Neural Tube Defects

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Neural tube defects (NTDs) are among the most common severe congenital malformations of the central nervous system.

Approximately 1 in 500 to 1 in 1000 pregnancies result in NTDs. About 4000 fetuses are affected each year in the US.

The incidence varies with geographic areas and ethnic groups.

The incidence, however, appears to be decreasing recently.

GENETICS/BASIC DEFECTS

1. Caused by a defect in closure of the neural tube, which is normally closed by 28 days

2. Multifactorial trait: environmental and genetic factors play a role in the causation of NTDs

3. Specific causes are identified in less than 10% of affected infants

a. Chromosomal abnormalities b. Single gene mutations c. Teratogens

4. Defects in the neural tube closure linked to 5,10 methyl- enetetrahydrofolate reductase deficiency and defects in the metabolism of folic acid

5. Mildly elevated homocysteine in some pregnant women who subsequently give birth to infants with NTDs 6. A specific mutation known as C677T polymorphism

a. More common in parents of children affected with NTDs

b. This polymorphism affects the enzyme methylenete- trahydrofolate reductase (MTHFR), causing it to require more folic acid to work properly

7. Low erythrocyte folate in the first trimester of pregnancy:

associated with an increased risk of neural tube defects

CLINICAL FEATURES

There are several morphologic types of NTDs: open NTDs (anencephaly, cranial or spinal rachischisis, iniencephaly, meningomyelocele, cranioectomesodermal hypoplasia), closed NTDs (cranial meningocele, cranial encephalocele, spinal meningocele alone or with spinal cord abnormality), and myelocystocele.

1. Anencephaly

a. Refers to an absence of the brain and the calvarium covering the brain

b. The most severe form of NTDs c. Incidence: about 1/1000 live births d. Responsible for about 50% of all NTDs e. Infants with anencephaly

i. Stillborn

ii. Die shortly after birth

f. Anterior pituitary, eyes, and brainstem usually spared g. Remaining tissue covering the basal cranium: a highly vascular and friable membrane referred to as area cerebrovasculosa

h. Striking craniofacial appearance i. Absent cranial vault

ii. An angiomatous membranous mass lying on the floor of the cranium

iii. An absent or backward sloping of the forehead iv. Frog-like eyes (ocular proptosis)

v. Puffy eye-lids vi. A flattened nose vii. Large folded-down ears viii. Often an open mouth

ix. A short neck

i. Syndromes associated with anencephaly

i. Chromosomal disorders [e.g., r(13), trisomy 18, del(13q)]

ii. Monogenic disorder (e.g., Meckel syndrome) iii. Disruptive sequences (e.g., amniotic bands,

maternal hyperthermia)

iv. Associations (e.g., spina bifida, holopros- encephalic face syndrome, craniofacial dupli- cation)

2. Craniorachischisis or spinal rachischisis

a. Rachischisis: refers to anencephaly with a contiguous spinal defect involving at least the cervical spine region and extending for varying degrees down the spinal column

b. The area cerebrovasculosa and the area medullovas- culosa fill the skeletal defects of the cranium and of the spinal column

c. Short neck

d. Upward-turned face e. Ears touching the shoulders

f. Frequent polyhydramnios g. Frequently stillborn h. Neurologic involvement

i. Primarily limited to brainstem and spinal reflexes

ii. Occasional seizures resembling infantile spasms 3. Iniencephaly

a. The name iniencephaly derived from an abnormality of the neck (inion) and the brain (cephaly)

b. Triad

i. Deficient cranial bone

ii. Cervical dysraphism (rachischisis)

iii. Fixed retroflexion of the fetal head and severe lordosis of the cervicothoracic spine

c. Closed or open lesions

i. A closed lesion when the occipital bone is not malformed

ii. An open lesion when the occipital bone is hypoplastic

d. Site of the neural tube lesion: at the level of the cervical spine

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e. Severity of lesion

i. Spina bifida with intact skin ii. Meningomyeloencephalocele iii. Open rachischisis

f. Associated CNS malformations i. Anencephaly

ii. Encephalocele iii. Microcephaly

iv. Hydrocephaly v. Holoprosencephaly vi. Posterior fossa defects

vii. Spinal defects such as cervical dysraphism viii. Fixed cervical hyperlordosis

g. Other associated malformations i. Diaphragmatic hernia ii. Omphalocele

iii. Thoracic cage deformities iv. Hypoplastic lungs

v. Genitourinary malformations vi. Cyclopia

vii. Cleft lip and palate viii. Imperforate anus

ix. Clubfoot

x. Single umbilical artery

h. Die within a few hours in most newborns 4. Cranium bifidum occultum

a. The most benign type b. Generally asymptomatic

c. Skull defects often close over time

d. Persistent parietal foramina (sometimes called

“Caitlin marks” after the family for which it was described; transmitted as an autosomal dominant trait via a gene located on 11p)

e. Persistent wide fontanelle 5. Cranial meningocele

a. Associated with a defect in the skull

b. Associated with protrusion of the leptomeninges 6. Encephalocele

a. A type of cephalocele (a herniation of cranial contents through a skull defect) that contains brain b. Incidence: 1/10,000 live births

c. Occurring most frequently in the occipital region (80–90%) and commonly associated with a variety of syndromes, notably Meckel-Gruber syndrome and Walker-Warburg syndrome

d. Anterior encephaloceles: found more commonly in Roberts syndrome

e. An isolated malformation of frontal encephalocele:

more commonly seen in southeast Asia

f. Outcome depending on the position of the defect and on the associated anomalies

g. Chromosome syndromes associated with encephalocele i. Trisomy 13

ii. Trisomy 18 iii. Del(13q)

iv. Del(2)(q21→ q24) v. Dup(1q)

vi. Dup(6) (q21→ qter) vii. Dup(7)(qter→ p11) viii. Dup(8)(q23→ qter)

ix. Turner syndrome

h. Monogenic disorders associated with encephalocele i. Meckel syndrome

ii. Cryptophthalmos syndrome

iii. Silverman-Handmaker type and Rolland- Desbuquiois type of dyssegmental dysplasias iv. Knobloch syndrome

v. Chemke syndrome vi. Roberts syndrome

vii. Walker-Warburg syndrome viii. Van Voss-Cherstovy syndrome

i. Disruptive sequences associated with encephalocele i. Maternal hyperthermia

ii. Warfarin embryopathy iii. Amniotic bands

j. “Associations” associated with encephalocele i. Absent corpus callosum

ii. Dandy-Walker malformations iii. Arnold-Chiari malformation

iv. Holoprosencephaly v. Craniosynostosis vi. Ectrodactyly

vii. Frontonasal dysplasia

viii. Hypothalamic-pituitary dysfunction ix. Klippel-Feil anomaly

x. Iniencephaly xi. Myelomeningocele

xii. Oculoauriculovertebral spectrum 7. Spina bifida cystica (the most common lesion)

a. Myelomeningoceles (meningomyeloceles)

i. A herniation of the spinal cord and/or nerves through a bony defect of spine

ii. Usually open defects in which meninges and/or neural tissue is exposed to the environment associated with leaking CSF

iii. The most common type of spina bifida cystica (about 90%)

iv. Approximately 20% of affected infants have additional congenital anomalies, such as gastrointestinal, cardiac, and urogenital malformations

v. Surviving infants with spina bifida likely have severe, life-long disabilities, and psychosocial maladjustment

vi. Medical problems a) Paralysis b) Hydrocephalus

c) Arnold-Chiari type II malformation (herniation of the cerebellar vermis and brainstem below the foramen magnum)

d) Endocrine abnormalities e) Tethered cord

f) Syringomyelia (cavitation of the spinal cord whose walls are comprised of glial tissue) g) Syringobulbia

h) Deformed limbs and spine i) Bladder/bowel/sexual dysfunction j) Learning disabilities

vii. Neonates with Arnold-Chiari malformation presenting with:

a) Stridor secondary to vocal cord paralysis b) Central apnea

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c) Aspiration d) Dysphagia e) Hypotonia

f) Progressive brainstem dysfunction g) Myelopathy

h) Quadriparesis i) Nystagmus j) Strabismus k) Poor sucking

l) Swallowing difficulties b. Meningoceles

i. A saccular herniation of meninges and CSF through a bony defect of spine and usually covered by normal skin

ii. No herniation of the spinal cord or nerve roots into the dorsal dural sac

iii. A cystic mass full of cerebrospinal fluid iv. Without associated neurologic problems such as

hydrocephalus and Chiari II malformation c. Lipomeningocele or lipomyelomeningocele

i. A lipomatous mass herniating through the bony defect and attaching to the spinal cord, tethering the cord and often its nerve roots

ii. Presentation with a skin-covered mass above the buttocks and eventual neurologic deficits iii. Absent associated hydrocephalus d. Myelocystocele

i. A large terminal cystic dilatation of the spinal cord secondary to hydromyelia giving rise to a large terminal skin-covered sac

ii. Constituting 4–6.5% of the skin-covered masses overlying the lower spine

iii. The majority of cases are dorsally located; only rarely (about 0.5%) are ventral in location iv. The ventral type is an anterior sacral meningocele,

most often presenting as a pelvic mass in females v. Cervical myelocystocele

vi. Lumbar myelocystocele

vii. Terminal myelocystoceles accompanying midline abdominal and pelvic defects such as part of the OEIS (omphalocele-exstrophy of the bladder-imperforate anus-spinal defects) complex viii. Chiari malformation less frequent since the

lesion is covered by dura with regular hydrody- namics of the cerebrospinal fluid

ix. Other associate malformations a) Genitourinary tract anomalies b) Intestinal malrotation

c) Club feet

x. Differential diagnoses a) Meningomyelocele

b) Lumbosacral and sacrococcygeal teratomas c) Lipomas

d) Lipomyelomeningoceles e) Hamartomas

e. Life-long disability risks in infants with spina bifida i. At risk for psychosocial maladjustment

ii. Medical problems resulting from the neurologic defects or from its repair

a) Paralysis b) Hydrocephalus

c) Arnold-Chiari malformation d) Endocrine abnormalities e) Tethered cord

f) Syringomyelia g) Syringobulbia

iii. Medical problems as sequelae of the neurologic deficits

a) Deformations of the limbs and spine b) Bowel, bladder, and sexual dysfunction c) Learning disabilities

8. Spina bifida occulta

a. A bony defect of spine occurs most often at S1 and/or S2 and is covered by normal skin (a closed lesion).

b. No herniation of the meninges through the bony defect c. Without associated hydrocephalus or Chiari II mal-

formations

d. Paraspinal cutaneous lesions with high index of suspicion pointing towards the underlying spina bifida

i. Hypertrichosis or hairy patches

ii. Lumbosacrococcygeal dimples and sinuses iii. Acrochordons (skin tags): a small, flesh-colored

to dark brown, sessile or pedunculated lesion consisting of a hyperplastic epidermis enclosing a dermal stalk of connective tissue

iv. True tails: a caudal midline appendage capable of spontaneous or reflex motion consisting of skin covering muscle, adipose, connective tissue, blood vessels, and nerves but lack vertebrae and abnormal tissue

v. Pseudotails: a caudal protrusion composed of adipose (lipoma), teratomatous elements, or cartilage vi. Lipomas

vii. Hemangiomas: indicator for tethered-cord syndrome

viii. Aplasia cutis congenita (congenital absence of skin) or scar

ix. Dermoid cyst or sinus: 12–35% of children with spina bifida occulta have sacrococcygeal dermoid cysts or sinuses, which rarely connect with the intraspinal canal. Lesions above these levels along the spine are more likely to connect with the intraspinal canal and increasingly associated with spina bifida occulta

e. Paraspinal cutaneous lesions with low index of suspicion

i. Telangiectasia

ii. Capillary malformation (port-wine stain) iii. Hyperpigmentation (lentigines or cafè-au-lait-

like lesions) iv. Melanocytic nevi

v. Teratomas: most common in the sacrococcygeal region in infancy

f. Neurologic deficits

i. Weakness of leg or legs ii. Leg atrophy or asymmetry iii. Loss of sensation

iv. Painless sores v. Hyperreflexia vi. Unusual back pain vii. Abnormal gait viii. Radiculopathy

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ix. Neurogenic bladder x. Incontinence

DIAGNOSTIC INVESTIGATIONS

1. Neurological examination of neonates a. Size, site and level of the lesion b. Motor and sensory level

c. Presence of associated hydrocephalus

d. Presence of associated symptomatic hindbrain herniation such as Chiari II malformation

e. Presence of associated orthopedic deformity

2. Neonatal cranial ultrasonography to demonstrate hydrocephalus

3. Radiography

a. Occult spinal disorders in children i. Lamina defects

ii. Hemivertebrae iii. Scoliosis

iv. Widening of interpedicular distance v. Butterfly vertebrae

b. Generally to detect bony defects 4. CT

a. Cranial defects b. Spinal defects

5. MRI: provide exquisite detail of both the cranial defect and the herniated contents

a. Cranial defects b. Cerebral defects

i. Hydrocephalus

ii. Gray matter heterotopia iii. Schizencephaly

iv. Gyral abnormalities

v. Agenesis and thinning of the corpus callosum vi. Abnormal thalami

vii. Abnormal white matter

c. Herniated contents in Chiari malformations d. Associated lesions

i. Diastematomyelia ii. Syringomyelia iii. Hydromyelia

iv. Tethered cord

GENETIC COUNSELING

1. Recurrence risk

a. Affected first-degree relatives i. 1 sib affected (5%) ii. 2 sibs affected (10%) iii. 3 sibs affected (21%)

iv. 1 parent affected (3–4.5%)

b. Affected second-degree relative: uncle/aunt; half sib (2%) c. Third-degree relative: first cousin (1% or less) 2. Prenatal diagnosis

a. Measurement of maternal serum alpha-fetoprotein (MSAFP): a useful tool for mass screening of pregnant women for NTDs

b. All cases of anencephaly and about 65% of cases of spina bifida are identified by measurement of MSAFP and ultrasonography

c. The most significant risk factor: a history of having a previous child affected with neural tube defect d. Ultrasonography

i. Used both as a screening test and as a follow-up test after positive results on MSAFP screening ii. Direct demonstration of the spinal defect iii. Indirect signs

a) Lemon sign (referring to a symmetrical bifrontal narrowing of the skull)

b) Banana sign (cerebellar abnormality) e. Prenatal diagnosis of iniencephaly by careful sonog-

raphy

i. Marked fixed retroflexion of the head and neck ii. Rachischisis

iii. Extreme lordosis of the fetus

f. Amniotic fluid alpha-fetoprotein (AFAFP) and amniotic fluid acetylcholinesterase (AFAChE): confirma- tory tests for spina bifida

3. Management: complex and challenging a. Prevention

i. Folic acid supplementation of 0.4 mg/day to all woman capable of becoming pregnant:

decrease the first occurrence of NTDs by at least 40%

ii. Folic acid supplementation of 4 mg/day in fami- lies with previous children born with NTDs:

decrease risk of recurrence by 70%

iii. Periconceptional use of folic acid supplementation will prevent 50–70% of NTDs

b. Medical management

i. Antibiotic prophylaxis to prevent meningitis and ventriculitis

ii. Urological management

iii. Management of rectal incontinence iv. Preventable conditions

a) Urinary tract infections b) Calculi

c) Skin ulcerations

d) Latex allergy and sensitization c. Surgical treatment

i. Closing all but the prognostically worst cases ii. Concurrent shunting of co-existing hydrocephalus

often necessary

iii. Decompression of the posterior fossa and/or cervical cord in Chiari II malformations

iv. Spina bifida occulta: prophylactic surgical repair more effective than waiting for patients to experience a significant neurologic deficit such as a neurogenic bladder or leg weakness from these occult spinal lesions

v. Orthopedic management of scoliosis

vi. Several reports of intrauterine repair of meningomyelocele with benefits to motor function and a decreased incidence of shunt-dependent hydrocephalus and hindbrain herniations d. Rehabilitation programs

i. Physical therapy ii. Occupational therapy iii. Speech therapy

iv. Recreational therapy

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Fig. 1. Inward scalloping of the frontal bones, known as “lemon sign”

(short arrows) and “banana” configuration of the cerebellum (long arrows), in a fetus with open spina bifida.

Fig. 2. A paraspinal unilocular cyst (arrow) in a fetus with lum- bosacral meningocele.

Fig. 3. Ventriculomegaly (arrows) observed in a fetus with lumbar meningomyelocele.

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Fig. 4. A stillbirth with classic anencephaly showing absent cranial vault, an angiomatous mass on the skull base, an absent forehead, protuberant, puffy “frog-like” eyes, an open mouth, large folded- down ears, and a short neck. Radiographs show the absent calvarium.

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Fig. 5. A newborn with anencephaly/meningocele showing the pres- ence of a meningeal sac above the base of the skull without contain- ing the brain tissue, illustrated by transillumination and MRI of the brain with or without contrast.

Fig. 6. Another neonate with anencephaly/meningocele showing sim- ilar craniofacial anomalies.

Fig. 7. Newborns with an occipital encephalocele.

Fig. 8. Encephalocele associated with amniotic band syndrome.

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Fig. 9. Newborns with a lumbosacral myelomeningocele.

Fig. 10. A fetus with trisomy 18 and open lumbosacral spina bifida.

Fig. 11. Two infants with a large lumbosacral myelocystocele covered with skin.

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Fig. 12. A stillborn with iniencephaly showing deficient cranium, short neck, cervical rachischisis, fixed retroflexion of the head, and severe lordosis of the cervicothoracic spine.

Fig. 13. A stillborn with caniorachischisis showing anencephaly with a contiguous spinal defect involving cervical spine region and extending down the spinal column, short neck, upward-turned face, and ears touching the shoulders.