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
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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
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