Latin American Course in Pediatric Neurosurgery April 5-9, 2005 Puerto Igazu, Argentina

Neural Tube DefectsEmbryological Considerations

Michel ZERAHDepartment of Pediatric Neurosurgery

Hopital Necker Enfants-MaladesUniversité Paris V

France

Spinal Dysraphism

Spinal Dysraphism

All form of developpmental

abnormalities occuring in the midline of the

back from the skin to the vertebral bodies

internally(0.05 to 3/ 1000 births)

All form of developpmental

abnormalities occuring in the midline of the

back from the skin to the vertebral bodies

internally(0.05 to 3/ 1000 births)

Spina Bifida aperta

Myelomeningocele

(0.1 to 6 / 1000)

Spina Bifida aperta

Myelomeningocele

(0.1 to 6 / 1000)

Spina Bifida Occulta

Spina Bifida Occulta

Spina Bifida Occulta

Benign bone cleftin the L5 or S1 Spinal

Process(17% in adult, 30% <

10y)

Spina Bifida Occulta

Benign bone cleftin the L5 or S1 Spinal

Process(17% in adult, 30% <

10y)

Occult spinal Dysraphism

(5 to 10/ 100 000)- Lipoma-Diastematomyelia- Neurenteric Cyst- Dermal Sinus

Occult spinal Dysraphism

(5 to 10/ 100 000)- Lipoma-Diastematomyelia- Neurenteric Cyst- Dermal Sinus

Epidemiology of NTD

• Geographic Variation (Folic Acid)

• Race and Ethnicity

• California

• Hispanic 1.12‰

• Non Hispanic Caucasian : O.96‰

Black and Asian : 1.12 ‰

Epidemiology of NTD• Heterogenicity

• T13, T18, T21

• Single Gene disordres (Mecker-Gubler, Waadenburg ...)

• X-linked, autosomal recessive inheritence

• Teratogenic exposure (diabetes, valproic acid, Carbamazepine ...)

• Risk Factor

Maternel Obesity (x1.5 to 3.5)

Normal Embryology• Primary NeurulationPrimary Neurulation

• Secondary NeurulationSecondary Neurulation

• Embryology of the Embryology of the filum terminalefilum terminale

• Para-axial mesoderm Para-axial mesoderm and spine and spine developpmentdeveloppment

Caudal regression ?Caudal regression ?

Never trust the Embryologists

• Animal models

• Short and often old series

• Artefacts

Genetic and molecular biology revolution

All (?) is done during the first month

All (?) is done during the first month

QuickTime™ et undécompresseur Animation

sont requis pour visionner cette image.

St Somites Age Features1 1 Fertilization2 1.5-3 2-16 cells3 4 Bilaminar Blast.4 5-6 Attaching Blast.5 7-12 Amniotic cav. & Yolk sac5a 7-8 Solid Trophoblast5b 9 Troph. Lacunae5c 11-12 Lacunar Vasc Circle6a 13 Chorionic Villi

6b 13 Prim. Streak. Prot. Plate plate

7 16 Notochordal Process

8 17-19 Primitive pit. Neural Fold9 1-3 19-21 First somites10 4-12 21-23 Neural fold fusion11 13-20 23-25 Cranial neuropore closes12 21-29 25-27 Caudal neuropore closes13 30-? 28 Secondary Neurulation14 32 End of spinal occlusion

Primary Neurulation (D15-D27)

• Asynchron (rostro-Caudal)

• Neuroectoderm /Ectoderm

• Needs Induction

• Prismatic Epithelium (Neural Plate)

• 2 Stages :

• Shaping

Bending

Primary Neurulation (D15-D27)

• Shaping

• Dorso-ventral Thickening

• Mediolateral Narrowing

• Craniocaudal growing

Intrinsic mechanism

Primary Neurulation (D15-D27)

• Bending

• Furrowing

• Folding

• Needs induction by the para-axial mesoderm

• Fusion

Delamination from the ectoderm

Secondary Neurulation (D28-D30)

• Different mechanism

• Mass of undifferenciated cells under the notochord (caudal bud)

Progressive differenciation, cavitation, convergence of the vacuoles in continuity with the primitive central canal

Filum Terminale

• M0 - M3 : Spine and neural tube have the same size

• M5 : Conus at the level of S1

• Birth : L2-L3

Differential Growth

Vert.Vert. RootRoot

T 10T 10

L1L1

L5L5

FetusFetus

RootRoot

T 10T 10

L1L1

L5L5

S5S5AdultAdult

Vert.Vert.

Para-axial mesoderm and developpment of the spine

• D20-D30 : Somites

• D33-D35 : Dorsal Mesoderm• 3 periods of spinal dvpt

• Membraneous• Cartilagineous• osseous

• Rostrocaudal and ventrodorsal gradient• Cerv & Thor. : W5• Sacrum : W6

Coccyx : W7

Physiological caudal regression ?

• Classical explanation : dedifferenciation and regression of the human tail

• In fact, differential and limited growth (O’Rahilly 1990)

• D28 : ∅ caudal neural tube = 90 μm

W8 : ∅ caudal neural tube = 110 μm

So What ?

• How Embryology can help ?

There is absolutely no relationship between open and occult dysraphism (almost all our patients and all our colleagues do not know the difference )

Open VS Occult dysraphism

Open Occult

CNS MalformationLoco-Regional Malformation

Accidental Genetic

Very frequent Rare

M = F F >>> M

Spine and Spinal Cord± Chiari, brain ...

Spinal Cord ± Spine,Kidney, bladder, bowel ...

MyelodysplasiaCompression, Tethering,

microtraumatism, Myelodysplasia

Embryology and MMC• Failure of Neural Tube closure

• Non Closure VS Overdistension

• MMC VS Myelodysplasia

• Teratogenic agents

• Antimitotic, CCBA, Vit A ...

• Deficience in Folate

• 5 Methyltetrahydrofolate, donating a methyl group to homocysteine to produce methione (mediates by the methionine synthetase)

Genetic model (animal)

Candidate Genes

Candidate Gene Analysis in Human Neural Tube Defects. Boyles and al. American Journal of Medical Genetic 135C:9-23 (2005)

Folic Acid• The results of 2 randomized controlled trial and several

observational studies showed that 50% or more of NTDs can be prevented if women consume a folic acid-containing supplement before and during the early weeks of pregnancy (Lancet 1991, NEJM 1992)

• Prevention for Women With No History of a Previous NTD-Affected Pregnancy : 400 μg/d

Prevention for Women Who Have Had a Previous NTD-Affected Pregnancy : 4000 μg/d

Prevention for Other High-Risk Persons. No intervention or observational studies address prevention for other high-risk persons. Women with a close relative (eg, sibling, niece, or nephew) who has an NTD (risk is approximately 0.3% to 1.0%), women with type 1 diabetes mellitus (risk is approximately 1%), women with seizure disorders being treated with valproic acid or carbamazepine (risk is approximately 1%), and women or their partners who have an NTD (risk may be 2% to 3%) and are planning a pregnancy should discuss with their physician the risk for an affected child and the advantages and disadvantages of increasing their daily periconceptional folic acid intake to 4000 μg.

Conclusion

• Solid knowledge in Chronological events

• Tiny knowledge in the true mechanism of Spinal Dysraphism

• Phenotype / Genotype

Multifactorial Problem