The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Kaipo T. Pau. This current second edition chapter is a revision and update of the original author’s work. We would also like to thank Dr. Roshan Raja for his kind review of this chapter.
This patient is a 3 year old male who is brought to the emergency room because his mother noticed whole body convulsions at home that lasted for 15 minutes. He also had two days of poor appetite, vomiting, and irritability. Mother also reports that her son has not started walking, speaks a total of five words, and does not like to interact with other children his age. She strongly believes that his development is much delayed when compared to his older brother when he was his age. Mother denies her son having fever, diarrhea, constipation, urinary abnormalities, sick contacts, or recent travel. Mother does not follow up with a pediatrician routinely but immunizations are up-to-date.
He was born to a 27 year old G3P2 mother via normal spontaneous vaginal delivery, with a birth weight of 2480 grams, length of 45 centimeters, head circumference of 30 centimeters, and Apgar scores of 9 and 9 at 1 and 5 minutes respectively. Mother denied any prenatal or postnatal complications and there is no family history of recurrent abortions, consanguinity, or mental retardation.
Physical exam reveals T 37.4, HR 98, RR 34, BP 82/54, weight 11.8 kilograms (<5th%ile), height 92 centimeters (10th%ile), and head circumference 52.2 centimeters (95th%ile). Patient is in no acute distress but appears lethargic and inactive. His head is macrocephalic with a prominent occiput. His forehead is broad and he has downward-deviated eyes that are reactive to light. Deep tendon reflexes are brisk (3+) bilaterally with hypotonic extremities and bilateral positive Babinski signs.
Laboratory tests were ordered to reveal a normal CBC and chemistry panel. A CT scan of the brain shows partial absence of the cerebellar vermis with a large posterior fossa cyst contiguous with the fourth ventricle, and anterior displacement of the cerebellar hemispheres, all findings consistent with a Dandy-Walker malformation. After consulting a pediatric neurosurgeon and obtaining consent from the mother, the patient is scheduled for insertion of a ventriculoperitoneal shunt.
Congenital malformations occur among all ethnic groups, cultures, and socioeconomic groups. Approximately 3 million fetuses and infants are born with major congenital malformations each year, with 10 per 1000 being attributed to the brain alone (1). There are four stages to brain development and failure at each stage can result in multiple anomalies. Stage 1 occurs during the 3rd and 4th weeks of gestation, allowing formation and closure of the neural tube, failure of which can result in anencephaly, cephaloceles, and Chiari malformations. Stage 2 occurs between weeks 5 and 10 of gestation with formation of the brain segments (prosencephalon, mesencephalon, and rhombencephalon) and face, with abnormalities resulting in holoprosencephalies, corpus callosal agenesis, and Dandy-Walker malformations. Stage 3 of brain development involves the cerebral cortex, with proliferation, migration, and organization of the growing neurons, occurring between 2 and 5 months of gestation. Abnormal proliferation can lead to micro-lissencephalies, schizencephalies, tuberous sclerosis, or neurofibromatosis type 1. Abnormal migration can cause lissencephaly or heterotropias. And abnormal organization may result in polymicrogyria or cortical dysplasias. Stage 4 involves myelination, which lasts until 15 months after birth and matures by 3 years of age, and as a result, failure of this process can result in demyelinating diseases (2).
Neural Tube Defects
Neural tube defects (NTDs) result from failure of the first stage of brain development during gestation, with a wide variety of potential causes: malnutrition, chemical exposure, maternal obesity or diabetes, hyperthermia, drugs such as valproic acid, and genetic factors (3). The different types of NTDs include spina bifida occulta, meningocele, myelomeningocele, encephalocele, anencephaly, caudal regression syndrome, tethered cord, and syringomyelia. These are covered in more detail in the Neural Tube Defects chapter (XVIII.10). The U.S. Public Health Service recommends all women of childbearing age to take 0.4 milligrams of folic acid daily to prevent NTDs (3).
|Spina Bifida Occulta||Midline defect of vertebral bodies without involvement of spinal cord or meninges. Primarily asymptomatic. Associated with cutaneous manifestations (hairy patch, dermal sinus, pit, lump, skin discoloration, or hemangioma). Typically involves L5 and S1.||Imaging indicated with subcutaneous masses or lipomas, hairy patch, dermal sinus, atypical dimples (>5 mm in size or >25 mm from the anal verge), hemangiomas, skin appendages, or scar-like lesions.|
|Meningocele||Herniation of meninges through posterior vertebral defects or anterior sacrum with a normal spinal cord. Can be associated with leakage of CSF(cerebrospinal fluid), bladder dysfunction, and renal deterioration.||Requires thorough examination with x-rays, ultrasonography, and MRI, and extensive neurological, orthopedic, and urologic evaluation.|
|Myelomeningocele||Herniation of meninges AND spinal cord through the posterior vertebral column, associated with a genetic predisposition. The degree of deficit depends on the location of the defect. (1) Low sacrum: bowel and bladder incontinence, perineal anesthesia. (2) Mid-lumbar/High lumbo-thoracic: lower extremity flaccid paralysis and deformities (clubfeet, hip subluxation), absence of DTRs, loss of pain & touch sensation, urinary dribbling. (3) Mid-thoracic region: increasing neurologic deficit. (4) High-thoracic/Cervical region: paradoxically minimal neurologic deficit.||Mortality rate is 10% to 15% with most deaths occurring prior to age 4 years. Affected children require multidisciplinary specialty care follow-up for life. Renal dysfunction is an important determinant of mortality. Surgical intervention is usually done within a day. Most infants require ventriculoperitoneal shunting in case of hydrocephalus development.|
|Encephalocele||Neural tissue (cerebral cortex, cerebellum, or brainstem components) extension through cranium bifidum in a skin-covered sac, commonly in the occipital lobe and can exceed size of the cranium. Ultrasound can be used to detect contents of the sac. At risk for vision problems, mental retardation, microcephaly, and seizure disorder.||At increased risk for developing hydrocephalus secondary to Chiari malformation, Dandy Walker malformation, or aqueductal stenosis. Often associated with syndromes, e.g., Meckel-Gruber Syndrome.|
|Anencephaly||Failure of closure of the rostral end of the neural tube, with relatively absent cerebral hemispheres and cerebellum. Also associated with cleft palate, heart defects, and folding of the ears.||Most newborns die within a few days of life.|
Disorders of Neuronal Migration
During stage 3 of brain development, the radial glial fiber system instructs neurons to migrate to predetermined sites that will eventually form the six-layered cerebral cortex. As a result, any variation of insult can result in minor CNS complications or devastating abnormalities with compromising function. These insults can range from exposure to radiation, methylmercury, or retinoic acid during gestation, to viral infections in utero. These anomalies are frequently associated with developmental delay, failure to thrive, microcephaly, and a severe seizure disorder.
Lissencephaly (smooth brain), also known as agyria, results from an abnormal neuroblast migration, and imaging shows a smooth cerebral cortex with thickening and abundance of gray matter. Schizencephaly (cleft brain) is a result of abnormal morphogenesis, resulting in unilateral or bilateral clefts within the cerebral hemispheres. Cerebral heterotopias are characterized by focal or multifocal nodules of gray matter distributed in various regions of the cerebrum, including periventricular and subcortical. The presenting feature of these children is intractable seizures that can be focal, multifocal, or generalized. Polymicrogyria (small gyri) and pachygyria (thick gyria) are other consequences of migrational defects with drug-resistant epilepsy being a common feature.
Brainstem and Cerebellar Anomalies
Many developmental brain anomalies also consist of structural abnormalities within the posterior fossa, resulting in defects such as Chiari malformation and Dandy Walker Syndrome.
Chiari malformation (CM) result in herniation of the cerebellar tonsils through the foramen magnum. CM is classified into 3 different types based on increasing severity (type I being the least severe). The diagnosis can be made with imaging (preferably MRI). Type I CM is characterized by caudal displacement of the cerebellar tonsils below the foramen magnum by 5 millimeters, presenting with hydrocephalus, lower cranial neuropathies, nystagmus, vertigo, eye muscle paralysis, and skull base abnormalities (4). It usually presents later in life, commonly with symptoms that reflect increased intracranial pressure. Type II CM (also known as Arnold-Chiari malformation)is the most common type of Chiari malformation and reveals an increased displacement of the cerebellum and lower brainstem into the foramen magnum. This type is often associated with myelomeningocele. Patients develop progressive hydrocephalus, with similar signs and symptoms as Type I CM. They will also present with symptoms associated with hindbrain dysfunction, such as stridor, apnea, vocal cord paralysis, poor feeding, and spasticity of the upper extremities. Type III CM is rare and is manifested by displacement of the cerebellum into an occipital encephalocele.
Dandy-Walker Syndrome involves a variety of posterior fossa anomalies characterized by enlargement of the fourth ventricle, partial or complete absence of the cerebellar vermis, and/or cyst formation near the occiput. Affected individuals can present with symptoms of increased intracranial pressure, such as vomiting, seizures, and irritability, as well as signs of cerebellar dysfunction, such as jerky movements or lack of coordination. It presents with variable degrees of neurological impairment and can be a result of single gene disorders, chromosomal abnormalities, or teratogen exposure. It can be diagnosed with an MRI and treatment can begin with relief of intracranial pressure, such as with a VP shunt.
A microcephalic child will have a head circumference that is greater than 3 standard deviations below the mean for age and sex. It is a common anomaly seen frequently in children with developmental delay. There are numerous causes, divided into primary (genetic) and secondary (nongenetic) causes, with treatment specified for each cause. It is frequently associated with intellectual disability. As a result, it remains a priority for all pediatricians to measure a patient’s head circumference and diagnose microcephaly as early as possible.
|Type of Microcephaly||Causes|
|Primary (genetic)||autosomal recessive, autosomal dominant, Down (trisomy 21) syndrome, Edward (trisomy 18) syndrome, Cri-du-chat (5p-) syndrome|
|Secondary (non-genetic)||cytomegalovirus, rubella virus, toxoplasmosis, Zika virus, fetal alcohol syndrome, fetal hydantoin syndrome, radiation exposure, meningitis/encephalitis, malnutrition, hyperthermia, hypoxic-ischemic encephalopathy|
Hydrocephalus is defined as an increase in intracranial pressure secondary to impaired circulation, increased absorption, or increased chorioid plexus production of CSF. There are two types of hydrocephalus: communicating (or non-obstructive) and non-communicating (obstructive). Non-communicating hydrocephalus develops due to an obstruction of CSF flow through the ventricular system, most commonly due to an abnormality of the aqueduct, such as stenosis, or a lesion within the 4th ventricle. Communicating hydrocephalus is commonly seen following a subarachnoid hemorrhage (post-hemorrhagic) or meningitis, where blood or thick exudates can lead to impaired outflow of CSF. This topic is covered in more detail in the Hydrocephalus chapter (XVIII.9).
Affected children can present in many different ways, with variability depending on the age of onset, nature of the obstructive lesion, and duration and rate of increase of the intracranial pressure. Infants may present with brisk tendon reflexes, spasticity, drastic increases in head circumference as well as a wide open and bulging anterior fontanelle. In contrast, older children may present with lethargy, decreased appetite, vomiting, and headache. The diagnosis can be made with careful investigation of the patient’s family history, suggesting a genetic etiology, as well as birth and past medical history. Imaging can also be considered to identify specific causes and the severity of hydrocephalus. A lumbar puncture is contraindicated if there is suspicion of hydrocephalus due to the increased risk of neural herniation.
|Type of Hydrocephalus||Causes|
|Communicating (Non-obstructive)||achondroplasia, chorioid plexus papilloma, meningitis, post-hemorrhagic (i.e. subarachnoid), benign enlargement of subarachnoid space|
|Non-Communicating (Obstructive)||aqueductal stenosis (infectious or X-linked), genetic (mitochondrial, autosomal recessive, autosomal dominant), Chiari malformation, Dandy-Walker malformation, Klippel-Feil Syndrome, mass lesions (hematoma, abscesses, tumors)|
Treatment depends on the cause of hydrocephalus. Medications such as acetazolamide and furosemide can reduce the rate of CSF production, thereby providing temporary relief. Insertion of a ventriculoperitoneal shunt can provide more long-term relief; however, the procedure is associated with its complications. Children can return to seek medical attention in case of shunt obstruction or bacterial infection, usually secondary to Staphylococcus epidermidis. They will present with emesis, papilledema, headache, mental status changes, and possibly even fever.
1. Which CNS structure is displaced in Chiari malformations?
2. Which stage of brain development involves myelination?
3. What medications can be used to treat hydrocephalus temporarily?
4. What basic abnormality is revealed with lissencephaly on MRI imaging and gross inspection?
5. Name 3 indications for imaging in patients with spina bifida occulta?
1. Kumar, P, Burton, BK. Congenital Malformation: Evidence-Based Evaluation and Management. 2008, United States: McGraw-Hill Companies, Inc., pp. 3-11.
2. Abdelhaim, AN, Alberico, RA. Pediatric Neuroimaging. NeuroJ Clin 27 (2008) pp. 285-301
3. Kinsman, ST, Johnston MV. Chapter 585 – Congential Anomalies of the Central Nervous System. In: Behrman RE, Kleigman RM, Jenson HB et all (eds). Nelson Textbook of Pediatrics, nineteenth edition. 2012, Philadelphia: W/B/ Saunders Company, pp. 1998-2013.
4. Goetz CG, Pappert EJ. Chapter 28 – Developmental Structural Disorders. In: Golden JA, Bonnemann CG (eds). Textbook of Clinical Neurology. 2007, Philadelphia: W.B. Saunders Company, pp. 561-592.
5. Mlakar J, Korva M, Tul N, et al. Zika Virus Associated with Microcephaly. N Engl J Med. 2016 Epub ahead of print. DOI: 10.1056/NEJMoa1600651.
Answers to questions
2. Stage 4.
3. Acetazolamide or furosemide.
4. Smooth surface of the cerebral cortex.
5. Subcutaneous masses or lipomas, hairy patch, dermal sinus, atypical dimples (size >5 mm, or >25 mm from the anal verge), hemangiomas, skin appendages, or scar-like lesions.