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
Epidemiology
• 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
• 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
Historical Background
• 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
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
Fetal transmission
http://healthdefine.com/medical-advice/what-is-toxoplasmosis-toxoplasma-gondii
Clinical manifestations of
Toxoplasmosis infection
Acquired in utero
• Congenital
Toxoplasmosis
Acquired later in life
• in older
immunocompetent
children and adults
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 (2030%),
Clinical Manifestations
• Other rare manifestations:
– hepatomegaly, hepatitis,
– reactive lymphocytosis,
– meningitis, brain abscess, encephalitis, confusion,
– malaise, polymyositis,
– pneumonia
– pericarditis, pericardial effusion, and myocarditis.
Congenital Toxoplasmosis
Asymptomatic/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 Toxoplasmosis
Triad:
Chorioretinitis
Hydrocephalus
Calcifications
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.
(A) Severe, active
retinochoroiditis.
(C) Central,
healed
retinochoroiditis.
(B) Peripheral
retinochoroiditis.
(D) Multiple
chorioretinal
scars.
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.
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: positive reaction (tachyzoites + human Ab to Toxoplasma +
FITC-labelled antihuman IgG = fluorescence.)
Formalin-fixed Toxoplasma gondii tachyzoites, stained by immunofluorescence
(IFA).
B: Negative IFA for antibodies to T. gondii.
(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.
Prevention
Nelson Pediatrics 19th ed: Figure 282-1
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/congenitaltoxoplasmosis-treatment-outcome-andprevention?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