This is an 5 month boy who is brought to the emergency room after his mother noted that he had a seizure. His mother adds that she is also concerned because her son has always seemed weak for his age and that his head seems to be progressively swelling, increasing out of proportion to the rest of his body. In addition, his strength and degree of development does not seem to follow that of his older brother. There is no recent history of fever, vomiting, diarrhea, poor appetite or urinary abnormalities.
He is the second child born to 31 year old parents. There is no family history of recurrent abortions, consanguinity, or mental retardation. Pregnancy was uncomplicated and he was born with a weight of 2500 g, a length of 47 cm, a head circumference of 32 cm, and Apgar scores of 8 and 9.
Exam: VS T 37.2, P 100, RR 38, BP 75/55. Height 64 cm (25%ile), weight 6.8 kg (25%ile), and head circumference 45 cm (98%ile). He is subdued in no distress. He is not irritable, but he does not move about much. Diffuse hypotonia is obvious upon visual inspection and the child is lethargic and inactive. His head is macrocephalic. His anterior fontanelle is open and rather large for age. Abnormal facies showing a short nose with nostrils displaced forward is noted. Deep tendon reflexes are very brisk (3+) and there is a positive Babinski sign bilaterally. His eyes are opened wide and a downbeat nystagmus is present.
A CBC and chemistry panel are normal. A CT scan of the brain shows a smooth appearance of the cerebral cortex, with shallow sulci and thick gyri (pachygyria). The ventricles are dilated (hydrocephalus) and a Chiari malformation obstructing CSF outflow is noted. After his mother agrees, he is taken to the operating room for insertion of a ventriculoperitoneal shunt.
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).
1. What is the most common type of Chiari malformation?
2. What CNS structure is displaced in Chiari malformations?
3. What are the 3 general categories of neuronal migration abnormalities?
4. What basic abnormality is revealed with lissencephaly on MRI imaging and gross inspection?
5. What other abnormalities are often found with type II Chiari malformations?
1. Hay WH, Hayward RH, Levin JL, Sondheimer JM. Chapter 22 - Neurologic & Muscular Disorders. In: Moe PG, Seay AR (eds). Current Pediatric Diagnosis & Treatment, fifteenth edition. 2001, Philadelphia: McGraw-Hill Companies, Inc., pp. 665-670.
2. Goetz CG, Pappert EJ. Chapter 28 - Developmental Structural Disorders. In: Golden JA, Bonnemann CG (eds). Textbook of Clinical Neurology. 1999, Philadelphia: W.B. Saunders Company, pp. 523-527.
3. Goldman L, Bennett JC. Chapter 456 - Neurocutaneous Syndromes. In: Barkovich JA, Kuznieky RI (eds). Cecil Textbook of Medicine, 21st edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1805, 1810, 2075-2076.
4. Rudolph CD, Rudolph AM. Chapter 25 - The Nervous System. In: Pleasure D, De Vivo DC (eds). Rudolph's Pediatrics, 21st edition. 2001, Philadelphia: McGraw-Hill Companies, Inc., pp. 2186-2188.
5. Haslam RA. Chapter 601 - Congenital Anomalies of the Central Nervous System. In: Behrman RE, Kleigman RM, Jenson HB et al (eds). Nelson Textbook of Pediatrics, sixteenth edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1806-1807.
Answers to questions
1. Type II (Arnold-Chiari malformation).
3. Lissencephaly/pachygyria, polymicrogyria, heterotopia.
4. Smooth surface of the cerebral cortex.
5. Myelomeningocele and hydrocephalus.