Case Conference

Maria Victoria B. Pertubal, M.D.PGY1

21 September 2011

The Case

• 1 week old male born to a 26 yo mother with positive prenatal Toxoplasma serology

Congenital T x plasmosis

• incidence of congenital infection (USA)– 1/1,000 to 1/8,000 live births.

• Toxoplasmosis seroprevalence – USA 9% (2004)

– France, Brazil, and Central America - 50-80%

• higher prevalence of infection in warmer, more humid climates.

Epidemiology

Epidemiology • risk of transmitting infection to the fetus increases

steeply with gestational age at seroconversion – (Meta-analysis study on Risk of Transmission):

• 15 % - 13 weeks AOG

• 44 % - 26 weeks AOG

• 71 % - 36 weeks AOG• 7-60% of lamb • 3-35% of pork• 0-9% of beef

• 1908 – Nicolle & Manceux Observed parasites in blood, liver and spleen of a North African rodent Ctenodactylus gondii (gundi)

• 1909 – named “Toxoplasma” (bow or arc shape)

• 1923 – Janku - Discovered parasite cysts on retina of an infant with hydrocephalus + seizures + ocular anomalies

• 1937 - Wolf & Conan - T.gondii as cause of neonatal enceph.

• 1942 – Paige, Cowen & Wolf - infection acquired congenitally

• 1948 – became a worldwide concern with development of precise serologic Dx procedures

Historical Background

The Parasite: Toxoplasma gondii

• An obligate intracellular coccidian protozoan

• 3 forms:– Oocysts

• Non-infective /unsporulated• Infective/ sporulated

– Tachyzoites – Bradyzoites

Life cycle within the definitive host: Cat (Felidae)

http://www.cdc.gov/parasites/toxoplasmosis/biology.html

http://healthdefine.com/medical-advice/what-is-toxoplasmosis-toxoplasma-gondii

Fetal transmission

Clinical manifestations of Toxoplasmosis infection

Acquired later in life • in older

immunocompetent children and adults

Acquired in utero• Congenital

Toxoplasmosis

Clinical Manifestations in the immunocompetent host

• Asymptomatic – in 80-90%

• Symptomatic– Benign self-limited flu-like

symptoms (from weeks to months)

• any combination of fever, stiff neck, myalgia, arthralgia, maculopapular rash that

spares the palms and soles, localized or generalized lymphadenopathy (20-30%),

Clinical Manifestations

• Other rare manifestations: – hepatomegaly, hepatitis, – reactive lymphocytosis, – meningitis, brain abscess, encephalitis, confusion, – malaise, polymyositis, – pneumonia – pericarditis, pericardial effusion, and myocarditis.

Congenital ToxoplasmosisAsymptomatic/subclinical• >50% - considered

normal in the perinatal period, but almost all develop ocular involvement later in life if not treated during infancy.

Symptomatic disease• in the neonatal period• during first few months of life• Sequelae or relapse

– (usually ocular) of undiagnosed infection later in infancy, childhood or adolescence

• characteristic triad of chorioretinitis, hydrocephalus, and cerebral calcifications.

Clinically apparent /symptomatic congenital toxoplasmosis

• Chorioretinitis (86 %)• Abnormal cerebrospinal fluid (63 %)• Anemia (57 %)• Seizures (41 %)• Intracranial calcification (37 %)• Jaundice (43 %)• Fever (40 %)• hepatosplenomegaly (41 %)• Lymphadenopathy (31 %)• Pneumonitis (27 %)• Others: hydrocephalus (20 percent), vomiting (25 percent), eosinophilia (9

percent), rash (8 percent), and abnormal bleeding (7 percent)

Congenital ToxoplasmosisTriad:

ChorioretinitisHydrocephalusCalcifications

occurs in less than 10% of cases

CNS

– CSF abnormalities occur in at least 30%• CSF protein level of >1 g/dL is characteristic of

severe CNS toxoplasmosis.

– Calcifications in the brain • Propensity for:

–caudate nucleus and basal ganglia, –choroid plexus and subependyma.

Figure 282-3 Head CT scans of infantswith congenital toxoplasmosis. (Nelson Pediatrics 19th ed)

A, CT scan at birth that shows areas of hypolucency, mildly dilated ventricles, and small calcifications.

B, CT scan of the same child at 1 yr of age (after antimicrobial tx for 1 yr).

Eye : Chorioretinitis• most common late manifestation • incidence of new-onset retinal lesions in untreated

children is almost 90 %, --risk extends into adulthood • Relapse after treatment is common• focal necrotizing retinitis is the typical lesion• Associated findings : microphthalmia, strabismus,

cataract, and nystagmus. • Complications : vision loss, retinal detachment, and

neovascularization of the retina and optic nerve.

from Uptodate, reproduced from Centers for Disease Control and Prevention. Parasite Image Library. Available at: http://www.dpd.cdc.gov/dpdx/HTML/Image_Library.htm. Accessed sep20,2011.

(A) Severe, active retinochoroiditis. (B) Peripheral

retinochoroiditis.

(C) Central, healed retinochoroiditis.

(D) Multiple chorioretinal scars.

Evaluation• Must be done on infants born to women who are/have..

– with evidence of primary T. gondii infection during gestation – immunosuppressed and have serologic evidence of past

infection with T. gondii

• Toxoplasmosis is not part of routine prenatal screening the USA– Pregnant women who experience a mononucleosis-like illness,

but with a negative heterophile test, should be tested for toxoplasmosis as part of their diagnostic evaluation.

Evaluation

• Serology – Detection of antibodies (IgG, IgM etc..)– Serial serology is necessary to confirm or exclude

congenital toxoplasmosis in asymptomatic infants

• Identification of T.gondii– PCR – amniotic fluid, CSF, vitreous fluid (ocular toxoplasma), urine,

peripheral blood, bronchoalveolar lavage fluid, cord blood, newborn peripheral blood, cerebrospinal fluid, or placenta

– Observation of parasites /cysts– Tissue culture – innoculation in mouse

Immunoflurescence Assay (IFA)

(A) Unstained cyst of T. gondii.

(B) Toxoplasma gondii cyst in brain tissue stained with hematoxylin and eosin.

Interpretation of serology:Infection is confirmed if there is…

• An increase in anti-Toxoplasma IgG titer during the first year of life or increasing IgG titer compared with the mother’s; – the congenitally infected infant usually can synthesize Toxoplasma IgG by

the third month of life if he or she is not treated; – in treated infants synthesis may be delayed until six to nine months of age

• Persistence of anti-Toxoplasma IgG at one year of age – by which time transplacentally acquired maternal IgG should have

disappeared)

*Serology is most ideally performed or confirmed in a reference laboratory

– Toxoplasmosis Serology Laboratory at the Palo Alto Medical Foundation Research Institute, California --www.pamf.org/serology;

– WHO/FAO International Centre for Research and Reference on Toxoplasmosis, Staten Serum Institute, Copenhagen, Denmark;

– Toxoplasma Reference Laboratory, Public Health Laboratory, Singleton Hospital, Swansea, United Kingdom).

• The same serologic tests should be performed on maternal serum; maternal serum should also be obtained for differential agglutination test.

Treatment

1. Antiparasitic therapy is indicated for infants with:– Diagnosed congenital toxoplasmosis prenatally– clinical findings compatible with congenital

toxoplasmosis in the infant (chorioretinitis, intracranial calcifications, and/or hydrocephalus) with evidence of recent maternal T. gondii infection

– suspected congenital toxoplasmosis who have confirmation serology or PCR performed by a *reference laboratory.

Treatment regimen for Congenital toxoplasmosis

• Pyrimethamine – 2 mg/kg (maximum 50 mg/dose) once daily for two days; – then 1 mg/kg (maximum 25 mg/dose) once daily for six months;– then 1 mg/kg (maximum 25 mg/dose) every other day (ie, Monday,

Wednesday, and Friday) to complete one year of therapy, plus

• Sulfadiazine – 100 mg/kg per day divided in two doses every day for one year, plus

• Folinic acid (leucovorin) – 10 mg three times per week during and for one week after

pyrimethamine therapy

• Glucocorticoids – (prednisone 0.5 mg twice per day) – added if cerebrospinal fluid (CSF) protein is >1 g/dL – or when active chorioretinitis threatens vision

Prognosis : for the untreated infants• Poor for untreated infants with overt congenital

toxoplasmosis disease at birth

• Untreated infants with subclinical infection may develop chorioretinitis, seizures, and severe psychomotor retardation.

Prognosis: with treatment• overall ocular prognosis usually is satisfactory• late-onset retinal lesions and relapse can

occur many years after birth • may result in diminution or resolution of

intracranial calcifications

Prognosis

• Treated infants remain at risk for developing sequelae later in life – Currently available antiparasitic drugs are active against

the tachyzoite form of T. gondii but do not effectively eradicate the bradyzoite form from the CNS and eye.

• recurrence of CNS and ocular disease may occur after cessation of treatment and should be monitored closely.

Nelson Pediatrics 19th ed: Figure 282-1 

Prevention

References

• Mcleod, R. Chapter 282 Toxoplasmosis. Nelson Textbook of Pediatrics May 2011

• Guerina, N. et al, Congenital toxoplasmosis: Clinical features and diagnosis. Uptodate May 2011. Accessed sep20, 2011. URL http://www.uptodate.com.elibrary.einstein.yu.edu/contents/congenital-toxoplasmosis-treatment-outcome-and-prevention?source=related_link#H4829823

• Division of Parasitic Diseases, Centers for Disease Control. DPDx Image Library. Accessed 20 sep 2011 URL http://www.cdc.gov/parasites/toxoplasmosis/biology.html

• http://faculty.mwsu.edu/nursing/betty.bowles/toxoplasmosis.pdf