NEURAL TUBE NEURAL TUBE DEFECTSDEFECTS

C. Ramos Perea, MD. FAAP.C. Ramos Perea, MD. FAAP.Associate Professor Associate Professor

Universidad Central del Caribe Universidad Central del Caribe y Escuela Medicina Poncey Escuela Medicina Ponce

INTRODUCTIONINTRODUCTION Deformities involving CNS coveringDeformities involving CNS covering

Vary in severity – from the simples Vary in severity – from the simples Spina Bifida Aperta (incomplete fusion Spina Bifida Aperta (incomplete fusion of vertebral arches)of vertebral arches)

Extreme Forms; Anencephaly and Extreme Forms; Anencephaly and Raquischisis where wide openings in Raquischisis where wide openings in cranial and vertebrae bones also cranial and vertebrae bones also absence of brain, nerves and meninges.absence of brain, nerves and meninges.

Vertebral Vertebral anatomyanatomy

Vertebral arches(lamina)

Spinous process

Vertebral canal

Vértebra body

TRANSVERSE FORAMEN

Articular process

Contains arteries & veins

Intro - cont.Intro - cont. Most malformation especially NTD’S Most malformation especially NTD’S

occuroccur

early embryogenesis – are likely aberrant early embryogenesis – are likely aberrant

expression of yet undefined expression of yet undefined developmentaldevelopmental

gene.gene. CNS develops in a precise embriologic CNS develops in a precise embriologic

sequence; therefore interruption of one sequence; therefore interruption of one area affects remaining developmentarea affects remaining development..

Intro – cont.Intro – cont. NTD’S – mainly embryologic NTD’S – mainly embryologic

induction disorder failure to induction disorder failure to properly form mesoderm-properly form mesoderm-neuroectoderm.neuroectoderm.

Primary defect = failure of N. tube Primary defect = failure of N. tube to close affecting neural-cutaneus to close affecting neural-cutaneus ectodermal structures.ectodermal structures.

Inciting events traced to 17-30 Inciting events traced to 17-30 days gestation.days gestation.

Events in the 3-4 weekEvents in the 3-4 week

Intro – cont.Intro – cont.

Primary defect – failure of neural Primary defect – failure of neural folds to fuse in midline and form folds to fuse in midline and form neural tube (Neuroectoderm).neural tube (Neuroectoderm).

Also maldevelopment of Also maldevelopment of mesoderm (forms skeletal and mesoderm (forms skeletal and muscular structures that cover muscular structures that cover neural structures).neural structures).

Defects can be open Defects can be open (communicate-atmosphere) or (communicate-atmosphere) or closed (skin covered).closed (skin covered).

They can be ventral or dorsalThey can be ventral or dorsal

EpidemiologyEpidemiology Anencephaly major CNS Anencephaly major CNS

malformation in western world. malformation in western world. Neonates=100% mortalityNeonates=100% mortality

37 times more frequently in females.37 times more frequently in females.

Recurrence rate in families can be Recurrence rate in families can be 35%.35%.

Incidence highest in: Ireland, Incidence highest in: Ireland, Scotland, Wales,Scotland, Wales,

Egypt and New Zealand. Lowest Egypt and New Zealand. Lowest in Japan.in Japan.

AnencephalyAnencephaly

Neurological lesions Neurological lesions cont.cont.

Anencefalia – Anencefalia – one of the most one of the most common – no common – no survival possible. survival possible. Absence of Absence of calvarium, calvarium, posterior bone posterior bone elements and elements and deficiency in deficiency in procencephalusprocencephalus..

Epidemiology – cont.Epidemiology – cont. People of Celtic origin highest rate.People of Celtic origin highest rate. British Isles having highest rate than British Isles having highest rate than

Asian Countries.Asian Countries. In USA and New England drop fromIn USA and New England drop from 2.3/1000 in 1930’s to .7/1000 births in 2.3/1000 in 1930’s to .7/1000 births in

the 60’s.the 60’s. Reasons: Prenatal screening (AFP) and Reasons: Prenatal screening (AFP) and

ultrasound – termination of pregnancy ultrasound – termination of pregnancy increase 50 fold in Britain & USA increase 50 fold in Britain & USA probably accounting for that decline in probably accounting for that decline in NTD.NTD.

Epidemiology Epidemiology cont.cont.

In Atlanta 1990’s more than 30% of In Atlanta 1990’s more than 30% of affected pregnancies were terminated affected pregnancies were terminated based on prenatal test.based on prenatal test.

In Sept. 1992 – US Public Health In Sept. 1992 – US Public Health Service all woman childbearing age, Service all woman childbearing age, capable of becoming pregnant – capable of becoming pregnant – should take 0.4 mg Folic Acid per day should take 0.4 mg Folic Acid per day for purpose of reducing risk of NTD’S.for purpose of reducing risk of NTD’S.

Epidemiology cont.Epidemiology cont. Higher intakes not well known, but can Higher intakes not well known, but can

complicate Vit. Bcomplicate Vit. B12 12 deficiency.deficiency.

Ingestion of preconception folate Ingestion of preconception folate decreases the risk of a child with NTD.decreases the risk of a child with NTD.

In USA highest rates in Boston and Irish In USA highest rates in Boston and Irish descents – lower rates in African and descents – lower rates in African and Asians.Asians.

Recurrence risk of NTB – 10.4% in Recurrence risk of NTB – 10.4% in Belfast -Belfast -

4.2% in London – USA 1-3%.4.2% in London – USA 1-3%. 50-70% are females.50-70% are females.

EmbryologyEmbryology 2 processes form the C.N.S.2 processes form the C.N.S. 1-Neurulation1-Neurulation – formation o neural – formation o neural

structures into a tube thereby structures into a tube thereby forming brain – spinal cord.forming brain – spinal cord.

2-Neurulation 2-Neurulation – formation lower spinal – formation lower spinal cordcord

lumbar and sacral elements.lumbar and sacral elements.

First Neural plate at 17 days, then First Neural plate at 17 days, then neuronal fold at 21 days and fusion of n. neuronal fold at 21 days and fusion of n. folds at 23 days.folds at 23 days.

Any disruption in this 3 stages = Any disruption in this 3 stages = Craniorachischisi (most severe form Craniorachischisi (most severe form NTD)NTD)

Embryology contEmbryology cont.. By 23-26 days closure Ant. Neuropore By 23-26 days closure Ant. Neuropore Failure = Anencephaly.Failure = Anencephaly. By 26-30 days closure of caudal By 26-30 days closure of caudal

neuroporeneuropore Failure = Myelomeningocele.Failure = Myelomeningocele. Notocord = (precursor of skeletal axis).Notocord = (precursor of skeletal axis). Somites = Derived from mesodermSomites = Derived from mesoderm

(form most of v. column-skeletal (form most of v. column-skeletal muscles and dermis)muscles and dermis)

Embryology cont.Embryology cont. Studies on mice embryos – provided some Studies on mice embryos – provided some

unifying theories for explaining associated unifying theories for explaining associated anomalies (hydrocephalus, hindbrain(post.) anomalies (hydrocephalus, hindbrain(post.) malformations as Chiari II.malformations as Chiari II.

1992 McLane theories – initial event = failure 1992 McLane theories – initial event = failure of neural fold to close completely leaving a of neural fold to close completely leaving a dorsal defect (Myeloschisis). This permits dorsal defect (Myeloschisis). This permits CSF to leak into A. Fluid creating collapse of CSF to leak into A. Fluid creating collapse of V. System.V. System.

Failure of ventricular system to increased in Failure of ventricular system to increased in size leads to downward herniation of small size leads to downward herniation of small developing cerebellum.developing cerebellum.

EtiologyEtiology Teratogens-(hyperthermia, Teratogens-(hyperthermia,

sulfas,antihistaminics, nutr. sulfas,antihistaminics, nutr. deficiencies and anticonvulsivants use).deficiencies and anticonvulsivants use).

Most strongly tied = carbamazepine, Most strongly tied = carbamazepine, valproic acid (folate antagon).valproic acid (folate antagon).

Folate deficiency.Folate deficiency. Woman taking v. acid a risk of 2% Woman taking v. acid a risk of 2%

(NTD) (important for epileptics (NTD) (important for epileptics undergo prenatal screen (AFP).undergo prenatal screen (AFP).

Etiology cont.Etiology cont. 1970’s Smithhells noted erythrocyte folate 1970’s Smithhells noted erythrocyte folate

and low a. acid in WBC in first trimester and low a. acid in WBC in first trimester pregnancies with NTD. This work led to two pregnancies with NTD. This work led to two important randomize studies on the use of important randomize studies on the use of periconception folate by British and periconception folate by British and Hungarians.Hungarians.

British study was terminated early due to British study was terminated early due to the protection noted in the folic acid group. the protection noted in the folic acid group. Multivitamins has no protective effect. Multivitamins has no protective effect. Preconception Folic Acid prevented 72% of Preconception Folic Acid prevented 72% of recurrent NTD.recurrent NTD.

Hungarian study results were the same.Hungarian study results were the same. Number of patients more than 2000.Number of patients more than 2000.

Etiology cont.Etiology cont. Ingestion of preconception F. Acid is Ingestion of preconception F. Acid is

not easy (less than 50% of not easy (less than 50% of pregnancies are planned).pregnancies are planned).

Folic Acid is not protective unless Folic Acid is not protective unless ingested in periconception period.ingested in periconception period.

NTD occurs 26 days post-fertilization NTD occurs 26 days post-fertilization – when many woman don’t know they – when many woman don’t know they are pregnant.are pregnant.

The precise mechanism of F. Acid The precise mechanism of F. Acid protection is unclear.protection is unclear.

Normal Folate

Adequate Folate – Healthy Cells

Deficient Folate – Unhealthy Cells

Perspective on Folate Deficiency

Megaloblastic Anemia

50% of U.S. pregnancies are 50% of U.S. pregnancies are unplannedunplanned

Folic acid is needed before Folic acid is needed before conceptionconception

NTDs occur very early in pregnancyNTDs occur very early in pregnancy

Importance of timing in getting folic acid

Median serum and red blood cell folate levels, before and after folic acid fortification,

U.S. women, aged 15-44 years, NHANES

SOURCE: CDC/NCHS, National Health and Nutrition Examination Surveys, 1988-94 and 1999-2000

4.8

0

5

10

15

20ng/mL

Serum folate

13.0

Before After

ng/mL

159.9

263.6

0

50

100

150

200

250

300

350Red blood cell folate

Before After

Diagnostic Detection and Diagnostic Detection and Associated Associated

Neurological Lesions.Neurological Lesions. Alpha-Feto-Protein _ Amniotic Fluid or Alpha-Feto-Protein _ Amniotic Fluid or

maternal blood stream. *Major serum maternal blood stream. *Major serum protein in early embryonic life and is 90% of protein in early embryonic life and is 90% of serum globulin. It’s believe to prevent fetal serum globulin. It’s believe to prevent fetal immune rejection.immune rejection.

Can leak from NTD in to a. fluid.Can leak from NTD in to a. fluid. Prenatal screen 15-20 weeks (at 20 weeks Prenatal screen 15-20 weeks (at 20 weeks

higher than 1000 ng/ml is indicative of NTD.higher than 1000 ng/ml is indicative of NTD. Ultrasound in 98% reliable in skill hands. Ultrasound in 98% reliable in skill hands.

(Close defects can be undetected). (Close defects can be undetected).

Conditions Associated Conditions Associated with AFPwith AFP

AnencephalyAnencephaly Spina Bifida cysticaSpina Bifida cystica

EncephaloceleEncephalocele Conjoined twinsConjoined twins

Onphalocele + GastroschisisOnphalocele + Gastroschisis Polycistic kidneysPolycistic kidneys OligohydramniosOligohydramnios

Urinary tract obstructions.Urinary tract obstructions.

Neurological lesionsNeurological lesions

Spina Bifida OccultaSpina Bifida Occulta – Mildest – Mildest form, one or more vertebrae form, one or more vertebrae (usually L5 and S1) are not closed (usually L5 and S1) are not closed but no protrusion of spinal cord.but no protrusion of spinal cord.

Could be associated with Could be associated with Syrinomelia or tethered cord.Syrinomelia or tethered cord.

17% of population – most 17% of population – most asymptomatic – just skin dimple asymptomatic – just skin dimple with hair or discoloration over with hair or discoloration over lumbar area.lumbar area.

Spina Bifida OccultaSpina Bifida Occulta

Neurological lesions Neurological lesions cont.cont.

MeningoceleMeningocele – – meninges meninges protrude trough a small opening – protrude trough a small opening – defect closed.defect closed.

Neurological lesions Neurological lesions cont.cont. MyelomeningoceleMyelomeningocele - saccular - saccular

protrusion containing neural placode protrusion containing neural placode and CSF. Surface covered by and CSF. Surface covered by arachnoid but no dura nor skin. The arachnoid but no dura nor skin. The sac appears yellow with fragile sac appears yellow with fragile vessels. Nerve roots pass into the vessels. Nerve roots pass into the sac.sac.

Spine tethered by bony defect.Spine tethered by bony defect.

MeningomyeloceleMeningomyelocele

Neurological lesions Neurological lesions cont.cont. Chiari II Chiari II

malformation – malformation – herniation of herniation of cerebelar vermis cerebelar vermis and B. Stem below and B. Stem below F. Magnum into C. F. Magnum into C. canal. Paresis of canal. Paresis of C. nerves (3,6,9 y C. nerves (3,6,9 y 10) 10) require require decompression of decompression of hind brain as an hind brain as an emergency.emergency.

Neurological lesions Neurological lesions cont.cont.

Large occipital encephaloceleLarge occipital encephalocele Skin covered sac representing close Skin covered sac representing close

NTD.NTD. Often cranium bifidum – represent a Often cranium bifidum – represent a

failure of a neuropore.failure of a neuropore. Needed to have V-P shunt to Needed to have V-P shunt to

controlled associated hydrocephalus.controlled associated hydrocephalus. At 5 years moderate developmental At 5 years moderate developmental

delayed.delayed.

Large occipital Large occipital encephaloceleencephalocele

LypomyelomeningoceleLypomyelomeningocele

The left child is a dorsal lipoma – The left child is a dorsal lipoma – pedunculated.pedunculated.The right child lypomatous mass The right child lypomatous mass beneath the skin.beneath the skin.

Both passed through the dura to the Both passed through the dura to the intradural space.intradural space.

                                                   

Spinal cord (close up)  location of spina bifida

OccultaOuter part of vertebrae not completely joined. Spinal

cord and covering (meninges) usually undamaged. Hair

often at site of defect.Meningocele

Outer part of vertebrae split. Spinal cord usually normal.

Meninges damaged and displaced through opening.

MyelomeningoceleOuter part of vertebrae split.

Spinal cord and meninges damaged and displaced

through opening. Usually hydrocephalus.

Anomalies Associated Anomalies Associated with with MyelomeningoceleMyelomeningocele

Approximate Percent Approximate Percent of Patientsof Patients

Chiari II malformationChiari II malformation 90%+90%+

Hydrocephalus Hydrocephalus 90%+90%+

Syringomyelia Syringomyelia 88%88%

Brainstem Brainstem malformations (cranial malformations (cranial nerve) nerve)

75%75%

Cerebral ventricle Cerebral ventricle abnormalities abnormalities

90%+90%+

Cerebellar heterotopias Cerebellar heterotopias 40%40%

Cerebral heterotopias Cerebral heterotopias 40%40%

Agenesis of the corpus Agenesis of the corpus callosumcallosum

12%12%

PolymicrogyriaPolymicrogyria 15-30%15-30%

Signs and SymptomsSigns and Symptoms

Radiologic Signs:Radiologic Signs: Lamina DefectsLamina Defects HemivertebraeHemivertebrae ScoliosisScoliosis Widening of Widening of

interpedicular Distanceinterpedicular Distance Butterfly VertebraeButterfly Vertebrae Cutaneous Stigmata:Cutaneous Stigmata: Capillary HemangiomaCapillary Hemangioma Caudal appendageCaudal appendage Dermal SinusDermal Sinus HypertrichosisHypertrichosis

Orthopedic finding:Orthopedic finding: Extremely asymmetryExtremely asymmetry Foot deformitiesFoot deformities Neurological Neurological

Problems:Problems: Weakness of leg- Weakness of leg-

radiculopathyradiculopathy Leg atrophy or Leg atrophy or

asymmetryasymmetry Loss of sensation, Loss of sensation,

Abnormal gaitAbnormal gait

Urologic Problems:Urologic Problems: Neurogenic bladderNeurogenic bladder IncotinenceIncotinence Anal wink Anal wink

Spina Bifida OccultaSpina Bifida Occulta

The child has long hairy tail with underline spina bifida occulta.

Treatment and optionTreatment and optionss If parents decide If parents decide notnot to terminate to terminate

pregnancy:pregnancy: Extensive counseling and Extensive counseling and

expectations once the child is born.expectations once the child is born. If diagnosed early enough fetal If diagnosed early enough fetal

surgery promising??surgery promising?? Two major sequelae: Hydrocephalus Two major sequelae: Hydrocephalus

shunt dependent + CMII malf.shunt dependent + CMII malf.

Initial Exam + Initial Exam + TreatmentTreatment Neonate born with NTD – Exam focus on Neonate born with NTD – Exam focus on

N. Sequelae.N. Sequelae. a) Site and level of lesion b) Motor and a) Site and level of lesion b) Motor and

sensory level c) presence of hydrocephalus sensory level c) presence of hydrocephalus or CMII d) ortho deformities.or CMII d) ortho deformities.

Covered with saline sponge (drying of Covered with saline sponge (drying of neural placode).neural placode).

Prone positionProne position NPO + IVF’s + Antibiotics (meningitis due NPO + IVF’s + Antibiotics (meningitis due

to leaking lesion – ventriculitis.to leaking lesion – ventriculitis.

Treatment cont.Treatment cont. Ultrasound of the head for early detection of Ultrasound of the head for early detection of

hydrocephalus – MRI for CMII and hydrocephalus – MRI for CMII and migrational problems.migrational problems.

Ortho evaluation – 10–20% NTD – hip disloc.Ortho evaluation – 10–20% NTD – hip disloc. Scoliosis – Kyphosis (no skin flaps possible).Scoliosis – Kyphosis (no skin flaps possible). Once repair 95% need V-P shunt.Once repair 95% need V-P shunt. Repair within 72 hrs. after birth.Repair within 72 hrs. after birth. Any signs of CMII (stridor, apnea, dysphagia, Any signs of CMII (stridor, apnea, dysphagia,

quadriparesis) urgent posterior fossa quadriparesis) urgent posterior fossa decompression.decompression.

Innovative Fetal Innovative Fetal Surgery Surgery Vanderbilt Univ. researchers Vanderbilt Univ. researchers

(Tulipan & Brunner) published their (Tulipan & Brunner) published their experience in JAMA-99 29 patients experience in JAMA-99 29 patients underwent intrauterine NTD repair underwent intrauterine NTD repair between 24-30 wks. gestation and between 24-30 wks. gestation and compare with control group.compare with control group.

Intrauterine fixed patients Intrauterine fixed patients experience a lower incidence of experience a lower incidence of hydrocephalus (59% vs. 91%) and a hydrocephalus (59% vs. 91%) and a lower incidence of hindbrain lower incidence of hindbrain herniation (38% vs. 95%).herniation (38% vs. 95%).

HAND OF HOPE

Innovative Fetal Surgery Innovative Fetal Surgery cont.cont.

Only one death occurred due to Only one death occurred due to oligohydramnios, reason why amniotic oligohydramnios, reason why amniotic fluid was returned to the uterus once fluid was returned to the uterus once repair was finished.repair was finished.

Extremely encouraging results but Extremely encouraging results but several questions remain unanswered. several questions remain unanswered.

Long term intellect?? Risk for the Long term intellect?? Risk for the mother and the fetus?? Decreased mother and the fetus?? Decreased shunt dependency hold for how long?? shunt dependency hold for how long??

HydranencephalyHydranencephaly

Sirenomelia-mermaidSirenomelia-mermaid

OnphaloceleOnphalocele

ExencephalyExencephaly

GastroschisisGastroschisis

Encephalocele; Encephalocele; Rachischisis; IniencephalyRachischisis; Iniencephaly

Holoprocencephaly Holoprocencephaly sequencesequence

Mid line anomaliesMid line anomalies

“El bosque seria muy triste si solo cantaran los pájaros que lo hacen mejor”rabindranath tagore

““Y los humanos deberían saber que deY los humanos deberían saber que de solo el solo el encéfalo y nada masencéfalo y nada mas provino el provino el

gozo, la alegría, la risa,la broma,la gozo, la alegría, la risa,la broma,la tristeza, la aflicción, el desaliento y el tristeza, la aflicción, el desaliento y el lamento por esto en forma especial lamento por esto en forma especial adquirimos sabiduría y adquirimos sabiduría y conocimiento,vemos,oimos,conocemos conocimiento,vemos,oimos,conocemos lo nefasto ,lo justo, lo dulce y lo lo nefasto ,lo justo, lo dulce y lo desabridos.”desabridos.”

Escritos hipocráticosEscritos hipocráticos