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Successful Treatment of an Adolescent With Naegleria fowleri Primary Amebic Meningoencephalitis W. Matthew Linam, MD, MS a , Mubbasheer Ahmed, MD b , Jennifer R. Cope, MD, MPH c , Craig Chu, MD b , Govinda S. Visvesvara, PhD c , Alexandre J. da Silva, PhD c , Yvonne Qvarnstrom, PhD c , Jerril Green, MD b abstract Naegleria fowleri is a thermophilic, free-living ameba that causes primary amebic meningoencephalitis. The infections are nearly always fatal. We present the third well-documented survivor of this infection in North America. The patients survival most likely resulted from a variety of factors: early identication and treatment, use of a combination of antimicrobial agents (including miltefosine), and management of elevated intracranial pressure based on the principles of traumatic brain injury. Naegleria fowleri is a thermophilic, free-living ameba found in warm fresh water. Infection is rare and occurs when water containing the ameba enters the nose and subsequently invades the brain. Infection with N fowleri causes primary amebic meningoencephalitis (PAM), resulting in destruction of brain tissue and cerebral edema. There have been 2 well-documented survivors in North America: 1 subject in California in 1978 1,2 and 1 subject in Mexico in 2003. 3 We present the third documented survivor of PAM in North America. CASE REPORT The patient, a previously healthy 12-year-old girl, presented to the emergency department with a 2-day history of headache and a 1-day history of fever (39.4°C), along with nausea, vomiting, and somnolence. Results of her neurologic examination were normal. She reported swimming at an outdoor water park 7 days before the onset of symptoms. Her initial laboratory evaluation included a peripheral white blood cell count of 18.4 cells per mL (77% segmented, 13% banded neutrophils). Analysis of cerebrospinal uid (CSF) revealed a white blood cell count of 3675 cells per mL (86% segmented neutrophils), a red blood cell count of 53 cells per mL, protein of 374 mg/dL, and glucose of 22 mg/dL. The Giemsa-Wright stain of the CSF revealed amebae consistent with N fowleri. The initial computed tomography scan of the patients brain was normal. The patient was admitted to the PICU on July 19, 2013, and the following treatment was initiated: conventional amphotericin B 1.5 mg/kg per day intravenously in 2 divided doses, uconazole 10 mg/kg per day, rifampin 10 mg/kg per day, and azithromycin 10 mg/kg per day. 1,3 Dexamethasone was initiated concurrently. After 3 days, the daily dose of amphotericin B was decreased to 1 mg/kg. 1 Approximately 36 hours after admission, the patient was started on miltefosine 50 mg every 8 hours. Consent was obtained from the family before administering miltefosine. Almost 24 hours after admission, the patient developed a right-sided abducens nerve palsy. An external ventricular drain was placed while the patient was in the operating room, and her initial intracranial pressure (ICP) a Pediatric Infectious Diseases Section and b Pediatric Critical Care Section, Arkansas Childrens Hospital, Little Rock, Arkansas; and c Centers for Disease Control and Prevention, Atlanta, Georgia Dr Linam provided medical care for the patient, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Ahmed, Chu, and Green provided medical care for the patient and critically reviewed the manuscript; Dr Cope advised the medical care of the patient and reviewed and revised the manuscript; Drs Visvesvara, da Silva, and Qvarnstrom performed diagnostic studies, interpreted results, and critically reviewed the manuscript; and all authors approved the nal manuscript as submitted. The ndings and conclusions in this report are those of the authors and do not necessarily represent those of the Centers for Disease Control and Prevention. www.pediatrics.org/cgi/doi/10.1542/peds.2014-2292 DOI: 10.1542/peds.2014-2292 Accepted for publication Nov 26, 2014 Address correspondence to W. Matthew Linam, MD, MS, Arkansas Childrens Hospital, Pediatric Infectious Diseases Section, 1 Childrens Way, Slot 512-11, Little Rock, AR 72202-3500. E-mail: wlinam@ uams.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2015 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: All authors have indicated they have no nancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: All authors have indicated they have no potential conicts of interest to disclose. CASE REPORT PEDIATRICS Volume 135, number 3, March 2015 by guest on April 8, 2019 www.aappublications.org/news Downloaded from

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Page 1: Successful Treatment of an Adolescent With Naegleria fowleri … · Successful Treatment of an Adolescent With Naegleria fowleri Primary Amebic Meningoencephalitis W. Matthew Linam,

Successful Treatment of an AdolescentWith Naegleria fowleri Primary AmebicMeningoencephalitisW. Matthew Linam, MD, MSa, Mubbasheer Ahmed, MDb, Jennifer R. Cope, MD, MPHc, Craig Chu, MDb,Govinda S. Visvesvara, PhDc, Alexandre J. da Silva, PhDc, Yvonne Qvarnstrom, PhDc, Jerril Green, MDb

abstract Naegleria fowleri is a thermophilic, free-living ameba that causes primaryamebic meningoencephalitis. The infections are nearly always fatal. Wepresent the third well-documented survivor of this infection in North America.The patient’s survival most likely resulted from a variety of factors: earlyidentification and treatment, use of a combination of antimicrobial agents(including miltefosine), and management of elevated intracranial pressurebased on the principles of traumatic brain injury.

Naegleria fowleri is a thermophilic,free-living ameba found in warm freshwater. Infection is rare and occurswhen water containing the amebaenters the nose and subsequentlyinvades the brain. Infection withN fowleri causes primary amebicmeningoencephalitis (PAM), resultingin destruction of brain tissue andcerebral edema. There have been2 well-documented survivors in NorthAmerica: 1 subject in California in19781,2 and 1 subject in Mexico in2003.3 We present the thirddocumented survivor of PAM in NorthAmerica.

CASE REPORT

The patient, a previously healthy12-year-old girl, presented to theemergency department with a 2-dayhistory of headache and a 1-day historyof fever (39.4°C), along with nausea,vomiting, and somnolence. Results ofher neurologic examination werenormal. She reported swimming at anoutdoor water park 7 days before theonset of symptoms. Her initiallaboratory evaluation includeda peripheral white blood cell count of18.4 cells per mL (77% segmented,13% banded neutrophils). Analysis of

cerebrospinal fluid (CSF) revealeda white blood cell count of 3675 cellsper mL (86% segmented neutrophils),a red blood cell count of 53 cells per mL,protein of 374 mg/dL, and glucoseof 22 mg/dL. The Giemsa-Wright stainof the CSF revealed amebae consistentwith N fowleri. The initial computedtomography scan of the patient’s brainwas normal.

The patient was admitted to the PICUon July 19, 2013, and the followingtreatment was initiated: conventionalamphotericin B 1.5 mg/kg per dayintravenously in 2 divided doses,fluconazole 10 mg/kg per day, rifampin10 mg/kg per day, and azithromycin10 mg/kg per day.1,3 Dexamethasonewas initiated concurrently. After 3 days,the daily dose of amphotericin B wasdecreased to 1 mg/kg.1 Approximately36 hours after admission, the patientwas started on miltefosine 50 mgevery 8 hours. Consent was obtainedfrom the family before administeringmiltefosine.

Almost 24 hours after admission, thepatient developed a right-sidedabducens nerve palsy. An externalventricular drain was placed while thepatient was in the operating room, andher initial intracranial pressure (ICP)

aPediatric Infectious Diseases Section and bPediatricCritical Care Section, Arkansas Children’s Hospital, LittleRock, Arkansas; and cCenters for Disease Control andPrevention, Atlanta, Georgia

Dr Linam provided medical care for the patient,drafted the initial manuscript, and reviewed andrevised the manuscript; Drs Ahmed, Chu, and Greenprovided medical care for the patient and criticallyreviewed the manuscript; Dr Cope advised themedical care of the patient and reviewed andrevised the manuscript; Drs Visvesvara, da Silva,and Qvarnstrom performed diagnostic studies,interpreted results, and critically reviewed themanuscript; and all authors approved the finalmanuscript as submitted.

The findings and conclusions in this report arethose of the authors and do not necessarilyrepresent those of the Centers for Disease Controland Prevention.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-2292

DOI: 10.1542/peds.2014-2292

Accepted for publication Nov 26, 2014

Address correspondence to W. Matthew Linam, MD,MS, Arkansas Children’s Hospital, PediatricInfectious Diseases Section, 1 Children’s Way, Slot512-11, Little Rock, AR 72202-3500. E-mail: [email protected]

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

Copyright © 2015 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: All authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: All authors haveindicated they have no potential conflicts of interestto disclose.

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was ∼50 mmHg. Intrathecalamphotericin B was started at a doseof 1.5 mg daily for 2 days followed bya dose of 1 mg every other day for8 days.1 On the third day ofhospitalization, the patient’s ICPworsened. Management of hercerebral edema (goal ICP: ,20 mmHg) included drainage of CSF,hyperosmolar therapy with mannitoland 3% saline, moderatehyperventilation (goal PaCO2:30–35 mmHg), and inducedhypothermia (32°C–34°C). The cerebraledema resolved after ∼2 weeks (Fig 1).

The patient’s initial CSF specimengrew N fowleri on culture and waspositive for N fowleri according toresults of polymerase chain reaction.By day 3, her CSF specimen wasnegative for N fowleri. Serial CSFspecimens revealed decreasing whiteblood cell counts and diminishingamounts of N fowleri DNA onpolymerase chain reaction.

Magnetic resonance imaging (MRI) ofthe patient’s brain 2 weeks into herillness revealed blood in the frontallobes and multiple areas of restricteddiffusion, primarily in the cerebellum,

right internal capsule, and corpuscallosum (Fig 2). A repeat MRI of herbrain 1 week later showedimprovement. The patient completed26 days of a planned 28-day course ofantimicrobial agents (miltefosine,azithromycin, rifampin, andfluconazole); the regimen was stoppedearly due to nausea and vomiting.Upon transfer to the rehabilitationunit, the patient had left-sidedweakness, dysarthria, and dysphagia.After 55 days of hospitalization, shewas discharged from the hospital.At 6 months’ postinfection, the patienthad normal levels of functioning andno residual deficits.

DISCUSSION

We report the third documentedsurvivor of N fowleri PAM in NorthAmerica. The patient’s survival waslikely the result of a variety of factors:early diagnosis and treatment, use ofa combination of antimicrobial agents(including miltefosine4), andmanagement of elevated ICP based onthe principles of traumatic braininjury. This report is the first ofa patient with PAM successfully

treated by using a regimen thatincluded miltefosine. This report isalso the first to document successfuluse of induced hypothermia(32°C–34°C) in the management ofPAM.

Between 1962 and 2013, a total of132 cases of N fowleri PAM werereported to the Centers for DiseaseControl and Prevention (CDC).5,6 Thenumber of infections reported eachyear (0–8 infections) remained stable,and the majority of these infectionsoccurred in southern-tier states.Approximately 75% of infections areassociated with swimming in warmfreshwater lakes and rivers. Themedian age of infection is 11 years(range: 8 months–66 years). Recently,the epidemiology of N fowleri PAM haschanged. Since 2010, two cases werereported in Minnesota6,7 and singlecases were identified in Indiana andKansas.6 These findings suggest thatthe geographic range of thisthermophilic organism may beexpanding. In addition, infections havebeen reported in patients exposed tononsterile tap water that was used forsinus irrigation8 or ritual ablution.9

FIGURE 1The relationship between mean arterial pressure (MAP), cerebral perfusion pressure (CPP), ICP, and core body temperature (Temp) during themanagement of a 12-year-old girl with N fowleri PAM. The graph illustrates our management strategy for maintaining CPP .60 mmHg and ICP ,20 mmHg.With induction of hypothermia (7/22/13, 22:00), ICP was sustained at ,20 mmHg. Early attempts to rewarm the patient on 7/24/13 and 7/26/13 led toelevations of ICP. After 5 days of cooling, rewarming the patient was met with minimal elevation in ICP.

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The time from exposure to N fowlerito the onset of symptoms is ∼5 days(range: 1–7 days).5 The initialsymptoms of PAM areindistinguishable from bacterialmeningitis. Patients experience rapiddeterioration, with death resultingfrom brain injury and edemaoccurring within ∼5 days (range:1–12 days). In the 2 weeks beforesymptom onset, our patient swam ina number of locations. Epidemiologicinvestigation by the state healthdepartment suggested that a local

water park was the likely source ofinfection. Water samples from onlythis site tested positive for N fowleri,and our patient developed symptoms7 days after this exposure. Shepresented to the hospital ∼30 hoursafter initial symptoms and wasstarted on recommended therapywithin 36 hours of symptom onset.By comparison, the median time fromsymptom onset to hospitalpresentation for patients with PAM is2 days, and the median time fromsymptom onset to initiation of

recommended therapy is 3 days (CDC,unpublished data). Because N fowleriPAM is rare and not often consideredas a diagnosis, premortemidentification of the ameba is oftendelayed or not attempted, precludingthe timely initiation of recommendedtherapy. Early identification andinitiation of recommended therapyare critical for survival; however, thistime frame is likely affected bymultiple factors, including strainvirulence, inoculum, and hostimmune response.

FIGURE 2Noncontrast axial magnetic resonance images of the patient’s brain with N fowleri PAM. A, The axial fluid-attenuated inversion recovery image shows focaledema in the left frontal lobe (arrow). B, Axial susceptibility-weighted image shows hemorrhage within the left frontal edematous lesion (arrow). C, Axialfluid-attenuated inversion recovery image demonstrates multiple areas of edema in the cerebellum bilaterally (arrows). D, Axial diffusion-weighted imageshows areas of restricted diffusion consistent with acute cerebellitis (arrows).

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The only documented survivor in theUnited States received amphotericinand miconazole intravenously andintrathecally and rifampinintravenously.1,2 The survivor fromMexico received intravenousamphotericin, fluconazole andrifampin.3 Conventional amphotericinhas a lower minimum inhibitoryconcentration compared with theliposomal formulation and is thuspreferred even though the liposomalform has better CSF penetration.10

Other medications such asfluconazole, voriconazole, andazithromycin have shown activityagainst N fowleri.10–12 Studiessuggest that azithromycin may havea synergistic effect when used incombination with amphotericin.13

Recently, the antiparasitic agentmiltefosine has shown in vitroeffectiveness against N fowleri andother clinically important free-livingamebae.11 Although miltefosine hasrecently been used to successfullytreat patients with other free-livingamebae infections,14,15 our patient isthe first to be successfully treated withmiltefosine for PAM. Miltefosine isavailable directly from the CDC fortreatment of infections caused by free-living amebae in the United States.4

Current neuroprotective managementprinciples of brain injuries are basedon maintaining adequate cerebralperfusion, tempering oxygenconsumption, and limiting ICP.16 Thedata suggest that mild to moderatehypothermia (32°C–34°C) may have

neuroprotective effects, includinglowering ICP, reducing production ofreactive oxygen and nitrogen species,reducing proinflammatory cytokinelevels, and preventing neuronalapoptosis.16–18 Clinical studiesevaluating the effects of mild tomoderate hypothermia in patientswith traumatic brain injury andbacterial meningitis have shownconflicting results.19–22

N fowleri initially causes directdamage to surrounding neuronal andother cells through direct cell-to-cellinteraction as well as the release ofa number of cytotoxic proteins.2 Inaddition, cytotoxic proteins releasedby N fowleri and debris from lysedneuronal and other cells generate acascade of proinflammatory cytokines,resulting in hyperinflammation andfurther injury.23 It is possible that thebeneficial effects of hypothermia seenin patients with traumatic brain injuryand bacterial meningitis may alsoattenuate the inflammatory responsethat occurs in patients with N fowleriPAM. Cytokine levels were notmeasured in our patient, and it is thusunclear whether the use of hypothermiaaffected the host inflammatory response.Although N fowleri is a thermophilicorganism, it is also unclear whether thedegree of hypothermia used in ourpatient resulted in reducedpathogenicity of the ameba.

The changing epidemiology ofN fowleri necessitates its inclusion inthe differential of patients withmeningoencephalitis, particularly

those who report a recent history ofswimming in warm fresh water(regardless of geographic location) oruse of nonsterile water for nasalirrigation or ritual ablution. Becauseearly diagnosis and therapy arecritical, laboratory technicians mustbe able to quickly identify amebae onCSF specimens. Prompt initiation ofa regimen including conventionalamphotericin, fluconazole,azithromycin, and rifampin isrecommended (Table 1). Miltefosineshould be added to this regimen assoon as possible. If there are signs ofincreased ICP, we recommendplacement of an external ventriculardrain and administration of intrathecalamphotericin. Elevated ICP should bemanaged aggressively, maintaining an ICP,20 mm Hg. Because dexamethasonewas used in all 3 documentedsurvivors and has shown benefit incentral nervous system insults due toinfectious etiologies,1–3,24 it should beadministered concurrently with theantimicrobial agents. The treatingphysicians should also considerlowering the patient’s core bodytemperature (32°C–34°C) becausethis action may have beneficialeffects beyond lowering ICP.Additional data are needed todetermine the adequate length oftherapy and to determine the effectsof hypothermia in the managementof PAM. Ongoing surveillance andcontinued reporting of PAM casesare needed to continue to learn thebest way to manage these infections.

TABLE 1 Recommended Treatment Regimen for N fowleri PAM

Medication Dose Route Maximum Dose Duration Comments

Amphotericin Ba1 1.5 mg/kg per d in 2 divided doses, then Intravenous 1.5 mg/kg per d 3 d1 mg/kg per d once daily Intravenous 11 d 14-d course

Amphotericin Ba1 1.5 mg once daily, then Intrathecal 1.5 mg/d 2 d1 mg/d every other day Intrathecal 8 d 10-d course

Azithromycin12 10 mg/kg per d once daily Intravenous/oral 500 mg/d 28 dFluconazole3 10 mg/kg per d once daily Intravenous/oral 600 mg/d 28 dRifampin1,3 10 mg/kg per d once daily Intravenous/oral 600 mg/d 28 dMiltefosine13 Weight ,45 kg: 50 mg BID Oral 2.5 mg/kg per d 28 d 50-mg tablets

Weight .45 kg: 50 mg TIDDexamethasone3,24 0.6 mg/kg/d in 4 divided doses Intravenous 0.6 mg/kg per d 4 d

All medications should be started in combination as soon as the diagnosis is suspected. Intrathecal amphotericin B should be initiated if the patient develops signs or symptoms ofincreased ICP, and miltefosine should be started once available. BID, twice daily; TID, thrice daily.a Conventional amphotericin preferred.

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ACKNOWLEDGMENTS

The authors acknowledge theincredible teamwork andcommunication of the countlessmembers of the health care team whoeach played a role in this patient’ssurvival. The authors also thankDr Charles M. Glasier for hisassistance in providing the MRIimages for this case. They are alsograteful for the diligent work of theCDC staff whose contributionsensured timely access to miltefosineonly days before it was needed in thiscase. Finally, they dedicate this reportto Dr Govinda Visvesvara, whodiagnosed the first US survivor ofNaegleria infection 35 years ago andhas worked tirelessly to ensure thatthere would be another. None of theindividuals received compensationother than their salaries.

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originally published online February 9, 2015; Pediatrics Visvesvara, Alexandre J. da Silva, Yvonne Qvarnstrom and Jerril Green

W. Matthew Linam, Mubbasheer Ahmed, Jennifer R. Cope, Craig Chu, Govinda S.Meningoencephalitis

Primary AmebicNaegleria fowleriSuccessful Treatment of an Adolescent With

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