Neural Tube Defects

Neural tube defects (NTDs) are the 2nd-most common type of congenital birth defects. Neural tube defects can range from asymptomatic (closed NTD) to very severe malformations of the spine or brain (open NTD). Neural tube defects are caused by the failure of the neural tube to close properly during the 3rd and 4th week of embryological development. The most common type of open NTD is meningomyelocele, which involves both the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges and neural tissue. The etiologies of NTD are multifactorial, ranging from maternal nutrition to genetic determinants. Prenatal diagnosis by ultrasound and maternal α-fetoprotein level is common. Management of open NTDs is mainly surgical.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

A neural tube defect (NTD; spinal dysraphism) is a congenital defect in the covering of the central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System, resulting from a failure of the neural tube to close spontaneously during the 3rd or 4th week of embryonic development.

Classification

  • Open NTD (80% of cases): a midline defect of the vertebral bodies with different degrees of protrusion of the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges and central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (CNS)
    • Defect along the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord:
      • Meningocele: Only the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges protrudes.
      • Meningomyelocele: Both meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges and spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord protrude (most common NTD).
    • Defect of the cranium:
      • Cranial meningocele: Meninges protrude.
      • Cranial encephalocele: Both the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges and brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem/ cerebellum Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum/ cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex protrude. 
      • Anencephaly: complete failure of the cephalic neural tube to close resulting in fully exposed fetal brain (not compatible with life)
  • Closed NTD: a midline defect of the vertebral bodies without protrusion of the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges or neural tissue
    • Without subcutaneous mass: spina bifida occulta
    • With subcutaneous mass: 
      • Lipomyelomeningocele
      • Lipomeningocele

Epidemiology

  • 1 in 1,500 births in the United States 
  • 2nd-most common major congenital anomalies (most common are cardiac anomalies)
  • Incidence:
    • Has decreased with prenatal folic acid supplementation and screening
    • Varies by ethnicity and geographic region
  • Female neonates are affected more commonly.
  • Maternal risk factors during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care:
    • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency 
    • History of NTD in previous children (5%10% recurrence with 12 affected siblings)
    • Folic acid-depleting medications (valproic acid, triamterene, trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim, sulfasalazine)
    • Poorly controlled maternal diabetes
    • Maternal obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity

Embryology

  • Conception to 3rd week of gestation ( gastrulation Gastrulation Both gastrulation and neurulation are critical events that occur during the 3rd week of embryonic development. Gastrulation is the process by which the bilaminar disc differentiates into a trilaminar disc, made up of the 3 primary germ layers: the ectoderm, mesoderm, and endoderm. Gastrulation and Neurulation): 
  • 3rd4th week:  
    • Ectoderm → differentiates into neuroectoderm (creating neural plate) → cell replication in neural plate →  neural crests + neural fold
    • Mesoderm → differentiates into notochord  signals neural fold to enlarge/fuse →  neural tube ( neurulation Neurulation An early embryonic developmental process of chordates that is characterized by morphogenic movements of ectoderm resulting in the formation of the neural plate; the neural crest; and the neural tube. Improper closure of the neural groove results in congenital neural tube defects. Gastrulation and Neurulation)
    • Neural tube “zips up” from the middle outward → cranial (head) and caudal (tail) openings close approximately on days 24 and 28
Timeline neurulation

Neurulation: the differentiation and growth of the neural plate into the neural tube during the first trimester of gestation.
PNS: Peripheral nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System

Image by Lecturio.

Clinical Presentation

Most NTDs are discovered during prenatal screening. Open NTDs are evident at birth, but closed NTDs may have more subtle presentations.

Table: Clinical features of major neural tube defects
Name Description Clinical features
Myelomeningocele Spinal cord and meningeal herniation The higher the lesion in the spine, the more severe the symptoms:
  • Brainstem: type 2 Chiari malformation (cerebellar tonsillar herniation) with hydrocephalus
  • Neck: quadriplegia
  • Lumbosacral defect:
    • Paraplegia/flaccid paralysis
    • Loss of touch and pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain sensations in lower limbs
    • Anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts in perianal area
    • Bowel + bladder incontinence
Meningocele Meningeal herniation without spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord involvement
  • Fluctuant mass
  • Transilluminates
  • Covered by skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
Encephalocele Meninges ± brain tissue protruding from cranial defect
  • Hydrocephalus
  • Spasticity
  • Paralysis
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Microcephaly
  • Developmental delay
  • Vision problems
  • Developmental and growth retardation
Anencephaly Major component of the brain and skull Skull The skull (cranium) is the skeletal structure of the head supporting the face and forming a protective cavity for the brain. The skull consists of 22 bones divided into the viscerocranium (facial skeleton) and the neurocranium. Skull is absent.
  • Stillbirth/early death
  • Spastic with deafness/blindness
Spina bifida occulta Midline vertebral body fusion defect without protruding dura or neural tissue
  • Usually asymptomatic
  • If spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord is involved (tethered cord syndrome), may develop incontinence, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, or ataxia
  • May be accompanied by abnormal overlying skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin with a hemangioma, discoloration, pit, lump, dermal sinus, or hairy patch
Types of ntd and their respective defect

Types of NTD and their respective defect

Image by Lecturio.

Diagnosis

Prenatal screening

  • Serum/amniotic α-fetoprotein (maternal serum α-fetoprotein; MSAFP): high levels at 1520 weeks of gestation suggestive of NTD, but not diagnostic
  • Ultrasound: Visualization of defect is 98% specific and can be used to confirm diagnosis (closed NTD may not be detected).

Postnatal imaging

  • Open NTD: ultrasound commonly used; magnetic resonance imaging (MRI) can be used if further detail required
  • Closed NTD: ultrasound indicated with following cutaneous signs:
    • Palpable subcutaneous mass
    • Hairy patch overlying spine
    • Dermal sinus
    • Dimples > 5 mm deep or > 25 mm from anal verge
    • Skin tags or tail-like appendages
    • Hyperpigmented patches or deviation of the gluteal cleft

Management

Prenatal

  • Prevention with folic acid (vitamin B9) supplementation:
    • Decreases the incidence of NTD by around 70%
    • Preconception dose: 0.4 mg/day of folic acid for at least 1 month prior to conception and throughout pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care 
    • A higher dose (usually 4 mg/day) is indicated for the following:
      • A previous pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care affected by an NTD
      • A positive family history for NTD
      • Use of folic acid-depleting medications
      • Pre-gestational diabetes
  • Delivery: cesarean section recommended

Postnatal

  • Closed NTD: 
    • May require no intervention
    • Ongoing follow-up for lower neurological symptoms (incontinence, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, difficulty ambulating) 
  • Open NTD:
    • Keep warm and in prone position.
    • Cover NTD with sterile wet dressing. 
  • Surgical management:
    • Neurosurgical intervention for all open NTDs
    • Closed NTD typically does not require surgery

References

  1. Boon, R. L. (2010). Textbooks of Paediatrics.
  2. Winn, H. R. (2011). Youmans Neurological Surgery E-Book. Elsevier Health Sciences.
  3. Goetzl, L.M. Folic acid supplementation in pregnancy. UpToDate. Retrieved Nov 2, 2020, from https://www.uptodate.com/contents/folic-acid-supplementation-in-pregnancy?search=neural%20tube%20defects&topicRef=460&source=see_link#H17
  4. Dukhovny, S., Wilkins-Haug, L. Open neural tube defects: Risk factors, prenatal screening and diagnosis, and pregnancy management. UpToDate. Retrieved Nov 2, 2020, from https://www.uptodate.com/contents/open-neural-tube-defects-risk-factors-prenatal-screening-and-diagnosis-and-pregnancy-management?search=neural%20tube%20defects&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H27

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