Congenital Toxoplasmosis Presentingas Eosinophilic Encephalomyelitis WithSpinal Cord HemorrhageCasey N. Vera, CPNP,a W. Matthew Linam, MD, MS,a,b Judith A. Gadde, DO, MBA,a,b David S. Wolf, MD, PhD,a,b Karen Walson, MD,a

Jose G. Montoya, MD,c,d Christina A. Rostad, MDa,b

abstractA 4-week-old male neonate with a history of intermittent hypothermia in thenewborn nursery presented with an acute onset of bilateral lower extremityparalysis and areflexia. Extensive workup demonstrated eosinophilicencephalomyelitis and multifocal hemorrhages of the brain and spinal cord.Funduscopic examination revealed bilateral chorioretinitis with macularscarring. The laboratory values were notable for peripheral eosinophilia andcerebrospinal fluid eosinophilic pleocytosis (28 white blood cells/µL, 28%eosinophils), markedly elevated protein (1214 mg/dL), andhypoglycorrhachia (20 mg/dL). Toxoplasma gondii immunoglobulin M (IgM)test result was positive. Reference testing obtained at the Palo Alto MedicalFoundation Toxoplasma Serology Laboratory confirmed the diagnosis ofcongenital toxoplasmosis in the infant with a positive immunoglobulin G (IgG)dye test result, immunoglobulin A enzyme-linked immunosorbent assay, andIgM immunosorbent agglutination assay. The diagnosis of an infectionacquired during gestation in the mother was established by a positivematernal IgG dye test result, IgM enzyme-linked immunosorbent assay,immunoglobulin A, immunoglobulin E, and low IgG avidity. At 6-monthfollow-up, the infant had marginal improvement in his retinal lesions andresidual paraplegia with hyperreflexia and clonus of the lower extremities. Arepeat MRI demonstrated interval development of encephalomalacia withsuspected cortical laminar necrosis and spinal cord atrophy in the areas ofprevious hemorrhage. Clinicians should be aware of this severe spectrum ofcongenital toxoplasmosis disease and should remain vigilant for subtler signsthat may prompt earlier testing, diagnosis, and treatment.

Toxoplasma gondii is a commonprotozoan parasite, affectingapproximately one-third of the world’spopulation.1,2 Acquisition occursprimarily via 3 routes: consumption ofundercooked infected meats, ingestionof water contaminated with oocystsfrom cat feces, or transplacentaltransmission from a newly infectedmother.1,2 Most immunocompetentpeople develop asymptomaticinfections or a flulike illness.2,3

However, immunocompromised

individuals or infants infected in uterocan develop severe clinicalmanifestations, includingchorioretinitis, seizures, and cognitiveimpairment. Many European countrieswith historically high seroprevalencerates of toxoplasmosis haveimplemented antepartum screeningand treatment programs to preventmaternal–fetal transmission andcongenital disease. Severe cases, rarelyseen in countries with antepartumscreening and treatment programs, are

aChildren’s Healthcare of Atlanta, Atlanta, Georgia;bDepartment of Pediatrics, School of Medicine, EmoryUniversity, Atlanta, Georgia; cToxoplasma SerologyLaboratory, Palo Alto Medical Foundation, Palo Alto,California; and dDivision of Infectious Diseases andGeographic Medicine, Department of Medicine, School ofMedicine, Stanford University, Stanford, California

Mrs Vera and Dr Rostad provided direct care for thepatient and wrote the manuscript; Drs Linam, Wolf,and Walson provided direct care for the patient andcritically reviewed and revised the manuscript; DrGadde provided magnetic resonance images andinterpretations for the figures, and she criticallyreviewed and revised the manuscript; Dr Montoyaprovided laboratory confirmation of the diagnosisand critically reviewed and revised the manuscript;and all authors approved the final draft as submittedand agree to be accountable for all aspects ofthe work.

DOI: https://doi.org/10.1542/peds.2019-1425

Accepted for publication Sep 30, 2019

Address correspondence to Christina A. Rostad, MD,Assistant Professor of Pediatrics, Department ofPediatrics, Emory University School of Medicine, 2015Uppergate Dr NE, Atlanta, GA 30322. E-mail:christina.rostad@emory.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2020 by the American Academy ofPediatrics

To cite: Vera CN, Linam WM, Gadde JA, et al.Congenital Toxoplasmosis Presenting asEosinophilic Encephalomyelitis With Spinal CordHemorrhage. Pediatrics. 2020;145(2):e20191425

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seen with greater frequency in theUnited States.4,5 In this article, wepresent one such case of an infant whodeveloped eosinophilic encephalomyelitisand acute flaccid paralysis attributable tospinal cord hemorrhage from congenitaltoxoplasmosis.

CASE

A 4-week-old male infant presentedto the emergency department with anacute onset of bilateral lowerextremity paralysis and areflexia. Theinfant had been born at 37 weeks’

gestation via induced vaginal deliverybecause of decreased fetal movementand oligohydramnios. The mothertested positive for group B Streptococcusand received 2 doses of intrapartumpenicillin. Her other prenatal laboratoryresults were unremarkable, and shereported no fevers or infections duringpregnancy. At delivery, the infant’sApgar scores were 8 and 9 at 1 and5 minutes, respectively. He experiencedno perinatal trauma and required noresuscitation after delivery. He weighed2.77 kg (29th percentile) with a lengthof 50.8 cm (71st percentile) and head

circumference of 33 cm (30thpercentile). He stayed an additional dayin the hospital because of hypothermiabut was then discharged with hismother.

The patient was reportedly doing welluntil the day before admission when theparents noted absent lower extremitymovement. They brought him to theemergency department, where he wasfound to have mild hypopnea requiringrespiratory support via nasal cannula.Notable physical examination findingsincluded flaccid paralysis of the bilaterallower extremities with areflexia andlack of response to painful stimuli. Hismuscle strength, tone, and sensation inthe upper extremities were normal.Funduscopic examination revealedbilateral central scarring of the maculaand extensive chorioretinitis in the lefteye. The patient had no evidence ofaltered mental status, diabetesinsipidus, or seizures at the time ofpresentation, nor did he havehepatosplenomegaly or rash.

A sepsis evaluation showed a normalwhite blood cell (WBC) count withperipheral eosinophilia (9000WBCs/µL, 14% neutrophils, 39%lymphocytes, 8% monocytes, 35%eosinophils), hemoglobin level of14.8 g/dL, platelet count of 197 000cells/µL, and a minimally elevatedC-reactive protein level (1.2 mg/dL).The patient had hypoalbuminemia(2.3 g/dL) but normal transaminases,prothrombin time, and partialthromboplastin time. Thecerebrospinal fluid (CSF) was notablefor eosinophilic pleocytosis (28WBCs/µL, 0.6% neutrophils, 30%lymphocytes, 32% monocytes, 28%eosinophils), markedly elevatedprotein levels (1214 mg/dL), andhypoglycorrhachia (20 mg/dL). MRIof the brain showed multipleabnormal foci of T2 hypointensitywith corresponding susceptibility onsusceptibility weighted imaging(SWI) within the bilateralcaudothalamic grooves (Fig 1A and B)and cerebral hemispheres (Fig 1C andD), consistent with hemorrhage.

FIGURE 1Axial T2-weighted image (A) demonstrates abnormal T2 hypointensity within the left caudothalamicgroove (yellow arrow) and abnormal T2 hyperintensity within the bilateral cerebral white matter(red arrow). There is associated susceptibility in the left caudothalamic groove (yellow arrow) onSWI (B). Axial T2-weighted image (C) demonstrates multiple abnormal foci of T2 hypointensity in thecortex of the bilateral cerebral hemispheres (arrows) with corresponding susceptibility (arrows) onSWI (D).

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Abnormal T2 hyperintensity withinthe cerebral hemispheres (Fig 1A)and spinal cord (Fig 2A)demonstrated encephalomyelitis, andfoci of T1 hyperintensity at thoracicvertebrae levels T2 to T4 and T10 toT11 (Fig 2B) demonstrated spinalcord hemorrhage.

Diagnostic testing included CSFbacterial, acid-fast bacillus, and fungalcultures; cryptococcal antigen; CSFpolymerase chain reactions (PCRs)for herpes simplex virus 1 and 2 andenterovirus; and West Nile virusimmunoglobulin G (IgG) by enzyme-linked immunosorbent assay (ELISA),which all ultimately resulted negative.A rapid plasma reagin test, HIV-1 and2 fourth-generation test, urinecytomegalovirus PCR, and a multiplex

viral respiratory PCR specimen alsoresulted negative. T gondiiimmunoglobulin M (IgM) resultedpositive (34.1 AU/mL, reference #7.9AU/mL). Confirmatory testingobtained at the Palo Alto MedicalFoundation Toxoplasma SerologyLaboratory was diagnostic fora maternal primary infection andcongenital toxoplasmosis. MaternalIgG dye test was 1:8000 (reference,1:16), IgM ELISA was 10.3(reference ,2.0), immunoglobulin Awas 3.7 (reference for adult, ,2.1),immunoglobulin E was 8.3 (reference,1.9), and avidity was 11.9 (low).Infant IgG dye test was 1:8000,immunoglobulin A ELISA was 12.6(reference ,1.0), and IgMimmunosorbent agglutination assaywas 12 (reference ,3). Confirmation

at a reference laboratory is necessarybecause of variability in specificity ofcommercially available serologicassays.3,4,6,7 After diagnosis, themother recalled exposures to coldpepperoni and other deli meatsduring her pregnancy.

Treatment was initiated with1 mg/kg of pyrimethamine daily for12 months, 100 mg/kg of sulfadiazinetwice daily, and 10 mg of folinic acid3 times per week. A dose of0.5 mg/kg of prednisolone daily wasalso added 72 hours after initiation ofantiparasitic medications because ofocular findings and elevated CSFprotein. At the time of discharge, thepatient continued to have flaccidparalysis of the bilateral lowerextremities with grade 0 out of 5strength and lack of response topainful stimuli. He continued to havenormal anal tone, normal voiding andelimination patterns, and normalmuscle tone and strength in bothupper extremities. At 6-month follow-up, he had marginal improvement inhis retinal lesions but residualparaplegia with hyperreflexia andclonus of the lower extremities.Follow-up MRI demonstratedresolution of the abnormal whitematter signal but intervaldevelopment of encephalomalaciaand likely cortical laminar necrosis(Fig 3A–C). SWI sequencesdemonstrated decrease insusceptibility within thecaudothalamic grooves and cerebralhemispheres (Fig 3D), consistent withevolving hemorrhage. MRI of thespine demonstrated focal atrophy ofthe spinal cord at the T2 to T4(Fig 4A) and T11 to T12 (Fig 4B)levels with mild residual T1hyperintensity, also consistent withevolving hemorrhage.

DISCUSSION

We describe a patient with congenitaltoxoplasmosis presenting as acuteflaccid paralysis attributable toeosinophilic encephalomyelitis with

FIGURE 2Sagittal T2-weighted image of the cervical and upper thoracic spine (A) shows multilevel expandedand edematous spinal cord with T2 hyperintensity (yellow arrows). Sagittal T1-weighted image of thecervical and thoracic spine (B) shows T1 hyperintensity within the spinal cord (relative to theedematous cord) at the T2 to T4 and the T10 to T11 levels (yellow arrows) consistent with myelitis.

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spinal cord hemorrhage. Althoughprevious reports have describedacute myelitis as a manifestation ofcongenital toxoplasmosis,8–11 thissevere spectrum of disease is rare.Other clinical characteristicsmanifested by our patient typical forcongenital toxoplasmosis includedhypothermia, multifocal brain lesions,

and bilateral chorioretinitis. Hislaboratory results were also notablefor elevated peripheral and CSFeosinophil levels and markedlyelevated CSF protein levels, which arecommon (although perhapsunderappreciated) features ofcongenital toxoplasmosis.2,8 Anyconstellation of these findings in

a young infant should prompt theclinician to consider further workupfor congenital toxoplasmosis. Inobservational studies, researchershave shown that early postnataltreatment improves manifestations ofacute infection and long-termsequelae including neurocognitiveoutcomes and chorioretinitis.4,12

This report also highlights theimportance of considering congenitaltoxoplasmosis in the differentialdiagnosis for acute flaccid paralysis inyoung infants because our patientmet the standardized case definitionof acute flaccid myelitis (AFM) usedfor surveillance by the Centers forDisease Control and Prevention.13,14

AFM is characterized by acute flaccidlimb weakness, mild CSF pleocytosiswith lymphocytic predominance, andcharacteristic MRI findings withspinal cord lesions spanning 1 or morevertebral segments. Most patients withAFM have had a preceding mildrespiratory illness, and a viral etiologyis suspected.15 In an era of increasingawareness of AFM, distinguishingfeatures that should alert the clinicianto an alternative diagnosis of congenitaltoxoplasmosis include many of thoseexhibited by our patient, such as thepatient’s younger age, characteristicphysical examination findings, CSFeosinophilia, and the presence ofconcomitant intraparenchymal lesions.

Our patient’s case also raisesconsideration of the optimal approachto diagnose and prevent congenitaltoxoplasmosis. Maternal–fetaltransmission of toxoplasmosis occurssecondary to transplacental transfer ofparasitic organisms during primarymaternal infection or less commonlyduring reactivation or reinfection witha more-virulent strain.3 The age-adjusted seroprevalence totoxoplasmosis in women of childbearingage (15–44 years) in the United Stateswas estimated to be 9.1% (95%confidence interval: 7.2%–11.1%) in2009 to 2010.16 Thus, the majority ofwomen of childbearing age in theUnited States are susceptible to primary

FIGURE 3Follow-up axial T2-weighted image (A) performed 6 months later demonstrates resolution of theprevious abnormal white matter signal (red arrow), decrease in size of the lateral ventricles (greenarrow), and decrease in size of the T2 hypointensity within the left caudothalamic groove (yellowarrow), corresponding to previous hemorrhage. Follow-up axial T2-weighted image (B) demon-strates interval development of encephalomalacia in the bilateral cerebral hemispheres (yellowarrows). These areas of encephalomalacia also demonstrate abnormal T1 hyperintensity (yellowarrows) on T1 inversion recovery sequence, likely representing cortical laminar necrosis. Theseareas of encephalomalacia also demonstrate abnormal T1 hyperintensity (yellow arrows) on T1inversion recovery sequence (C), likely representing cortical laminar necrosis. SWI (D) demonstratespersistent but decreased susceptibility within the left caudothalamic groove and cortex of thebilateral cerebral hemispheres (yellow arrows).

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infection and congenital transmission,leading to an estimated 0.23 cases per10000 per year.2 Unfortunately, onlyhalf of pregnant women with primaryinfection have obvious risk factors orclinical manifestations of the disease.3

These factors make targeted diagnosisof toxoplasmosis during pregnancychallenging.

Although no randomized controlledclinical trials have been performed toassess the efficacy of antepartumtreatment on the reduction ofmaternal–fetal transmission oftoxoplasmosis, evidence of treatmentbenefit has been shown in severalobservational studies. A meta-analysis

of 26 cohort studies describing 1438pregnant women primarily fromEurope showed significant reduction inmaternal–fetal transmission whentreatment was started within 3 weeksof seroconversion compared with after8 weeks (adjusted odds ratio: 0.48;95% confidence interval: 0.28–0.80,P = .05).17 On the basis of the availableevidence, several European countrieshave implemented routine antepartumscreening programs for toxoplasmosisover the past 3 decades. The AmericanAcademy of Pediatrics recentlypublished a technical report reviewingthe available evidence and itsapplicability for treatment andprevention of congenital toxoplasmosis

in the United States.2 They concludedthat further studies are needed tounderstand the benefits, limitations,and costs of universal prenatalscreening in the US population.

Currently recommended preventivestrategies in the United States includeeducation for pregnant women andtargeted prenatal and postnatalscreening for high-risk andsymptomatic individuals.2,3,18 TheAmerican College of Obstetricians andGynecologists recommendscounseling women on proper handhygiene techniques, pet caremeasures, and dietary restrictions,including avoiding undercookedmeats.19 Consumption of uncookedpepperoni during late gestation mayhave been a mode of acquisition ofacute primary toxoplasmosis in ourpatient’s mother. However, this riskfactor was only identified inretrospect, after her infant presentedwith severe neurologic sequelae ofundiagnosed congenital disease.Although unanswered questionsremain regarding the impact ofroutine antepartum screening andtreatment of congenitaltoxoplasmosis, the gravity of suchcases should cause reconsideration ofour approach and reinvigoration ofour research efforts. In the meantime,clinicians should be aware of thissevere spectrum of congenitaltoxoplasmosis disease and shouldremain vigilant for subtler signs thatmay prompt earlier testing, diagnosis,and treatment.

ABBREVIATIONS

AFM: acute flaccid myelitisCSF: cerebrospinal fluidELISA: enzyme-linked

immunosorbent assayIgG: immunoglobulin GIgM: immunoglobulin MPCR: polymerase chain reactionSWI: susceptibility weighted

imagingWBC: white blood cell

FIGURE 4Follow-up sagittal T2-weighted image (A) performed 6 months later demonstrates atrophy of thespinal cord at the T2 to T4 levels in area of previous hemorrhage (yellow arrow). Sagittal T1-weighted image postcontrast (B) demonstrates minimal residual T1 hyperintensity in the ventralspinal cord at the T11 to T12 level (yellow arrow).

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FINANCIAL DISCLOSURE: Dr Rostad received research support to Emory University from BioFire Diagnostics, LLC; Micron Biomedical; MedImmune; Sanofi Pasteur;

Pfizer; Janssen; and PaxVax outside the submitted work. In addition, she has a patent (US20180333477A1) pending for respiratory syncytial virus vaccine technology,

licensed to Meissa Vaccines, Inc, with royalties paid to Emory University. The other authors have indicated they have no financial relationships relevant to this

article to disclose.

FUNDING: Dr Rostad is supported by funding provided by the Emory 1 Children’s Pediatric Institute and by the Pediatric Infectious Diseases Society; the other

authors received no external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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