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TrakiaJournalofSciences,Vol.
10,Suppl.
2,2012262TrakiaJournalofSciences,Vol.
10,Suppl.
2,262-266,2012Copyright2012TrakiaUniversityAvailableonlineat:http://www.
uni-sz.
bgISSN1313-7050(print)ISSN1313-3551(online)ETIOPATHOGENETICSIMILARITIESANDDIFFERENCESINNEURALTUBEDEFECTSM.
Korpova1,M.
Miklosova1*,R.
Dankovcik2,3,M.
Dudas1,D.
Sivrev41FetalMedicineProgram,DepartmentofCellBiology,P.
J.
SafarikUniversity,Kosice,SlovakRepublic22ndDepartmentofObstetricsandGynecology,P.
J.
SafarikUniversityandL.
PasteurUniversityHospital,Kosice,SlovakRepublic3CenterforPrenatalDiagnosis,s.
r.
o.
,Kosice,SlovakRepublic4FacultyofMedicine,TrakiaUniversity,StaraZagora,BulgariaABSTRACTThetermneuraltubedefects(NTDs)ismostoftenusedtorefertothemostcommoncongenitaldefectsofthecentralnervoussystemthatinvolveexposednervoustissue,suchasspinabifida,anencephalyorcephalocele.
NTDsrankasthesecondmostfrequentgroupofcongenitalanomalies.
Malformationsoftheneuraltubeemergebetweenthethirdandthefourthgestationalweekinhumans,whichistheperiodofvulnerabledevelopmentalprocessesofneurulation-invagination,formation,closure,anddifferentiationoftheneuraltube.
Etiologicfactorsactinginthiscriticalperiodincludegenetics,infections,andnutritionalimpactswiththeextremelyimportantroleoffolicacid,maternalhyperterm.
Theexactpathogenesisofneuraldefectsisbasedonvariousmodelsanditisstillcontroversaryandnotfullyunderstood;evensuchabasicprocessasthemidlinefusionoftheneuralplateremainsunresolveduptodateandthenumberoffusioninitiationsitesinthehumanembryoisstilldiscussed.
WhiletheexactdevelopmentalmechanismsarebeingelucidatedandthepathogeneticmechanismsunderlyingNTDsareexperimentallyaddressed,itappearsthatdifferentNTDsdonothavesimilarmechanismsoforigin,andthatagreatportionoftheriskfactorsvaryamongtheindividualnosologicunits.
Keywords:Neuraltubedefects,neurulation,anencephaly,spinabifida,cephaloceleINTRODUCTIONNeuraltubedefects(NTDs)arethesecondmostcommontypeoflethalbirthdefectsinthehumanpopulation(rightaftercardiovascularanomalies),occurringworldwideinapproximatelyin1of1000births.
Neuraltubedefectsinvolvethespine(spinabifida)orthecranium(anencephaly,cephaloceles)(1).
Theycanoccurisolatedorsimultaneouslywithothermalformations.
NTDscanalsobeclassieddependingonwhichstageoftheneurulationisaffected.
Primaryneurulationtubedefectscouldbeeitherduetotubeclosureormesodermaldefects,whereassecondaryneurulationdefectsaremainlyspinalandareseeninthelumbosacralregion(2).
*Correspondenceto:MáriaMiklosovaDVM,PhD,AssociateProfessor,InstituteofBiologyandEcology,Moyzesova11,SK-04001Kosice,SlovakRepublic,E.
U.
,Tel.
:+421903961487,E-mail:miklosdr@yahoo.
comEmbryologyNeurulationisafundamentalembryonicprocessofthedevelopmentoftheneuraltube(3),whichgivesrisetothebrainandthespinalcord(4).
Buildingtheneuraltubeisanextremelycomplexprocessduringwhichcellschangeinshape,migrate,anddifferentiatetotransformaatsheetofthickenedepithelialcells(theneuralplate)intoahollowtube(3).
Neurulationinmammalianembryosoccursintwophases:primaryandsecondaryneurulation.
Thesetwophasesoccurinadistinctareasalongtherostro-caudalaxisoftheembryo(4).
Incontrasttoprimaryneurulation,secondaryneurulationischaracterizedbyproliferationofstemcells,whichformarod-likecondensationthatsubsequentlycavitates(5).
Primaryneurulation(weeks3-4)leadstotheformationofthebrainandformationofthemajorityofthespinalcordtilltheuppersacrallevel,followedbysecondaryneurulation(weeks5-6)thatisKORPOVAM.
,etal.
TrakiaJournalofSciences,Vol.
10,Suppl.
2,2012263limitedtothetailbudandcreatestheminorportionofthespinalcord,includingthemajorityofthesacralandtheentirecoccygealregion(6).
First,themidlinedorsalectodermoftheembryothickensandformstheneuralplatewhilecellshapechanges.
Theneuralplatefirstappearsatthecranialendoftheembryoanddifferentiatesinthecaudaldirection.
Theedgesoftheplatethickenandbegintomoveupwardformingtheneuralfold.
Theneuralplatebecomesnarrower,longer,andistransformedfromanellipticaltoakey-holeshapedstructure.
Thistransformationoccursbypolarizedcellmovementsinthemedialdirectionandcellintercalationinthemidline.
Themechanismofthesemovements,knownasconvergentextension,isnotspecifictoneuraltubeformation(4).
Normally,bonemorphogeneticproteinspreventtheectodermtofollowitsdefaultpathwaytoformneuroectodermandinsteadinstructittoformepidermis.
Neuralinductionoccursbysuppressionofthisepidermalfatewherebonemorphogeneticproteinantagonists,includingchordin,noggin,andfollistatin,emanatingfromtheprimitivenode,allowtheectodermtoformneuroectoderm.
Convergentextensioniscontrolledbythenon-canonicalWnt/frizzledpathway(3).
Afterward(day19),theborderoftheneuralplatebecomesgraduallymorepronouncedandelevated.
Theneuralplatefoldslongitudinallyalongthemidlineoftheplatefromtheheadtowardsthetailtoformtheneuralgroove.
Thefoldsriseupdorsally,theyapproachtoeachother,andultimatelymergetogether(4).
Neuralfoldmorphologydiffersrostrocaudally.
Atthefuturebrainlevel,theneuralfoldsarebroad,mediolaterally-elongatedstructures,whereastheyarecomparativelynarroweratthefuturespinalcordlevel.
Atthesinusrhomboidalislevelthatisneartheclosingcaudalneuropore,theneuralfoldsarerelativelybroadincomparisonwiththewidthoftheneuralplate,buttheextentofattachmentbetweenneuralplateandepidermalectodermisnarrow(7).
Therostralandcaudalopeningsarecalledneuroporesandarebestdistinguishedaroundtheday23(4).
Thelastphase,thefusionofneuralfoldsisstilldiscussed.
Thenumberofinitiationsitesoffusionandtheirlocationarethesubjectofthediscussion.
Severalmodelsofclosureofneuraltubeareknown.
ZippermodelandVanAllenmodelarethemostdiscussed.
Thesinglesitemodelisclosurefromoneplace.
Neuraltubeclosureistraditionallybelievedtoproceedbidirectionallyinazipperlikefashion.
Closureofthetwoextremitiesoftheneuraltubeisnotsimultaneous.
Thecranialend(rostralneuropore)closesattheday25,whereasthecaudalend(caudalneuropore)closesattheday27or28,therebyterminatingprimaryneurulation(8).
Alternativemodelistheclosureoftheneuraltubeinthehumansandittakesplaceatmultiplesites,similarlytothatobservedinmiceandtheotherexperimentalanimals(9).
Inhumanbeings,multiplesitesofneuraltubefusionwerehypothesizedonthebasisofobservationalstudiesoffetuses,buttheexactnumberofthesesitesremainscontroversial,varyingbetween2,3,and5sites(10).
Thismultiplesitemodelmayhelptoexplainthevariationsintheanatomiclocationofthedefectintheskullfoundinpatientswithcephalocele(11).
Ifthemechanismoforiginforcephaloceleisdifferentfromthatofspinabifidaandanencephaly,itispossiblethattheriskfactorsmightdifferbetweentheselesions(11).
Secondaryneurulationbeginsafterclosureoftheposteriorneuroporeandcompletionofprimaryneurulationandproceedsuntilgestationalday48(8).
Duringsecondaryneurulation,anadditionalpartoftheneuraltubeisproducedbythetailbud;amassofcellsderivingfromthecaudalportionoftheprimitivestreak.
Thesecondaryneuraltubeisinitiallysolid,butsubsequentlybecomescavitated(12).
Thesecondaryneuraltubeeventuallyresultsinthetipoftheconusmedullarisandthelumterminale.
EtiologyTheetiologyofNTDsisnotfullyknown,butmanyetiologicfactorshavebeenidentifiedsuchasgeneticfactors,nutrition,intoxication,firsttrimesterhyperthermiaorothermaternaldiseases,irradiation,geographicandracialfactors.
Geneticfactorsaremainlyprominentinsyndromes.
Theimpactofvalproicacidandotherantimetabolitsoffolicacidisstilldiscussed.
Folicacidandcongenitalmalformationshavebeenstudiedforoverfivedecades.
Theconnectionwasdiscoveredinanimalstudiesofaminopterin,anantimetaboliteofpteroylglutamicacid,orfolicacidasitisusuallycalled(13).
Hyperhomocysteinaemiamaybecausedbyfolateorcobalamindeficiencyandisariskfactorforneuraltubedefects.
Changesintheactivityofcertainfolate-dependentenzymesduringfetaldevelopmentinduceanincreasedneedformethyltetrahydro-folateandanincreasedsensitivitytohomocysteineinthedevelopingfetus.
Theteratogeniceffectsoffolatedeficiencymaypossiblybecausedbythedecreasedactivityoffolate-dependentenzymesleadingtoalteredDNAsynthesis,cytogeneticdamage,ortoabnormalitiesofmethylationofDNA(14).
KORPOVAM.
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TrakiaJournalofSciences,Vol.
10,Suppl.
2,2012264SpinabifidaSpinabidaisageneraltermthatincludesabroadrangeofmalformations(15).
About70–80%ofallhumanspinabifida(SB)casesareconsideredtobecausedbyacombinationofgenetic,lifestyle,andenvironmentalfactors.
Nutrition,inparticulartheB-vitaminfolate,isanimportantlifestylefactorinvolvedinthepathogenesisofSB.
Periconceptionalfolicacidsupplementationreducestheoccurrenceandre-occurrenceofriskofSBinhuman.
OthernutrientsassociatedwithSBaretheglucosederivativemyoinositol(MI)andthetraceelementzinc.
ObesityandalcoholconsumptionarebothlifestyledeterminantsaffectingcarbohydratemetabolismandassuchNTDrisk(16).
1.
Spinabifidaoccultaiscleftofvertebralarchescoveredbyskin.
Mostcommonincidenceisinlumbo-sacralarea.
Placewithexcessivehairedskinisatypicalforspinabifidaocculta.
2.
Meningoceleisastate,whenmeningespenetratethroughthecleftonly,usuallyCSFispresent.
3.
Myelomeningoceleisadevastatingcongenitaldefectofthecentralnervoussystemforwhichthereisnocure.
Itischaracterizedbyprotrusionofthemeningesandspinalcordthroughopenvertebralarchesleadingtolifelongparalysis(17).
CephalocelesCephalocelesarefurtherclassifiedaccordingtothecontentoftheherniatedsac:meningocele–onlymeningespenetratedthroughtheskulldefect;encephalocele-whenherniationofthebrainparenchymaoccurs(18);meningoencephalocele-herniatedbrainwithmeninges;encephalocystocele-herniatedbraintissueandapartoftheventricularsystem.
Meningocystoencephalocystocelediffersfromencephalocystocelebythepresenceofthetwocavities(19).
Thefirstcavityisformedbetweenmeningesandbraintissue,thesecondcavityisformedbyherniatedventriclesystem.
ThisnosologicunitisintroducedunderthetermencephalocystomeningocelebyKuhlenbeck(20).
Ourproposedterminologyclearlydepictsstateddiagnose.
Whenencephalocystocele,meningesremainadheringtothebraintissue.
Mostauthorsdonotdistinguishbetweenmeningoencephaloceleandencephalocele.
Theruptureofmeningesoccurswhenencephaloceleandbraintissueisobtainedonlyextracranial.
TheHerniatonofthebrainwithmeninges,whichareadheredtothebraintissue,isdescribedwhenmeningoencephalocele.
Basedonlocalization,encephalocelescanbesubclassifiedasoccipital,parietalandanterior.
Anteriorcephalocelesoccurbetweenthebregmaandtheanteriorpartoftheethmoidbone(21),andcanbefurthersubclassifiedintofrontal(sincipital)andbasal(22).
Frontalcephalocelesarealwaysexternalandtheyaresubclassifiedintofrontonasal,nasoethmoidal,andnasoorbital.
Basalcephalocelesareinternalandtheyoccurwithinthenose,pharynxortheorbit(21).
70%ofcephaloceleslocalizeintheoccipitalarea,whichisthepredilectionsite;mostencephalocelesarelocalizedinthemidline,whileonlyafewshowalateralposition(23).
Nageretalclassiedcephalocelesinto2majorgroups:(1)cephalocelesinvolvingtheconvexityand(2)cephalocelesinvolvingtheskullbase(24).
Basedonliteraturesearch,the13thgestationweekistheearliestperiodofdiagnosingcephaloceleby3dimensionalultrasounds(25).
Thepresenceofaskulldefectisnecessaryrequisitetoconfirmadiagnosis.
AnencephalyAnencephalybelongstothegroupofprimarytubeclosuredefectstogetherwithexencephaly(2).
Anencephalyischaracterizedasanopeningoftheneuraltubeintheheadareawithpresentingmassofdegenerativetissueoftheskull.
Theabsenceofcranialvault,bulgingofeyesandabsenceoftheneckarecharacteristicforanencephaly.
Fromtheanatomicalview,anencephalyisclassifiedinto:merocrania–wherethedefectdoesnotincludeforamenmagnum,andholoacrany–wherethedefectreachesbehindtheforamenmagnum(22).
Thespineisalwaysabnormalinanencephalywithmultiplesegmentalanomaliesandanabsentordysplasticspinalcord.
Whenmerocrany,coveringofskinisabsent,whatdifferentiateitfromcephalocele.
Whenanencephalicfetuses,swallowingreflexesarenotdeveloped,thoughtlastmonthsofpregnancyareaccompaniedwithpolyhydramnion.
CONCLUSIONSThegroupofneuraltubedefectsincludesvariousmalformations.
Whilethepathogeneticmechanismsunderlyingthesemalformationsarestilldiscussed,itappearsthatthesemalformationsdonothavesimilarmechanismsoforigin,andthatagreatportionoftheriskfactorsvaryamongtheindividualnosologicunits.
ACKNOWLEDGMENTSThisworkwassupportedbygrantprojectsAPVVVVCE-0001-07(MD),ASFEUITMS26220120024-SEPO,ASFEUITMS26220120039-SEPOII,andMZSR2007/65-UPJS-02(MD).
LanguagesupportwasprovidedbyMgr.
IvanaAugustinska.
KORPOVAM.
,etal.
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10,Suppl.
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