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Figure 6-1: The three layers of the embryonic plate showing the folding to form the neural tube
Neural tube defects (NTDs) are congenital malformations of the neural tube, caused by failure of the neural tube to close at the end of the fourth week after conception. Neural tube defects include the following three conditions:
Neural tube defects are typical examples of a multifactorial congenital malformation. These birth defects result from an interaction between genetic factors (usually a number of inherited genes) and an environmental factor (probably viral, dietary, toxic or radiation). Multifactorial defects, such as neural tube defects, occur in both males and females.
At 22 days after conception, the embryo is a flat, pear-shaped plate made up of three layers of cells. By a process of folding in the midline, the top layer of cells forms a tube within the middle layer of the plate. This tube, the neural tube, runs from top to bottom of the developing embryo and is formed by 28 days post conception.
The neural tube is the structure from which the skull, brain, spinal cord and nerves will develop, as well as the spinal column (made up of vertebrae). If the neural tube fails to close at the head end, the defect results in anencephaly or an encephalocoele. If it fails to close lower down along the spine, the result is spina bifida.
Anencephaly, encephalocoele and spina bifida are the three types of neural tube defect.
Anencephaly (no brain) is the most serious of all neural tube defects and always results in stillbirth or early neonatal death. The top (vault) of the skull is absent, exposing the brain, which is malformed. The cerebral hemispheres do not develop with anencephaly.
Anencephaly is called an open neural tube defect because brain (neural tissue) is exposed.
An encephalocoele is a failure of closure in the midline of the skull anywhere from a position between the eyes (frontal area) to the back of the skull (occipital area). With an encephalocoele the brain coverings (the meninges), with or without brain tissue, protrude through the skull defect into a membranous sac which is covered by skin. The most common site of an encephalocoele is in the occipital area. Frontal encephalocoeles are also seen.
Encephalocoeles are called closed neural tube defects because neural tissue is not exposed as the defect is covered by skin.
Spina bifida (split spine) is an opening in the spinal column due to failure of closure of the bony vertebral arches. Spina bifida may occur anywhere down the spinal column. There are three forms of spina bifida:
Spina bifida may be either open or closed, depending on the type.
Figure 6-2: A cross section of the spinal column showing a meningomyelocoele with both the spinal cord and meninges protruding through a defect in the vertebral arches.
Figure 6-3: A cross section of the spinal column showing a meningocoele with only the meninges protruding through a defect in the vertebral arches
Figure 6-4: A cross section of the spinal column showing spina bifida occulta with neither the spinal cord nor the meninges protruding through a defect in the vertebral arches
A meningomyelocoele is an opening anywhere along the spinal column, due to failure of one or more vertebral arches to close. Neural tissue (spinal cord and nerves) and the coverings of the spinal cord (the meninges) bulge through the opening. The skin over this defect does not close, but the defect may be covered by a thin membrane which tears easily. The neural tissue that bulges through the bony defect is usually damaged, resulting in nerve abnormalities below the level of the defect.
Meningomyelocoeles are open neural tube defects because neural tissue (spinal cord and nerves) is exposed and not covered by skin.
A meningocoele is an opening anywhere along the spinal column, due to failure of closure of one or more vertebral arches. Only the coverings of the spinal cord (the meninges) protrude through the defect, forming a sac which is filled with cerebrospinal fluid (CSF). The spinal cord and nerves are normal and do not bulge through the opening. There is no associated spinal cord or nerve damage. The meningocoele usually is covered on the outside by skin.
A meningocoele is a closed neural tube defect when it is covered by skin.
Spina bifida occulta is a defect of the spinal column, due to failure of one or more vertebral arches to close. This usually occurs in the lumbar and sacral regions of the spine (lower back). Unlike a meningomyelocoele or meningocoele, the spinal cord and meninges are normal and do not protrude through the defect. The defect may be covered by an overlying abnormality such as a midline patch of hair, a lipoma or a dimple. Neurological abnormality is usually not associated with spina bifida occulta although spina bifida occulta may present later in life with back problems. The diagnosis of spina bifida occulta can be confirmed on X-ray which shows the defect in the spinal column.
Spina bifida occulta is a closed neural tube defect.
Neural tube defects occur throughout the world. Their birth prevalence (number of infants with neural tube defects per 1000 live births) varies according to the area (geographic location), the ethnicity and the socio-economic status of the population. In industrialised countries the birth prevalence of neural tube defects has decreased significantly over the last 40 to 50 years, and is now about 1/1000 live births. Of these infants about 50% spina bifida, 40% have anencephaly and 10% encephalocoeles.
In urban areas of South Africa (Cape Town, Johannesburg and Pretoria), the birth prevalence in the Black population is about 1/1000 live births. In contrast, the birth prevalence has been recorded as 6.1/1000 in rural areas of the Eastern Cape Province and 3.6/1000 in rural Limpopo Province. The reason for the difference in birth prevalence between urban and rural populations is not known.
The prevalence (number of infants with neural tube defects per 1000 in a population) of neural tube defects in South Africa is small as most infants born with these defects die young. In rural Limpopo more than 90% of infants born with anencephaly, encephalocoele or meningomyelocoele die before the age of two years.
In black populations in South Africa, the birth prevalence of neural tube defects in urban areas is about 1/1000 live births while in rural areas it is about 4/1000 live births.
The development of the neural tube, including its closure, is under the control of several genes working together with environmental factors. Most neural tube defects are, therefore, caused by multifactorial inheritance, i.e. they result from an interaction between genetic and environmental factors.
Most neural tube defects are due to multifactorial inheritance.
Folic acid is one of the important fetal environmental factors involved in closure of the neural tube.
Folic acid is an important fetal environmental factor in the cause of neural tube defects.
Neural tube defects can also be caused by chromosomal abnormalities, single gene defects and teratogens including alcohol and sodium valproate (Epilim or Convulex). Sodium valproate is used to treat epilepsy. Some of these drugs may cause neural tube defects by working against the effect of folic acid.
The clinical presentation of neural tube defects depends on the type of defect, whether it is open or closed, its position and size. The different presentations vary greatly, from no obvious clinical features in spina bifida occulta to a gross abnormality in anencephaly.
Infants with anencephaly are often born preterm and may be stillborn. If they are live born they seldom live longer than 24 hours. The infants are born with the top of their skull missing and brain exposed. The eyes appear to bulge. General examination of the rest of the infant is usually normal but may reveal other abnormalities.
An encephalocoele develops because of failure of complete closure of the skull. The infant presents at birth with a midline mass anywhere from between the eyes to the back of the skull (occiput). The most common site for an encephalocoele is over the occiput. The clinical presentation will depend on the size and site and whether the encephalocoele contains neural tissue (brain matter) or not. Encephalocoeles that only contain meninges and no neural tissue usually have problems only related to the defect in the skull. However, if the encephalocoele contains brain tissue, this can be damaged or be associated with severe brain abnormalities. The resulting neurological abnormalities will depend on the size and site of the encephalocoele. In severe cases, most of the brain may be in the encephalocoele.
Associated neurological abnormalities include:
Depending on the size and site of the encephalocoele, early death, even with treatment, is a common outcome in many of these infants.
A meningomyelocoele presents at birth with a mass anywhere along the spine, but usually in the thoracic, lumbar or sacral regions. The mass may or may not be covered by a thin membrane, but neural tissue (spinal cord and nerves) is usually visible. The associated clinical features depend on the site and size of the defect.
As a meningomyelocoele contains neural tissue which is usually damaged, the body and limbs of the affected infant are paralysed below the level of the defect. The effect is similar to traumatic cutting of the spinal cord. The associated clinical features include:
Complications of meningomyelocoele may present early or repeatedly. These include:
In low resource countries, infant and early childhood death is a common outcome of meningomyelocoeles.
A meningocoele presents at birth with a skin-covered mass in the midline anywhere along the spine. As the spinal cord and nerves are not involved there usually are no neurological abnormalities in the trunk, limbs, bladder and bowels. However, hydrocephalus is present as a complication in 20% of infants with meningocoeles.
Hydrocephalus develops in 80% of infants with meningomyelocoele and in 20% of infants with meningocoele.
Most people with a spina bifida occulta do not know that they have a neural tube defect, i.e. it often remains hidden for life, therefore, the use of the word ‘occulta’ (hidden). They usually have no signs or symptoms. Occasionally, spina bifida occulta is diagnosed on an X-ray which is taken for some other reason. In some infants the presence of the bony defect in the vertebral arches is suggested by an overlying midline abnormality, usually a hairy patch.
The care required will depend on the type of neural tube defect, its site and size, and the available health facilities. In all patients the best possible care available must be given. This will include:
Because of the obvious physical features of most forms of neural tube defect the diagnosis is made at birth or shortly thereafter. The exception is spina bifida occulta which is usually not clinically obvious at birth.
Infants with anencephaly do not survive and are given palliative (hospice) care with warmth, feeds if hungry and support for the parents.
Medical treatment may be needed for the complications of encephalocoele, and meningomyelocoele. These include:
Genetic counselling and psychosocial support
This is an important part of the care of people with neural tube defects and their families.
Genetic counselling is a very important part of the care of people with neural tube defects and their family, especially the parents and siblings. The parents need to be educated and informed about:
The parents, family and child with a neural tube defect need to be offered ongoing psychosocial support, as do all individuals who have a congenital disability. They have problems that require lifelong care. The burden of the disorder and the care is experienced not only by the affected person, but also the family, especially parents, brothers and sisters.
Support, help and reassurance may be obtained from:
Yes. There are two approaches for the prevention of neural tube defects. These are:
Primary prevention: This aims to ensure the conception of infants without neural tube defects. The pre-conception approach is the preferred method of prevention. It is based on the knowledge, confirmed in Europe in the early 1990s, that if a woman takes periconceptional folic acid supplements, she can reduce her risk of having an infant with a neural tube defect by 50 percent. It was also confirmed, that if a woman had previously had an infant with a neural tube defect, her increased risk of having another child with a neural tube defect could be decreased by 70 percent.
Secondary prevention: This is based on genetic screening, prenatal diagnosis of neural tube defects, and genetic counselling.
Many neural tube defects can be prevented by periconceptional folic acid, and by genetic screening, prenatal diagnosis and genetic counselling.
Folic acid is a group B vitamin. It is very cheap and safe to give as it has few and only minor side effects even in large doses.
If folic acid is given as a medicine in the form of a pill, capsule or tablet, this is called supplementation.
With periconceptional supplementation folic acid is given around the period of conception, i.e. for three months before and three months after conception. This is the recommendation. However, even if the folic acid is given for only a month, there is some benefit.
The recommended dose of folic acid to prevent the occurrence of neural tube defects is a minimum of 0.4 mg daily. This can be taken alone or in combination with other vitamins in a multivitamin tablet. One periconceptional multivitamin tablet containing folic acid a day is recommended.
Vitamins A and D, if given to a pregnant mother in high doses, are teratogenic and can damage the fetus. Therefore, more than one multivitamin tablet a day can be dangerous for the fetus and the mother.
Yes. If a mother had a previous child with a neural tube defect she is at greater risk for having another infant with a neural tube defect in future pregnancies. To reduce this increased risk for an infant with a neural tube defect it is recommended that she take 1 mg of folic acid daily for three months before conception and for three months after conception in all future pregnancies.
No. As many pregnancies are not planned, it is important to put folic acid into a staple food to reduce the risk of neural tube defects. When an essential nutritional factor, such as folic acid, is added to the diet of the general population in this manner, this is called food fortification. Research of folic acid fortification of flour and other wheat products (from Canada, the USA, Chile and South Africa) has shown that this reduces the birth prevalence of neural tube defects.
In South Africa maize meal and wheat flour are now fortified by law with folic acid. Since the start of fortification in 2004 there has been a more than 30% decrease in the birth prevalence of neural tube defects.
Although food fortification with folic acid is being done, it is recommended that women still take periconceptional folic acid supplementation as some people may not get sufficient folic acid from fortification.
Periconceptional supplementation and food fortification with folic acid reduces the birth prevalences of neural tube defects.
Women who have previously had an infant with a neural tube defect of multifactorial origin are at greater risk of having future children affected with the same type of neural tube defect. This is also true for the children of a parent who has a neural tube defect. The risks involved in these situations are:
|Family relationship||Approximate risk|
|One affected sibling (brother or sister)||5% (1 in 20)|
|Two affected siblings||10% (1 in 10)|
|Three affected siblings||20% (1 in 5)|
|One affected parent||5% (1 in 20)|
|One affected second degree relative (uncle or aunt)||2% (1 in 50)|
Although most neural tube defects are caused by multifactorial inheritance, care must always be taken to exclude other causes of neural tube defects before genetic counselling, including risk assessment, is given.
There are a number of methods which can be used to screen the fetus for neural tube defects. In countries that have well organised screening programmes, all fetuses with anencephaly and 70–80% of fetuses with spina bifida can be detected. The screening includes:
Maternal serum alpha-fetoprotein (AFP) levels are significantly raised in ‘open’, but not in ‘closed’, neural tube defects. This is why different types of neural tube defects are classified into ‘open’ or ‘closed’ defects. Maternal serum alpha-fetoprotein screening will not detect ‘closed’ defects.
Maternal serum alpha-fetoprotein screening is best performed at around 16 weeks (between 15 and 18 weeks) gestation on a sample of the mother’s blood. It is important to ensure that the gestational age is correct. Ultrasound dating of the fetus confirms the gestation based on the date of the last menstrual period. A raised serum level of alpha-fetoprotein indicates a high risk for an open fetal neural tube defect.
Other fetal causes of a raised maternal serum alpha-fetoprotein include incorrect estimation of the gestational age, multiple pregnancy, exomphalos, nephrotic syndrome, fetal death, Turner syndrome, ectodermal dysplasia and Rhesus disease. Maternal causes include diabetes, liver or gut cancer, and hepatitis. Rarely no cause for a raised alpha fetoprotein can be found. The prognosis of these pregnancies is poor.
It is recommended that a screening ultrasound scan for fetal abnormalities is done at 18 weeks gestation (18–23 weeks). During this scan signs of neural tube defects should be detected by an experienced ultrasonographer. Fetal ultrasound scanning can detect both open and closed neural tube defects.
Whenever a maternal serum alpha-fetoprotein (AFP) screening test is abnormal, a fetal ultrasound examination must be done to decide whether a neural tube defect or other birth defect is present or not.
If a prenatal diagnosis of a neural tube defect is confirmed, the woman, preferably with her partner, should urgently receive genetic counselling regarding the diagnosis and their choices of management. For women at increased risk, or with a prenatal diagnosis of a neural tube defect, the choice of which options to take is theirs alone. Many will choose a termination of pregnancy. Their medical care providers must respect this choice. Parents must also know that no matter what their choice, this will not influence their future routine care.
With genetic screening and prenatal diagnosis people are entitled to genetic counselling and always have the right of choice.
A female infant is born at term and a severe abnormality is noticed by the midwife as soon as the infant is delivered. A doctor is called to examine the infant. She notices that the top of the infant’s skull is missing and the brain is visible. The parents are told that their infant has a serious birth defect.
It is an abnormality of the neural tube which does not close correctly towards the end of the first month after conception. The neural tube is a structure in the embryo from which the brain, spinal cord, spinal column and nerves develop.
Anencephaly. This results from failure of closure of the midline of the skull, exposing the brain. The brain is always very abnormal with most of it (the cerebral hemispheres) missing.
No. Infants with anencephaly are usually stillborn or die in the first day of life.
No. All forms of neural tube defect, including anencephaly, may occur equally in both male and female infants.
An encephalocoele is less severe than anencephaly. In an encephalocoele, only part of the skull does not close completely in the midline. As a result, the meninges and often part of the brain push through the hole in the skull. Unlike anencephaly, which is an open neural tube defect, encephalocoeles are closed neural tube defects as they are covered with skin. The defect is usually in the occipital region but may also occur in the frontal region.
After delivery, a newborn infant is noticed to have an abnormality over the lower spine and also has club feet. The infant has a big head and does not move his legs. Otherwise he appears healthy and feeds well at the breast.
The infant has spina bifida. This is a defect in the spinal column due to failure of one or more vertebral arches to close normally. The defect is usually in the lower spine (lumbosacral region).
This infant must have a meningomyelocoele because the nerves to the legs have been damaged. As a result he has paralysed legs and club feet.
A midline mass which is covered by a thin membrane. Neural tissue is visible through the membrane. A meningomyelocoele is not covered with skin.
About 80% of infants with a meningomyelocoele develop a hydrocephalus. This may be present at birth but can also develop in early infancy.
A meningocoele is a less severe defect as only the meninges bulge through the hole in the vertebral column. As there is no neural tissue in the meningocoele, there usually will be no paralysis of the legs. A meningocoele is covered with skin. Therefore, it is called a ‘closed’ defect and would not be detected with a maternal serum alpha-fetoprotein screen.
This is a mild form of spina bifida, which is often not noticed clinically. There is a small defect in the arch of a vertebra but the meninges do not prolapse. There may be a patch of hair or abnormal skin over the defect.
A young couple, who plan to start a family, visit their general practitioner, as they want to know about neural tube defects. Their neighbour recently delivered an infant with a meningocoele. The defect was successfully corrected by surgery.
In industrialised countries the prevalence of neural tube defects is about 1/1000 live births. In rural populations in South Africa, the birth prevalence is about 4/1000.
The failure of the neural tube to close normally is usually due to multifactorial inheritance. The influence of several genes, acting together with environmental factors, results in the birth defect. Rarely, the neural tube defect may be due to chromosomal or single gene defects, or teratogens.
Folic acid. A relative lack of folic acid in the diet may act together with genetic factors to result in neural tube defects.
By fortifying an essential food, such as maize meal or wheat flour, with folic acid. Fortification of maize meal in South Africa started in 2004 and has reduced the birth prevalence of neural tube defect by more than 30%.
Urgent referral to a neurosurgical unit for assessment. A meningomyelocoele should be covered with sterile gauze after birth.
A young mother has a child with a meningomyelocoele. She and her partner want another child but are unsure of the risk of further children also having a neural tube defect. They attend a genetic clinic for counselling.
There is an increased risk if there is a family history of neural tube defects. If a previous child has a neural tube defect the risk is 5% (1 in 20).
She should take 1 mg folic acid daily until she falls pregnant and then continue to take folic acid until three months after conception.
It should significantly lower the risk of neural tube defect by up to 70%.
Either with maternal serum alpha-fetoprotein screen around 16 weeks of pregnancy or by fetal ultrasound scanning at around 18 weeks of pregnancy. Ultrasound examination is also used to confirm gestational age needed for maternal serum alpha-fetoprotein screening.
It is recommended that all women take at least 0.4 mg folic acid daily for three months before and three months after falling pregnant. This is often taken in the form of one multivitamin tablet containing folic acid daily, and could lower the risk of having an infant with a neural tube defect by up to 50%. However, most women falling pregnant in South Africa are provided with extra folic acid through the fortification of maize meal.
They must be referred for genetic counselling.