Although the incidence of
nervous system malformations in living newborns is 1%-3%, such malformations
are present in 40% of infant deaths. The etiologies associated with
developmental anomalies may result from a variety of insults from genetic to
environmental. Abnormalities associated with the neural tube and the neural
plate generally occur within the first 28 days of gestation. On the other hand,
abnormalities associated with cellular proliferation and migration in the CNS
generally occur after the 28th day of gestation. This chapter will cover
malformations associated with both of these periods. Included among these
malformations are Arnold-Chiari malformations and a group of disorders
collectively referred to as neuronal migration defects (1).
Professor Hans Chiari, a German
pathologist described a group of malformations characterized by the
displacement of the cerebellum. He classified the manifestations into types
based on the order of increasing severity (type I being least severe) and these
became known as Chiari malformations (2). Of note, type II Chiari malformations
(CM) are also known as the Arnold-Chiari malformation. However, other
publications use "Arnold Chiari" malformations as the umbrella term
for the four types of cerebellar displacement. This chapter will look at the
Chiari malformations that are more commonly seen (1,3).
Type I CM is defined as a caudal
displacement of the cerebellar tonsils below the foramen magnum by 5 mm.
Hydrocephalus is present in 90% of patients and syringomyelia may also be
present. Patients may live asymptomatically up until the third or fourth decade
of life or later, when signs and symptoms of this disorder may present. The
presentation is dependent upon the degree of the abnormality and associated
manifestations, on neural structures. These can include lower cranial
neuropathies, downbeat nystagmus, ataxia, vertigo, vocal cord paralysis, and
eye movement abnormalities (3). Additional skeletal anomalies include scoliosis
(especially from syringomyelia) and skull base abnormalities (2). The
differential diagnosis of type I can vary tremendously, depending on the neural
structures involved. A diagnosis of type I can be made on the basis of imaging
(MRI is preferred) along with clinical information. Treatment is done
surgically by cervical bony decompression of structures in the foramen magnum
and along the spinal cord if necessary. This process involves removal of bone
(usually by cutting through bones of the spine). Relief of signs and symptoms
related to the compression of the brain stem is better than those related to
the spinal cord (2). Treatment of hydrocephalus involves finding an alternative
route of drainage of the cerebrospinal fluid in the ventricles. This is usually
accomplished by a ventriculoperitoneal shunt (4). Successful interventions may
allow the individual to have normal mental development, if there are no
additional CNS malformations (2).
Type II (Arnold-Chiari)
malformation is the commonest type of CM malformation (4). It is manifested by
an increased caudal displacement of the cerebellum into the foramen magnum,
along with the lower brainstem. Myelomeningocele is usually associated with
this type II malformation usually resulting in hydrocephalus (80% or more).
There is an increased likelihood to develop hydrocephalus if the
meningomyelocele is more rostral. As in type I, the presentation of signs and
symptoms depends upon the degree of the abnormality and associated
manifestations, on neural structures. Symptoms related to hindbrain dysfunction
may develop which include difficulty feeding, choking, stridor, apnea, vocal
cord paralysis, pooling of secretion, and spasticity of the upper extremities.
An increased head circumference may be present due to hydrocephalus.
Ventricular enlargement may be slow or rapid and cause a bulging anterior
fontanel, dilation of scalp veins, irritability, and vomiting. Diagnosis is the
same as type I but a more severe displacement is seen, and a myelomeningocele
is usually obvious on gross inspection. Treatment is done surgically to repair
the myelomeningocele and to relieve the hydrocephalus. Bony decompression may
also be performed. Prognosis depends on the site and severity of
myelomeningocele. Improved prognosis is associated with a more caudal lesion.
It is also advisable to recommend a multivitamin with folate for expectant
mothers to reduce the risk of subsequent neural tube defects (3).
Type III (rare) CM is
characterized by a cerebellar displacement into an occipital encephalocele. An
occipital encephalocele is a defect in the closure of the neural tube near the
base of the skull, a condition known as occipital encephalocele. Prognosis is
poor (4).
Neuronal migration defects form
a group of developmental brain anomalies. Abnormal cerebral cortical development
is generally viewed as an improper migration of neural tissue. In other words,
neurons fail to reach their destination in the cortex in the period of cortical
neurogenesis beginning around 10 to 12 weeks of gestational age or earlier.
Environmental factors such as retinoic acid, radiation, and methylmercury have
been implicated in the pathogenesis. Viral infections in utero are also known
to result in migrational abnormalities, although the mechanism of action is
unknown. The abnormalities, which may present together, can be grouped into
three general categories. They include lissencephaly/pachygyria,
polymicrogyria, and heterotopia.
It is thought that lissencephaly
and pachygyria are different representations of the same manifestation.
Lissencephaly (means smooth brain) refers to a more diffuse bilateral brain
abnormality and pachygyria (thick gyri) is a more focal or multifocal
abnormality. The basic abnormality, seen on imaging and on gross pathologic
examination, is the smooth surface of the cerebral cortex. The cortex is also
noticeably thickened with a relative abundance of gray matter, compared to
white matter which is variably preserved. There are at least 2 types of
lissencephaly (2).
Autosomal and X-linked forms of
type I lissencephaly have been identified, but this type may also be associated
with other syndromes such as the Miller-Dieker Syndrome (about 15% of cases)
(5). A cross-section of the brain reveals an extremely thick cortex organized
into four abnormal layers, rather than the usual six. In type I lissencephaly,
seizures and severe mental/psychomotor retardation are present. Most cases of
type I present in the neonatal period with marked hypotonia, and later with
weakness in all four extremities. In the Miller-Dieker syndrome, characteristic
facial features are present in childhood and include a prominent forehead,
bitemporal hollowing, a short nose with anteverted nostrils, a prominent upper
lip, and jaw abnormalities. Lissencephaly as an isolated abnormality is
distinguished from the Miller-Dieker Syndrome based on these facial
characteristics. Diagnosis of lissencephaly is based on the smooth surface
finding along with a widely opened Sylvian fissure on neuroimaging. Cytogenetic
studies may often reveal a deletion on the LIS-1 (lissencephaly gene) in
chromosomal region 17p13.3. Treatment of the disorder involves seizure
medications and supportive care. The prognosis for type I lissencephaly, when
associated with other entities, is generally poor and many patients do not
survive into childhood.
The inheritance for type II is
autosomal recessive but there has not been any association with a specific gene
or locus. In contrast to type I, type II lissencephaly is often associated with
congenital muscular dystrophies that often involves the eyes as well. Examples
are the Walker-Warburg syndrome and the Finnish muscle-eye-brain disorder. In
type II lissencephaly the surface of the cerebral cortex usually presents as a
diffuse smooth brain appearance. A cross-section reveals an increased thickening
of grey matter. Clinical manifestations, when seen with associated muscular
dystrophies will involve abnormalities of muscle and CNS development. This may
include neonatal hypotonia and eye abnormalities (e.g., retinal dysplasia,
cataracts, microphthalmia), and joint contractures. Laboratory results reveal
elevated creatine kinase levels (from the muscular dystrophy). Diagnosis is
made by careful examination of the MRI of the cortex. Treatment and prognosis
of type II is basically the same as in type I.
Polymicrogyria (also known as
microgyria, meaning small gyri) is also considered to be a migrational disorder
(defects seem to occur between week 17 to 18 and weeks 24 to 26 gestation).
Unlike lissencephaly and pachygyria, the border between the polymicrogyria and
normal cortex is distinct. Polymicrogyria usually reveals a cerebral cortex
with a complex set of small gyri appearing fused together. This gives the
surface of the cortex a fine stubbling appearance. A number of malformations
and abnormalities have polymicrogyria as one part of an overlying CNS
manifestation. For instance the polymicrogyria-schizencephaly complex is a
disorder with clinical features including delayed development, pyramidal signs,
motor speech dysfunction and epilepsy. Schizencephaly (means cleft brain) is
the presence of fused or unfused, unilateral or bilateral clefts within the
cerebral hemispheres as a result of abnormal morphogenesis (3). Polymicrogyria
presents with psychomotor retardation and frequent focal seizures. The differential
diagnosis for this disorder can include Aicardi's, Neu-Laxova, Zellweger, and
Smith-Lemli-Opitz syndromes. Removal of a focal area of polymicrogyria may be
curative. Multifocal removal may result in improved seizure control. The
prognosis is variable, but usually poor.
Cerebral heterotopia are defined
as focal or multifocal disorganized nodules of gray matter at inappropriate
places in the cerebrum. The heterotopia may be found incidentally on imaging or
there may be associated clinical manifestations that present itself. The main
presenting feature is a childhood seizure disorder of various types including
focal, multifocal, and generalized. Motor and mental retardation may also be
present depending upon the extent of the heterotopia abnormality. Focal area
heterotopia removal may improve seizures (2).
Department of Pediatrics,
University of Hawaii John A. Burns School of Medicine.
Kaipo T. Pau
December 2002
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