Neural Tube Defects

Overview

Definition

A neural tube Neural tube A tube of ectodermal tissue in an embryo that will give rise to the central nervous system, including the spinal cord and the brain. Lumen within the neural tube is called neural canal which gives rise to the central canal of the spinal cord and the ventricles of the brain. Gastrulation and Neurulation defect (NTD; spinal dysraphism Dysraphism Teratogenic Birth Defects) is a congenital defect in the covering of the central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification, resulting from a failure of the neural tube Neural tube A tube of ectodermal tissue in an embryo that will give rise to the central nervous system, including the spinal cord and the brain. Lumen within the neural tube is called neural canal which gives rise to the central canal of the spinal cord and the ventricles of the brain. Gastrulation and Neurulation 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: Anatomy and central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification (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: Anatomy:
    • 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: Anatomy 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: Anatomy 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: Anatomy protrude (most common NTD).
  • Defect of the cranium Cranium 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: Anatomy:
    • Cranial meningocele: 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: Anatomy 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: Anatomy and brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 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: Anatomy/ 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: Anatomy protrude. 
    • Anencephaly: complete failure of the cephalic neural tube Neural tube A tube of ectodermal tissue in an embryo that will give rise to the central nervous system, including the spinal cord and the brain. Lumen within the neural tube is called neural canal which gives rise to the central canal of the spinal cord and the ventricles of the brain. Gastrulation and Neurulation to close resulting in fully exposed fetal brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification (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: Anatomy or neural tissue
  • Without subcutaneous mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast: spina bifida occulta
  • With subcutaneous mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast:
    • Lipomyelomeningocele
    • Lipomeningocele

Epidemiology

• 1 in 1,500 births in the United States 
• 2nd-most common major congenital anomalies (most common are cardiac anomalies)
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency:
  • Has decreased with prenatal folic acid supplementation and screening Screening Preoperative Care
  • Varies by ethnicity and geographic region
• Female neonates are affected more commonly.
• Maternal risk factors during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care:
  • Folate deficiency Folate deficiency A nutritional condition produced by a deficiency of folic acid in the diet. Many plant and animal tissues contain folic acid, abundant in green leafy vegetables, yeast, liver, and mushrooms but destroyed by long-term cooking. Alcohol interferes with its intermediate metabolism and absorption. Folic acid deficiency may develop in long-term anticonvulsant therapy or with use of oral contraceptives. This deficiency causes anemia, macrocytic anemia, and megaloblastic anemia. It is indistinguishable from vitamin B12 deficiency in peripheral blood and bone marrow findings, but the neurologic lesions seen in B12 deficiency do not occur. Megaloblastic Anemia 
  • History of NTD in previous children (5%–10% recurrence with 1–2 affected siblings)
  • Folic acid-depleting medications ( valproic acid Valproic acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs, triamterene Triamterene A pteridinetriamine compound that inhibits sodium reabsorption through sodium channels in renal epithelial cells. Potassium-sparing Diuretics, 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 Sulfasalazine A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid released in the colon. Sulfonamides and Trimethoprim)
  • Poorly controlled maternal diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • 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):
  • Single cell → single-layered blastula  → 3-layer gastrula: ectoderm Ectoderm The outer of the three germ layers of an embryo. Gastrulation and Neurulation, endoderm Endoderm The inner of the three germ layers of an embryo. Gastrulation and Neurulation, and mesoderm Mesoderm The middle germ layer of an embryo derived from three paired mesenchymal aggregates along the neural tube. Gastrulation and Neurulation
• 3rd–4th week:
  • Ectoderm Ectoderm The outer of the three germ layers of an embryo. Gastrulation and Neurulation → differentiates into neuroectoderm Neuroectoderm Development of the Nervous System and Face (creating neural plate Neural plate The region in the dorsal ectoderm of a chordate embryo that gives rise to the future central nervous system. Tissue in the neural plate is called the neuroectoderm, often used as a synonym of neural plate. Gastrulation and Neurulation) → cell replication in neural plate Neural plate The region in the dorsal ectoderm of a chordate embryo that gives rise to the future central nervous system. Tissue in the neural plate is called the neuroectoderm, often used as a synonym of neural plate. Gastrulation and Neurulation →  neural crests + neural fold
  • Mesoderm Mesoderm The middle germ layer of an embryo derived from three paired mesenchymal aggregates along the neural tube. Gastrulation and Neurulation → differentiates into notochord Notochord A cartilaginous rod of mesodermal cells at the dorsal midline of all chordate embryos. In lower vertebrates, notochord is the backbone of support. In the higher vertebrates, notochord is a transient structure, and segments of the vertebral column will develop around it. Notochord is also a source of midline signals that pattern surrounding tissues including the neural tube development. Gastrulation and Neurulation →  signals neural fold to enlarge/fuse →  neural tube Neural tube A tube of ectodermal tissue in an embryo that will give rise to the central nervous system, including the spinal cord and the brain. Lumen within the neural tube is called neural canal which gives rise to the central canal of the spinal cord and the ventricles of the brain. Gastrulation and Neurulation ( 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 Neural tube A tube of ectodermal tissue in an embryo that will give rise to the central nervous system, including the spinal cord and the brain. Lumen within the neural tube is called neural canal which gives rise to the central canal of the spinal cord and the ventricles of the brain. Gastrulation and Neurulation “zips up” from the middle outward → cranial (head) and caudal (tail) openings close approximately on days 24 and 28

Clinical Presentation

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

Diagnosis

Prenatal screening Screening Preoperative Care

• Serum/amniotic α-fetoprotein (maternal serum α-fetoprotein; MSAFP): high levels at 15–20 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 Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
  • Hairy patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes overlying spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy
  • Dermal sinus
  • Dimples > 5 mm deep or > 25 mm from anal verge
  • 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. Skin: Structure and Functions tags or tail-like appendages
  • Hyperpigmented patches Patches Vitiligo or deviation of the gluteal cleft

Management

Prenatal

• Prevention with folic acid (vitamin B₉) supplementation:
  • Decreases the incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency 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 The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care 
  • A higher dose (usually 4 mg/day) is indicated for the following:
    • A previous pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care affected by an NTD
    • A positive family history Family History Adult Health Maintenance for NTD
    • Use of folic acid-depleting medications
    • Pre-gestational diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
• Delivery: cesarean section recommended
• Fetal surgery

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 Sterile Basic Procedures wet dressing. 
• Surgical management:
  • Neurosurgical intervention for all open NTDs
  • Closed NTD typically does not require surgery