Embryologyofspinalcord

Thespinalcordismadefrompartoftheneuraltubeduringdevelopment.Asthe
neuraltubebeginstodevelop,thenotochordbeginstosecreteafactorknownasSonic
hedgehogorSHH.Asaresult,thefloorplatethenalsobeginstosecreteSHH,and
thiswillinducethebasalplatetodevelopmotorneurons.Meanwhile,theoverlying
ectodermsecretesbonemorphogeneticprotein(BMP).Thisinducestheroofplateto
begintosecreteBMP,whichwillinducethealarplatetodevelopsensoryneurons.
Thealarplatendthebasalplateareseparatedbythesulcuslimitans.
Additionally,thefloorplatealsosecretesnetrins.Thenetrinsactaschemoattractants
todecussationofpainandtemperaturesensoryneuronsinthealarplateacrossthe
anteriorwhitecommissure,wheretheythenascendtowardsthethalamus.
Lastly,itisimportanttonotethatthepaststudiesofViktorHamburgerandRitaLevi
Montalciniinthechickembryohavebeenfurtherprovenbymorerecentstudies
whichdemonstratedthattheeliminationofneuronalcellsbyprogrammedcelldeath
(PCD)isnecessaryforthecorrectassemblyofthenervoussystem.
Overall,spontaneousembryonicactivityhasbeenshowntoplayaroleinneuronand
muscledevelopmentbutisprobablynotinvolvedintheinitialformationof
connectionsbetweenspinalneurons.
Congenitaldeformitiesinvolvingthecoveringsofthenervoussystemarecalled
neuraltubedefects(NTDs).Neuraltubedefectsvaryinseverity.Themildestformis
spinabifidaaperta,inwhichosseousfusionofoneormorevertebralarchesislacking,
withoutinvolvementoftheunderlyingmeningesorneuraltissue.Aslightlymore
severeformofspinabifida,whichisdiscussedindetailinthisarticle,isspinabifida
cystica,ormyelomeningocele,inwhichasaclikecasingisfilledwithcerebrospinal
fluid(CSF),spinalcord,andnerverootsthathaveherniatedthroughadefectinthe
vertebralarchesanddura,asshownbelow.
Atrialseptaldefect(ASD)isaformofcongenitalheartdefectthatenablesblood
flowbetweentheleftandrightatriaviatheinteratrialseptum.Theinteratrialseptum
isthetissuethatdividestherightandleftatria.Withoutthisseptum,orifthereisa
defectinthisseptum,itispossibleforbloodtotravelfromtheleftsideoftheheartto
therightsideoftheheart,orviceversa.[1]Thisresultsinthemixingofarterialand
venousblood,whichmayormaynotbeclinicallysignificant.Thismixtureofblood
mayormaynotresultinwhatisknownasa"shunt".Theamountofshuntingpresent,
ifany,dictateshemodynamicsignificance(seePathophysiologybelow).A"rightto
leftshunt"typicallyposesthemoredangerousscenario(seePathophysiologybelow).
Therightsideoftheheartcontainsvenousbloodwithalowoxygencontent,andthe
leftsideoftheheartcontainsarterialbloodwithahighoxygencontent.Anormal
hearthasaninteratrialseptumthatpreventsoxygenrichbloodandoxygendeficient
bloodfrommixingtogether.

Duringdevelopmentofthefetus,theinteratrialseptumdevelopstoseparatetheleft
andrightatrium.However,theforamenovale( /frem
novli/)allowsblood
fromtherightatriumtotheleftatriumduringfetaldevelopment.Thisopeningallows
bloodtobypassthenonfunctionalfetallungswhenthefetusobtainsitsoxygenfrom
theplacenta.Alayeroftissuecalledtheseptumprimumactsasavalveoverthe
foramenovaleduringfetaldevelopment.Afterbirth,thepressureinthepulmonary
circulatorysystemdrops,thuscausingtheforamenovaletocloseentirely.In
approximately25%ofadults,[2]theforamenovaledoesnotentirelyseal.[3]Inthis
case,elevationofpressureinthepulmonarycirculatorysystem(i.e.:pulmonary
hypertensionduetovariouscauses,ortransientlyduringacough)cancausethe
foramenovaletoremainopen.Thisisknownasapatentforamenovale(PFO).
Aventricularseptaldefect(VSD)isadefectintheventricularseptum,thewall
dividingtheleftandrightventriclesoftheheart.
Theventricularseptumconsistsofaninferiormuscularandsuperiormembranous
portionandisextensivelyinnervatedwithconductingcardiomyocytes.
Themembranousportion,whichisclosetotheatrioventricularnode,ismost
commonlyaffectedinadultsandolderchildrenintheUnitedStates.[1][2]Itisalsothe
typethatwillmostcommonlyrequiresurgicalintervention,comprisingover80%of
cases.[3]
Membranousventricularseptaldefectsaremorecommonthanmuscularventricular
septaldefects,andarethemostcommoncongenitalcardiacanomaly.[4]
Tetheredcordsyndrome(TCS)isastretchinducedfunctionaldisorderofthespinal
cord.ThemechanicalcauseofTCSisaninelasticstructureanchoringthecaudalend
ofthespinalcordthatpreventscephaladmovementofthelumbosacralcord.
Stretchingofthespinalcordoccursinpatientseitherwhenthespinalcolumngrows
fasterthanthespinalcordorwhenthespinalcordundergoesforcibleflexionand
extension.
Researchinpatientsandexperimentalanimalssuggeststhatthereisalinkbetween
theclinicaldysfunctionsthatcharacterizeTCSandputativepathophysiological
changesthataccompanythissyndrome.Amongthesechangesaredepressionof
electrophysiologicalactivityandshiftsinthereduction/oxidationratioofcytochrome
oxidase.Thelattersuggeststhatthereisimpairmentofoxidativemetabolism.These
putativepathophysiologicalchangesinTCSoccurmainlywithinthelumbosacralcord
underexcessivetension.
TheauthorsdiscussthepathophysiologyofTCSandexaminerelatedsymptoms.
GeneralConceptsofTetheredCordSyndrome
ThesymptomatologyofTCSincludeslowerlimbmotorandsensorydeficits,
incontinence,andmusculoskeletaldeformities.Itisbelievedthatthelesionscausing
TCSsymptomsarelocatedinthelumbosacralcordandthatsignsandsymptomsof

TCScanbereversedinmanypatients.Mechanicalcausesofcordtetheringincludea
thickeningoftheterminalfilumattachedtotheelongatedspinalcord[8]orany
inelasticstructures,suchasfibrousorfibroadiposefilum,[32,37]tumors,lipoma,
epidermoidtumor,myelomeningoceles,lipomyelomeningoceles,orscarformations
thatarefastenedtothecaudalspinalcord[38]orosseousorduralseptum.These
structureslackviscoelasticity,andthustheirqualityisthedeterminingfactorfortight
fixationofthespinalcord.
AlthoughthefollowingfindingsinpatientswithTCSarerecognizedbyclinicians,
theircorrelationtotheTCSpathophysiologymaynothavebeenwellexplained.First,
TCSlesionsarepredominantlyrestrictedtothelumbosacralcord.Second,the
associatedsensorydeficitsareoftendistributedinapatchypattern.Third,TCS
inducedincontinencebecomesirreversibleearlierthanmotorandsensory
dysfunction.Fourth,scoliosisandexaggeratedlumbosacrallordosisarecommon
findings.Fifth,whatappeartobeadequateuntetheringproceduresinpatientswith
myelomeningocelesareoftennotfollowedbyneurologicalimprovement,whichis
differentfromthosewith"tetheredspinalcord."[8]
Definingthemechanismofcordtetheringinducedpathophysiologymayprovidea
keystepinaddressingtheseissuesandinexplainingthepatient'sclinicalsignsand
symptoms.Suchdefinitionmayalsoprovideausefulmeanstoformulatearationale
fordiagnosticandsurgicalapproachestothisdisorder.Insightsintothe
pathophysiologyofTCShavebeenderivedfromcorrelationsamongresearchdata
andclinicalfindingssuchassymptomatology,diagnosis,andsurgeryrelated
outcome.Inourresearchonspinalcordtethering,emphasishasbeenonoxidative
metabolismandelectricalactivitiesinspinalcordsofhumansandofexperimental
animals,becauselinksareproposedbetweenimpairmentsofthesefactorsandthe
pathophysiologyofTCS.[26,38]Thisresearchhassuggestedthatthepathophysiological
effectsofspinalcordtetheringareanalogoustothosethatoccurinanimalmodelsof
hypoxemia[2,16,33]andbrain[17]andspinalcordischemia.[38]
Pathophysiology of the Tethered Cord
Theproposednormalfunctionsoftheterminalfilumaretofixate,stabilize,andbuffer
thedistalcordfromnormalandabnormalcephalicandcaudaltraction.Thefilumisa
viscoelasticbandthatusuallyallowstheconusmedullaristomoveslightlyduring
flexionandextensionofthespine.Itisbelievedthat,ifthisviscoelasticityofthe
filumislostorcompromisedbyeitherfattyinfiltration[29]orabnormalthickening,
thencaudaltensionandtractionmaycauseunduestressupontheconus,resultingin
TCS.Itisbelievedthatthisabnormalinelasticfiluminterfereswithnormalcord
ascensionandresultsinalowlyingconusmedullaris(thatis,aconusbelowthe
L12interspace).ThisisclassicallybelievedtobethehallmarkoftheTCS,butwe
havepublisheddatathatdemonstratethatTCScanexistwhentheconusispositioned
normally.[44,49,50,54]
Yamadaetal.[52]definedTCSas"astretchinducedfunctionaldisorderofthe
lumbosacralspinalcordduetoexcessivetension"betweenthelowestpairofdentate
ligamentsandthecaudalendofthespinalcordanchoredtoaninelasticterminal
filum.Inananatomicalstudyofthedentateligament,however,weobservedno

evidencethatthisstructuresignificantlyinterferedwitheithercranialorcaudal
tractiononthespinalcord.[45]Nevertheless,Yamadaetal.showedthatcaudaltraction
onthedistalcordresultedinimpairmentofoxidativemetabolismandthatthedegree
ofimpairmentcorrelatedwiththeseverityoftheneurologicaldeficits.Usinganimal
models,theyalsoshowedthatthedysfunctionseeninTCSinvolvesthegraymatter
ofthedistalcord(belowL1)andoccursbecauseofderangementofoxidative
metabolism.Thismetabolicdysfunctionisatthemitochondrialevelwithasignificant
reductionshiftofcytochromeaanda3(similartowhatisseeninhypoxiaand
ischemiabrain/spinalcordmodels).Thisreductionshiftisproportionaltotheamount
ofcaudaltractionappliedtothedistalcord.Theseauthorsalsodemonstrateda
correspondingreductioninspinalcordbloodflowinproportiontothetractionforce.
Theythenpostulatedthatsuchcordtractioncaused"tractioninducedhypoxia"and
neuronalmembranestretchwith"lossoftransmembraneionhomeostasisand
electricalactivitydepression."[40,5456]
Developmentoftheskull

Thelowerinnersurfaceoftheneurocranium11weeks'fertilizationage
Theskullisacomplexstructure;itsbonesareformedbothbyintramembranousand
endochondralossification.Theskullroof,comprisingthebonesofthe
splanchnocranium(face)andthesidesandroofoftheneurocranium,areformedby
intramembranous(ordermal)ossification,thoughthetemporalbonesareformedby
endochondralossification.Theendocranium,thebonessupportingthebrain(the
occipital,sphenoid,andethmoid)arelargelyformedbyendochondralossification.
Thusfrontalandparietalbonesarepurelymembranous.[3]Thegeometryofthecranial
baseanditsfossas:anterior,middleandposteriorchangesrapidly,especiallyduring
thefirsttrimesterofpregnancy.Thefirsttrimesteriscrucialfordevelopmentofskull
defects.[4]
Atbirth,thehumanskullismadeupof44separatebonyelements.Asgrowthoccurs,
manyofthesebonyelementsgraduallyfusetogetherintosolidbone(forexample,the
frontalbone).Thebonesoftheroofoftheskullareinitiallyseparatedbyregionsof
denseconnectivetissuecalled"fontanels".Therearesixfontanels:oneanterior(or
frontal),oneposterior(oroccipital),twosphenoid(oranterolateral),andtwomastoid

(orposterolateral).Atbirththeseregionsarefibrousandmoveable,necessaryfor
birthandlatergrowth.Thisgrowthcanputalargeamountoftensiononthe
"obstetricalhinge",whichiswherethesquamousandlateralpartsoftheoccipital
bonemeet.Apossiblecomplicationofthistensionisruptureofthegreatcerebralvein
ofGalen.Asgrowthandossificationprogress,theconnectivetissueofthefontanelles
isinvadedandreplacedbybonecreatingsutures.Thefivesuturesarethetwo
squamous,onecoronal,onelambdoid,andonesagittalsutures.Theposteriorfontanel
usuallyclosesbyeightweeks,buttheanteriorfontanelcanremainopenupto
eighteenmonths.Theanteriorfontanelislocatedatthejunctionofthefrontaland
parietalbones;itisa"softspot"onababy'sforehead.Carefulobservationwillshow
thatyoucancountababy'sheartratebyobservinghisorherpulsepulsingsoftly
throughtheanteriorfontanel.