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Developmental abnormalities of the central nervous system 

Developmental abnormalities of the central nervous system

Developmental abnormalities of the central nervous system

C.M. Verity

, and C. ffrench-Constant



Further reading updated.

Updated on 31 May 2012. The previous version of this content can be found here.
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date: 24 April 2017

The brain and spinal cord arise from a sheet of cells that develop through a series of distinct transformations into the final complex structure. Congenital abnormalities of the central nervous system are considered in the context of this process, which may fail at distinct stages of development.

General clinical approach

A rigorous approach to the diagnosis of and counselling for developmental abnormalities of the central nervous system is required. Referral for specialist advice is recommended because of the far-reaching consequences of misdiagnosis. Many abnormalities can be identified by detailed ultrasonography, and MRI in utero is proving to be particularly useful for accurate investigation of the fetal brain. Prenatal diagnosis and termination is available for some conditions. In the absence of a specific diagnosis genetic advice is usually limited and empirical, but where a specific gene is implicated parental questions can often be accurately addressed. Where there are strong environmental factors, it is imperative to reduce the risk to future pregnancies by taking appropriate measures, e.g. folic acid or iodide supplementation before conception.

Neural tube defects

Clinical features and epidemiology—neural tube defects such as spina bifida and anencephaly reflect a failure of closure of the ectoderm folds that normally fuse 18 to 26 days after ovulation. Prevalence rates are very variable, but are over 8 per 1000 births in several regions. Most cases are caused by interactions between genes and environmental factors such as nutritional folic acid.

Screening—many serious (open) neural tube defects lead to an increased concentration of α‎-fetoprotein in maternal serum, and at-risk women with this elevated biomarker on screening—or those with a history of an affected pregnancy—are recommended to have fetal ultrasonography from 12 weeks onwards. This screening method has largely supplemented measurement of α‎-fetoprotein and neuronal acetylcholinesterase in amniotic fluid obtained by amniocentesis, but this remains an alternative for prenatal diagnosis.

Prevention—the incidence of neural tube defects can be markedly reduced by avoidance of certain drugs in pregnancy (e.g. folate antagonists, anticonvulsants), as well as by preconceptual supplementation of folic acid (400 μ‎g daily), which has been effectively introduced in some countries by fortification of foods with folic acid.

Treatment and prognosis—the major focus is on prevention, but neurosurgical procedures are employed for closure and for relief of hydrocephalus by diversion of cerebrospinal fluid through shunt procedures. The outcomes and prognosis of affected children vary greatly and surgical management remains controversial, except for those with mild abnormalities.

Other developmental abnormalities of the spinal cord—these include syringomyelia, which usually presents in later life and is associated with the Chiari malformation and hydrocephalus. Agenesis of the sacrum with abnormalities of the distal cord is associated with maternal diabetes mellitus.

Disorders of regionalization of the fully formed neural tube

Numerous genes, including those encoding signalling molecules that induce the expression of homeotic genes involved throughout evolution in regional and segmental development, are implicated in the complex process of regionalization of the neural tube. Disorders affecting these pathways often involve gene–environment interactions and give rise to abnormalities of the specification of cells in the forebrain, midbrain, hindbrain, and spinal cord, e.g. holoprosencephaly.

Holoprosencephaly—this condition may vary from severe to mild developmental abnormalities affecting the formation of the cerebral hemispheres, eyes, palate and mouth. At least nine genes have been implicated, including sonic hedgehog and its signature receptor, patched. The different associations and variants of the condition reflect defects in one or more of the stages leading to formation of the rostral parts of the brain and associated structures. Maternal diabetes possibly increases the probability of this abnormality in the infant.

Disorders of cortical development

Numerous genetic determinants have been identified for disorders of cortical development such as microcephaly and lissencephaly, which reflect abnormalities of proliferation and cellular migration (respectively). Microcephaly may also be caused by environmental influences in pregnancy, including radiation, drugs, and maternal hyperphenylalanemia (a preventable factor of importance in the management of women with phenylketonuria).

Disorders of development of other parts of the brain

Hindbrain—development is disturbed in the Chiari II malformations and the Dandy–Walker syndrome (a kind of agenesis of the vermis, with dilatation of the fourth ventricle and enlargement of the posterior fossa; associated with trisomies 13 and 18).

Complex malformations of the brain and cord—many types are recognized, including agenesis of the corpus callosum and porencephaly. These disorders are rare, but are increased in children with other developmental abnormalities. They may be caused by mutations in as yet unknown genes, chromosomal rearrangement, and some rare metabolic syndromes.

Disorders of the developing brain caused by extrinsic factors

Hydrocephalus—this results from expansion of the ventricles secondary to a block in the normal flow pathway of cerebrospinal fluid. It may be (1) communicating—due to failure of reabsorption of cerebrospinal fluid, e.g. following subarachnoid bleeding or (2) obstructive/noncommunicating—due to blockage at one of the ventricular levels. Mental retardation can result from both the damage associated with ventricular expansion and other abnormalities associated with the underlying cause of the problem.

Alcohol—fetal alcohol syndrome is one of the commonest causes of learning difficulty and neurobehavioural disturbance in young children. Other clinical features include microcephaly, structural anomalies of the brain such as partial or complete agenesis of the corpus callosum, cerebellar hypoplasia, and a dysmorphic appearance.

Congenital infections—e.g. toxoplasmosis, herpes simplex, cytomegalovirus, rubella, and syphilis. Primary maternal infection is implicated in most instances, hence measures to prevent these infections are important.

Maternal iodine deficiency—this leads to cretinism (spastic diplegia and deafness), which is a common, potentially preventable disorder in many regions of the world that can be addressed by screening for neonatal hypothyroidism.

Cerebral palsies

These are an important but heterogeneous group of nonprogressive disorders of the immature brain that cause defects of movement and posture that may have associated manifestations such as deafness, seizures and learning difficulties. Several clear genetic factors have been identified, and environmental exposure to toxins such as carbon monoxide, alcohol, and methyl mercury may also be responsible. Although cerebral palsy has in the past been attributed to ‘asphyxia’ at birth, this view is now changing; premature infants are at a greatly increased risk.

Acknowledgements: We are very grateful to Dr Nagui Antoun (Addenbrooke’s Hospital, Cambridge), Dr Fred Pickworth (Norfolk and Norwich Hospital), and Mr Paul Chamberlain (John Radcliffe Hospital, Oxford) for the scans shown in this chapter and for advice on their interpretation. Many thanks to Mr Michael Cafferkey (Senior Illustrator, Medical Photography and Illustration, Addenbrooke’s Hospital, Cambridge) for producing Figs. 24.18.1 and 24.18.4.

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