sequences

›Ventriculomegaly characterization

›Aqueductal stenosis identification

›Periventricular edema

›Corpus callosum integrity

›Limitations in neonates

›Sedation required for adequate study

›Calcifications better seen on CT than standard MRI

›Availability in acute neonatal setting

›Timing considerations

›Initial MRI at diagnosis if CT incomplete

›Follow-up MRI to monitor hydrocephalus after shunting

›Serial neuroimaging for progressive ventriculomegaly monitoring

CT

›Brain CT indications

›Initial neuroimaging of choice for calcification detection

›Diffuse scattered parenchymal calcifications

›Basal ganglia calcifications

›Periventricular calcifications less common than in CMV

›Hydrocephalus assessment

›Ventricular size quantification

›Third and fourth ventricular patency

›Lateral ventricle enlargement pattern

›CT findings associated with poor prognosis

›Dense diffuse calcifications

›Marked hydrocephalus

›Cortical atrophy pattern

›Radiation considerations

›Minimize radiation dose in neonates

›Pediatric low-dose protocols

›Single acquisition unless clinical change

›Serial CT for hydrocephalus monitoring

›Balance imaging need against cumulative radiation

›MRI preferred for longitudinal follow-up

Ultrasound

›Cranial ultrasound

›Primary bedside neuroimaging in neonates

›No radiation

›Portable at bedside

›Performed through open anterior fontanelle

›Hydrocephalus detection

›Lateral ventricular width measurement

›Third ventricular dilatation

›Resistive index measurement in severe cases

›Calcification visualization

›Echogenic foci throughout parenchyma

›Less sensitive than CT for punctate calcifications

›Large calcifications well visualized

›Serial monitoring advantage

›Repeat without radiation for hydrocephalus progression

›Shunt function assessment post-placement

›Abdominal ultrasound

›Hepatosplenomegaly quantification

›Liver and spleen size measurement

›Portal hypertension signs in severe hepatic involvement

›Ascites detection in severe systemic disease

›Prenatal ultrasound findings (maternal)

›Ventriculomegaly on fetal scan

›Lateral ventricular atrial width > 10 mm

›Associated with worse prognosis

›Intracranial hyperechogenicities

›Calcifications visible prenatally

›Placental thickening or echogenicity

›Marker of placental infection

07Disposition/dispo51

Admission criteria

›Inpatient admission indications

›All symptomatic neonates

›Seizures

›Hydrocephalus with neurologic signs

›Severe jaundice requiring phototherapy or exchange transfusion

›Significant thrombocytopenia with bleeding risk

›Hepatosplenomegaly with clinical compromise

›Treatment initiation and monitoring

›Baseline workup completion including LP and neuroimaging

›First CBC monitoring after pyrimethamine initiation

›Ophthalmologic evaluation completion

›ICU level indications

›Seizures refractory to initial management

›Status epilepticus

›Multiple anticonvulsants required

›Respiratory compromise

›Aspiration or pneumonitis

›Ventilatory support

›Hemodynamic instability

›Sepsis physiology

›Vasopressor requirement

Outpatient management criteria

›Asymptomatic neonate outpatient eligibility

›Completion of initial inpatient workup

›LP, neuroimaging, ophthalmologic exam completed

›Treatment plan established with ID consultation

›Reliable caregiver with clear follow-up plan

08Treatment/t84

Standard pharmacologic treatment

›First-line neonatal regimen (12-month course)

›Pyrimethamine

›Loading dose 2 mg/kg/day PO for 2 days

›Then 1 mg/kg/day PO for 2-6 months

›Then 1 mg/kg PO three times weekly for remainder of 12 months

›CBC monitoring weekly on daily dosing

›CBC monthly on thrice-weekly dosing

›Sulfadiazine

›50 mg/kg PO twice daily for 12 months

›Ensure adequate hydration to prevent crystalluria

›Leucovorin (folinic acid)

›10 mg PO or IM with each dose of pyrimethamine

›Prevents hematologic toxicity from pyrimethamine

›Continue for 1 week after pyrimethamine discontinued

›Increase dose if myelosuppression develops

Corticosteroids

›Indications for corticosteroids

›CSF protein > 1 g/L (1000 mg/dL)

›Prednisone 1 mg/kg/day or dexamethasone equivalent

›Continue until CSF protein normalizes

›Taper as soon as clinically feasible

›Active chorioretinitis threatening the macula

›Corticosteroids in conjunction with antiparasitic therapy

›Ophthalmology-guided duration

›Significant mass effect from hydrocephalus

›Adjunct to neurosurgical management

Alternative regimens

›Pyrimethamine unavailable

›TMP-SMX (trimethoprim-sulfamethoxazole)

›Age-appropriate weight-based dosing

›Less well studied but evidence supports use

›Monitor CBC for myelosuppression

›Sulfonamide intolerance

›Clindamycin with pyrimethamine and leucovorin

›Clindamycin 5-7.5 mg/kg/dose four times daily

›Reserve for documented sulfonamide allergy or intolerance

›Azithromycin

›Limited evidence, case reports with response

›Consider when standard agents not tolerated

›Prenatal maternal treatment

›Before 14-18 weeks gestation (amniocentesis PCR negative or not available)

›Spiramycin macrolide

›Not commercially available in US: requires FDA assistance

›Reduces placental transmission

›Confirmed fetal infection or >= 14-18 weeks gestation

›Pyrimethamine 25 mg/day PO

›Sulfadiazine 4 g/day PO divided twice daily

›Leucovorin 10-15 mg/day PO

›Note: pyrimethamine teratogenic, not used in first trimester

Seizure management

›Anticonvulsant therapy

›Phenobarbital first-line in neonates

›Loading dose 20 mg/kg IV

›Maintenance 3-5 mg/kg/day

›Levetiracetam alternative

›Loading dose 20-50 mg/kg IV

›Weight-based maintenance dosing

›Duration guided by EEG normalization and clinical seizure freedom

Hydrocephalus management

›Neurosurgical interventions

›VP shunt placement

›For progressive hydrocephalus

›Programmed to low or medium pressure setting initially

›Shunt malfunction monitoring

›Endoscopic third ventriculostomy

›Approximately 50% success in selected cases

›Avoids shunt hardware complications

›Requires patent basal cisterns on imaging

›Serial cranial ultrasound for monitoring

›Post-procedure ventricular size trend

Treatment monitoring and toxicity

›Pyrimethamine toxicity monitoring

›Bone marrow suppression signs

›Pallor from anemia

›Petechiae and bruising from thrombocytopenia

›Sore throat from neutropenia

›Glossitis

›Action if severe myelosuppression

›Increase leucovorin to 20 mg with each pyrimethamine dose

›Consider temporary interruption of pyrimethamine

›ID consultation for management modification

›FDA drug label caution: pyrimethamine is teratogenic (relevant for maternal treatment)

›Sulfadiazine toxicity monitoring

›Crystalluria and renal stones

›Maintain adequate hydration

›Urinalysis for crystals if renal symptoms

›Hypersensitivity reactions

›Rash

›Drug fever

09Special Populations/sp53

Pregnancy

›Maternal management during pregnancy

›Serologic screening programs

›Universal screening in France and some European countries

›Monthly serologic monitoring in seronegative mothers

›US has no universal screening program

›Timing-dependent treatment algorithm

›Seronegative at conception: no treatment needed before seroconversion

›Seroconversion confirmed: initiate spiramycin immediately

›Amniocentesis at >= 18 weeks to confirm fetal infection

›Pyrimethamine-sulfadiazine-leucovorin if amniocentesis PCR positive

›Pyrimethamine safety in pregnancy

›Teratogenic: avoid in first trimester

›Use after first trimester only for confirmed fetal infection

›Leucovorin supplementation mandatory

›Spiramycin safety

›Safe throughout pregnancy

›Reduces risk of fetal transmission

›RR 0.34 for infection and RR 0.30 for clinical manifestations

›Prenatal imaging

›Monthly fetal ultrasound for ventriculomegaly when infection confirmed

›Fetal MRI for detailed brain assessment if ultrasound abnormal

›Breastfeeding

›Not contraindicated in toxoplasmosis

›Treatment medications require individual assessment

Geriatric

›Geriatric considerations (maternal age-related)

›Advanced maternal age and infection risk

10Background/b87

Epidemiology

›Global disease burden

›Incidence of congenital toxoplasmosis

›Estimated 190,000 cases per year worldwide

›Highly variable by geographic region and screening practices

›France: approximately 2.9 per 10,000 live births with screening

›Brazil: higher incidence due to virulent atypical strains

›US: approximately 400-4000 cases per year estimated

›Seroprevalence by region

›France, Brazil, parts of Africa: high seroprevalence in women of childbearing age

›USA and UK: lower seroprevalence (approximately 10-30%)

›Higher seroprevalence correlates with higher congenital risk

›Transmission rate by gestational trimester

›First trimester: 10-15% transmission, highest severity

›Second trimester: ~25-30% transmission

›Third trimester: >60% transmission, lower severity

›Natural history without treatment

›Subclinical at birth: 70-90% of infected neonates

›Up to 90% develop late sequelae without treatment

›Chorioretinitis in 50-80% by adulthood

›Neurodevelopmental delay, hearing loss

›Prevention impact

›Prenatal treatment programs reduce infant clinical disease

›Neonatal treatment prevents late sequelae

›National Collaborative Study: treatment normalizes outcomes

Pathophysiology

›Organism and life cycle

›Toxoplasma gondii

›Obligate intracellular protozoan parasite

›Three main life stages: tachyzoites, bradyzoites (cysts), oocysts

›Definitive host: cats (sexual cycle)

›Intermediate hosts: warm-blooded mammals including humans

›Primary maternal infection mechanism

›Ingestion of oocysts from cat feces or contaminated soil

›Ingestion of tissue cysts in undercooked meat

›Tachyzoites disseminate hematogenously

›Placental and fetal infection

›Tachyzoites cross placenta during maternal parasitemia

›Placental infection precedes fetal infection

›First trimester: placenta relatively impermeable but fetal infection more severe

›Third trimester: placenta more permeable, higher fetal transmission

›Mechanisms of organ damage

›Direct cellular destruction

›Tachyzoites lyse host cells as they replicate

›CNS neurons, retinal cells, hepatocytes, myocytes affected

›Immune-mediated injury

›Inflammatory response to parasite antigens

›Contributes to retinal scarring in chorioretinitis

›CNS calcifications

›Areas of necrosis calcify

›Diffuse distribution reflects hematogenous seeding

›Hydrocephalus mechanism

›Aqueductal obstruction from periventricular inflammation

›CSF flow obstruction from ependymitis

Therapeutic Considerations

›Treatment evidence base

›Pyrimethamine-sulfadiazine combination

›Synergistic inhibition of Toxoplasma folate synthesis

›Pyrimethamine inhibits dihydrofolate reductase

›Sulfadiazine inhibits dihydropteroate synthase

›Most studied and recommended regimen

›12-month treatment duration rationale

›Eliminates active tachyzoites and suppresses tissue cysts

›Prevents new retinochoroidal lesions

›National Collaborative Study demonstrated benefit of full 12-month course

›Leucovorin co-administration rationale

›Bypasses the folate synthesis step blocked by pyrimethamine

›Protects human cells from folate depletion

›Toxoplasma cannot utilize exogenous leucovorin (parasite selectivity)

›Unresolved management questions

›TMP-SMX vs pyrimethamine-sulfadiazine comparison

›Emerging evidence for cotrimoxazole as better-tolerated alternative

›Less bone marrow suppression potential

›Head-to-head trials limited

›Optimal duration in asymptomatic infants

›12-month course recommended regardless of symptom status

›Evidence strongest for symptomatic infants

›Screening program effectiveness

›Universal neonatal screening not implemented in US

›Targeted screening in high-risk populations

›Austrian and French models show benefit of prenatal screening

›Prevention strategies

›Primary prevention counseling for seronegative pregnant women

›Avoid raw and undercooked meat

›Avoid cat litter box handling

›Handwashing after gardening

›Wash fruits and vegetables

›Secondary prevention: prenatal serologic screening

›Monthly IgG in seronegative women in endemic areas

›Immediate treatment initiation on seroconversion

11Patient Discharge Instructions/pdi39

copy discharge instructions

›Congenital toxoplasmosis home care

›Medications: give all medications exactly as prescribed

›Pyrimethamine: give every day (or as scheduled) without missing doses

›Sulfadiazine: give twice daily with meals and plenty of water

›Leucovorin (folinic acid): give with every pyrimethamine dose

›Do not stop medications without speaking to your doctor

›Lab monitoring: weekly blood tests are required

›Weekly CBC while on daily pyrimethamine

›Monthly CBC when switched to three-times-weekly schedule

›Attend all scheduled blood draw appointments

›Eye exams: keep all scheduled ophthalmology appointments

›Eye exams every 3 months during the first year

›Then at least once a year for life

›New eye problems can appear throughout childhood and adulthood

›Hearing tests: scheduled audiology evaluations

›Hearing loss can develop late

›Attend all scheduled audiology appointments

›Developmental follow-up: keep all neurodevelopment appointments

›Developmental delays can be caught early and helped with therapy

›Warning signs to return to ER immediately

›Head size growing rapidly or fontanelle (soft spot) bulging outward

›May indicate hydrocephalus worsening

›New seizure activity or return of seizures

›Pallor, unusual bruising, petechiae (small red or purple spots on skin)

›May indicate bone marrow suppression from medication

›High fever, sore throat, or signs of infection

›May indicate neutropenia from pyrimethamine

12References/r25

Guidelines and key sources

›Primary guidelines

›Office of AIDS Research Advisory Council (2025): Guidelines for the Prevention and Treatment of Opportunistic Infections in Children With and Exposed to HIV

›Comprehensive neonatal and pediatric dosing protocols

›Available at clinicalinfo.hiv.gov

›ACOG Practice Bulletin No. 151: Cytomegalovirus, Parvovirus B19, Varicella Zoster, and Toxoplasmosis in Pregnancy (Obstetrics and Gynecology 2015)

›Maternal screening and treatment guidance

›IDSA/ASM Guide to Utilization of the Microbiology Laboratory 2024 (Clinical Infectious Diseases 2024)

›Diagnostic testing recommendations including PCR methods

›Landmark clinical studies

›McLeod R et al. Outcome of Treatment for Congenital Toxoplasmosis 1981-2004: National Collaborative Chicago-Based Congenital Toxoplasmosis Study (Clinical Infectious Diseases 2006)

›Defined benefit of 12-month treatment regimen

›Demonstrated normal outcomes achievable with treatment

›Guerina NG et al. Neonatal Serologic Screening and Early Treatment for Congenital Toxoplasma gondii Infection (NEJM 1994)

›Established framework for neonatal screening and early treatment

›Ribeiro SK et al. Treatment Protocols for Gestational and Congenital Toxoplasmosis Systematic Review (Microorganisms 2025)

›RR 0.34 for infection and RR 0.30 for clinical manifestations with treatment

›Recent reviews

›Cerisola A et al. Congenital Toxoplasmosis (Seminars in Pediatric Neurology 2025)

›Current clinical presentation and management overview

›Nguyen TG et al. Diagnosis and Treatment of Congenital Toxoplasmosis: An Updated Overview (Expert Review of Anti-Infective Therapy 2026)

›Updated diagnostic and therapeutic guidance

›Journé A et al. Long-Term Ocular Outcomes in Congenital Toxoplasmosis Treated Perinatally (Pediatrics 2024)

›Ophthalmic outcome data with treatment

›Caceres A et al. Toxoplasma Gondii Infections in Pediatric Neurosurgery (Childs Nervous System 2024)

›Neurosurgical management of hydrocephalus

Evidence & Review