DISORDERS OF NEURAL TUBE FORMATION

The neural tube usually fuses 18–26 days after ovulation. Failure of closure may lead to anencephaly, encephalocele, spina bifida or spina bifida occulta. Liveborn anencephalic babies usually die in hours or days.

Epidemiology

Neural tube defects (NTDs) are among the most common congenital abnormalities but prevalence varies between countries and races. The prevalence of NTDs in England and Wales fell from the 1970s onwards to just under 0.8/1000 total births by 1994. Some of the decline was due to antenatal diagnosis but some is unexplained. In the UK anencephaly and spina bifida are of approximately equal prevalence and together make up 95% of all NTDs.

Aetiology

Most NTDs result from a complex interaction between several genes and poorly understood environmental factors.

Genetic factors

NTDs occur in many syndromes and chromosome disorders. However, an NTD may be the only anomaly in a member of a family in which case the relatives have an increased risk for all types of NTD.

Environmental factors

Periconceptual multiple vitamin supplements containing folic acid reduce the incidence of neural tube defects. In England it is recommended that women planning pregnancy take 400 μg of folic acid daily before conception and during the first 12 weeks of the pregnancy. Some drugs taken during the pregnancy may increase the risk. These include sodium valproate and folic acid antagonists such as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbitone, and primidone.

Prenatal diagnosis

α Fetoprotein (AFP) concentrations in maternal serum provide a means of screening for open NTDs which allow AFP from the fetal liver to leak into amniotic fluid and then maternal blood, best detected at 16–18 weeks of pregnancy. Ultrasonography is recommended for at-risk women (positive serum AFP screening, previously affected child, taking drugs associated with NTDs in the fetus). Ultrasound can detect anencephaly from 12 weeks gestation and spina bifida from 16–20 weeks. However, spina bifida may be missed, particularly in the L5–S2 region. Amniocentesis to detect raised amniotic fluid AFP has been largely superseded by detailed ultrasound imaging.

Spinal dysraphism

Spina bifida cystica

This is a cystic lesion which in 80–90% is a myelomeningocele in which the spinal cord is a component of the cyst wall. It is lumbosacral in about 80% of cases. There is usually a mixture of upper and lower motor neurone signs depending on the level and there is always disturbance of bladder and bowel function. Surviving infants require complex orthopaedic and urological support, including surgery. About 5% of cases of spina bifida cystica are meningoceles in which there is no neural tissue in the cyst wall, there is no associated hydrocephalus, and neurological examination may be normal.

Hydrocephalus complicates most cases of lumbosacral meningomyelocele. Ultrasound shows hydrocephalus in about 90% of cases at birth. Usually it is associated with the Chiari II malformation, which is present in about 70% of cases of meningomyelocele and consists of downward protrusion of the medulla below the foramen magnum to overlap the spinal cord. Distortion of the medulla and midbrain can cause lower cranial nerve palsies and central apnoea (which may be misdiagnosed as epilepsy).

Treatment of infants with meningomyeloceles became possible with the development of ventriculo-atrial and ventriculo-peritoneal shunts. The early active management involves closing the defect and inserting a shunt. Active intervention in all cases was questioned in the 1970s and a more selective approach was advocated. However, selective surgical management is not universally practised and this remains a controversial area.

Occult spinal dysraphism

The term spina bifida occulta is often applied to a defect of the posterior arch of one or more lumbar or sacral vertebrae (usually L5 and S1). It is found incidentally by x ray in 25% of hospitalised children and may be regarded as a normal variant. However, it must not be assumed that spina bifida occulta is always benign. If examination of the skin over the spine reveals a naevus, hairy patch, sinus or subcutaneous mass, magnetic resonance imaging of the spinal cord is probably indicated, particularly if there are associated neurological abnormalities of sphincter or limb control. Several different abnormalities may be found, such as an open sinus tract which could cause recurrent meningitis, a lipoma attached to a low lying spinal cord, or diastematomyelia which is a sagittal cleft dividing the spinal cord into two halves often with a bony or cartilaginous spur transfixing the cord. If an abnormality involving the cord or nerve roots is found there is a case for neurosurgical intervention, but the indications for this are controversial.

Syringomyelia

This is a tubular cavitation of the spinal cord which tends to be in the cervical region but may involve the whole cord. It rarely becomes symptomatic in children. Shunting of the cavity is sometimes performed and posterior fossa exploration may be undertaken. It is often associated with the Chiari I malformation in which there is downward displacement of the lower cerebellum, including the tonsils (fig 1).

Figure 1Chiari I malformation. Sagittal T1 weighted magnetic resonance image showing an enlarged cerebellar tonsil which extends below the level of the foramen magnum (arrow). The corpus callosum is normal with the cingulate gyrus just above it (compare to figure 5). This 12 year old boy presented with headaches. The Chiari I malformation can be associated with hydrocephalus and syringomyelia, which he did not have.

DISORDERS OF REGIONALISATION

Abnormal development of the anterior portion of the neural tube (the mediobasal prosencephalon) and associated structures caused by disturbances in ventral induction (described above) may cause abnormalities of the brain and face. The most severe is holoprosencephaly in which there is failure of the prosencephalon to separate into two cerebral hemispheres. The mildest is olfactory aplasia without other cerebral malformations. The severity of associated facial abnormalities often parallels those in the brain. In the most severe facial abnormality there is anophthalmia and absence of the nose. However, there may be just mild hypotelorism (closely set eyes), a single central incisor tooth or the face may be normal.

DISORDERS OF CORTICAL DEVELOPMENT

Disorders of proliferation and differentiation

Microcephaly

This is an abnormally small head circumference (< 0.4th centile on occipito-frontal head circumference charts), which is disproportionately small in relation to the rest of the body. The usual implication of this finding is that brain growth is not normal. However, if a small head circumference is detected in the neonatal period it is prudent to perform an x ray of the skull to look for evidence of early closure of all the cranial sutures (total craniosynostosis).

Genetic causes

There are familial cases where the neurological problems are relatively mild. However microcephaly is usually associated with significant abnormalities such as pyramidal tract signs and profound learning difficulties. It is part of more than 450 syndromes listed in the Oxford Dysmorphology Database.

Non-genetic causes

These include ionising radiation in the first two trimesters of pregnancy, intrauterine infections, drugs and other chemicals, circulatory disturbance, and perinatal hypoxic-ischaemic events. When there is a significant perinatal insult to the brain the head circumference may be normal at birth with subsequent failure of growth in the first few months of life. Equally in some types of genetic microcephaly the head size falls off as late as 32–34 weeks of gestation or even after birth, so prenatal diagnosis by ultrasound may be difficult.

Megalencephaly

Megalencephaly is increased size of the brain itself. Large heads can run in normal families but inherited megalencephaly can be associated with significant learning difficulties, neurological abnormalities, and seizures. Hemimegalencephaly is unilateral enlargement of one side of the brain, sometimes the hemisphere only. Associated neurological problems can be severe—intractable seizures, developmental delay, and sometimes hemiparesis.

Disorders of migration

Migrating neurones may fail to reach their intended destination in the cerebral cortex. The abnormalities may be focal or diffuse. If neurones fail to leave the ventricular zone, periventricular heterotopias result. If they fail to complete their migration in the cortex this causes lissencephaly. If only a subpopulation of neurones are affected and others complete migration this causes nodular or band heterotopias.

Agyria-pachygyria (lissencephaly)

There may be complete absence of gyri, in which case the terms agyria or lissencephaly (Greek: “smooth brain”) are used. Pachygyria describes a reduced number of broadened and flat gyri with less folding of the cortex than normal. There may be varying degrees of agyria/pachygyria in the same brain (fig 2).

Figure 2Type I lissencephaly. Coronal T1 weighted magnetic resonance image. Although the brain can be completely smooth in lissencephaly these patients may have areas of both agyria and pachygyria. This scan illustrates the point. The parietal lobe (arrow 1) shows large abnormal gyri (“pachygyria”). In the left temporal lobe there are more normal gyri (arrow 2). In this boy the occipital lobes (not seen) showed complete agyria. He presented in the first few months of life with developmental delay and infantile spasms; the scan was performed at 8 months of age.

Type I lissencephaly

Here the brain is small with only the primary and sometimes a few secondary gyri. The cortex is thick with the white matter forming a thin rim along the ventricles. Infants with type I lissencephaly may be divided into two groups. The minority have the dysmorphic features of the Miller-Dieker syndrome associated with deletions of 17p13.3, a region which includes the LIS1 gene. The majority have the isolated lissencephaly sequence (ILS) and have no dysmorphic features. This is a heterogeneous group. More than 40% have a deletion of, or mutations within, the LIS1 gene. Mutations in a second gene on the X chromosome, doublecortin (DCX), have also been shown to cause lissencephaly.

Type II lissencephaly or Walker-Warburg syndrome

This is also called “cobblestone lissencephaly” and is a different malformation from type I lissencephaly. The smooth cortex has a granular surface and is covered with meninges that are thickened as a result of mesenchymal proliferation. The clinical features include both nervous system and muscle abnormalities. The infants are very abnormal at birth. They have abnormal eyes with retinal dysplasia, microphthalmia, and anomalies of the anterior segment. There may be hydrocephalus or sometimes microcephaly. Usually there is necrosis of fibres in all muscles, similar to that seen in severe muscular dystrophy, and serum creatine kinase is raised.

Apart from the Walker-Warburg syndrome there are other disorders of muscle, eye, and brain. Recent work suggests that mutations within the dystrophin complex underlie these disorders.

Heterotopias

Periventricular heterotopias are abnormal collections of neurones in the subependymal region. They may be part of a complex malformation syndrome or they may be isolated. They may be clinically silent or associated with seizures and developmental problems. Subcortical heterotopias can be divided into two groups. Nodular heterotopias of grey matter are found in association with other migration disorders and may be the cause of partial seizures. Subcortical laminar heterotopias are also known as band heterotopias or “double cortex”.

Polymicrogyria (microgyria)

This developmental disturbance may occur after the fifth month of pregnancy. The causes are poorly understood but may be genetic, infective or hypoxic (perhaps associated with poor cerebral perfusion). The clinical manifestations depend on the location and extent of the abnormalities. There is a bilateral perisylvian syndrome (or anterior operculum syndrome) in which bilateral opercular abnormalities are seen on magnetic resonance imaging, some of which have the appearance of polymicrogyria (fig 3). These patients have a pseudobulbar palsy with dysarthria, loss of voluntary control of the face and tongue leading to drooling and difficulty feeding. Familial occurrence has been reported.

Figure 3Bilateral opercular polymicrogyria. Coronal T1 weighted magnetic resonance image. These bilateral abnormalities (arrows) are relatively subtle and were not identified on a computed tomographic examination. In the first year of life this boy developed right sided seizures and development was delayed, particularly in language. Later he had poor tongue and pharyngeal coordination and a right hemiplegia. Despite the lateralisation of some of his neurological signs, the scan abnormalities were bilateral.

Disorders of cortical organisation

Some patients have cortical microdysgenesis—microscopic abnormalities of cortical arrangement that have been described in the brains of patients with epilepsy, autism, schizophrenia, and the fetal alcohol syndrome. The extent to which these findings explain abnormal brain function is an area of active research. Other patients have areas of focal cortical dysplasia which are large enough to be seen on computed tomographic or magnetic resonance imaging scans (fig 4). These dysplasias are a cause of early onset seizures that may be focal or generalised. Resection of cortical dysplasias may improve seizure control.

Figure 4 Congenital cortical malformation. Axial T2 weighted magnetic resonance image. There is a cleft in the posterior parietal cortex (arrow) with associated gyral abnormalities more anteriorly. Such lesions are difficult to classify. The term schizencephaly is often used when there is a cleft that extends through the cerebral hemisphere, connecting the ventricle to the subarachnoid space; these clefts tend to be located near the pre- and postcentral gyri. In other cases the malformation may be a localised area of polymicrogyria and the term cortical dysplasia may be used to describe the lesion. This 7 year old girl suffered with partial seizures during which her right arm and hand would go into spasm and then jerk. Between attacks she had slight weakness of the right hand and difficulty performing fine movements.

COMBINED AND OVERLAPPING CEREBRAL MALFORMATIONS

There are distinct abnormalities that represent an overlap between different classes of malformation. This is not surprising—the teratogenic periods are so closely spaced that overlaps are likely if there is an environmental cause. Also in genetically determined syndromes more than one developmental process may be affected.

Agenesis of the corpus callosum

This can be present without symptoms so the true prevalence is not known. Estimated prevalence has varied from 0.05–70 per 10 000 in the general population, increasing to 230 per 10 000 in children with developmental disabilities.

“True” callosal agenesis should be distinguished from secondary types which are associated with major malformations of the embryonic forebrain such as holoprosencephaly. Agenesis of the corpus callosum may be complete or partial. When there is complete absence there is no cingulate gyrus (fig 5). Associated enlargement of the occipital horns of the lateral ventricles is known as colpocephaly.

Figure 5 Agenesis of the corpus callosum. Sagittal T1 weighted magnetic resonance image. The arrow indicates the complete absence of the corpus callosum and the cingulate gyrus (compare to fig 1). In this 11 year old girl there was also dysgenesis of the right temporal lobe (not seen). She had learning difficulties and complex partial

(temporal onset) seizures. Agenesis of the corpus callosum may be an isolated finding and there may be no associated developmental or neurological problems.

Isolated callosal agenesis may be inherited but no loci have been mapped and non-syndromic genetic transmission is rare. It has been associated with trisomy 18 and trisomy 13, and reported in more than 20 autosomal and many X linked malformation syndromes. Callosal agenesis is part of the fetal alcohol syndrome and is seen in lactic acidosis and non-ketotic hyperglycinaemia.

When agenesis of the corpus callosum is the only lesion there may be no symptoms although tests of perception and language may demonstrate disturbances of integration of hemispheric function. However, some patients have mental retardation, seizures or cerebral palsy.

Prenatal ultrasound allows diagnosis from 20 weeks gestation. When callosal agenesis is discovered on antenatal scan the prognosis is difficult to assess because the isolated lesion can be associated with normal development. A decision to terminate the pregnancy may depend on the demonstration of associated abnormalities.

Porencephaly

The term porencephaly is often used for any cavity in a cerebral hemisphere that commnunicates with a lateral hemisphere. However, it should probably be used only for circumscribed hemispheric necrosis that occurs in utero before the adult features of the hemisphere are fully developed. The relatively early development of these lesions is shown by their smooth walls and by associated developmental disturbances in the adjoining cortex such as polymicrogyria or distortion of the gyral pattern. This is relevant because unilateral or bilateral porencephalic cysts are found in children diagnosed as having cerebral palsy and there is often debate about the timing of the insult. Neuropathological texts debate whether or not there is a distinction between porencephaly and schizencephaly, and some cortical abnormalities do not fit neatly into any group (fig 4).

Schizencephaly

This term is used by radiologists to describe clefts which traverse the full thickness of the hemisphere, connecting the ventricle to the subarachnoid space. They are described as type I or “fused-lip” when the walls of the cleft are opposed, and type II or “open-lip” when cerebrospinal fluid separates the walls. Some of them are genetic—familial cases have been described and some sporadic cases are associated with mutations in the homeobox gene EMX2. The clefts are frequently bilateral and even when unilateral they are often combined with cortical dysplasia of the opposite hemisphere.

Epilepsy is common and sometimes the only problem is isolated partial seizures. There may be hemiplegia, quadriplegia, and learning difficulties of variable degree. If there is bilateral involvement of both opercular regions there may be facial apraxia and speech difficulties.

MALFORMATIONS OF POSTERIOR FOSSA STRUCTURES

At the end of the fourth week of gestation the neural tube divides into the three primary brain vesicles—the prosencephalon, the mesencephalon, and the rhombencephalon. The latter further subdivides into the metencephalon and the myelencephalon. The cerebellar hemispheres (neocerebellum) are derived primarily from the metencephalon, while the vermis (palaeocerebellum) is derived from the mesencephalon.

Malformations of posterior fossa structures include aplasia or hypoplasia of the cerebellar hemispheres (which may be combined with brainstem abnormalities). There may be abnormalities of the vermis, including the Dandy-Walker malformation (which consists of complete or partial agenesis of the vermis, dilatation of the fourth ventricle, and enlargement of the posterior fossa) and the Joubert syndrome (an autosomal recessive disorder characterised by absence or hypoplasia of the postero-inferior part of the vermis).

INVESTIGATIONS AND GENETIC COUNSELLING

Investigations

Magnetic resonance imaging is essential to delineate the anatomical abnormalities.

If a structural CNS abnormality is found consider chromosome analysis, especially if there are developmental problems or learning difficulties.

Further investigations will depend on the specific diagnosis. Metabolic disorders can cause structural abnormalities in the developing CNS.

Mutation analysis of specific genes may confirm a clinical diagnosis. Fluorescent in situ hybridisation (FISH) studies may detect microdeletion syndromes such as the Miller-Dieker syndrome.

Take blood to extract and store DNA or establish a lymphoblastoid cell line if no precise diagnosis can be reached, especially if life expectancy is short. Frozen tissue for DNA can be obtained when postmortem examinations are being performed.

Risk assessment

It is important to construct a three generation family tree, if necessary with examination and investigation of close relatives for subtle expression of a disorder, or evidence of carrier status.

The aim is to establish a diagnosis and give an accurate risk. If it is not possible to identify the precise aetiology it is usually possible to offer an empiric recurrence risk after examination of the parents.

Prenatal diagnosis

Prenatal diagnosis and termination of affected pregnancies is only one of a range of reproductive options open to parents, but for many couples it is the option of choice.

For the majority of developmental disorders of the nervous system, pre-implantation genetic diagnosis is not yet feasible.

For a condition following mendelian inheritance the option of donor gametes could be discussed.

For a condition with a strong environmental component it is imperative that measures are taken to minimise the risk of exposure in a future pregnancy. For neural tube defects, periconceptual supplementation with high dose folate has been shown to reduce the risk of recurrence in future pregnancies (see above).

When a specific diagnosis has been made and a chromosomal anomaly, genetic mutation or biochemical defect has been identified it is usually possible to offer prenatal diagnosis by chorion villus sampling at 11 weeks gestation in a future pregnancy. If this is not the case, detailed ultrasound scanning may be helpful in some instances.

Providing accurate genetic advice about developmental anomalies of the nervous system is a challenging task. Referral for specialist advice is strongly recommended.

Learning points

Neural tube defects (NTDs) are some of the most common congenital abnormalities of the CNS, although their prevalence in the UK has fallen. Nevertheless it is still important to counsel women of childbearing age about the need to take dietary supplements containing folate before becoming pregnant

There is an increased risk of NTDs in pregnant women who are taking certain drugs

Even small midline abnormalities over the spinal cord should be taken seriously in case there is underlying spinal dysraphism

Learning points

When assessing children the head circumference should be measured and plotted on a centile chart. The current measurement should be compared with previous measurements to determine whether or not there has been a progressive change with time

Some children with non-progressive abnormalities of head size are normal in their development, but children with micro- or macrocephaly and abnormal development should probably have magnetic resonance imaging of the brain

Learning points

The lissencephalies cause major developmental problems and may shorten life

In type II lissencephaly the cerebral malformations may be associated with eye or muscle abnormalities so that a comprehensive assessment is necessary

Some of the less severe migrational and organisational abnormalities may be clinically silent. However they may be associated with learning difficulties or seizures. Many will be discovered on magnetic resonance imaging of the brain. However some are microscopic, which is relevant in the assessment of some patients with refractory epilepsy

Learning points

Combined malformations may be found in infants with severe developmental and neurological problems

However, they may be present in patients with relatively minor learning difficulties or motor disability. Patients with agenesis of the corpus callosum may have no neurological problems. It is important to be guarded about the prognosis when such abnormalities are found on scanning in early life

KEY REFERENCES

1. Aicardi J. Diseases of the nervous system in childhood, 2nd ed. London: Mac Keith Press, London, 1998. ▸ This is a standard work, which contains an excellent chapter on malformations of the nervous system.

2. Baraitser M. (1997). The genetics of neurological disorders, 3rd ed. Oxford Monographs on Medical Genetics. 34. Oxford: Oxford University Press, 1997. ▸Another standard reference book, which remains useful despite the evolution of computerised neurogenetic databases.

3. Barkovitch AJ. Pediatric neuroimaging, 2nd ed. Philadelphia: Lippincott-Raven, 1996. ▸This comprehensive textbook has a useful chapter that includes scans illustrating the normal development of the nervous system. There are also chapters on congenital abnormalities of the brain and spine.

4. Faerber EN, ed. CNS Magnetic resonance imaging in infants and children. Clinics in Developmental Medicine No.134. London: Mac Keith Press, 1995. ▸More useful scans of children with developmental problems.

5. Friede RL. Developmental neuropathology, 2nd revised and expanded edition. Berlin: Springer-Verlag, 1989. ▸This is a neuropathology textbook dealing with these complicated developmental abnormalities. It supplements and underpins the more recent work, which is based more on imaging and genetic studies than neuropathology.

6. Gleeson JG, Walsh CA. Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends in Neuroscience2000;23:352–9. ▸An excellent recent review.

[CrossRef] [Medline] [Web of Science]

7. Govaert P, de Vries LS. An atlas of neonatal brain sonography. Clinics in Developmental Medicine Nos. 141–142. London: Mac Keith Press, 1997.

▸Ultrasonography is now the means of performing early and non-invasive examinations of the infant brain so this is an important reference work for those looking after newborns.

http://jnnp.bmj.com/content/74/suppl_1/i3.full#sec-2

Birth defects - central nervous system 

Summary

Neural tube defects (NTDs) include spina bifida, anencephaly and encephalocele. Folate deficiency and some epilepsy medications are risk factors for these conditions. Taking folic acid before and during early pregnancy can significantly reduce the risk of neural tube defects. Tests in pregnancy such as ultrasound can diagnose these birth defects.

Birth defects of the central nervous system are called neural tube defects (NTDs). NTDs include conditions called spina bifida, anencephaly and encephalocele. They are all present at birth and are due to a problem with the development of the brain and/or spinal cord in the developing baby (fetus).

The brain and spinal cord of a growing fetus develop from a simple structure called the neural tube. The neural tube ‘zips up’ along its length to close and protect the brain and spinal cord. If the neural tube doesn’t close at any part along its length, the baby will have a neural tube defect. The types of neural tube defects (spina bifida, anencephaly and encephalocele) are due to the place along the neural tube that hasn’t closed, leaving parts of the brain and/or spinal cord exposed.

A range of genetic and environmental factors are thought to be responsible for NTDs, including the mother having not enough of the vitamin folate and some epilepsy medications. Taking folate (folic acid) before and during early pregnancy can significantly reduce the chance that a mother will have a baby with this kind of birth defect.

The central nervous system (CNS)

The central nervous system consists of the brain and spinal cord. Both are wrapped in a thin lining called meninges and are surrounded by a fluid called cerebrospinal fluid. The brain is attached to the spinal cord by the brain stem, located at the base of the brain. The spinal cord runs the length of the backbone and is protected by the bones (vertebrae) of the spine. Nerves branch off from the spinal cord into the parts of the body.

Development of the fetal CNS

The central nervous system of a growing fetus starts with a simple structure called the ‘neural groove’ that folds in to form the ‘neural tube’. This then develops into the spinal cord and brain. By day 28 after conception, the neural tube should be closed and fused. If it doesn’t close, the result is a neural tube defect. In many cases, these defects can be diagnosed during pregnancy with ultrasound scans and, rarely, with other tests such as amniocentesis (analysing a sample of amniotic fluid).

Risk factors and prevention of CNS birth defects

Neural tube defects are thought to be caused by a range of genetic and environmental factors working in combination. Some of these factors include:

The mother has a folate deficiency – if the mother is lacking some nutrients, especially the B-group vitamin called folate (folic acid), the chance of having a baby with a NTD is increased. If folate is taken before conception and at least for the first four weeks of pregnancy, around seven out of 10 cases of NTDs can be prevented. You should talk to your doctor about how much folate you should take if you are thinking of becoming pregnant.

Genetics – the exact genetic association is unclear, but a woman is at increased risk of having a baby with a neural tube defect if she has a close relative who has had a baby with the condition (a family history). A woman who has already given birth to a child with a neural tube defect is also at increased risk of having subsequent babies with a similar condition.

Having a personal or family history of a NTD can influence the amount of folate needed to reduce the chance of having a baby with a neural tube defect. You should talk to your doctor about how much folate you should take if you are thinking of becoming pregnant.

In some cases, however, there is evidence to suggest that some forms of neural tube defects are caused by specific genetic changes (mutations) that are not related to folate. In these cases, the neural tube defect is caused by the baby inheriting faulty gene copies from both parents. These faulty genes prevent the baby from making use of folate that is necessary to grow and develop in pregnancy (even if the folate is present in the right amount). In these cases, taking folate before and during pregnancy will not prevent the condition.

Medication – particular medications used to treat and control epilepsy are thought to contribute to the risk of neural tube defect.

Spina bifida

In a baby with spina bifida, the bones (vertebrae) of the spine fail to fuse. The spinal cord and nerves protrude (or ‘pop out’) through the gap that has been created due to a failure of closure of the neural tube. This can affect the nerves that spread from this area into the abdomen and legs. Spina bifida can occur anywhere along the length of the spine, but more commonly appears in the lower back.Nine out of 10 affected babies also have a build-up of cerebrospinal fluid inside the brain. This condition is called hydrocephalus and is sometimes referred to as ‘water on the brain’. The incidence of spina bifida in Victoria is around one in every 1,235 births.Spina bifida can be mild, moderate or severe and is graded according to the degree of the defect into:

Occulta – the bones (vertebrae) have not closed completely, but the spinal cord is unharmed. The characteristic soft lump may be missing, which is why this form of spina bifida is sometimes diagnosed later in life.

Meningocele – the membrane (meninges) covering the spinal cord protrudes or bulges out through the gap in the spine.

Myelomeningocele – the meninges, spinal cord and blood vessels protrude through the gap.

Spina bifida is incurable. The main form of treatment is surgery to seal the gap. If the baby has hydrocephalus, a shunt is inserted into the brain to drain the excess cerebrospinal fluid.

Anencephaly

When the neural tube doesn’t close at the head, this may cause the uppermost brain tissue, the meninges, top of the skull (calvarium) and the scalp to be partially or completely missing. For reasons unknown, anencephaly occurs twice as often in females as males. Around one in 10 affected babies is one of a pair of twins. In some cases, the baby has other problems such as congenital heart disease and cleft palate. The incidence of anencephaly in Victoria is around one in every 1,370 births.A baby with anencephaly is not able to live. Most are stillborn or die within a few days of birth.

Encephalocele

In this rare form of neural tube defect, the meninges and brain tissue bulge out through a gap in the skull. In severe cases, the brain is pushed out to such an extent that the bundle of brain tissue covered by the meninges (membranes) may be larger than the baby’s head. Infection can occur if the membrane breaks and exposes the brain tissue. Other problems associated with encephalocele can include cleft lip or palate, additional fingers (polydacty) and abnormalities of the sex organs. The incidence of encephalocele in Victoria is around one in every 6,667 birthsIf there is a significant amount of brain tissue that has been pushed out, surgery may not be possible. Treatment options include the use of a shunt to remove the fluid build-up (treat the hydrocephalus), if necessary. The baby will experience a range of difficulties that can include intellectual impairment, difficulty in controlling muscles (spasticity) and fits (convulsions). Physiotherapy and anticonvulsant medication may help.

Things to remember

The brain and spinal cord of a growing fetus develop from a simple structure called the neural tube.

If the neural tube doesn’t fuse together, the baby will have a neural tube defect.

Types of neural tube defects include spina bifida, anencephaly and encephalocele.

Taking the right amount of folate before and during early pregnancy can prevent seven out of 10 cases of neural tube defects.

If you would like to link to this fact sheet on your website, simply copy the code below and add it to your page:

<a href="http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Birth_defects_central_nervous_system?open">Birth defects - central nervous system - Better Health Channel</a><br/>

Neural tube defects (NTDs) include spina bifida, anencephaly and encephalocele. Folate deficiency and some epilepsy medications are risk factors for these conditions. Taking folic acid before and during early pregnancy can significantly reduce the risk of neural tube defects. Tests in pregnancy such as ultrasound can diagnose these birth defects.

http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Birth_defects_central_nervous_system

HydrocephalusWater on the brain

Last reviewed: November 12, 2012.

Hydrocephalus is a buildup of fluid inside the skull that leads to brain swelling.

Hydrocephalus means "water on the brain."

Causes, incidence, and risk factors

Hydrocephalus is due to a problem with the flow of the fluid that surrounds the brain. This fluid is called the cerebrospinal fluid, or CSF. It surrounds the brain and spinal cord, and helps cushion the brain.

CSF normally moves through the brain and the spinal cord, and is soaked into the bloodstream. CSF levels in the brain can rise if:

The flow of CSF is blocked It does not get absorbed into the blood properly Your brain makes too much of it

Too much CSF puts pressure on the brain. This pushes the brain up against the skull and damage brain tissue.

Hydrocephalus may begin while the baby is growing in the womb. It is common in babies who have a myelomeningocele, a birth defect in which the spinal column does not close properly.

Hydrocephalus may also be due to:

Genetic defects Certain infections during pregnancy

In young children, hydrocephalus may be due to:

Infections that affect the central nervous system (such as meningitis or encephalitis), especially in infants

Bleeding in the brain during or soon after delivery (especially in premature babies) Injury before, during, or after childbirth, including subarachnoid hemorrhage Tumors of the central nervous system, including the brain or spinal cord Injury or trauma

Hydrocephalus most often occurs in children. Another type, called normal pressure hydrocephalus, may occur in adults and the elderly.

Symptoms

Symptoms of hydrocephalus depend on:

Age Amount of brain damage What is causing the buildup of CSF fluid

In infants with hydrocephalus, it causes the fontanelle (soft spot) to bulge and the head to be larger than expected. Early symptoms may also include:

Eyes that appear to gaze downward Irritability Seizures Separated sutures Sleepiness Vomiting

Symptoms that may occur in older children can include:

Brief, shrill, high-pitched cry Changes in personality, memory, or the ability to reason or think Changes in facial appearance and eye spacing Crossed eyes or uncontrolled eye movements Difficulty feeding Excessive sleepiness Headache Irritability, poor temper control Loss of bladder control (urinary incontinence)

Loss of coordination and trouble walking Muscle spasticity (spasm) Slow growth (child 0 - 5 years) Slow or restricted movement Vomiting

Signs and tests

The doctor or nurse will examine the baby. This may show:

Stretched or swollen veins on the baby's scalp Abnormal sounds when the health care provider taps lightly on the skull, suggesting a

problem with the skull bones All or part of the head may be larger than normal, usually in the front part Eyes that look "sunken in" White part of the eye appears over the colored area, making it look like a "setting sun" Reflexes may be normal

Head circumference measurements, repeated over time, may show that the head is getting bigger.

A head CT scan is one of the best tests for identifying hydrocephalus. Other tests that may be done include:

Arteriography Brain scan using radioisotopes Cranial ultrasound (an ultrasound of the brain) Lumbar puncture and examination of the cerebrospinal fluid (rarely done) Skull x-rays

Treatment

The goal of treatment is to reduce or prevent brain damage by improving the flow of CSF.

Surgery may be done to remove a blockage, if possible.

If not, a flexible tube called a shunt may be placed in the brain to re-route the flow of CSF.  The shunt sends CSF to another part of the body, such as the belly area, where it can be absorbed.

Other treatments may include:

Antibiotics are given if there are signs of infection. Severe infections may require the shunt to be removed.

A procedure called endoscopic third ventriculostomy (ETV), which relieves pressure without replacing the shunt.

Removing or burning away (cauterizing) the parts of the brain that produce CSF.

The child will need regular check-ups to make sure there are no further problems. Tests are regularly done to check the child's developmental and for intellectual, neurological, or physical problems.

Visiting nurses, social services, support groups, and local agencies can provide emotional support and assist with the care of a child with hydrocephalus who has significant brain damage.

Expectations (prognosis)

Without treatment, up to 6 in 10 people with hydrocephalus will die. Those who survive have different amounts of  intellectual, physical, and neurological disabilities.

The outlook depends on the cause. Hydrocephalus that is not due to an infection has the best outlook. Persons with hydrocephalus caused by tumors usually do very poorly.

Most children with hydrocephalus that survive for 1 year will have a fairly normal life span.

Complications

The shunt may become blocked. Symptoms of such a blockage include headache and vomiting. Surgeons may be able to help the shunt open without having to replace it.

There may be other problems with the shunt, such as kinking, tube separation, or infection in the area of the shunt.

Other complications may include:

Complications of surgery Infections such as meningitis or encephalitis Intellectual impairment Nerve damage (decrease in movement, sensation, function) Physical disabilities

Calling your health care provider

Seek immediate medical care if your child has any symptoms of this disorder. Go to the emergency room or call 911 if emergency symptoms occur, which include:

Breathing problems Extreme drowsiness or sleepiness Feeding difficulties Fever High-pitched cry No pulse (heart beat) Seizures Severe headache Stiff neck Vomiting

You should also call your health care provider if the child has been diagnosed with hydrocephalus and the condition gets worse and you are unable to care for him or her at home.

Prevention

Protect the head of an infant or child from injury. Prompt treatment of infections and other disorders associated with hydrocephalus may reduce the risk of developing the disorder.

References

1. Kinsman SL, Johnston MV. Hydrocephalus. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 585.11.

2. Rosenberg GA. Brain edema and disorders of cerebrospinal fluid circulation. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice. 5th ed. Philadelphia, Pa: Butterworth-Heinemann; 2008:chap 63.

Review Date: 11/12/2012.

Reviewed by: Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine. Also reviewed by A.D.A.M. Health Solutions, Ebix, Inc., Editorial Team: David Zieve, MD, MHA, David R. Eltz, Stephanie Slon, and Nissi Wang.

A.D.A.M., Disclaimer

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only — they do not constitute endorsementscof those other sites. © 1997–2011 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

Copyright © 2013, A.D.A.M., Inc.

Microcephaly

Last reviewed: November 13, 2011.

Microcephaly is a condition in which a person's head is significantly smaller than normal for their age and sex, based on standardized charts. Head size is measured as the distance around the top of the head.

Common Causes

Microcephaly most often occurs because the brain fails to grow at a normal rate. Skull growth is determined by brain growth. Brain growth takes place while in the womb and during infancy.

Conditions that affect brain growth can cause microcephaly. These include infections, genetic disorders, and severe malnutrition.

Genetic conditions that cause microcephaly include:

Cornelia de Lange syndrome Cri du chat syndrome Down syndrome Rubinstein-Taybi syndrome Seckel syndrome Smith-Lemli-Opitz syndrome Trisomy 18 Trisomy 21

These additional conditions may indirectly cause microcephaly:

Uncontrolled phenylketonuria (PKU) in the mother Methylmercury poisoning Congenital rubella Congenital toxoplasmosis Congenital cytomegalovirus (CMV) Use of certain drugs during pregnancy, especially alcohol and phenytoin

Call your health care provider if

Microcephaly is often diagnosed at birth or during routine well-baby examinations when the infant's height, weight, and head circumference is measured. If you suspect your infant's head size is too small or not growing normally, consult your health care provider.

What to expect at your health care provider's office

Microcephaly is usually discovered by the health care provider during routine examination. Head measurements are part of all well-baby examinations up to 18 months (longer in certain

circumstances). They are painless and take only a few seconds while the measuring tape is placed around the infant's head.

Documenting microcephaly in detail may include:

What is the head circumference? Is the head growing at a slower rate than the body? What other symptoms are there?

Note: A record of the head circumference should be maintained over time.

Although the health care provider maintains records on your baby, it may be helpful to maintain your own records, and bring them to the health care provider's attention if you notice that the infant's head growth pattern seems to be decreasing.

If your health care provider diagnoses your child with microcephaly, you should note that in your child's personal medical records.

References

1. 2. Kinsman SL, Johnston MV. Congenital anomalies of the central nervous system.In: Kliegman

RM, Stanton BF, St. Geme JW III, Schor NF, Behrman RE, eds.Nelson Textbook of Pediatrics. 19th ed.Philadelphia,Pa: Saunders Elsevier; 2011:chap 585.10.

Review Date: 11/13/2011.

Reviewed by: David C. Dugdale, III, MD, Professor of Medicine, Division of General Medicine, Department of Medicine, University of Washington School of Medicine; Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M., Disclaimer

Copyright © 2013, A.D.A.M., Inc

Microcephaly facts*

*Microcephaly facts medical author: Charles Patrick Davis, MD, PhD

Microcephaly is a condition where the head (circumference) is smaller than normal.

Microcephaly may be caused by genetic abnormalities or by drugs, alcohol, certain viruses, and toxins that are exposed to the fetus during pregnancy and damage the developing brain tissue.

Signs and symptoms of microcephaly may include a smaller than normal head circumference that usually remains smaller than normal as the child grows, dwarfism or short stature, delayed motor and speech functions, mental retardation, seizures, facial distortions, hyperactivity, balance and coordination problems, and other brain-related or neurological problems; although some with the disorder may develop normal intelligence.

There is no treatment to change the head size; programs are available to help these individuals reach their maximum potential and genetic counseling may help explain the risk for microcephaly in future pregnancies.

Research on microcephaly is ongoing; for example, researchers found that amino acid therapy may reduce seizure activity in some patients.

What is microcephaly?

Microcephaly is a medical condition in which the circumference of the head is smaller than normal because the brain has not developed properly or has stopped growing. Microcephaly can be present at birth or it may develop in the first few years of life.

What causes microcephaly?

It is most often caused by genetic abnormalities that interfere with the growth of the cerebral cortex during the early months of fetal development. It is associated with Down's syndrome, chromosomal syndromes, and neurometabolic syndromes. Babies may also be born with microcephaly if, during pregnancy, their mother:

abused drugs or alcohol, became infected with a cytomegalovirus, rubella (German measles), or varicella (chickenpox) virus, was exposed to certain toxic chemicals, or had untreated phenylketonuria (PKU).

Babies born with microcephaly will have a smaller than normal head that will fail to grow as they progress through infancy.

What are the signs and symptoms of microcephaly?

Comment on this Share Your Story

Depending on the severity of the accompanying syndrome, children with microcephaly may have:

mental retardation , delayed motor functions and speech , facial distortions, dwarfism or short stature, hyperactivity, seizures,

difficulties with coordination and balance, and other brain or neurological abnormalities.

Some children with microcephaly will have normal intelligence and a head that will grow bigger, but they will track below the normal growth curves for head circumference.

Is there any treatment for microcephaly?

Comment on this Share Your Story

There is no treatment for microcephaly that can return a child's head to a normal size or shape. Treatment focuses on ways to decrease the impact of the associated deformities and neurological disabilities. Children with microcephaly and developmental delays are usually evaluated by a pediatric neurologist and followed by a medical management team. Early childhood intervention programs that involve physical, speech, and occupational therapists help to maximize abilities and minimize dysfunction. Medications are often used to control seizures, hyperactivity, and neuromuscular symptoms. Genetic counseling may help families understand the risk for microcephaly in subsequent pregnancies.

What is the prognosis for microcephaly?

Some children will only have mild disability. Others, especially if they are otherwise growing and developing normally, will have normal intelligence and continue to develop and meet regular age-appropriate milestones.

What research is being done on microcephaly?

The National Institute of Neurological Disorders and Stroke (NINDS) conducts research relating to microcephaly in its laboratories at the National Institutes of Health (NIH) and supports additional research through grants to major medical institutions across the country. A small group of researchers studying a rare neurometabolic syndrome (3-PGDH), which causes microcephaly, have successfully used amino acid replacement therapy to reduce and prevent seizures.

DefinitionBy Mayo Clinic staff

Microcephaly (my-kroh-SEF-uh-lee) is a rare neurological condition in which an infant's head is significantly smaller than the heads of other children of the same age and sex. Sometimes detected at birth, microcephaly usually is the result of the brain developing abnormally in the womb or not growing as it should after birth.

Microcephaly can be caused by a variety of genetic and environmental factors. Children with microcephaly often have developmental issues. Generally there's no treatment for microcephaly, but early intervention may help enhance your child's development and improve quality of life.

Coping and supportBy Mayo Clinic staff

When you learn your child has microcephaly, you may experience a range of emotions, including anger, fear, worry, sorrow and guilt. You may not know what to expect, and you may worry about your child's future. The best antidote for fear and worry is information and support. Prepare yourself:

Find a team of trusted professionals. You'll need to make important decisions about your child's education and treatment. Seek a team of doctors, teachers and therapists you trust. These professionals can help evaluate the resources in your area and help explain state and federal programs for children with disabilities.

Seek out other families who are dealing with the same issues. Your community may have support groups for parents of children with developmental disabilities. You may also find online support groups.

PreventionBy Mayo Clinic staff

Learning your child has microcephaly may raise questions about future pregnancies. Work with your doctor to determine the cause of the microcephaly. If the cause is genetic, you and your spouse may want to talk to a genetic counselor about the risk of microcephaly in future pregnancies.

Coping and support

Mayo Clinic products and services Book: Mayo Clinic Family Health Book, 4th Edition Newsletter: Mayo Clinic Health Letter Give today to find cures for tomorrow

References DS01169 May 30, 2012

© 1998-2013 Mayo Foundation for Medical Education and Research (MFMER). All rights reserved. A single copy of these materials may be reprinted for noncommercial personal use only. "Mayo," "Mayo Clinic," "MayoClinic.com," "EmbodyHealth," "Enhance your life," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research

http://www.mayoclinic.com/health/microcephaly/DS01169/DSECTION=prevention

Anencephaly facts*

*Anencephaly facts medical author: Melissa Conrad Stöppler, MD

Anencephaly is an example of a neural tube defect, a condition that results from an error in the first weeks of embryonic development.

In anencephaly, the bones of the skull and brain do not develop properly. Babies with anencephaly are missing large areas of the brain and have an incomplete skull.

Anencephaly affects about 1 out of every 1,000 pregnancies, but most cases end up as miscarriages. About 1 out of every 10,000 babies in the U.S. is born with anencephaly.

In most cases, anencephaly is sporadic, meaning it does not run in families. Anencephaly is not compatible with life. Most babies with anencephaly are stillborn

or die within days or hours of birth. The exact cause of anencephaly is unknown, but it is likely the result of an interaction

among several genetic and environmental factors.

Reviewed on 10/23/2012

What is anencephaly?

Anencephaly is a condition that prevents the normal development of the brain and the bones of the skull. This condition results when a structure called the neural tube fails to close during the first few weeks of embryonic development. The neural tube is a layer of cells that ultimately develops into the brain and spinal cord. Because anencephaly is caused by abnormalities of the neural tube, it is classified as a neural tube defect (NTD).

What are the causes, signs, and symptoms of anencephaly?

If the neural tube fails to close properly, the developing brain and spinal cord are exposed to the amniotic fluid that surrounds the fetus. This exposure causes the nervous system tissue to break down (degenerate). As a result, people with anencephaly are missing large parts of the brain called the cerebrum and cerebellum. These brain regions are necessary for thinking, hearing, vision, emotion, and coordinating movement. The bones of the skull are also missing or incompletely formed.

Almost all babies with anencephaly die before birth or within a few hours or days after birth.

How common is anencephaly?

Anencephaly is one of the most common types of neural tube defect, affecting about 1 in 1,000 pregnancies. However, most of these pregnancies end in miscarriage, so the prevalence of this condition in newborns is much lower. An estimated 1 in 10,000 infants in the United States is born with anencephaly.

What genes are related to anencephaly?

Anencephaly is a complex condition that is likely caused by the interaction of multiple genetic and environmental factors. Some of these factors have been identified, but many remain unknown.

Changes in dozens of genes may influence the risk of anencephaly. The best-studied of these genes is MTHFR, which provides instructions for making a protein that is involved in processing the B-vitamin folate (also called folic acid or vitamin B9). Changes in other genes related to folate processing and genes involved in the development of the neural tube have also been studied as potential risk factors for anencephaly. However, none of these genes appear to play a major role in causing the condition.

Researchers have also examined environmental factors that could contribute to the risk of anencephaly. A shortage (deficiency) of folate appears to play a significant role. Studies have shown that women who take supplements containing this vitamin before they get pregnant and very early in their pregnancy are significantly less likely to have a baby with anencephaly or a related neural tube defect. Other possible risk factors for anencephaly include diabetes mellitus, obesity, exposure to high heat (such as a fever or use of a hot tub or sauna) in early pregnancy, and the use of certain anti-seizure medications during pregnancy. However, it is unclear how these factors may influence the risk of anencephaly.

Reviewed on 10/23/2012