Disorders of Primary Neurulation
Anencephaly occurs because of a failure of anterior neuropore closure. Since the anterior neuropore closes at less than 24 days, this disorder occurs within the first month of fetal development. Anencephaly affects the forebrain and variable portions of brainstem but several different subtypes may occur depending on the level of the defect. Holoacrania occurs with a defect to the foramen magnum. Meroacrania occurs with the defects slightly higher than the foramen magnum.
Approximately 75% of these children are stillborn. It is most common in whites, Irish, females, and children born to either very old or very young mothers. The risk of anencephaly in subsequent pregnancies is 5% to 7%.
Myeloschisis develops with failure of posterior neuropore closure. It is associated with iniencephaly, or a malformation of skull base. Most of these children are stillborn.
An encephalocele is a restricted defect in anterior neural tube closure. These defects consist of a protrusion of brain and intracranial structures through a skull defect. These are typically migration defects or heterotopia involving these patients. Approximately 75% occur in the occipital region and 50% are associated with hydrocephalus.
A myelomeningocele develops secondary to a restricted defect in posterior neural tube closure. There is a herniation of the spinal cord or meninges through a vertebral defect. Most of these defects occur in the lumbar region. Approximately 90% of the cases with lumbar defects have associated hydrocephalus. If the defect occurs in some other region, only 60% of the patients have hydrocephalus. The symptoms include motor, sensory, and sphincter dysfunction. Spina bifida occulta occurs with a defect in the vertebral arch but no abnormalities of the spinal cord or meninges.
Type I Chiari malformation is an isolated displacement of the cerebellar tonsils into the cervical canal. This may be either congenital or acquired in patients with low intracranial pressure. The type I malformation can be associated with a syrinx, a kinked cervical spinal cord, and hydrocephalus. Most of the type I patients have no associated symptoms. In rare cases, the patient may have headaches, tinnitus, or ataxia. In severe cases, surgical decompression is the primary treatment.
Type II Chiari malformation occurs with displacement of the cerebellum into cervical canal, displacement of the medulla and fourth ventricle into the cervical canal, a long, thin medulla and pons, tectum deformity, and skull base and upper cervical spine defects. Hydrocephalus is a common complication secondary to fourth ventricle obstruction or aqueductal stenosis. Myelomeningocele occurs in all patients and 96% have cortex malformations (heterotopia, polymicrogyria, etc.). Brainstem malformations are less common but occur in three-quarters of patients. Other common findings include cerebellar dysplasia, thoracolumbar kyphoscoliosis, diastematomyelia (bifid cord), and syringomyelia. The patient usually presents as a neonate with neurological deterioration including respiratory failure, stridor, and hydrocephalus. Treatment includes surgical decompression and shunting. Severe neurological sequelae typically persist.
Type III Chiari malformation includes all of the features of the type II malformation with herniation of the occipital lobes, cerebellum, and brainstem into an associated low occipital or high cervical encephalocele. The neurological consequences are severe and the outcome is poor.
Meckel syndrome occurs in some patients following maternal hyperthermia or fever on days 20 to 26 following conception. The features includes encephalocele, microcephaly, microphthalmia, cleft lip, polydactyly, polycystic kidneys, and ambiguous genitalia.
Neural tube defects occur in association with a number of disorders including chromosomal abnormalities (trisomy 13, trisomy 18), teratogens (thalidomide, valproate, phenytoin), single mutant gene (Meckel syndrome), and as a multifactorial syndrome. Diagnosis is made by increased alpha-fetoprotein, increased acetylcholinesterase, and by ultrasound. These defects can in some cases be prevented by maternal supplemental folate. The recurrence rate in subsequent children is 2% to 3%.
Disorders of Secondary Neurulation—Occult Dysraphic States
The disorders of secondary neurulation have an intact dermal layer over the lesion but 80% have an overlying dermal lesion (dimple, hairy tuft, lipoma, or hemangioma). The spinal cord is frequently tethered. All patients have an abnormal conus and filum terminale. Most patients have vertebral defects. Siblings have a 4% chance of a disorder of primary neurulation.
Caudal regression syndrome—dysraphic sacrum and coccyx with atrophic muscle and bone
Myelocystocele—cystic central canal
Meningocele—rare with no associated hydrocephalus
Disorders of Prosencephalic Development
Aprosencephaly is the absence of the telencephalon and diencephalon. Atelencephaly is the absence of the telencephalon but a normal diencephalon. The skull and skin are intact. These disorders are frequently associated with cyclopia, absent eyes, and abnormal limbs and genitalia.
Holoprosencephaly occurs with a defect in prosencephalic cleavage resulting in defective division of the hemispheres. All patients have anosmia because of absent olfactory bulbs and tracts. A single-lobed cerebrum and single ventricle are common. The optic nerve is either hypoplastic or single. There is agenesis of the corpus callosum. Neuronal migration defects are common. A number of caial defects can occur, including ethmocephaly (hypertelorism with proboscis between eyes), cebocephaly (single nostril), cyclopia (single eye with or without proboscis), and a cleft lip. Patients typically present with or develop seizures, apnea, decreased hypothalamic function, developmental delay, anosmia, and a single maxillary incisor. Several chromosomal abnormalities can lead to holoprosencephaly including trisomy 13, ring 13, and the SHH gene on chromosome 7. The recurrence rate for siblings is approximately 6%, and 2% are infants of diabetic mothers.
Disorders Associated with Agenesis of the Corpus Callosum
- Absent septum pellucidum
- Neuronal migration disorders, schizencephaly
- Chiari II malformation
- Septo-optic dysplasia/septo-opto-hypothalamic dysplasia
- Aicardi syndrome
Disorders Associated with Congenital Hydrocephalus
- Aqueductal stenosis—33%
- Chiari malformation—28%
- Communicating hydrocephalus—22%
- Dandy-Walker Malformation—7%
- Vein of Galen obstruction
- X-linked aqueductal stenosis
The Dandy-Walker malformation occurs secondary to failed or delayed development of the foramen of Magendie. There is systic dilation of the fourth ventricle and cerebellar agenesis with maldevelopment of the cerebellar vermis. Hydrocephalus is a common complication. Many patients have agenesis of the corpus callosum, neuronal migration disorders (70%), a large inion, a large posterior fossa, cardiac anomalies, and urinary tract abnormalities. Seizures are a common complication.
Neuronal Proliferation and Migration Disorders
Disorders of Proliferation
- Microcephaly—decreased size of proliferative units
- Radial microbrain—decreased number of proliferative units
- Macrencephaly—well-formed but large
- Unilateral macrencephaly (hemimegencephaly)
Schizencephaly occurs with a cleft or space connecting the ventricle and the subarachnoid space. There is no associated gliosis. Heterotopia frequently occur in the wall of the cleft. In type I, the lips of the cleft are closed or in contact with each other. In type II, the lips of the cleft are open and do not touch. Schizencephaly may be genetic or related to a sporadic ischemic insult early in gestation.
Porencephaly is a variable communication between the ventricles and the subarachnoid space. Unlike schizencephaly, there is gliosis in the cleft wall. Porencephaly is felt to be secondary to ischemia later in gestation.
Lissencephaly is a disorder of migration with the development of few or no gyri. This results in a "smooth brain." Heterotopia occur frequently in lissencephaly. Type I lissencephaly is associated with a partial deletion of chromosome 17 (the LIS1 gene). Type II lissencephaly is associated with a disorganized cortex, neuronal overmigration, and a thickened, somewhat cobblestone-appearing cortex. Pachygyria is a subtype of lissencephaly with a few broad thick gyri. Seizures, mental retardation, and death at an early age are common.
Miller–Dieker syndrome is associated with lissencephaly. There is a large chromosome 17 deletion in 90% of cases. The clinical presentation includes microcephaly, seizures, hypotonia, poor feeding, craniofacial defects, cardiac defects, and genital abnormalities.
Polymicrogyria occurs with too many small gyri, giving the brain the appearance of a wrinkled chestnut. This disorder usually occurs secondary to an ischemic injury or infection resulting in poor migration. Polymicrogyia occurs in X-linked dominant Aicardi syndrome. Inherited peroxisomal disorders such as Zellweger syndrome (cerebro-hepato-renal syndrome) may also result in polymicrogyria.
Heterotopia or remains of neurons in the white matter occur secondary to arrested radial migration. These heterotopia are frequently associated with seizures. There are several subtypes: periventricular, laminar (in deep white matter), and band-like (between cortex and ventricular surface).