PRES in Children Undergoing Hematopoietic Stem Cell or ...PRES in Children Undergoing Hematopoietic Stem Cell or Solid Organ Transplantation Riccardo Masetti, MD, PhD a, Duccio Maria

PRES in Children UndergoingHematopoietic Stem Cell or Solid OrganTransplantationRiccardo Masetti, MD, PhDa, Duccio Maria Cordelli, MDb, Daniele Zama, MD, PhDa, Francesca Vendemini, MDa,Carlotta Biagi, MDa, Emilio Franzoni, MD, PhDb, Andrea Pession, MD, PhDa

abstract Posterior reversible encephalopathy syndrome (PRES) is a clinicalneuroradiologic entity that is becoming increasingly well known anddocumented in pediatrics. It is characterized by a variable association ofseizures, headache, vomiting, altered mental status, visual disturbances,and seizures, as well as imaging suggesting white-gray matter edema involvingthe posterior regions of the central nervous system in most cases. Thepathophysiology of PRES remains unclear. Although PRES has been associatedwith a widespread range of clinical conditions, namely infections, adversedrug events, autoimmune diseases, and many others, its onset afterhematopoietic stem cell and solid organ transplantation remains the mostcommonly reported. Historically, PRES has proved to be generally reversibleand associated with good clinical outcomes; however, severe complications,sometimes life-threatening, can also occur. Most reported cases of childhoodPRES after hematopoietic stem cell or solid organ transplantation havebeen case reports or series across a broad spectrum of different transplantsettings, and no clear consensus exists regarding how best to manage thesyndrome. Thus, in this article, we provide a comprehensive review of thepathophysiological, clinical, and diagnostic aspects of PRES in children,with a specific focus on the transplant scenario. Differential diagnoses withother neurologic complications after pediatric transplantation are reviewed,and crucial issues in the management of PRES and the development of futureresearch are ultimately addressed.

It has been almost 20 years sincethe seminal report by Hinchey et al,1

which first reported a reversible,predominantly posteriorleukoencephalopathy associated withsubcortical edema without infarction.Today, this defined clinicoradiologicentity is commonly identified asposterior reversible encephalopathysyndrome (PRES). It is characterized bya variable association of seizures,headache, vomiting, visualdisturbances, and impairedconsciousness, typically accompaniedby radiologic findings showinga posterior-predominant pattern of

bilateral gray and white matteredema.1,2 Although PRES is usuallyreversible, it can lead to life-threatening complications andpermanent neurologic damage if notpromptly recognized and treated.3

Since the report by Hinchey et al,1

PRES has been associated with manyother clinical conditions, namelyinfections, drug-related adverse events,and autoimmune diseases.4,5 Inpediatrics, PRES has become knownover the past 10 years as an entityincreasingly diagnosed in differentclinical settings, such as kidneydiseases,6 vasculitis and hematologic

aDepartment of Pediatrics, “Lalla Seràgnoli,” Hematology-Oncology Unit, University of Bologna, Bologna, Italy; andbDepartment of Pediatric Neurology, Sant’Orsola MalpighiHospital, Bologna, Italy

Drs Masetti and Cordelli coordinated the work,supervised the reviewed literature, and drafted themanuscript; Dr Zama contributed to the collection ofdata, the critical revision of the literature, andwriting of the manuscript; Drs Vendemini and Biagicontributed in writing the draft of the manuscriptand created the figures and tables after reviewingthe literature; Drs Franzoni and Pession criticallyreviewed the manuscript; and all authors approvedthe final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-2325

DOI: 10.1542/peds.2014-2325

Accepted for publication Jan 29, 2015

Address correspondence to Duccio Maria Cordelli,MD, Department of Pediatric Neurology, Sant’Orsola-Malpighi Hospital, Via Massarenti 11, 40137 Bologna,Italy. E-mail: [email protected]

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

Copyright © 2015 by the American Academy ofPediatrics

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

FUNDING: No external funding.

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

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mailto:[email protected]

diseases (eg, sickle celldiseases,7 hemophagocyticlymphohistiocytosis8). PRES in adultsand children, however, remainsmostly described as a complicationof both solid organ transplantation(SOT) and allogeneic hematopoieticstem cell transplantation(allo-HSCT).3,6,9 Consistent with theincrease in transplant procedures inchildren, PRES has emerged asa considerable concern forpediatricians involved in this field.

The incidence of PRES in childrenwho have undergone an organ orhematopoietic stem cell transplant(HSCT) has ranged from 1% to10%,3,6,9–11 similar to the 1% to8% rate for adults.10,12,13 Expertise inthe peculiar field of PRES in thischildhood population remainslacking, and it is a topic of growinginterest among pediatricians. Theaims of this review, then, are toaddress from a pediatric prospectivethe many aspects concerning thepathogenesis and clinical andradiologic features of PRES in thesetransplanted children and to providea useful guide for the management ofPRES after transplantation.

PATHOPHYSIOLOGY AND RISK FACTORS

The pathophysiology of PRES remainsunclear and is still debated. Twocompeting theories exist, both ofwhich entail blood-brain barrierdysfunction and leakage of fluid intothe interstitium, leading to thedevelopment of cerebral vasogenicedema.14 The first theory identifieshypertension as the “primummovens.” Specifically, a rapid increasein blood pressure overcomes thecerebral vessels’ autoregulatorymechanism with cerebralhyperperfusion, causing injury to thecapillary bed and vasogenic edema.14

On the basis of this theory, thepredominant involvement of theposterior cerebral area in PRES mightoccur because sympatheticinnervation, which has the abilityto increase the upper limit of

autoregulation, is less represented inthe vertebrobasilar circulationcompared with the carotid system.15

Approximately 20% to 30% ofpatients with PRES have normal oronly slightly high blood pressure.16 Infact, whereas the hypertension/hyperperfusion theory has been themost popular, a second pathogenetictheory of PRES speculates on T-cell/endothelial cell activation, resultingin leukocyte trafficking and systemic/cerebral vasoconstriction andcerebral hypoperfusion (Fig 1).14 Inthese cases, endothelial dysfunctionand subsequent cerebral edema couldbe induced by the cytotoxicity ofimmunosuppressive therapy,infections, and autoimmune diseases.Hypoxia increases endothelialpermeability through the activation ofthe vascular endothelial growthfactor, causing vasogenic edema.Several imaging studies havesupported this hypothesis, revealingbrain hypoperfusion in patientswith PRES.17,18 Neuroimaging studieshave documented vasospasm,hypoperfusion, and ischemia19 andautopsy studies have confirmeda predominance of ischemicmicroinfarcts or cerebralvasculitis.19,20 As a consequence,some authors have hypothesized thatsystemic hypertension could bea reactive and protective responserather than a cause of PRES becauseof the ability to improve perfusionand reduce cerebral edema.14,15 Incontrast, increasing hypertensioncould stimulate cerebralautoregulatory vasoconstriction;and this stimulation, together withtoxicity-induced vasoconstriction,might result in further brainhypoperfusion, inducingischemia.14,21 Finally, vasospasmmight also play a role in the genesis oflocal ischemia and cerebral edema.22

This second theory might be relevantin the transplantation setting, inwhich the putative involvement ofthe vasculature and endothelialdamage to it seem to play criticalroles in the pathophysiology of many

transplant-associated complications,namely microangiopathy, veno-occlusive disease, and graft-versus-host disease (GvHD).23

Peculiarities in the pathophysiologyof PRES are certainly present acrossdifferent transplantation settings.These differences are evidentbetween HSCT and SOT, in both ofwhich endothelial damage andactivation, cytokine release, and T-cellrecruitment can occur throughvarious mechanisms (ie,chemotherapy-induced damagebefore HSCT, onset of acute GvHD,graft rejection, etc). Moreover, itseems that even in SOT, particularlykidney and liver transplantation, thepathophysiology of PRES couldpresent different peculiarities,possibly influencing the respectivetime of onset.21,24

Many triggers and risk factors forPRES after SOT and HSCT have beendescribed. GvHD prophylaxis withcalcineurin inhibitors (CNIs), such astacrolimus and cyclosporine A (CSA),has been recognized as a majortrigger of PRES in patients whounderwent HSCT.25 The use of lowerdoses of the same drugs forimmunosuppressive treatment afterSOT has been credited with loweringthe incidence of PRES in thesepatients.21 Medication withdrawaloften results in the alleviation oftoxicity, despite a frequent lack ofcorrelation in the literature betweencirculating blood levels of CNIs andthe occurrence of PRES.14 In fact, CSAand FK-506 levels have been found tobe in the therapeutic ranges at theonset of many cases of PRES.14,26,27

CNIs could cause direct endothelialdysfunction mediated by enhancedsystemic endothelial activation,leukocyte trafficking, andvasoconstriction or demyelinizationin patients with PRES.

CNI administration was associatedwith chronic hypomagnesemia,25 andmagnesium is a competitiveantagonist of calcium that hasvasodilatatory effects on cerebral

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vasculature, as well as a blood-brainbarrier protective effect. Thus, ithas been suggested thathypomagnesemia might be associatedwith PRES because it enhances CNIneurotoxicity.25,28 There have beenfewer reports of PRES development

in association with otherimmunosuppressive agents usedmainly in SOT, particularlysirolimus.29

Because a high incidence of GvHD hasbeen noted in patients with PRESafter allo-HSCT, acute GvHD has been

suggested to contribute to thepathophysiology of PRES.25,30 Theadministration of fludarabine duringthe conditioning regimen was alsorecognized to be a risk factor forthe development of PRES in adultrecipients after HSCT.31 In a cohort of

FIGURE 1The figure summarizes the 2 competing theories on pathophysiology of PRES, both of which entail blood-brain barrier dysfunction, leading to thedevelopment of cerebral vasogenic edema. The first theory identifies as the “primum movens” a rapid increase in blood pressure that overcomes thecerebral vessels’ autoregulatory mechanism with cerebral hyperperfusion, causing injury to the capillary bed and vasogenic edema. The second theoryspeculates on T-cell/endothelial cell activation, resulting in leukocyte trafficking and systemic/cerebral vasoconstriction and cerebral hypoperfusion. It isreasonable to hypothesize that many of the crucial events described in both the 2 theories could occur concomitantly in a transplantation setting,suggesting a multifactorial hypothesis of pathogenesis. APC, antigen presenting cell; CTL, cytotoxic T lymphocyte; ICAM, intercellular adhesion molecule;IFN, interferon; IL, interleukin; TNF-a, tumor necrosis factor a; VCAM, vascular cell adhesion molecule;

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allo-grafted children, wedemonstrated significantrelationships of the use of steroidsand the use of cord blood as a stemcell source with the development ofPRES.32

With regard to SOT, transplantrejection, cytomegalovirus, andbacterial infections have all beenidentified as being associated withPRES.6,9,10,21 Moreover, the fewstudies available in the literature onthe risk factors significantlypredisposing children who undergoSOT to the development of PRES haverecognized risk factors similar tothose of HSCT, mainly hypertensionand the use of CNI and otherimmunosuppressive drugs such assirolimus.10,21,29

CLINICAL MANIFESTATIONS,DIAGNOSIS, AND COMPLICATIONS

Clinical Features

The onset of symptoms is usuallyrapid, reaching their peak in 12 to48 hours. Prodromes have rarelybeen described and have consistedmainly of tiredness and headache.33

The severity of the clinicalmanifestations varies among patientsand can require intensive caremanagement to support vitalfunctions.2,4 Symptoms of PREStypically improve within 1 week, andcomplete clinical recovery is usuallyobtained earlier than neuroimagingresolution.

Seizures, usually with occipital onset,are the primary, and often presenting,manifestation of PRES.4,34–36 Theyfrequently start with nonconvulsivefocal signs, such as gaze deviation,oculoclonic movements, visualhallucinations, and impairedconsciousness. Evolution toa convulsive, often bilateral, seizure iscommon. Status epilepticus (SE), alsofrequently presenting withnonconvulsive features, has beendescribed in these patients as well.27,37

Other common symptoms of PRES,often associated with seizures, in

descending order of frequency areas follows: nonepileptic visualdisturbances, such as corticalblindness, hemianopsia, and blurredvision; headache, usually bilateral;various grades of impairedconsciousness until coma; and nauseaand vomiting. Only occasionally dopatients with PRES show focalneurologic signs, includinghemiparesis and aphasia.2,31

PRES tends to present earlier inHSCT than in SOT.13,26 In a series ofadults with PRES after allo-HSCT, themedian time to onset was 30 days,with 82% of cases developing PRESwithin 100 days.13 Consistent withthese data, we reported a series of14 allo-grafted children with PRES,11

of whom all but 1 patient developedPRES during the first 100 days afterHSCT, with a median time of 65 days;in 1 case, PRES occurred at day 352.

In contrast, research has documenteddifferences in PRES onset afterliver and kidney transplantation.21

Specifically, PRES appeared tooccur within 2 months after livertransplantation and was associatedwith mild rejection, cytomegalovirus,or systemic bacterial infection. Incontrast, patients who underwentkidney transplantation developedPRES after $1 years, coinciding withmoderate rejection or bacterialinfection.9,10,21,38 Ghosh et al6 alsodescribed a case of early onset ofPRES within 2 weeks after a pediatrickidney transplant.

Neuroimaging

MRI is the gold standard for thediagnosis of PRES. The typical lesionin PRES consists of vasogenic edema,located predominantly in thesubcortical white matter withfrequent involvement of the cortex(Fig 2A). These lesions show a highsignal on T2-weighted images andfluid attenuated inversionrecovery(FLAIR) sequences: the lattersequences are more sensitive for thedetection of subcortical and corticallesions.39 Diffusion-weighted imaging

is required to differentiate PRES fromischemic stroke. In the majority ofpatients the administration ofgadolinium chelates does not revealany contrast enhancement of thebrain tissue; nevertheless, in somecases, it may show mild signs ofdisruption of the blood-brain barrier.Although gadolinium can be helpfulto exclude possible differentialdiagnosis (progressive multifocalleukoencephalopathy, opportunisticinfections), its administration has tobe carefully evaluated in transplantedchildren at high risk of acute and/orchronic renal failure.

Most patients show involvement ofboth hemispheres,1,39–41 sometimesasymmetrically. Predominantlyparieto-occipital involvement isusually observed (from 50% to99% of cases), whereas the frontaland temporal lobes are affected inhalf of cases.1,39,42 The cerebellum,basal ganglia, and brainstem areinvolved in approximately one-thirdof cases.

As transplanted children can presentwith a wide spectrum of acuteneurologic complications, theevaluation with MRI is fundamentalto obtain a secure diagnosis of PRES.However, computed tomography(CT) is usually the first investigationrecommended for children withacute neurologic complications aftertransplantation, mainly to excludehemorrhagic events related or not toPRES. Unfortunately, the CT findingsin PRES are sometimes normal ornonspecific. A study comparing thedifferent sensitivities of bothassessment modalities after PRESfound negative or nonspecificradiologic patterns on CT scans inmore than half of patients, whereasMRI was able to detect typical PRESlesions in all the cases.40

EEG

Performing EEG at the onset ofneurologic symptoms in children whohave undergone transplantation is animportant tool for distinguishing


between an epileptic and nonepilepticnature of specific neurologic signs.Intercritical EEG recordings duringthe acute phase of PRES often revealencephalopathic changes, such asfocal slowing and/or periodiclateralized epileptiform dischargesinvolving unilateral or bilateralparieto-occipital or temporal-occipitalregions.43 EEG could be particularlyuseful to diagnose nonconvulsive SE.

In nonconvulsive SE due to PRES, EEGusually shows continuous or near-continuous rhythmic epilepticdischarges involving unilateral orbilateral parieto-occipital or temporo-occipital regions27 and associatedwith subtle clinical signs, such as gazedeviation and altered mental status.Considering the difficulty indiagnosing nonconvulsive SE, wesuggest EEG monitoring for detectingsubtle electrographic seizures inpatients with suspected PRES.

Laboratory Tests

Laboratory tests are recommended toexclude metabolic disturbances andelectrolyte imbalances, namelyhyponatremia, hypocalcemia, andparticularly hypomagnesemia.Furthermore, renal and liver function,as well as the dosages of plasmalevels of immunosuppressant agents,should be evaluated. The coagulativefunction must be investigated due tothe possible risk of hemorrhagiccomplications.44 Cerebrospinal fluidfindings are not specific in PRES;however, lumbar puncture should beperformed in children with fever orclinical suspicion of meningitis toexclude central nervous system (CNS)infections.

Complications

Although considered to be a benignself-limited entity, sometimes theoccurrence of PRES has been

described in association withpotential life-threatening events.Severe cerebral hemorrhage,cerebellar herniation, and refractorySE have been reported ascomplications in some patientsdiagnosed with PRES. These eventsmay not be always directly caused byPRES, but they can share with PRESmany pathogenic aspects. Cerebralhemorrhage is reported to beassociated with PRES in 5% to 19%of cases41,42,44 and usually manifestsas parenchymal hematoma, smallhemorrhages ,5 mm in size, orsubarachnoid hemorrhage.Intracerebral hemorrhages (ICHs) inthe context of PRES are usually small,but lethal cases associated withmassive ICHs have been described.45

The risk of ICH is significantly higherafter allo-HSCT than after SOT, andpatients receiving therapeuticanticoagulation were statisticallymore likely to develophemorrhages.45

Other studies have supporteda relationship between PRES andassociated ICH and bleeding diathesisor coagulopathy in both the HSCT andSOT settings.44,46 In our experience,20% of patients with PRES afterallo-HSCT presented with cerebralhemorrhage47 (Fig 2C). None of thesepatients presented with bleedingdiathesis at the time thatcomplications emerged.

A rare but catastrophic complicationof PRES is the occurrence ofcerebellar herniation (Fig 2D) asa consequence of severe edema ofthe posterior fossa structures(cerebellum and brainstem).45 Weobserved this complication in 2 of26 patients.47 In both patients,cerebellar edema was present fromthe beginning of PRES, suggestingthat patients with cerebellar orbrainstem involvement should beclosely monitored for the appearanceof neurologic signs and symptoms ofcerebellar herniation, such asneurologic deterioration, gradualconsciousness impairment with

FIGURE 2A, FLAIR T2-weighted MRI image of typical bilateral posterior vasogenic edema during the acutephase of PRES. B, Complete resolution of the vasogenic edema. C, CT scan showing a hemorrhagiccomplication of PRES in the right hemisphere. D, T2-weighted MRI image of cerebellar swelling andherniation during PRES.


hypotension, and bilateral mydriasis.A prompt diagnosis of thiscomplication is essential because ofthe possible need of neurosurgicalposterior fossa decompressionand/or placement of a ventriculardrain.

Finally, another possiblecerebrovascular complication ofPRES, until now reported only insettings other than pediatrictransplantation, is the development ofcerebral ischemic stroke. Thiscomplication has mainly beendescribed in adult patients, and thefew cases reported showed pooroutcomes.46,48

DIFFERENTIAL DIAGNOSIS

PRES occurring after HSCT or SOTmust be distinguished from otheracute neurologic complications,namely CNS infections, metabolic

disturbances (electrolyte imbalancesor multiple organ failure),cerebrovascular disorders, and CNSinvolvement by an underlyingdisorder (Table 1).9,11,13 Thefrequency of transplant-relatedcomplications differs depending onthe type of transplant. In the contextof pediatric liver or combined liverand small bowel transplant,38 themost frequent causes of neurologicdisorders described in the literatureinclude metabolic encephalopathy,followed by PRES, CNS infection, andcerebrovascular accident. With regardto renal transplantation, PRESassumes a major role in the onset ofneurologic complications, followed byCNS infection and hypertensiveencephalopathy.6

PRES represents the main etiology forneurologic complications afterpediatric allo-HSCT.3,11,49,50 Othercauses of neurologic disturbances, in

descending order of frequency,include the following: CNS infection,CNS involvement by the underlyingdisease, encephalopathy of unknownorigin, metabolic disturbances, orneurotoxicity of certain drugs(ie, busulfan).

Instrumental, radiologic, andlaboratory findings can helpdifferentiate PRES from othercommon complications aftertransplantation. Ictal and/or postictalabnormalities on EEG (rhythmicepileptiform activity, periodiclateralized epileptiform discharges,and/or slowing) in the posteriorregions of the brain are particularlysuggestive of PRES.27

Although cerebral images are usuallynormal or scarcely informative incases of metabolic derangement orCNS involvement by hematologicdisease, CNS infections are associated

TABLE 1 Differential Diagnoses of PRES in Transplanted Children

PRES CNS infections Neoplastic (PTLD) Stroke PML

Type oftransplantation

All All All Ischemic: heart . otherSOT . HSCT

All

Hemorrhagic: HSCT . SOTTiming after

transplantationMostly ,100 d in HSCT Bacterial: ,30 d Usually delayed Perioperative or later Delayed (.6 mo)May be delayed in SOT Viral and others: .30 d

Type of onset Acute Acute/subacute Subacute Acute SubacutePresenting

signs/symptomsSeizures (often

nonconvulsive and SE)Mental status changes Mental status changes Focal neurologic signs Mental status

changesVisual symptoms Fever Headache Seizures (often hemiclonic) Focal neurologic

signsHeadache Headache SeizuresMental status changes Seizures

Location/pattern Subcortical WM/cortical,usually bilateralposterior lobes 6 otherlobes 6 brainstem andcerebellum

WM focal, multifocal, ordiffuse 6 cortical(depending on the type ofmicroorganism)

WM focal or multifocalmasses, meninges

Ischemic: unilateral WM/cortical

WM multifocal

Hemorrhagic: unilateralbleeding

NeuroimagingCT scan Normal or low-density Normal or low-density Normal or low-density Low-density or bleeding Normal or low-

densityConventional MRI High T2 signal High T2 signal Low or high T2 signal High T2 signal High T2 signalContrast Nonenhancing Enhancing Peripheral enhancing Nonenhancing NonenhancingDWI Normal Variable Restricted Restricted Normal

Laboratory findings Often hypomagnesemia Blood cultures and PCRsometimes diagnostic

Often not significant Ischemic: not significant Not significantHemorrhagic: bleeding

diathesisCSF findings Not significant Often diagnostic Rarely diagnostic (cytology) Not significant PCR for JCV often

diagnosticEEG features Rhythmic spikes (NCSE),

PLEDs, and/or slowing inthe posterior regions

Diffuse or focal slowing Sometimes focal slowing Unilateral PLEDs and/orslowing

Sometimes focalslowing

CSF, cerebrospinal fluid; JCV, John Cunningham Poliomavirus; NCSE, nonconvulsive status epilepticus; PCR, polymerase chain reaction; PLED, periodic lateralized epileptiform discharge;PML, progressive multifocal leukoencephalopathy; PTLD, posttransplant lymphoproliferative disease; WM, white matter.


with heterogeneous, but suggestive,imaging findings spanning from anabscess lesion, a focal lesionsurrounded by perilesional edema(ie, in the case of a cerebral Epstein-Barr Virus (EBV)-posttransplantlymphoproliferative disorders), ordiffuse edema.11 In bacterialmeningitis, abnormal thickening andenhancement of the leptomeningesare detectable on MRI with contrastenhancement. In the case of CNSaspergillosis, CT or MRI can detectvasculopathy and multiple septicinfarcts involving the basal ganglia,thalami, and the corticomedullaryarea, often in association withhemorrhage and abscess formation.51

In patients with clinical suspicion ofCNS infection or involvement byhematologic disease, cerebrospinalfluid analysis and related bloodexaminations are useful in reachinga diagnosis. Diffusion-weightedimaging is required to differentiatePRES from cerebrovascular disorders,such as ischemic stroke.

OUTCOMES

The clinical and radiologicreversibility of PRES has beenextensively described since its firstdescription,1,33 but over the years,the recognition of nonreversible caseshas revealed the heterogeneousevolution of this syndrome.52–54

Globally, limited and conflicting dataare available on functional outcomes.Some authors have reported goodoutcomes in children with PRES afterSOT or allo-HSCT because all of theirpatients recovered from symptomsand none developed neurologicabnormalities.6,11,26 However, otherstudies have noted the presence ofresidual or late-onset neurologicsequelae or epilepsy secondary topermanent brain lesions.4,52

The impact of PRES on survival ratesis particularly difficult to definebecause the relative effects of PRESand other factors (baseline disease,therapies) remain unclear. Moreover,data concerning mortality rates after

PRES have derived mainly from casereports or small retrospective studies,from which it is difficult to drawaccurate conclusions.

Our pediatric patients who developedPRES after allo-HSCT had a highermortality rate than patients who werefree from neurologic disturbances(5-year survival: 32.3% vs45.8%).11,32 This finding was alsoemphasized in a large study ofallo-HSCT in adults.13

RECOMMENDATIONS FORMANAGEMENT AND FOLLOW-UP

Supportive care is the cornerstone oftreatment of patients with PRES afterSOT or HSCT. The management ofthese patients can require an ICU orintermediate care unit admission toallow for continuous monitoring ofvital and cerebral functions and, inparticular, to avoid the upper airwayobstruction and respiratory failurethat can occur in patients withimpaired consciousness or seizures(Fig 3). Antiepileptic drugs (AEDs)should be administered as early aspossible to control ongoing seizures.Benzodiazepines (diazepam 0.5mg/kg given rectally [maximum of10 mg] or intravenous midazolam0.1–0.2 mg/kg over 2–3 minutesfollowed by continuous infusion atrates of 0.5–2 mg/kg per minute,titrated to efficacy) are often used asfirst-line agents. In patients withrefractory seizures, intravenousphenytoin (15–18 mg/kg at a rate of1 mg/kg per minute; maintenance at5 mg/kg per day divided twice daily)or phenobarbital (10–15 mg/kg ata rate of 1–2 mg/kg per minute;maintenance at 5 mg/kg per daydivided twice daily) or an anestheticwith anticonvulsant effects, such aspropofol or thiopental, might berequired. We suggest obtaining anEEG as soon as possible at the onsetof neurologic signs/symptoms; inaddition, serial EEG recordingsshould be obtained during the acutephase to monitor treatment efficacyand to investigate for the presence of

nonconvulsive seizures. Hereafter,EEG follow-up is not required inpatients who fully recover after PRES.

A particularly controversial issue isthe duration of antiepileptic therapyafter PRES. In most studies, AEDswere discontinued after the patientswere seizure-free for at least 3 to6 months.4 Other studies, however,have suggested continuing AEDs ona longer-term basis.52 Consideringthe occasional or provoked natureof seizures, our practice is toadminister prophylactic treatmentwith AEDs (benzodiazepines and/orphenytoin) only during theacute phase of the neurologiccomplications. We then discontinueAEDs upon MRI evidence of edemaresolution.11 We believe thatprolonged prophylactic treatmentwith AEDs is unnecessary in patientswith occasional or provoked seizuresdue to PRES, but it should beconsidered in cases of laterdevelopment of secondary epilepsy.

Blood pressure is commonlymeasured at least once per day inpatients undergoing transplantation,but in case of PRES the monitoringshould be switched to a moreintensive way and tailored accordingto specific clinical conditions. Littlepediatric experience is available onthe best pharmacologic approach forlowering blood pressure in childrenwith PRES. In the case of severehypertension during the acute phaseof PRES, blood pressure should belowered gradually after excludingcerebral infarction. Arterial pressureshould be reduced by ∼25% withinthe first hour, followed bysubsequently slower reduction.55

Indeed, a sudden reduction in bloodpressure is not recommendedbecause it can worsen the cerebralperfusion pressure and promoteischemic lesions. In these cases,vasodilators (sodium nitroprusside:0.53–10 mg/kg per minute viaintravenous infusion56) and calciumchannel blockers (nicardipine:1–3 mg/kg per minute via


intravenous infusion56,57) arecommonly used antihypertensiveagents.

In nonemergency cases specificclasses of antihypertensive drugsshould be used preferentially becausetransplanted children are at risk ofspecific comorbidities such as renalfailure or being exposed toconcurrent medical conditions.Examples include the use ofangiotensin-converting enzymeinhibitors (enalapril: 0.08 mg/kg perday administered orally up to 5mg/day, once or twice a day56) in

children with concomitantproteinuric renal diseases.

After the clinical recovery of PRES,patients should be treated forhypertension until predisposing riskfactors are present. In any case theefficacy of antihypertensiveprophylaxis to prevent PRESrecurrence is not documented.

In an attempt to remove potentialpromoting factors, patients should beevaluated for metabolic disturbances,particularly hypomagnesemia, and forbleeding diathesis, either of whichcan require prompt correction.44

Upon the occurrence of PRES, inmost studies, ongoing CNI treatmentwas discontinued, and a differentimmunosuppressant agent wasintroduced (CSA to tacrolimus, orvice versa), with monitoring ofthe drug level according to theindividual GvHD and rejectionrisks, respectively.13,31,58

Discontinuation of other agentspotentially involved in PRESpathogenesis should be considered(Table 2).

Neuroimaging is also needed uponthe appearance of symptoms toobtain a correct diagnosis. CT isusually the first investigationrecommended at the onset of anacute neurologic complication aftertransplantation, mainly to excludehemorrhagic events. Nevertheless,MRI must be performed to definesecure diagnosis and the extentof encephalopathy. Moreover,neuroimaging must be obtainedduring PRES, at the appearance ofnew focal neurologic deficits and/orat the occurrence of neurologicdeterioration, to excludecomplications, such as ICH andcerebral herniation. Patient follow-up using neuroimaging studies hasbeen controversial. Some authorshave reported that in the presence oftypical initial imaging findings andclinical presentation withsubsequent total clinical recovery,a follow-up study is redundantbecause there is strong evidence inthe literature of the reversible natureof cerebral lesions.58 However, asmentioned above, PRES can lead topersistent brain damage.41 The idealtiming for repeat brain imaging todocument radiologic recovery isunclear, although improvements inabnormalities have usually beenreported 7 to 15 days after symptomonset.26,31

PROSPECTIVES

Although substantial advanceshave been made in recent yearswithin the transplantation

FIGURE 3Diagnostic and management flowchart for PRES in transplanted children. BP, blood pressure; HR,heart rate; NCSE, nonconvulsive status epilepticus; PML, progressive multifocal leukoencephalop-athy; PTLD, posttransplant lymphoproliferative disease.


community in the recognition andmanagement of PRES, severalquestions remain unanswered. Therisk factors predisposing one todeveloping PRES remain an openissue. The modification ofidentifiable risk factors before orduring transplantation wouldsignificantly impact the outcomes.Few studies involving large series ofpatients and variables areavailable.13,32

A significant role of hypertension inthe onset of PRES has been suggestedacross different transplant settings,but the exact nature of this roleremains unclear; clarification wouldhave significant implications fortransplant patients, who are usuallyexposed to drugs that promotehypertension. Other potentialpromoting factors, such as baseline

disease, electrolyte abnormalities,concurrent infections, and plasmalevels of CNIs, have not yet beenelucidated. Moreover, researchershave yet to identify a circulatingserologic biomarker possiblyimplicated in the development ofPRES. Many candidates are ofpotential interest: inflammatorycytokines, such as tumor necrosisfactor a, interleukin-1, andinterferon-g; markers of endothelialactivation, such as p-selectin,e-selectin, intercellular adhesionmolecule 1, and vascular celladhesion molecule 1; andendothelin-1 upregulation.

The role of neuroimaging in thediagnosis of PRES has been welldefined; nevertheless, it would beinteresting to investigate whethernew functional neuroimaging

methods, such as magneticresonance (MR) perfusion,arterial spin-labeled MR, and MRspectroscopy, could play majorroles in understanding thepathophysiology of PRES.

Once a diagnosis has been made, thewithdrawal or modification ofimmunosuppressive drugs is theprimary matter of concern fortransplant physicians. Studiesfocusing on the reliable switching ofimmunosuppressive drugs and theidentification of a safe alternativeimmunosuppressant regimen,although challenging to conduct,would have undisputed importancebecause for both HSCT and SOTthe availability of relatively newdrugs (ie, belatacept or mammaliantarget of rapamycin [mTOR]inhibitors) for allograft rejectionand GvHD prophylaxis are nowencouraging the development ofa variety of alternative combinationsof immunosuppressive schedulesto be studied. Moreover, eachpediatric transplant communityshould emphasize the developmentof a uniform managementstrategy for PRES in terms of theoptimal timing for reevaluationwith MRI and subsequent follow-up.

Pediatricians who care for childtransplant patients have certainlybecome increasingly accustomed torecognizing and managing PRES overthe years. Nevertheless, PRESremains an intriguing and evolvingmatter of interest in the field ofneurologic complications afterpediatric organ or hematopoieticstem cell transplantation, and newknowledge is needed.

ACKNOWLEDGMENTS

We thank Dr Francesco Toni for hisuseful support in neuroimagingreview. We also thank FondazioneUmberto Veronesi (Milan) (R.M.) andFamiglie Neurologia Pediatrica(Bologna) (D.M.C) for theircontinuous support of our researchactivity.

TABLE 2 Drugs Associated With PRES of Potential Use During Transplantation

Drugs Source

Cytotoxic agentsAntimetabolitesGemcitabine Bartynski (2)Cytarabine Bartynski (2)Methotrexate Dicuonzo et al (59)Fludarabine Beitinjaneh et al (31)

Monoclonal antibodiesRituximab (anti-CD20) Zito et al (60)Infliximab (anti-TNF-a) Zamvar et al (61)Alemtuzumab (anti-CD52) Cooksley et al (62)

Immunosuppressive agentsCNIsCyclosporine Bartynski et al (25)Tacrolimus Hammerstrom et al (63)

mTOR inhibitorsRapamicine Qin et al (64)Sirolimus Moskowitzet al (65); Bodkin and Eidelman (66)

Purine analogsAzatioprine Facchini et al (67)

AntibioticsLinezolid Nagel et al (68)Ciprofloxacin Ali (69)

Growth factorsGranulocyte-stimulating factor Stübgen (70)Erythropoietin Delanty et al (71)

ImmunoglobulinsHuman immunoglobulins Belmouaz et al (72)Antilymphocyte globulin Greaves et al (73)

MiscellaneousCorticosteroids Zama et al (32); McKinney et al (42)Intravenous contrast agents McKinney et al (42)Carbamazepine Furuta et al (74)Epinephrine Gharabawy et al (75)

mTOR, mammalian target of rapamycin; TNF, tumor necrosis factor a.


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THE HIGH COST OF TIPPING: The other day I took a young friend of mine out todinnerataverycasualestablishment.Weordereddrinksand foodat thebarandputthe number given to us by the barkeeper by our seats at a large communal table.A few minutes later the server brought us our food. At the end of dinner I clearedour dishes and then went to the bar to pay. The barkeeper typed in a few items onthe iPad and pushed it to me to sign. Generally speaking, I am a reasonably generoustipper but I was perplexed. The iPad showed I could automatically add 25%, 30%, or35% to the bill (the percentage was based on the total bill including the tax which inBurlington, Vermont is 10%). To enter another number I would have to calculate theamount on my own and manually enter it into the iPad.As reported in The New York Times (Business Day: January 31, 2015), tip creep iscommon. In the1940s,a10%tipwasthenorm.A15%tipat sitdownrestaurantshasbeen considered the norm formany years. However, nowmost feel that 20% iswhatis expected. Nowadays, restaurants, cab drivers, coffee shops and anyone usingubiquitous electronic payment tools offer automatic tipping options that generallyinclude much more generous tips. For example, after purchasing a cup of specialtycoffee, thebuyermaybeofferedtheoptionof tipping$1,$2,or$3–whichcouldmeana tip of 75%. Several ofmy children haveworked very lowwage jobs, so I amagreatsupporter of raising the minimum wage, but I am still having a bit of trouble withsometippingsuggestions.Fortunately, Icanmultiplyby10%inmyheadveryquicklyand always carry some bills in my wallet so, if confronted with a suggested tipamount with which I do not agree, I have options other than blindly accepting.

Noted by WVR, MD


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TransplantationPRES in Children Undergoing Hematopoietic Stem Cell or Solid Organ

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