DOI: 10.1542/neo.13-4-e2332012;13;e233 Neoreviews Jeffrey M. ChinskyHydranencephaly: Transillumination May Not Illuminate Diagnosishttp://neoreviews.aappublications.org/content/13/4/e233located on the World Wide Web at: The online version of this article, along with updated information and services, isISSN: 1526-9906. 60007. Copyright 2012 by the American Academy of Pediatrics. All rights reserved. Online the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,it has been published continuously since . Neoreviews is owned, published, and trademarked by Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from Hydranencephaly:Transillumination May NotIlluminate DiagnosisJeffreyM. Chinsky, MD,PhD*AuthorDisclosureDrChinskyhasdisclosednonancialrelationshipsrelevanttothisarticle. Thiscommentarydoesnotcontain a discussion ofanunapproved/investigativeuseofa commercial product/device.AbstractHydranencephaly describes the condition of extensive absence of cerebral tissue that isreplaced by a saclike accumulation ofuid. Itrst may be suspected by neonatal bed-side transillumination, which is a screening tool but is not diagnostic. When noted atbirth, it is imperative to rapidly distinguish this condition from extensive hydroceph-alus, holoprosencephaly, large porencephalic cyst, and other conditions so that thoseconditionswithindicationsforprompttreatmentareidentied.Anillustrativecaseof hydranencephaly is presented with discussion of imaging techniques to distinguishbetween the diagnostic possibilities. Etiologies of the neuropathology of hydranence-phaly are discussed. The importance of distinguishing this condition, with an associ-atedpoor prognosis, fromextensive hydrocephalus, withpotential for improvedprognosis with early shunting procedures, is emphasized.Objectives Aftercompletingthisarticle, readersshouldbeableto:1. Describetheutilityandlimitationsofbedsideneonatalskulltransilluminationinscreeningforhydranencephalyandothercerebralanomalieswithextensiveabsenceofcerebraltissue.2. Describethedifferencesbetweenhydranencephaly, extensivehydrocephalus, andholoprosencephalyonbrainimaging.3. Explainthelikelydiverseetiologiesfortheneuropathologyassociatedwithhydranencephaly.4. Discussthedifferenceintherapeuticapproachestowardhydranencephalyversusextensivehydrocephalus.IntroductionHydranencephaly is a rare congenital anomaly of the brain that often presents difculties ininitial diagnosis and treatment strategies. It is one of several conditions to be consideredwhen newborn transillumination reveals marked absence of cerebral tissue. The followingcase example illustrates typical difculties that may be encountered.A 25-year-old gravida 3 para 2002 woman presented to the emergency department ofa community hospital with abdominal pain and no history of prenatal care. She was deter-mined to be in active labor with likely spontaneous rupture of membranes about 28 hoursbefore delivery. Bedside ultrasound demonstrated probable term intrauterine pregnancy invertex presentation. Because of reported previous history, cesarean delivery was performedbut required vacuum assistance to deliver the head. Routine stimulation and bulb suction-ing resulted in a good cry, leading to pink color and spontaneous movement of all fourextremities. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. An overtly largehead with widely splayed sutures was noted and the infant was transferred to the NICU forfurther evaluation. The infant weighed 3215 g and her length was 49 cm, both at the 50th %tilefor an estimated 38 weeks average for gestational age (AGA) infant. However, her head cir-cumference was 38.5 cm, >99th %tile. The sutures were markedly split: metopic at least 2 cm,coronal at least 1 cm, and the lambdoid sutures at least 3 cm split. Transillumination of theinfants head (see Fig 1) demonstrated extensive illumination throughout all areas of the skull.Thendings of the funduscopic examination were normal. Thendings of the physical ex-amination otherwise were normal, with the exception of mild dysmorphic features including*DepartmentofPediatricsandInstituteofGeneticMedicine, JohnsHopkinsUniversitySchool ofMedicine, Baltimore, MD.Article genetics/dysmorphismNeoReviewsVol.13No.4April2012 e233 at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from minimally hyperteloric upslantingpalpebral ssures, low-set but nor-mal ears, right hand transversecrease, and bilateral mildfthngerclinodactyly. The neurologic exami-nationndings were normal, includ-ing all normal neonatal automatisms.All maternal serologies werenor-mal. Infant cordvenous bloodpHwas 7.23, andcordarterial bloodpHwas 7.18. Subsequent arterialblood values were pH7.30, pO281 mm Hg, pCO2 52 mm Hg, butthese normalizedwithin24hours.Completebloodcell countandse-rumchemistrieswerenormal. Bed-sideheadultrasoundndingswerereported as a largeuid-lled cranium, consistent with hy-drocephalus with no visualization of normal cerebral hemi-spheres. A midline septum suggestive of falx cerebri andmidlineechogenicsoft tissuesuggestingintactthalamiandbrainstemtissues were noted. ConsultationwithbothPediatric Genetics andNeurology services sug-gested a differential diagnosis of severe hydrocephalus, hol-oprosencephaly, and hydranencephaly. Follow-up brainMRI results (see Fig 2) did notclearly differentiate hydranence-phalyversusextremelyseverehy-drocephalus. Only single vesselscouldbeidentiedonbrainMRIwhichwereconsideredtobethebasilar artery with no additional ves-sels of the circle of Willis. Subsequentbraincomputedtomography (CT)(see Fig 3) conrmed the most likelydiagnosis as hydranencephaly. Kar-yotype, comparative genomic hy-bridization microarray analysis,and 7-dehydrocholesterol levelswerenormal. Thetherapeuticplanfocused on comfort care and plansforhomehospice. Overthenextfewdays,theinfantprogressivelydeveloped exaggerated move-ments of the upper and lowerextremities andoverall increasedjitteriness. Intermittent vocaliza-tions and infant cries were odd,and occasionalsun setting of eyeswas noted. Feeding advancementwas slow, withasmall amount ofbottle-feedingattained, but most feedingsrequiredtheuse of a nasogastric tube. The infant was discharged fromthe hospital at 25 days of age with a weight at the 50th %tile, and a length at the 38th %tile. The head circumferencewas 43.5 cm(>99th %tile for age) with noted gain of 5 cmin 3.5 weeks. The patient developed overt seizures by 6weeksofageassociatedwithanadditional 3-to4-cmincrease in head circumference. She was started onFigure1. Transilluminationofneonatewithmacrocephalyandsplitsutures. Extensiveilluminationtoboththefrontalandoccipitalprominenceswasnoted.Figure2. BrainMRI of describedneonatesuggestinghydranencephaly. A. Saggital T1brainMRI sectionsdemonstratedtheabsenceof themajorityof cerebral hemispherictissues, butpreservationofcerebellar andmidbraintissues. Withinthecerebral areas,strandedsignals(whitecurvilinear signalsinseaofgrey) couldnotbeinterpretedaseither remnantsofcerebral tissuesor sometypeofseptatedtissue. B. Representativebrain T2 axial MRI image. Axial sections were difcult to interpret with very hyperintensesignal intensities, but suggested that majority, if not all of cerebral tissue space, was lledwith uid rather than tissue. It was suggested that the uid was more proteinaceous thanusual,accountingfortheheterogeneous hyperintenseT2 signal(white)distribution.genetics/dysmorphism hydranencephalye234NeoReviewsVol.13No.4April2012 at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from anticonvulsants (Keppra), but the overall seizure patternworsened. She underwent ventriculoperitoneal shuntplacement at 8 weeks of age, when the head circumfer-encewas 50cm(total 12-cmincreaseover 8weeks,more than twice the normal rate for head circumferencegrowth). She was noted to have panhypopituitarism in-cludingdiabetes insipidus followingventriculoperito-neal shunt placement and was placed on hormonalreplacement therapy. At this time, it was notedthatshe had developed multiple small (15 mm in size) skinhemangiomas (>15) over herscalp,arms,legs,hands,abdomen, external genitalia, and foot. A variant of therecently described PHACE syndrome, encompassing theassociationof posterior fossamalformations, hemangio-mas, arterial anomalies, cardiac defects, eye abnormalities,sternal cleftand/orsupraumbilical raphe(previouslyre-ferredtoasPHACESsyndrome), wassuggestedasapossibleetiologyforthemultiplehemangiomaswithhydranencephaly. The infant survives during her secondyear after birth in home hospice care.CaseinContextThis case typies the complexity of treatment issues asso-ciatedwithnewborns withhydranencephaly, knowingthatthemajorityof patientswill diewithinthe rst2years after birth, but occasionally longer survivals are re-ported even into the third decade. (1)(2) It is a diagnosisthat mayrst be suspected by macrocephalic appearance,but many hydranencephalic neonates do not exhibit overtmacrocephaly or split sutures. Neonatal skull transillumi-nation is a simple bedside tool that uses any high-intensitylight source applied directly over the open fontanelles orsutures. Complete skull transillumination, sometimeseven with red retinal reverse reex, may be noted withhydranencephaly, but other conditions needconsider-ation. (3)(4) The suggestion of some cerebral tissue lim-itingsuchcompletetransilluminationmayconfusethediagnosis. Additionalneuroimaging is mandatedto dif-ferentiate hydranencephaly, whichmay be consideredanuntreatableconditionwithrespecttooutcome, andextremehydrocephalus, whichisusuallyapproachedasa treatable condition with potential for benet frominter-vention (see Figs 4 and 5). (5)(6)(7) Lack of cerebral tis-sue may also reect a formof holoprosencephaly, which isusually dened as alobar, semilobar, or lobar holoprosen-cephaly depending on the presence, type, and amount ofresidual cerebral hemispheric brain tissue and the extentof absence of interhemisphericssure and other abnor-malities (see Fig 6). Often, holoprosencephaly is associ-atedwithanidentiable systemic etiology, suchas achromosomal anomaly (common in trisomy 13), or de-ned genetic syndrome, such as the Smith-Lemli-Opitzspectrum. Therefore, the patient was screened for theseanomalies, despite not having any of the associated syn-dromic features of either.The question of whether or not to immediately refersuch neonates with extensive transillumination to a neu-rosurgical specialist for shunting therefore depends uponthedenitionof thespecicbrainanomaly. Asinthiscase, manypreferbrainMRIasthefollow-upimagingof choice, because it provides more detail of the brain pa-renchyma than CT scan (or cephalic ultrasound). How-ever, difcultyintheinterpretationof somesignals asremnants of cerebral tissue often mandates additional im-aging with brain CT imaging, which may be very helpfulin establishing comfort with the diagnosis of hydranence-phaly. (8)(9)(10)(11)(12) More extensive CT angiogra-phystudies (felt superior toMRangiographytolimitFigure3. Axial headCTimagingof neonatewithextensivetransillumination.AD.SeriesofaxialheadCTimagesdemon-stratedtheabsenceofsupratentorialbraintissuewithineitherhemisphere, replaced by a large uid-lledcavity. The falx wasvisualized(seepanelsAandB) mostnotablyposteriorlywithsomeindicationsofbeingevidentintheanteriorandinferiorregions(notshown).Infratentorialregion(seepanelsCandD)demonstratedthecerebellumwithprominentCSFspaceposte-rior to the cerebellum. These ndings are most compatible withhydranencephaly.genetics/dysmorphism hydranencephalyNeoReviewsVol.13No.4April2012 e235 at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from motion artifacts) to identify abnormal patterns of cerebraland brainstem vessels may be available at certain tertiarycare pediatric institutions as well. (10) If it is felt that theimaging reveals extensive or extreme hydrocephalus,most agree that early ventriculoperitoneal shunting is in-dicated (see Fig 4), whereas hydranencephaly and holo-prosencephalymaynot leadtothat interventionwithrespect to consideration of benecial outcomes. (5)Theextensivecounselingissueswereevidentinthiscase, because the prognosis is grim and there are no clearparameters for improving outcomes or predicting lengthsof survival with or without ventriculoperitoneal shuntingintervention. For hydranencephaly, postnatal excessiverateof headcircumferencegrowthistypical, asinthiscase, andventriculoperitoneal shuntingmaybeofferedtolimiteventual headsizeforcomfortandeasiercare.Clinical progression, however, is generally unaffected,manifestingneurologicabnormalitiesassociatedwithfailureinthedevelopmentof normal cerebrocorticalinhibitoryprocesses. Over time, thepatients usuallydemonstrate irritability, hyperre-exia, hypertonia, quadriparesis, anddecerebrateposture. EEGs maybenormal at rst but with time, infantilespasms, seizures anddisconjugateextraocular movements are usuallyevident. Brainstemauditory-evokedresponsesarepreserved, butvisual-evokedresponses are absent. (13)(14) Lengths of survival may be veryvariable, most not surviving past2 years of age but surprisingly lon-ger periods of survival havebeenreported. (1)(2)DiscussionHydranencephaly is a rare congeni-tal brain anomaly occurring approx-imatelyinoneper 10,000births.Fetal autopsies may suggest slightlyhigher rates. It is dened by the ab-senceof cerebral tissuethat is re-placedbyaleptomeningeal saclikestructure, withpreservationof themidbrainandcerebellarstructures.The falx cerebri, partial or complete,is present, distinguishing it fromformsofholoprosencephaly.In hy-dranencephaly, partial remnants ofcerebral tissue may be present atbirth and they are often asymmetric.In contrast, marked hydrocephalus demonstrates symmet-rical thin cortical remnants. In both hydranencephaly andhydrocephalus, in contrast to holoprosencephaly, the falxcerebri and unfused thalami should be evident. The overallimage of hydranencephaly should be distinguishable froma very large porencephalic cyst or other cystic structures,especially if both head MRI and CTimaging are used. (15)The pathophysiology of development of hydranence-phalyreects aninterruptionbylikelydiversemecha-nisms of the normal embryonic brain development,affectingprimarilytheprosencephalon(forebrain)withrelative sparing of the mesencephalon and rhombenceph-alonderivatives, beginninganytime after thethirdtofourthgestational month. Animal models of occlusionof both internal carotid arteries produce subsequent fetalbrain anomalies similar to what is seen in human hydra-nencephaly. Therefore, intrauterine insults affecting thesevessels producing strokes is postulated as a mechanismforsome individuals. (16) A variety of etiologies, includingenvironmental factors and genetic mechanisms, haveFigure 4. AxialbrainCTimagingoftwoinfantswithminimalfrontalcerebraltissue.A.Axial brain CT (three scans) in infant with difcult-to-ascertain mixed hydranencephaly/extremehydrocephaluscharacteristicsonheadCT.Patientdidreceiveventricularshuntplacement. Afterfollow-upover1year, subsequentCTsconrmedinterpretationofmostlikelyhydranencephalywithminimalfrontalcerebralremnant.B.AxialbrainCTin infant with likely extreme hydrocephalus. Note symmetrical cerebral tissue remnantdistribution.genetics/dysmorphism hydranencephalye236NeoReviewsVol.13No.4April2012 at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from beenanecdotallyreportedtosupport this mechanism.Anymechanismforinternal carotidarteryocclusionorvasculopathymaybeassociatedwithhydranencephaly.Fowler syndromeis anautosomal recessivelyinheritedconditionconsistingof proliferativevasculopathywithhydranencephaly-hydrocephalybut withother lesionsalso identied in the brain stem, basal ganglia, and spinalcord. (17)(18) Mutations in the FLVCR2 gene are thebasisforthissyndrome. Mutationsinaseparategene,ARX, have also been associated with a pleiotropy of brainanomalies, including hydranencephaly. (19) Other likelygeneticinuences onembryonicvascular developmentaffectingtheinternal carotidarterial distributionlikelyplaya roleinthedevelopment of theprosencephalicanomalies associated with human hydranencephaly. Manyof these may similarly produce individuals with a spectrumofassociatedanomaliesperhapsrelatedtothevasculop-athy, such as the extensive number of hemangiomas notedin our described patient.PHACES syndrome previously was dened by seg-mental hemangioma(s) plus at least one of the following:posterior fossa and/or other structural brain anomalies,which may include hydranence-phaly; arterial cardiovascular anom-alies; cardiac defectsand/oraorticabnormalities; eyeanomalies; andsternal defects and/or supraum-bilical raphe. Now renamedPHACE syndrome, it may be asso-ciatedwithinternal carotidarteryagenesis or hypoplasia, predispos-ing to aneurysm and ischemia.(16)(20) In PHACE syndromeand hydranencephaly, observed ce-rebral anomalies are likely secondaryto poor development of the inuterocarotidvessel braindistribu-tion. (20) However, this infant didnot t the clinical criteria forPHACE syndrome, lacking the typ-ical segmental locations for heman-giomas and associated anomaliesother than hydranencephaly. None-theless, a PHACE-like vasculopathysyndromeproducinghydranence-phalyandhemangiomascertainlycould explain the clinical ndings.The varied anecdotal chromo-somal anomalies associated withhydranencephaly are in a minorityof overall cases, andit is unclearwhichgenesorchromosomal regionsmaybeassoci-atedwiththiscerebral anomaly. Nonetheless, karyo-type and comparative genomic hybridization assays(microarrays or similar) areindicatedintheworkupof patients with hydranencephaly. This not only allowsbetterunderstandingof possibleetiologies, but alsoa specic ndingoftenallows better acceptance ofthe patients condition by parents and caretakers.The structures observed to be preserved in hydranen-cephaly appear to be those supplied by the posterior cir-culation (the vertebrobasilar system) and variable derivedfeedervessels.Therefore,theposteriorfossastructures,occipitallobes, andthalami arepresentand portions oftheoccipital, temporal, andevensmall basilarportionsof thefrontal lobes, maybeintact. Either circulationmay supply the embryonic development of the basal gan-glia, and therefore its absence is a variablending in hy-dranencephaly. Thebrainstemispreservedbutmaybeatrophic at times. (13)(15)Other mechanisms for hydranencephaly include in-trauterineinfections, includingreports of associatedviruses (cytomegalovirus, rubella, herpes simplex virus,Figure 5. Extensive neonatal hydrocephalus. Neonate with arthrogryposis demonstratingmarked macrocephaly for body habitus who had extensive skull transillumination (notshown). Axial head CT series demonstrated prominent symmetric frontal cerebraltissueandincreasinglythinremnantsprogressivelytowardtheposteriorandcaudalregions until aquestionableabsenceof occipital tissuewas noted. Aninterhemi-sphericfalxwaspresentandthethalami werenotfused, rulingoutholoprosence-phaly. Thepattern and amount ofcortical rim tissue is mostconsistentwith extremehydrocephaly.genetics/dysmorphism hydranencephalyNeoReviewsVol.13No.4April2012 e237 at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from Epstein-Barr virus, adenovirus, parvovirus, respiratorysyncytial virus), toxoplasmosis, and others, (11) or otherintrauterine insults producing extensive fetal brain dam-ageandsubsequent resorptionandreplacement withcerebrospinaluid (CSF). Toxic effects of drugs (for ex-ample, cocaine), diffuse hypoxic ischemic damage, andanycauseof intrauterinestrokes and/or emboli mayproduce sufcient cerebral tissue necrosis to result in ul-timate appearance of hydranencephaly. The associationof hydranencephaly with a deceased co-twin in utero ispostulated to be an embolic product phenomenon. Sim-ilarly, severe genetic or environmentally inuenced de-fects incerebral embryogenesis mayresult incorticalagenesisorextremedysgenesisandmayplayaroleinthe development of hydranencephaly insome cases.Somehavereportedthepossibilityof extremehydro-cephalusthathasprogressedinuterototheextentofresembling hydranencephaly onimaging studies. (6)However,hydrocephalusistheendresultofblockageof CSF ow and hydranencephaly is more likelya disorder of embryonic brain tissue formation or/or ex-tensive destruction and resorption. For this reason,whencortical remnantsareobservedinboth,thepat-terns usually appear different (see Fig 4), and the appar-ent membrane structures surrounding the uid aredifferentin histology. Themembranous sacsin hydra-nencephaly are usually composed of glial tissue coveredby intact meninges. In hydrocephalus, thin cortical greymatter remnants should be observed. Theuid in hydra-nencephaly may be clear, cloudy, or blood stained, andit is usually more proteinaceous than typical CSFuid,such as that observed in hydrocephalus. Postnatal pro-cesses leading to massive cerebral tissue destructionmay also produce a hydranencephalic picture, such as in-fantile herpes simplex virus encephalitis. (21)Early prenatal imaging by ultrasound may demonstratean ongoing destructive process that ultimately evolves intoa classic hydranencephalic image, such as hypoxic ischemicdamage, severe hemorrhage, or other diffusely damagingprocesses. (22)Hydrocephalus, hydranencephaly, andFigure 6. Neonatalsemilobarholoprosencephaly.AxialheadCTininfantwithmarkedmidfacehypoplasia, hypotelorism, cleftlipand palate, ultimately diagnosed with trisomy 13. Head CT series suggested semilobar holoprosencephaly with uid-lled spaces inregionswithabsentcerebral tissuedevelopmentbutidentiablemidbraintissues, includingtwothalamiclobes, partiallyfused.Normalcerebralfalxwasnotevident.genetics/dysmorphism hydranencephalye238NeoReviewsVol.13No.4April2012 at Indonesia:AAP Sponsored on October 20, 2014 http://neoreviews.aappublications.org/ Downloaded from alobar holoprosencephaly may initially be difcult to dis-tinguishearlyonin utero. (12)(22) Inthesecases,fetalMRI may help suggest the likely diagnosis. Again, the im-portant distinguishing features include the absence ofacortical mantle(versusitspresenceinhydrocephalus),the presenceof a falx cerebri and unfused thalami andcortical tissue, and the extent of remaining nonfused ce-rebral tissue. In holoprosencephaly, there should be nofalx cerebri, and the thalami and cerebral tissue should atleastappearpartially, if nottotally, fused. Postnatally,MRI signals suggesting rims of cortical tissue, membra-nous septae, or movement artifacts may be distinguishedby follow-upCTscanning. Hydranencephaly shouldshowabsence of most supratentorial cerebral tissue,preservation of the falx, andunfused thalami, but mayhavevaryingamounts, especiallyof occipital tissueaswellasbasalganglia,parietal,andevenfrontaltissues.(5)(6)(8)(9)(22)Bedside transillumination of the skull, also known asskull diaphanoscopy, is a screening tool, not a diagnosticprocedure. (3)(4) If the cortical rim segment is