Congenital Brain Malformations in the Neonatal and Early Infancy Period

Congenital Brain Malformations in the Neonatal and Early Infancy Period Christine Kim, MD,* Kristen W. Yeom, MD,* and Michael Iv, MD† Congenital brain malformations are a major cause of morbidity and mortality in pediatric patients who are younger than 2 years. Optimization of patient care requires accurate diagnosis, which can be challenging as congenital brain malformations include an extensive variety of anomalies. Radiologic imaging helps to identify the malformations and to guide management. Understanding radiologic findings necessitates knowledge of central nervous system embryogenesis. This review discusses the imaging of congenital brain malformations encountered in patients who are younger than 2 years in the context of brain development. Semin Ultrasound CT MRI 36:97-119 C 2015 Elsevier Inc. All rights reserved.

Introduction

Embryogenesis

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Development of the central nervous system involves a number of complex molecular and cellular interactions during the prenatal and postnatal periods. A detailed description is beyond the scope of this review, but in brief, development begins with gastrulation. Gastrulation refers to the transition of the blastula, a single-layer sphere of cells, into the gastrula, which contains 3 germ cell layers: the ectoderm, mesoderm, and endoderm.2,3 The ectoderm, which becomes the epidermis and nervous system, gives rise to the central nervous system through the processes of dorsal induction and ventral induction. Many congenital brain anomalies can be categorized by disturbances during these processes.

ongenital brain malformations are a major cause of morbidity and mortality. Neural tube defects alone occur in 1 in 1000 live births and in as many as 1 in 250 conceptuses.1 Because of the intricacy of brain development, congenital brain malformations also encompass a wide variety of anomalies. Therefore, recognizing specific malformation types can be challenging, but it is essential for optimal management. Imaging evaluation helps to identify congenital brain malformations and guide management. Understanding and classifying structural abnormalities requires knowledge of central nervous system embryogenesis, including formation of the neural tube and its differentiation into the brain and spinal cord. This review discusses embryogenesis of the central nervous system and the imaging findings of congenital brain malformations that may be encountered in patients who are younger than 2 years, which are classified by the phases of development during which defects occur: dorsal induction, ventral induction, cerebral corticogenesis, and cerebellar formation. We also highlight the clinical presentation and treatment options available for many of these lesions.

*Department of Radiology, Lucile Packard Children's Hospital, Stanford University, Stanford, CA. †Department of Radiology, Stanford University and Stanford University Medical Center, Stanford, CA. Address reprint requests to Christine Kim, MD, Department of Neuroradiology, Stanford Medical Center, 300 Pasteur Dr, Room S047, Stanford, CA 94305. E-mail: [email protected]

http://dx.doi.org/10.1053/j.sult.2015.01.003 0887-2171/& 2015 Elsevier Inc. All rights reserved.

Dorsal Induction Dorsal induction encompasses the formation of the neural plate, notochord, neural groove, neural folds, and neural tube. In a 2-step process called neurulation, the neural plate develops into the neural tube, which is the precursor of the central nervous system. Neurulation begins at approximately 17-19 days of gestation and is completed by day 28.2,4 Primary neurulation refers to the formation of the part of the neural tube that becomes the brain and most of the spinal cord. The formation of the lower lumbar, sacral, and coccygeal portions occurs during secondary neurulation.2,5 In primary neurulation, the lateral aspects of the neural plate elevate fold over the midline to become apposed and fuse to form a tube with a central patent lumen. Fusion is thought to 97

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98 be multisite and bidirectional. The adjacent ectoderm then migrates to become the overlying skin. The neural tube separates from the overlying ectoderm in a process called disjunction.2,4,5 Primary neurulation defects are typically due to disruption of tube closure or mesoderm development. These anomalies include exencephaly, anencephaly, cephalocele, and Chiari malformation. Defects of secondary neurulation involve the lumbosacral spine.4,5 Causes of neural tube defects may be genetic, environmental, or a combination of both. Extrinsic risk factors include maternal diabetes, folic acid deficiency, and anticonvulsant medications.4

Malformations of Dorsal Induction Exencephaly and Anencephaly When the anterior neuropore does not close, the developing forebrain, called the prosencephalon, remains exposed to amniotic fluid. This is known as exencephaly. Anencephaly occurs when the exposed forebrain subsequently degenerates. Consequently, the brain and overlying skull are at least partially absent, though the brainstem and cerebellum may be preserved.4,5 The brain parenchyma in exencephaly and anencephaly is composed of disorganized masses of vascular neural tissue containing multiple cerebrospinal fluid–filled cavities and fibrosis called cerebrovasculosa. Because exposure to amniotic fluid promotes rapid brain necrosis, exencephaly is rarely seen in humans. Meroacrania refers to anencephaly primarily affecting the rostral brain and skull. In the severest forms of anencephaly, the defect extends to the foramen magnum and is known as holoacrania.4,5 The incidence of anencephaly is 1:1000, with a 4:1 female to male predilection. Diagnosis is often made antenatally by evaluation of elevated maternal serum alpha fetoprotein level and prenatal ultrasound, which is nearly 100% sensitive by 14 weeks of gestation. Ultrasound may detect anencephaly as early as 11 weeks. Sonographic findings include absent tissue and calvarium above the level of the orbits and a short crown-rump length. The absent calvarium and prominent orbits may form a “frog-eye” or “Mickey-Mouse” sign on coronal imaging. Polyhydramnios is also often present because of impaired swallowing.6,7 Inadequate folic acid intake has been well established as a risk factor for anencephaly. In general, anencephaly is rarely encountered because of improvements in nutrition, antenatal diagnosis, and subsequent pregnancy termination.3,4 Because neonates are stillborn or survive for only a few days, postnatal imaging is rarely performed.4 Anencephaly is usually associated with other congenital anomalies, including other neural tube defects, cleft lip or palate, congenital heart defects, skeletal anomalies, and gastrointestinal and urinary tract abnormalities. Spine defects, such

as segmental anomalies, absent spinal cord, or dysplastic spinal cord, always accompany anencephaly.4

Congenital Cephaloceles Congenital cephaloceles are protrusions of intracranial contents through congenital skull defects. Defects are midline and covered by epithelium, suggesting disruption of neural tube closure during the postneurulation period. An explanation involves failed disjunction of the neural tube from the overlying ectoderm. Consequently, mesoderm cannot form between the neural tube and ectoderm, producing a defect in the skull and dura.4,8 The incidence of cephalocele is 0.8-3 per 100,000 live births. Specific types of defects have sex, race, and geographic predilection. Several classifications of cephaloceles exist, including categorization by the contents of the cephaloceles or whether the skull base is involved. Clinically, cephaloceles are defined by the site of bony defect. Using this method, the types of cephaloceles are occipital, nasal (frontoethmoidal and basal), parietal, temporal, and atretic.4,8 Except for basal cephaloceles, most cephaloceles are diagnosed on prenatal ultrasound. Postnatally, the bony defect may be seen on computed tomography (CT), though magnetic resonance imaging (MRI) best evaluates the contents that have herniated through the defect.4,8 Occipital Cephalocele Occipital cephaloceles comprise 70%-80% of cases and are most common in female infants of North America, Europe, and Australia. Depending on the contents of the cephalocele sac, imaging characteristics vary. Leptomeninges and cerebrospinal fluid herniate through the defect, with a variable amount of infratentorial or supratentorial brain parenchyma, which may be normal or dysplastic (Fig. 1). Traction distorts and displaces the brain structures remaining in the cranium. If a cerebral hemisphere is pulled into the cephalocele preferentially, the contralateral cerebral hemisphere may cross the midline and occupy the bilateral anterior cranial fossae. Alternatively, the frontal lobes may occupy the middle cranial fossae, displacing the temporal lobes posteriorly to the petrous ridge.4 The ventricles and brainstem may also herniate into the cephalocele. Depending on where the cerebrospinal fluid spaces are narrowed, hydrocephalus of the ventricles may develop intracranially or within the cephalocele. Vascular compression at the neck of the cephalocele may cause ischemia or hemorrhage or a combination of both. The falx is hypoplastic and may herniate into the cephalocele. The tentorium is also often hypoplastic and inserts inferiorly to the petrous ridge, decreasing the size of the posterior fossa. Cervicooccipital cephaloceles are rare and involve defects of the inferior occipital bone and the posterior elements of the upper cervical spine.4 Occipital cephaloceles may be associated with a variety of other brain malformations, most commonly absence of the anterior commissure, septum pellucidum, and fornices.4

Congenital brain malformations in the neonatal and early infancy period

99 – Transsphenoidal: herniation through the sphenoid body into sphenoid sinus and nasopharynx – Transethmoidal: herniation through the cribriform plate into the nasal cavity – Sphenoethmoidal: herniation through the posterior nasal cavity – Sphenomaxillary: herniation between the sphenoid body and wing into the pterygopalatine fossa – Spheno-orbital: herniation through the superior orbital fissure CT can delineate bony defects, which typically have sclerotic margins. Examination of the sac contents is best performed with MRI. The herniated sac may be filled with cerebrospinal fluid with or without brain parenchyma, which may be gliotic or dysplastic. The pituitary gland, hypothalamus, third ventricle, optic nerves, and optic chiasm may extend through defects of the posterior ethmoid or sphenoid bone (Fig. 3). Associated anomalies typically involve midline structures, most

Figure 1 A 2-day-old female infant with cervico-occipital cephalocele. (A) Axial T2 image demonstrates cerebrospinal fluid, meninges, and a small amount of cerebellum extending extracranially through a defect in the occipital skull. (B) Sagittal T2 image again depicts the cervicooccipital bony defect with herniated cerebellum, cerebrospinal fluid, and meninges.

Nasal Cephalocele Collectively, frontoethmoidal and basal cephaloceles are known as nasal encephaloceles. Frontoethmoidal cephaloceles are further subdivided into nasofrontal, nasoethmoidal, and naso-orbital cephaloceles. Visible facial masses form from herniation of soft tissues of the forehead, nose, and orbit through a frontal and ethmoid bone defect (Fig. 2).4,9 Basal cephaloceles are posterior to the cribriform plate and present as masses in the nasal cavity. Therefore, basal cephaloceles are usually not visible on physical examination and may present as upper airway obstruction. Their subcategories include the following:

Figure 2 A 3-month-old male infant with a frontal cephalocele. (A) Axial T2 image shows herniation of the anterior right frontal lobe into a sac consistent with cephalocele. (B) Sagittal T2 image of the same patient again demonstrates the frontal cephalocele.

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C. Kim et al. commonly the corpus callosum. Ocular abnormalities, such as optic disk hypoplasia, coloboma, and retinal dysplasia, may also be present.4,9 Prenatal diagnosis of basal cephaloceles may be challenging because of the location. Clinical symptoms present in the first decade of life as nasal passage obstruction, nasal stuffiness, and mouth breathing. A nasal or pharyngeal mass that increases in size with the Valsalva maneuver may be seen on physical examination. Cerebrospinal fluid rhinorrhea and recurrent meningitis may also occur. Endocrine dysfunction can be present when the hypothalamic-pituitary axis is involved.4,8-10 Differential considerations include nasal glioma, nasal polyp, and dermoid cysts. Nasal gliomas and cephaloceles may be histologically indistinguishable, though the presence of ependymal cells favors cephalocele. Nasal polyps are rare in pediatric patients unless associated with cystic fibrosis. Imaging should be obtained before considering biopsy.4,9,11 Management of nasal encephaloceles requires a multidisciplinary approach involving neurosurgery, radiology, anesthesiology, and otolaryngology. Presurgical cerebral angiography may be necessary to delineate vascular supply. Surgical repair is required, and intervention should occur early in life for optimal repair. Overall, nasal encephaloceles are associated with good prognosis and low mortality.9,10 Parietal Cephalocele Parietal cephaloceles are midline defects between the lambda and bregma. Therefore, variations of the superior sagittal sinus and straight sinus may be present. Magnetic resonance (MR) venography should be performed in addition to conventional MRI before surgical repair (Fig. 4). Parietal cephaloceles are often associated with fenestration of the falx and midline brain anomalies, including findings of Dandy-Walker malformation, hypogenesis or agenesis of the corpus callosum, and holoprosencephaly.4 Temporal Cephalocele Congenital temporal cephaloceles are rarer than those acquired after surgery, infection, or trauma. Defects of the tegmen result in a herniated sac in the anterior epitympanum and mastoid antrum, usually with defects of the dural and arachnoid at the herniation site. Normal brain tissue herniates into the cephalocele sac. Patients present with cerebrospinal fluid otorrhea, rhinorrhea, recurrent meningitis, or progressive conductive hearing loss.4

Figure 3 A 4-month-old male infant with a basal sphenoethmoidal cephalocele. (A) Sagittal T1 image shows the cephalocele (n) as a dark cavity due to cerebrospinal fluid. In this patient, the sac herniates through a cleft palate into the oral cavity. (B) Sagittal T2 image showing the same cephalocele as a bright fluid-filled structure. Extension of the cephalocele through the cleft palate (arrow) is more conspicuous compared with the T1 image. (C) Coronal T2 image of the cephalocele

Atretic Cephalocele Atretic cephaloceles are thought to result from milder neural tube defects. They are hairless midline oval scalp lesions, which commonly appear in the parietal or occipital regions as cysts or nodules on imaging. The underlying calvarial defect has sharp margins and is best seen on CT. Fibrous cores may be seen through the calvarial defect. Midline anomalies, such as porencephaly and hypogenesis or agenesis of the corpus callosum, typically accompany parietal atretic cephaloceles. Associated venous anomalies include a fenestrated or bifid

Congenital brain malformations in the neonatal and early infancy period

Figure 4 An 11-week-old male infant with a parietal vertex cephalocele. (A) Axial T2 image shows a bright sac containing cerebrospinal fluid and meninges herniating through a parietal calvarial defect. A large dark emissary vein appears as a dark curvilinear structure coursing into the anterior aspect of the sac (black arrow). (B) Axial FLAIR image demonstrates the same cephalocele as a sac with low to intermediate signal intensity, which is due to suppression of cerebrospinal fluid (CSF) signal on this particular sequence. FLAIR, fluidattenuated inversion recovery.

superior sagittal sinus or a persistent embryonic falcine sinus. In contrast, occipital atretic cephaloceles are usually not seen with other brain anomalies.4

Chiari Malformations In general, 3 types of Chiari malformations are recognized. Because it is not considered an anomaly of dorsal induction, Chiari 1 malformation has not been discussed in this review. Chiari 0 has recently been identified and is considered a variant of Chiari 1 malformation. Chiari 4 malformation has been reclassified as cerebellar hypoplasia.

101 Chiari 2 Malformation Chiari 2 malformation is downward displacement of the fourth ventricle, medulla, and cerebellar vermis into the upper cervical spinal canal. A lumbar myelomeningocele always accompanies Chiari 2 malformation.4 The pathophysiology of Chiari 2 malformation remains unclear. McClone and Knepper suggested one of the most accepted explanations by combining several theories into the Unified Theory/Hydrodynamic Oligo-Cerebrospinal Fluid theory.12 They proposed that incomplete neural tube closure causes inadequate cerebrospinal fluid pressure required to provide sufficient distension and mechanical support for proper cerebral and cerebellar genesis. Lack of cerebrospinal fluid pressure causes an underdeveloped posterior fossa. Growth of the brain in the confined space forces cephalad and caudad extension of the cerebellum and caudad extension of the brainstem. In addition, the ventricles are initially underdistended, resulting in supratentorial anomalies. As the posterior fossa contents develop, obstruction of cerebrospinal fluid flow leads to ventriculomegaly.4,13,14 MRI best evaluates the multiple abnormalities of the supratentorial and infratentorial brain. As mentioned, underdevelopment of the posterior fossa leads to extension of the cerebellar vermis, brainstem, and fourth ventricle below the level of a widened foramen magnum. Superiorly, the cerebellum also extends above the tentorium and is displaced laterally into the cerebellopontine angle. The cerebellum is small with shallow fissures. Displacement of the cerebellum and absence of the cisterna magna produces the “banana sign,” a welldocumented finding on prenatal ultrasound where the cerebellum appears to wrap around the brainstem.14 Multiple abnormalities of the ventricles and supratentorial brain are present in Chiari 2 malformation. Downward ectopia of the posterior fossa contents caudally displaces and decreases the size of the fourth ventricle. The cerebral aqueduct is poorly visualized. Colpocephaly, where the occipital horns of the lateral ventricles are disproportionately enlarged in comparison with the frontal horns, is common with or without ventriculomegaly.14 Inadequate ventricular pressure during embryogenesis may prolong contact between the thalami, resulting in an enlarged massa intermedia and a deformed but rarely enlarged third ventricle. However, other studies suggest that the thalami form as localized thickenings of the lateral walls of the prosencephalic vesicle and later fuse to form the massa intermedia.13 Stenogyria, where the bases of gyri are small, can also be present and is most common in the medial parietal lobes and occipital lobes. The cerebral hemispheres may interdigitate, and the falx cerebri may be fenestrated. Approximately one-third of patients with Chiari 2 malformation have partial or complete agenesis of the corpus callosum. The tectal plate may also have a beaked appearance (Figs. 5).4,14 Descent of the posterior fossa structures through the foramen magnum produces abnormalities in the upper spine. Because the medulla is mobile within the cervical canal and the spinal cord is fixed by the dentate ligament, there is kinking of the dorsal medulla. Moreover, as previously stated, nearly all patients with Chiari 2 malformation have a myelomeningocele.

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C. Kim et al. laminectomies of C1 through the most caudally involved cervical segment. Because the foramen magnum is enlarged, suboccipital craniectomy may not relieve brainstem compression and may not be indicated. If patients do undergo suboccipital craniectomy, presurgical planning must include

Figure 5 A 4-day-old female infant with Chiari 2 malformation. Sagittal T2 image shows the brainstem and cerebellum extending into the upper cervical spinal canal to the level of C3-C4 (white arrow). The posterior fossa, brainstem, cerebellum, and fourth ventricle are small, and there is tectal beaking (black arrow). The corpus callosum is hypoplastic (arrowhead).

Similarly, nearly all patients with myelomeningocele have Chiari 2 malformation.14 Skull deformities also accompany Chiari 2 malformations. In addition to a small posterior fossa and enlarged foramen magnum, shortening of the clivus and Luckenschadel (rounded pitting of the inner table of the skull separated by bony ridges) may be seen (Fig. 6). Continuous pressure on the herniated cerebellum and cervicomedullary junction can cause scalloping of the posterior surface of the petrous bones.14 Patients with Chiari 2 malformations have significant morbidity and mortality. Complications related to myelomeningocele may cause death in patients who are younger than 2 years. One-third of patients who are younger than 5 years do not survive because of brainstem compression. Recognizing signs of increasing intracranial pressure from hydrocephalus and shunt malfunction is imperative in managing brainstem compression. The most common signs of Chiari 2 malformation in children who are younger than 2 years include cranial nerve palsies, respiratory difficulties, aspiration, prolonged expiratory apnea with cyanosis, diminished gag reflex, gastrointestinal disturbances with weight loss, paraparesis, quadriparesis, hypotonia, weak cry, nystagmus, opisthotonis, and developmental delay. Inspiratory stridor in patients with Chiari 2 malformation should prompt urgent evaluation to determine if vocal cord paresis from brainstem compression with cranial nerve traction is involved, which may require direct laryngoscopy and possible emergent surgical decompression. Respiratory symptoms should not simply be attributed to pathology common to other pediatric patients.14 Emergent and elective surgical decompression for Chiari 2 requires careful evaluation and planning. If the patient is symptomatic, physicians should exclude hydrocephalus or shunt malfunction as the cause. If the patient has a shunt, function may be evaluated in the operating room. If the shunt is functional, neurosurgeons may proceed to decompressing the malformation. Surgical decompression consists of

Figure 6 A 16-month-old female infant with Chiari 2 malformation and Luckenschadel (lacunar) skull. (A) Anterior posterior view of the skull from a shunt series demonstrates rounded indentations of the inner table of the calvarium separated by ridges of bone; this appearance is consistent with a Luckenshadel or lacunar skull. (B) Lateral view of the Luckenschadel skull.

Congenital brain malformations in the neonatal and early infancy period localization of the torcula as the tentorium tends to be hypoplastic and inserts low.14 Several risks of Chiari 2 decompression exist. Immediate risks include blood loss, infection, injury to the central nervous system, and failure of symptom relief. Later, patients may have recurrence of symptoms from shunt malfunction, inadequate initial decompression, bony regrowth, scarring, and syrinx. Other complications are cervical instability and kyphosis, the incidence of which varies widely in literature. The age of initial decompression and adequacy of cerebrospinal fluid flow through the fourth ventricle are among the factors considered for surgical revision. Current research focusing on intrauterine myelomeningocele repair and its effect on development may provide an earlier approach to managing Chiari 2 malformation.14

Chiari 3 Malformation Chiari 3 malformation combines the brain findings of Chiari 2 malformation with herniation of posterior fossa contents through a low occipital or upper cervical osseous defect. The reported incidence of Chiari 3 malformation ranges from 2 in 50 to 2 in 312 cases of Chiari malformation. Therefore, limited knowledge about the natural history and management of Chiari 3 malformations is available. Because of high early mortality and severe neurologic deficits in surviving patients, Chiari 3 is thought to have poorer outcomes than Chiari 2.15,16 CT helps identify bony abnormalities and ventriculomegaly. Bony defects are in the lower occipital bone or posterior arch of C1. Other bony abnormalities include a small posterior fossa with low tentorial attachment and scalloping of the clivus.16 MRI best evaluates the cephalocele contents, which may include the cerebellum, brainstem, fourth ventricle, upper cervical cord, and in severe cases, supratentorial brain. MRI also establishes the position of the brainstem and venous anomalies, which may alter surgical approach. Spinal MRI findings may detect a tethered cord, syringomyelia, or neural tube defects. Fetal MRI and ultrasound are essential for prenatal diagnosis.15,16 Patients with Chiari 3 malformation may present with respiratory and swallowing difficulties, seizures, developmental delay, hypotonia, spasticity, upper and lower motor neuron deficits, and low occipital or high cervical cephalocele on physical examination.15 The goal of surgical repair for Chiari 3 patients is to resect the cephalocele while preserving neurologic function. Some authors favor excising the contents of the cephaloceles, which are generally considered abnormal and often nonfunctional because of necrosis, gliosis, and heterotopia. However, surgery may be delayed several days to evaluate for possible functionality of cephalocele contents as cephaloceles tend to have normal skin covering. Therefore, they do not present an indication for urgent surgery from an infectious standpoint. Repair may be contraindicated in microcephalic patients who have a greater amount of neural tissue within the cephalocele sac than intracranially. One study suggested that surgical repair does not improve outcomes in patients with greater than 20 cm3 of brain tissue within the cephalocele.15

103 Historically, primary closure has been followed by ventriculoperitoneal shunting. However, newer approaches suggest cerebrospinal fluid shunting before closure may help reduce the amount of neural tissue herniating into cephaloceles. Other aspects of Chiari 3 repair include reconstruction of the dura and bone to maintain adequate cerebrospinal fluid flow. Furthermore, release of the filum terminale in patients with tethered cord syndrome can prevent progression of scoliosis.15,16

Ventral Induction Ventral induction involves the formation of the brain from the neural tube and occurs between the fifth and tenth weeks of gestation. After closure of the neural tube, 3 primordial brain vesicles are formed: the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain).2,17 The dorsal and rostral portion of the prosencephalon forms paired diverticula or telencephalic vesicles, which become cerebral hemispheres. The mesenchyme between the telencephalic vesicles becomes the falx. At the lateral aspects of the telencephalon, 2 outpouchings develop to form the retina and the optic nerve. The diencephalon forms from the caudal aspect of the prosencephalon and becomes the thalami, hypothalamus, epithalamus, optic cups, and neurohypophysis. The cavities within the telencephalon and diencephalon give rise to the lateral and third ventricles.2 The midbrain forms from the mesencephalon, including the colliculi, red nucleus, substantia nigra, tegmentum, and crus cerebri. The central cavity shrinks into the sylvian aqueduct.2 After the caudal neuropore closes, the rhombencephalon stretches laterally, forming the fourth ventricle. The rostral portion of the rhombencephalon becomes the metencephalon and then the pons, cerebellum, and cerebellar vermis. The caudal portion becomes the myelencephalon and then the medulla.2,18 Neuroblasts and glioblasts are progenitor cells that line the neural tube. The neuroblasts differentiate into neurons, and the glioblasts become support cells, such as astrocytes and oligodendrocytes.2

Malformations of Ventral Induction Defects in ventral induction can give rise to malformations such as holoprosencephaly, middle interhemispheric variant, septo-optic dysplasia, commissural hypogenesis and agenesis, and interhemispheric cysts and lipomas.

Holoprosencephaly Between the 18th and 28th days of gestation, inductive factors prompt the telencephalon to divide into the paired telencephalic vesicles. Disruption of the inductive pathway prevents normal division of the telencephalon and craniofacial structures. The single telencephalon then becomes the holoprosencephalon, resulting in a spectrum of disorders called

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holoprosencephaly. Holoprosencephaly is classified based on severity into alobar, semilobar, and lobar subtypes. These subtypes belong to a continuous spectrum and may be difficult to distinguish.19,20 Holoprosencephaly occurs in 1 in 10,000 live births and is the most common telencephalic developmental defect. The incidence has been reported as high as 1 in 250 conceptuses.21,22 Intrinsic genetic factors or extrinsic factors, such as maternal diabetes and teratogen exposure, are associated with holoprosencephaly.19 High-resolution MRI with thin sections in axial, sagittal, and coronal planes should be obtained to evaluate patients with suspected holoprosencephaly. Holoprosencephaly rarely may accompany other malformations, such as schizencephaly, Dandy-Walker malformation or variant, Chiari malformation, cephaloceles, and rhombencephalosynapsis.20 Other possibly related but distinct malformations from holoprosencephaly are middle interhemispheric variant and septo-optic dysplasia. Alobar Holoprosencephaly The most common and severest form of holoprosencephaly is alobar holoprosencephaly. The cerebral hemispheres completely or almost completely fail to separate. The holoprosencephalon consists of a large midline holoventricle surrounded by a crescent of brain parenchyma and typically communicates with a dorsal cyst. The basal ganglia and thalami do not separate into bilateral structures, resulting in absence of the third ventricle. There is poor differentiation of the deep gray matter. The olfactory bulbs and optic nerves may be aplastic. The interhemispheric fissure, falx, corpus callosum, gyri recti, and sylvian fissure are completely absent (Figs. 7).19,20 Craniofacial deformities are apparent on physical examination and include premaxillary agenesis, cleft lip or palate, ocular hypotelorism, ethmocephaly, and cyclopia. Patients are typically microcephalic, unless the dorsal cyst is large, in which case, they may have macrocephaly.19,20 Alobar holoprosencephaly is generally not compatible with life. Of those with severe craniofacial malformations, such as cyclopia, ethmocephaly, and cebocephaly, who survive to childbirth, nearly all die within a week. In a study reviewing 62 cases of alobar holoprosencephaly, approximately half the patients with premaxillary agenesis, unilateral or bilateral cleft lip, or more normal faces died before the age of 4-5 month, and; 20%-30% of patients lived at least 1 year.23 Affected patients who survive birth present with hypotonia and seizures.19,20 Semilobar Holoprosencephaly In semilobar holoprosencephaly, the brain is better developed posteriorly than anteriorly. Unlike the posterior aspects of the frontal lobe, which successfully separate, the anterior aspects do not separate and are small. The temporal lobes and hippocampi are also underdeveloped with nearly normal formation of the posterior brain. The olfactory bulbs are absent or hypoplastic. The genu and anterior body of the corpus callosum are absent and the splenium present. Further development of the more anterior portions of the corpus

Figure 7 A 5-day-old female infant with alobar holoprosencephaly. (A) Axial T2 image shows crescent of anterior brain parenchyma that has not separated into 2 hemispheres with presence of a monoventricle and dorsal cyst. The interhemispheric fissure, falx cerebri, corpus callosum, third ventricle, and sylvian fissures are absent. The basal ganglia and thalami are poorly defined and are fused at midline. (B) Sagittal T1 image of the same patient.

callosum correlates with a greater degree of interhemispheric fissure formation. The posterior falx cerebri is present, and the anterior portion is absent. The frontal horns of the lateral ventricles and septum pellucidum are absent. Because the basal ganglia and thalami separate in milder cases, the third ventricle forms; although the occipital and temporal horns are underdeveloped. Incomplete separation of the basal ganglia and thalami in severe cases results in dorsal cysts and a small third ventricle. The caudate heads typically do not separate (Fig. 8).19,20,24 The most common presentation of semilobar holoprosencephaly is microcephaly, though large dorsal cysts may cause hydrocephalus and macrocephaly. Therefore, patients require close follow-up for increased head circumference or other signs of hydrocephalus. Patients may also have developmental

Congenital brain malformations in the neonatal and early infancy period

105 the genu and rostrum may be absent or dysplastic. The septum pellucidum is absent. The anterior falx cerebri may be mildly hypoplastic. An azygous anterior cerebral artery is usually seen. Because of the milder phenotype of lobar holoprosencephaly, diagnosis may occur later in life. Patients present with visual abnormalities, hypopituitarism, or mild developmental delay.5,19,20 Middle Interhemispheric Variant Middle interhemispheric variant, or syntelencephaly, is a more recently recognized milder malformation that differs from classic holoprosencephaly. Although the poles of the frontal and occipital lobes separate, the posterior frontal and parietal lobes do not. The body of the corpus callosum is absent. These findings result in vertically oriented sylvian fissures, which connect at the vertex of the brain. The caudate nuclei and thalami do not separate, though hypothalamus and lentiform nuclei appear normal. Two-thirds of patients have gray matter heterotopia or cortical dysplasia, and the cortex along the anterior interhemispheric fissure is thickened. At times, patients may demonstrate features of both lobar holoprosencephaly and middle interhemispheric variant. Most patients have an azygous anterior cerebral artery. On physical examination, hypertelorism or a normal intraocular distance may be present (Fig. 9).20 Septo-optic Dysplasia Septo-optic dysplasia classically refers to hypoplasia of the optic nerves and chiasm with absence of the septum pellucidum (Fig. 10). However, this malformation represents a heterogeneous group of disorders. Establishing diagnosis generally entails meeting 2of the following 3 criteria:

Figure 8 A 19-day-old male infant with semilobar holoprosencephaly. (A) Axial T2 image shows that the anterior cerebrum has not separated, forming a large monoventricle (n). There is suggestion of an interhemispheric fissure posteriorly (arrow) and a simplified sulcation pattern. No septum pellucidum is present. (B) Coronal T2 image demonstrates persistent fusion of the thalami (#) at midline.

delay, choreoathetosis, spasticity, and dystonia. Unlike alobar holoprosencephaly, facial malformations are mild, if present.19,20,24 Lobar Holoprosencephaly If more than 50% of the frontal lobes separate, the diagnosis is generally considered lobar holoprosencephaly. However, this is an arbitrary marker and difficult to quantitate. Except for the most anterior and ventral portions of the frontal lobes and the olfactory bulbs and tracts, the cerebral hemispheres and deep gray nuclei completely separate and develop normally. Rudimentary frontal horns of the lateral ventricles and presence of a normal third ventricle help distinguish lobar holoprosencephaly from semilobar holoprosencephaly. There is no dorsal cyst, and the massa intermedia may be prominent. The body and splenium of the corpus callosum are well formed, whereas

– Optic nerve or chiasm hypoplasia – Absence of the septum pellucidum – Pituitary hormone deficiency Some authors describe an entity called septo-optic pituitary dysplasia, which also involves dysplasia of the anterior corpus callosum and hypothalamus. Although the etiology of these malformations remains unclear, maternal diabetes, intrauterine cytomegalovirus, and a genetic mutation have been linked with septo-optic dysplasia and septo-optic pituitary dysplasia.19,20 Clinical presentation prompts the diagnosis of septo-optic dysplasia. Patients have seizures or signs and symptoms of optic nerve hypoplasia with possible endocrine derangement. They may present with impaired vision and have nystagmus, optic nerve hypoplasia, paleness of the optic nerve head, and retinal vein tortuosity on physical examination. Hypothalamic deficiency may cause decreased growth hormone, thyroidstimulating hormone, or antidiuretic hormone in septo-optic pituitary dysplasia.19 One multicenter study found that patients with optic nerve hypoplasia and remnants of the septum pellucidum had milder clinical phenotypes than those with complete absence of the septum pellucidum. Overall, 12 patients with optic nerve hypoplasia and pituitary anomalies had a normal septum pellucidum and presented with similar neuroendocrine abnormalities as those with classic septo-optic

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Figure 9 A 16-day-old male infant with middle interhemispheric variant. (A) Axial T2 image through the level of the basal ganglia shows dysmorphic lateral ventricles with absence of the septum pellucidum. The thalami (#) are globular and partially separated. The single flow void in the anterior interhemispheric fissure, representing an azygous anterior cerebral artery (white arrow), should be noted. (B) Axial T2 image at the level of the centrum semiovale shows formation of the interhemispheric fissure anteriorly and posteriorly. Centrally, the cerebral hemispheres have not completely separated (black arrows). (C) Sagittal T1 image of the brain demonstrates absence of the body of the corpus callosum and dysmorphic appearance of the cingulate gyrus.

dysplasia. Therefore, the authors suggested that these cases of “septo-optic dysplasia–like” malformations belong on the same spectrum as septo-optic dysplasia and require the same diagnostic evaluation and management.25 The purpose of imaging is to confirm the clinical suspicion of septo-optic pituitary dysplasia. Findings include hypogenesis or agenesis of the corpus callosum with ventricular dysmorphia. Absence of the septum pellucidum leads to a lowlying fornix. Pituitary findings include an ectopic posterior pituitary gland, empty sella, or pituitary hypoplasia. The hypothalamus may be hypoplastic. Hippocampal abnormalities may also be seen. Optic nerve hypoplasia may not always be detectable by imaging.19

Commissural Agenesis There are 4 main telencephalic commissures in the brain: the anterior commissure, corpus callosum, hippocampal

commissure, and supraoptic commissure. The habenular and posterior commissures develop in the walls of the third ventricle. The corpus callosum consists of densely packed myelinated fibers connecting the cerebral hemispheres. The 4 segments of the corpus callosum are the genu anteriorly, the body in the middle portion, the splenium posteriorly, and the rostrum at the base of the genu. The forceps minor courses in the genu to connect the frontal lobes while the forceps major connects the occipital lobes via the splenium.26 During development, as the 2 telencephalic vesicles form, a small amount of tissue continues to bridge the hemispheres at the ventral aspect of the interhemispheric cleft. The rostral wall of the bridging tissue is divided into the chiasmatic plate, lamina terminalis, and lamina reuniens. The ventral part of the lamina reuniens becomes the anterior commissure. The posterior portion gives rise to the fornix, hippocampal commissure, corpus callosum, and cavum septum

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107 Because the development of the corpus callosum genu is followed by the body and then the splenium, late intrauterine insults result in absence of the splenium. Earlier insults at approximately 12-13 weeks lead to formation of the genu and absence of the body and splenium. If developmental disturbance occurs earlier, only the genu may be present. Midsagittal MR images can easily identify complete or partial agenesis of the corpus callosum.19 The cingulate gyrus inverts during formation of the corpus callosum. If inversion fails, the cingulate remains everted, and callosal axons extend parasagittally, parallel to the interhemispheric fissure, instead of across midline. The longitudinal fibers are called Probst bundles and have the same signal characteristics as white matter. Without a normal corpus callosum to guide ventricular development, the frontal horns of the lateral ventricles are underdeveloped whereas the temporal horns are enlarged. The trigone and occipital horns of the lateral ventricles become relatively expanded (colpocephaly) (Fig. 11). On coronal images, the lateral ventricles have a “steer-horn” configuration. Because corpus callosum development occurs at the same time as the cerebrum and cerebellum, insults affecting callosal development may influence other parts of the brain. Therefore, agenesis of the corpus callosum is often seen with other brain anomalies.19

Interhemispheric Cysts and Lipomas

Figure 10 A 3-month-old male infant with septo-optic dysplasia. (A) Axial T2 image at the level of the basal ganglia shows appropriate cleavage of the cerebral hemispheres but absence of the septum pellucidum. The corpus callosum is also thin. (B) Midsagittal T2 image of the brain demonstrates diminished size of the optic chiasm (arrow) with presence of a third ventricle and thin corpus callosum (arrowhead).

pellucidum. The lamina terminalis forms the anterior border of the third ventricle. By 10 weeks of gestation, pioneer fibers extend across the anterior commissure and then the hippocampal commissure. The corpus callosum develops third at approximately 7 weeks of gestation.27 Recent research has challenged the classic teaching of corpus callosum development starting at the genu and proceeding posteriorly to the splenium and finishing at the rostrum. Some researchers postulate that rostral fibers are the first to cross the midline but are detected after the genu and splenium due to differences in size. Myelination of the corpus callosum begins at 2 months of development, although it is not detectable by MRI until 4 months. Myelination begins at the splenium. Normal myelination of the genu is seen on T1-weighted MRI images by 6 months.19,26 By 20 weeks of gestation, corpus callosum formation is nearly complete. The corpus callosum continues to increase in thickness and length until reaching adult form at 6-9 years of age.27

Overall, 15% of corpus callosum agenesis cases are associated with interhemispheric cysts, which are categorized into 2 types. A type 1 cyst is a diverticulum communicating with the dorsal aspect of the third ventricle. Patients may present with neonatal macrocephaly, neonatal seizures, developmental delay, and focal neurologic deficits. Imaging shows hydrocephalus, thalamic fusion, and a small cerebral hemisphere. In contrast, multiloculated type 2 cysts do not communicate with the ventricles and are thought to result from dysplasia of the interhemispheric meninges (Fig. 12). This disrupts development of the commissural plate and adjacent cortex. Consequently, associated brain anomalies may be seen, such as polymicrogyria, subependymal heterotopia, and subcortical heterotopia.19 The meninx primitiva is undifferentiated mesenchyme that forms the leptomeninges and subarachnoid space. Intracranial lipomas are thought to derive from defective differentiation of the meninx primitiva into the subarachnoid layer. Intracranial lipomas are nonneoplastic, asymptomatic, and diagnosed incidentally. They are most commonly found in the interhemispheric fissure, quadrigeminal plate cistern, suprasellar cistern, cerebellopontine angle cistern, and sylvian fissures. On CT, intracranial lipomas are well-defined masses of fat density at
70 to
100 Hounsfield units. They follow fat signal intensity on MRI and may demonstrate chemical-shift artifact. Internal signal voids from traversing vessels and calcifications may be present (Fig. 13). If other lesions are considered in the differential diagnosis, fat-saturation sequences may help in problem solving.19

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Embryology of the Cerebral Cortex The cerebral cortex undergoes cellular proliferation, migration, and cortical organization during development. These processes overlap, and disruption at any stage results in disorders of cortical formation.28

Proliferation The first stage of cortical development is proliferation, which occurs between the second and fourth months of gestation. At this time, neuroblast precursors in the ventricular and subventricular germinal zones symmetrically divide to produce more stem cells. Eventually, cell division becomes asymmetric to produce a postmitotic cell and a stem cell.28 Disruption of proliferation is usually caused by imbalance of proliferation and apoptosis. Proliferation abnormalities may be categorized as follows: – Decreased proliferation or increased apoptosis: microcephaly and microlissencephaly – Increased proliferation or decreased apoptosis: macrocephaly and hemimegalencephaly – Nonneoplastic abnormal cell proliferation: cortical hamartoma and cortical dysplasia with balloon cells – Neoplastic abnormal cell proliferation: dysmembryoplastic neuroepithelial tumor, ganglioglioma, and gangliocytoma28,29

Migration During the third through fifth months of gestation, neurons begin to migrate from the germinal matrix to form the cortex in 6 stages. Guided by radial glial cells, neurons migrate further

Figure 11 A 4-month-old male infant with agenesis of the corpus callosum and basal cephalocele. This is the same patient as in Figure 3. (A) Axial T2 image demonstrates absence of the corpus callosum with Probst bundles running parallel to the interhemispheric fissures instead of across the midline. Without a corpus callosum, the frontal horns of the lateral ventricles are underdeveloped. The trigone and occipital horns disproportionately enlarge (colpocephaly). (B) Midsagittal T1 image of the brain shows absence of the corpus callosum, dysmorphia of the cingulate gyrus, and a radiating gyral pattern. This patient also has a basal cephalocele (n) with the sac extending through a cleft palate. (C) Coronal T2 image shows a steer-horn configuration of the lateral ventricles (arrows) due to absence of the corpus callosum.

Figure 12 A 4-month-old male infant with agenesis of the corpus callosum and multiloculated type 2 interhemispheric cysts. Axial T2 image shows absence of the corpus callosum and presence of multiple septated cysts, which do not communicate with the ventricles.

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109 with each phase, such that later stages form more superficial layers of the cortex. Disruption in the regulating mechanisms results in migration abnormalities, which include lissencephaly, cobblestone complex, and heterotopia.28,29

Organization Cortical organization begins between 17 and 22 weeks of gestation and finishes at 2 years of age. During this stage of development, neurite extension, synaptogenesis, and neuronal maturation occur. Disruption in cortical organization may also result in late neuronal migration abnormalities. Organizational anomalies include polymicrogyria, schizencephaly, cortical dysplasia without balloon cells, and microdysgenesis.28,29

Cerebral Cortex Malformations Cerebral cortex malformations included in this review are microcephaly, microlissencephaly, hemimegalencephaly, lissencephaly, focal cortical dysplasia, heterotopia, polymicrogyria, and schizencephaly.

Microcephaly and Microlissencephaly Decreased cell division or increased apoptosis in the germinal zone results in a small brain and head circumference. When the head circumference is 3 or more standard deviations less than normal, the patient has congenital microcephaly. The cortical pattern of the brain is also altered and best evaluated by MRI. The brain has a simplified gyral pattern and shallow sulci with normal or thinned cortical thickness. Milder forms of microcephaly are typically isolated anomalies most often due to an inherited autosomal recessive trait. Microlissencephaly is a more severe variant characterized by complete or nearcomplete agyria and a thickened cortex measuring 43 mm. Unlike microcephaly, microlissencephaly is commonly found with other congenital anomalies, such as agenesis of the corpus callosum and cerebellar hypoplasia.28,29

Hemimegalencephaly

Figure 13 A 4-month-old female infant with agenesis of the corpus callosum and interhemispheric lipoma. (A) Axial T2 image shows a lobulated interhemispheric mass with high signal intensity. Flowrelated signal voids within the mass represent traversing vessels. Dark signal outlining the mass is due to chemical-shift artifact. (B) Sagittal T1 image demonstrates absence of the corpus callosum and an interhemispheric mass of high signal intensity, consistent with lipoma. Traversing vessels are again seen. (C) Axial CT image of the same patient confirms fat density of the interhemispheric mass.

Hemimegalencephaly is cerebral overgrowth from increased cell division or decreased apoptosis. MRI best evaluates parenchymal abnormality and shows enlargement of an entire cerebral hemisphere or part of a cerebral hemisphere. Other imaging characteristics include differing degrees of gray-white junction distinctness and shallow sulci. The cortex widely varies in appearance, and identifying the abnormal portion of the brain can be challenging. Although the cortex may seem normal in some patients, most cases demonstrate cortical thickening with different grades of polymicrogyria or lissencephaly (Fig. 14). Gliosis may cause the subcortical white matter to be bright on T2-weighted MR images, and there may be asymmetrically advanced myelination of the ipsilateral white matter. The ipsilateral cerebellum and brainstem may be involved.28,29 Management of hemimegalencephaly primarily entails seizure control, which may require hemispherectomy. Therefore,

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C. Kim et al. lissencephaly, X-linked lissencephaly with agenesis of the corpus callosum, lissencephaly with cerebellar hypoplasia, and microlissencephaly.31 This group of disorders is caused by migrational abnormalities. For example, in classic lissencephaly, arrest of neuronal migration results in a 4 layers of immature neurons in the cortex instead of 6 mature layers. No organized layers are identified in cobblestone lissencephaly.32 Imaging of lissencephaly shows a thickened, smooth, featureless cortex. The gyral pattern can range from gyral reduction of pachygyria (where fewer and broad gyri are present) to agyria, (where gyri are absent). Agyria may be global or involve the parieto-occipital region. Pachygyria often occurs in the frontotemporal lobes.28,29,31 In classic lissencephaly, the insula fails to opercularize, which can give the brain an “hourglass” or “figure-of-eight” shape and shallow Sylvian fissures (Figs. 15 and 16).31,33

Figure 14 A 9-day-old male infant with hemimegalencephaly. (A) Axial T2 image shows asymmetric overgrowth of the right cerebral hemisphere with cortical thickening and simplified gyral pattern. The ipsilateral lateral ventricle is proportionately enlarged compared with the left. In this patient, there is also disproportionate enlargement of the temporal horn of the right lateral ventricle. (B) Coronal FLAIR image of the same patient demonstrates the same findings. FLAIR, fluid-attenuated inversion recovery.

imaging to exclude potential bilateral involvement should be performed. Bilateral findings would be a surgical contraindication. Hemimegalencephaly can be an isolated sporadic occurrence or associated with syndromes such as epidermal nevus syndrome, Proteus syndrome, unilateral hypomelanosis of Ito, neurofibromatosis type I, Klippel-Trénaunay syndrome, and tuberous sclerosis.28-30

Lissencephaly Lissencephaly encompasses a spectrum of brain malformations characterized by a reduced number of gyri. The 5 categories of lissencephaly are classical lissencephaly, cobblestone

Figure 15 A 4-month-old female infant with lissencephaly. (A) Axial T2 image shows a simplified gyral pattern with pachygyria in the occipital and frontoparietal lobes. Polymicrogyria (arrow) of the bilateral frontal lobes is also present. This patient also has dysmorphic ventricles and prominent leaflets of a cavum septum pellucidum. (B) Coronal T2 image of the same patient again demonstrates findings of lissencephaly.

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111 with seizures, developmental delay, hypotonia, microcephaly, and facial dysmorphia.28 Cobblestone lissencephaly is also known as congenital muscular dystrophy as patients also have ocular anomalies and a spectrum of congenital muscular disorders, including Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy.28

Heterotopia

Figure 16 A 6-day-old female infant with lissencephaly. Axial T2 image shows agyria with a smooth, featureless cortex. The sylvian fissures are absent. These findings give the brain an hourglass configuration.

Cobblestone lissencephaly occurs when neuroblasts and glia overmigrate into the subarachnoid space.28 Because of the severe disorganization, the cortex consists of clusters of neurons and irregular grooves. In addition, some associated syndromes show a hypoplastic “Z-shaped” brainstem (Fig. 17).34 The extent of lissencephaly may vary on imaging; and cases of mild pachygyria may be difficult to differentiate from polymicrogyria. Examination of the gray-white junction may help distinguish the 2 entities, as the interface is well delineated in pachygyria but irregular in polymicrogyria.28,29 Clinically, patients with lissencephaly present

Figure 17 A 3-day-old female infant with cobblestone lissencephaly. Axial T2 image shows an abnormal gyral and sulcal pattern throughout the brain with pachygyria and cobblestone appearance of the cortex. This patient also has severe ventriculomegaly.

Heterotopia occurs when normal neurons abnormally arrest along the migration pathway from the subependymal region to the cerebral cortex. On MRI, these clusters of arrested neurons do not enhance and are of gray matter signal intensity on all pulse sequences. When considering low-grade glioma as a differential diagnosis, MR spectroscopy may help to distinguish the 2 entities. Heterotopic gray matter has the same metabolite profile of normal brain parenchyma, whereas low N-acetylaspartate and high choline peaks are found in lowgrade gliomas.28 The 3 main groups of heterotopia are periventricular or subependymal heterotopia, subcortical heterotopia, and marginal glioneuronal heterotopia.31

Periventricular or Subependymal Heterotopia When neuronal migration arrest occurs near the ventricular wall, nodules that are isointense to the gray matter are seen along the ventricular walls or in the periventricular white matter (Fig. 18). Periventricular or subependymal heterotopia is further categorized into several subtypes based on whether lesions are bilateral or unilateral. Subependymal heterotopia may be seen in tuberous sclerosis.28,31,35

Figure 18 A 4-day-old female infant with subependymal heterotopia. Axial T2 image shows heterotopic nodules (arrows), which follow gray matter signal intensity, along the periphery of the lateral ventricles. This patient also has ventriculomegaly.

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Subcortical Heterotopia Neurons that are arrested in the subcortical or deep white matter during migration remain contiguous with the ventricles or overlying cortex, which is thin with shallow adjacent sulci. Nodular subcortical heterotopia appears as nodules that may range in size from subcentimeter to large mass-like lesions nearly occupying a cerebral hemisphere. Curvilinear subcortical heterotopia present as gray matter masses extending from the cortex to the white matter. Blood vessels and cerebrospinal fluid abnormally communicating with the subarachnoid space may be seen within these lesions. Nodular and curvilinear heterotopia may be seen concurrently as mixed subcortical heterotopia. Transmantle heterotopia refers to linear bands of heterotopia extending from the cortex to the underlying ventricle.28 Band or Laminar Heterotopia One form of subcortical heterotopia is characterized by formation of a subcortical layer of gray matter separated from the cerebral cortex by a thin layer of white matter. This continuous double cortex constitutes band or laminar heterotopia and may be associated with pachygyria (Fig. 19).28,31,36 Nearly all affected patients are female. The female predilection occurs because of a genetic mutation of the X-linked doublecortin gene.37,38 Most male patients with the same mutation develop X-linked lissencephaly instead. Rare cases of male patients with subcortical band heterotopia suggest that somatic mosaicism or missense mutations influence phenotypic expression of the doublecortin gene mutation, which can be inherited or sporadic.38-40

Focal Cortical Dysplasia Focal cortical dysplasia refers to dyslamination or disorganization of the normal cortical cytoarchitecture. Several subtypes of focal cortical dysplasia exist and are based on histopathology. Type 1 focal cortical dysplasia consists mostly of dyslamination. In type 2 focal cortical dysplasia, balloon cells, which have characteristics of neurons, astrocytes, and atypical neurons infiltrate the subcortical white matter and cortex. These neurons are increased in number and clustered in abnormal locations. Type 3 focal cortical dysplasia is similar to type 1 but also includes findings of other concurrent epileptic lesions.28-30,41 Imaging findings of focal cortical dysplasia are usually encountered on MRI as part of a seizure workup. Because of the abnormally distributed dysplastic neurons, focal cortical dysplasia appears as localized cortical thickening with indistinctness of the gray-white junction on imaging. A subcortical linear or curvilinear focus of abnormal signal intensity may extend radially from the gray-white junction into the underlying white matter. Abnormal signal reaching the underlying lateral ventricle is termed transmantle dysplasia. The features of this abnormal signal intensity depend on patient age. Before myelination, lesions are bright on T1-weighted images and not well visualized on T2-weighted images. After myelination, they become isointense to the cortex on T1-weighted images and are better appreciated as high signal intensities on T2-weighted images. The apparent shift in signal characteristics may reflect

Figure 19 A 2-day-old female infant with band heterotopia. (A) Coronal T2 image shows a thin layer of white matter (n) separating the superficial cerebral cortex (arrow) from a subcortical layer of gray matter (#), giving the appearance of a double cortex. The cortical pattern is also simplified. (B) Axial T2 image of the same patient again shows findings of band heterotopia.

relative axonal hypomyelination or gliosis against a background of maturing normal brain parenchyma (Fig. 20). Macrogyria and enlarged or deepened sulci are in the region of focal cortical dysplasia. Imaging findings of the different types of focal cortical dysplasia overlap, and severity of the findings widely varies. Some lesions encompass a large region of brain parenchyma with marked cortical abnormality. Other lesions may be very subtle and difficult to identify on imaging.28-30 Focal cortical dysplasia may present a diagnostic dilemma as there is often imaging overlap with gliomas. In general, frontal lesions tend to favor focal cortical dysplasia, whereas temporal lesions favor glioma. Gliomas may also cause mass effect and may enhance after contrast injection, in contrast to dysplasias.28 Patients with focal cortical dysplasia most commonly present with intractable seizures.28 Type 2 focal cortical

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113 is most common in the anterior frontal region and the cortex is of normal thickness. Patients older than 18 months typically have a coarser undulating cerebral cortex measuring 5-7 mm and irregularity in the gray-white junction. These findings are primarily frontal, parietal, and perisylvian in location.28,31 On imaging, the cortex is usually mildly thickened with small irregular gyri. The gray-white junction is indistinct. Evaluation of the gray-white junction is best on high-resolution T1-weighted MRI with 3-dimensional reconstruction. Anomalous venous drainage of the dysplastic cortex may be present. Increased signal intensity of the underlying white matter on T2-weighted images can be seen, possibly because of ischemia or undermyelination. Other brain anomalies may be seen with polymicrogyria, such as hypogenesis or agenesis of the corpus callosum, cerebellar hypoplasia, and heterotopia.28,31,45 Patients with polymicrogyria typically develop seizures by 4-12 years of age. Seizures are refractory to pharmaceutical treatment in approximately 65% of patients.31 Global developmental delay, esotropia, or pseudobulbar palsy may also be present. Polymicrogyria is often due to prenatal infection, ischemia, toxin exposure, or chromosomal abnormality. The prevalence of polymicrogyria is unknown because of heterogeneity of clinical presentation and etiologies.28,31,46

Schizencephaly

Figure 20 A 10-month-old female infant with transmantle cortical dysplasia. (A) Axial T2 image shows abnormal focal thickening of the left parasagittal posterior frontal lobe cortex (white arrow). An interhemispheric cyst (n) is also present. (B) Coronal T2 image of the same patient shows extension of the abnormal cortical thickening (black arrow) to the underlying left lateral ventricle.

dysplasia tends to present with more severe seizures at an earlier age than type 1. Most patients with type 2 focal cortical dysplasia present with their first seizure by 5 years of age and undergo surgery by 10 years of age.42 Outcome studies have suggested that incomplete resection of lesions predicts poor outcomes, including seizure recurrence and cognitive impairment. Because most focal cortical dysplasia lesions are poorly delineated and imaging often underestimates the extent, achieving complete resection can be challenging.30,43,44

Polymicrogyria Abnormal organization of the 6 neuronal layers of the cerebral cortex may result in very fine, undulating gyri called polymicrogyria. Polymicrogyria may be unilateral, bilateral, symmetric, asymmetric, focal, or diffuse. Most commonly, this malformation occurs in the posterior frontal lobe, superior temporal lobe, or inferior parietal lobe adjacent to the Sylvian fissure. In patients who are younger than 1 year polymicrogyria

Schizencephaly describes a congenital cleft lined by cortex spanning from the pial surface to the underlying ventricle. The cleft most commonly develops in the perisylvian region, though the location varies widely.31,47 Polymicrogyria of the cleft cortex is often found. Clefts may be unilateral, bilateral, symmetric, or asymmetric. Open-lip schizencephaly is characterized by enough separation of the cleft walls to see cerebrospinal fluid cleft extending to the underlying ventricle (Figs. 21 and 22). In closed-lip schizencephaly, the cleft walls are apposed.28,31,48 Other findings that may be associated with schizencephaly include septo-optic dysplasia, optic nerve hypoplasia, an absent septum pellucidum, pachygyria, polymicrogyria, or arachnoid cysts.28 Studies have implicated prenatal injury due to infection, ischemia, and chromosomal abnormalities as causes of schizencephaly.28,31

Development of the Cerebellum By the fourth week of gestation, the cranial neural tube fuses and the neuropore closes, forming the prosencephalon, mesencephalon, and rhombencephalon. Cephalic and cervical flexures form, followed by the pontine flexure at the sixth week of gestation. The rhombencephalon divides into 2 vesicles connected by the narrow isthmus rhombencephali. The floor of the upper vesicle, or the metencephalon, thickens to form the pons. Thickening of the floor and lateral walls of the myelencephalon becomes the medulla oblongata.49 The pontine flexure contributes to the shape of the fourth ventricle. The plica choroidea is the precursor to the choroid plexus within the fourth ventricle and divides the roof of the

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Figure 21 A 22-month-old female infant with open-lip schizencephaly. Axial T2 image shows a cleft (n) filled with cerebrospinal fluid extending from the pial surface of the left frontal lobe to the underlying left lateral ventricle. The cortex lining the cleft is thickened with an indistinct gray-white junction, consistent with polymicrogyria (arrow), which is often seen in schizencephaly.

C. Kim et al. Cystic dilatation of the fourth ventricle with complete or partial agenesis of the cerebellar vermis found without posterior fossa enlargement is known as Dandy-Walker variant.49,51,52 MRI is the imaging of choice for Dandy-Walker malformation, though prenatal ultrasound can make the diagnosis as early as 14 weeks of gestation. Dandy-Walker malformation is thought to result from arrested regression of the anterior membranous area. Because of cerebrospinal fluid pulsations, the anterior membranous area balloons into a fourth ventricular cyst and superiorly displaces the tentorium, torcula, and cerebellar vermis, which is dysplastic. This results in torcularlambdoid inversion. The cystic fourth ventricle may extend through openings of the tentorium between the occipital lobes. The pia mater lining the cerebellum limits the lateral extension of the fourth ventricle. Together, these findings produce a keyhole appearance of the fourth ventricle on axial imaging.

ventricle into the anterior membranous area superiorly and the posterior membranous area inferiorly. Neuroblasts proliferate and thicken along the lateral margins of the anterior membranous area to become the rhombic lips at 4-6 weeks of gestation. Eventually, the rhombic lips converge at the midline and fuse, becoming the cerebellar vermis and cerebellum. This process is in contrast to formation of the supratentorial brain, where the telencephalon cleaves at the midline to form the cerebral hemispheres.49,50 As the rhombic lips develop into the cerebellum, the anterior membranous area regresses and is incorporated into the choroid plexus. The posterior membranous area also diminishes and becomes a transient protrusion at the caudal aspect of the fourth ventricle. This protrusion is called the Blake pouch. Eventually, openings in the Blake pouch form and communicate with the cisterna magna as the foramen of Magendie and foramina Luschka, likely around the fourth month of gestation.49-51

Posterior Fossa Malformations The posterior fossa malformations included in this review are Dandy-Walker malformation, Dandy-Walker variant, persistent Blake pouch, mega cisterna magna, arachnoid cyst, Joubert syndrome, and rhombencephalosynapsis.

Dandy-Walker Malformation The classic triad of findings in Dandy-Walker malformation consists of the following: (1) Complete or partial agenesis of the cerebellar vermis, (2) Cystic dilatation of the fourth ventricle, and (3) Enlarged posterior fossa with upward displacement of the tentorium, torcula, and transverse sinuses.

Figure 22 A 10-month-old male infant with schizencephaly. (A) Axial T2 image of the brain demonstrates a cleft lined with dysplastic cerebral cortex extending from the surface of the right frontal lobe to the underlying right lateral ventricle. (B) Sagittal T1 image of the right frontal lobe again shows findings of schizencephaly. The thickened cortex and indistinct gray-white junction (polymicrogyria) (arrows) lining the cleft can be seen more clearly on T1-weighted images.

Congenital brain malformations in the neonatal and early infancy period The fourth ventricular cyst is lined by ependyma, neuroglia, and leptomeninges, though the walls may not always be apparent in entirety on imaging. Although the foramina of Luschka are patent, the foramen of Magendie may never develop, which could contribute to hydrocephalus. Increased distention of the fourth ventricle may prevent the migration of the straight sinus from the cranial vertex to the lambda, causing an enlarged posterior fossa. The falx cerebelli is usually absent.49,51,52 Vermian hypoplasia is more common in Dandy-Walker malformation than in agenesis. When the large fourth ventricular cyst superiorly displaces the cerebellar vermis, the vermis appears to have rotated in a counterclockwise position (Fig. 23). Dilatation of the fourth ventricle also splays the cerebellar hemispheres laterally. The cerebellar hemispheres and pons are hypoplastic. There is absence of the superior cerebellar peduncle decussation, giving the midbrain a butterfly appearance on axial images. More recently, an alternative

115 hypothesis has challenged the current concept of cerebellar development and proposed that the pathogenesis of DandyWalker malformation may be due to secondary degeneration or regression of the cerebellum at midline.18,49-52 Increased pressure from dilatation of the fourth ventricle and cerebrospinal fluid pulsation cause bony changes in Dandy-Walker malformation. There is scalloping of the occipital bone and petrous ridges. The occiput is enlarged. If sufficient pressure is present, diastases of the lambdoid sutures may develop.49,50 Dandy-Walker malformation is typically an isolated finding. However, several other brain malformations may also be present, mostly commonly brainstem dysplasia and dysgenesis of the corpus callosum. In addition, Dandy-Walker malformation can occur in a variety of other syndromes and chromosomal abnormalities.49,50 Clinical findings relate to hydrocephalus, cerebellar and cranial nerve dysfunction, and associated brain malformations. Treating Dandy-Walker malformation primarily involves management of hydrocephalus and the posterior fossa cyst. Patients often undergo shunting or cyst fenestration. Shunting has greatly reduced the mortality rates of Dandy-Walker malformations. The degree of cognitive impairment depends on other associated brain anomalies and on adequate and early management of hydrocephalus.49,52,53

Dandy-Walker Variant Dandy-Walker malformation and Dandy-Walker variant belong on a continuous spectrum. In Dandy-Walker variant, the fourth ventricular cyst does not dilate enough to enlarge the posterior fossa, though hypoplasia and counterclockwise rotation of the cerebellar vermis are still present. Rotation of the cerebellar vermis distinguishes Dandy-Walker malformation from other cystic malformations, such as mega cisterna magna. Hydrocephalus typically does not occur in DandyWalker variant unless caused by another concurrent malformation (Fig. 24).49,51

Persistent Blake Pouch When the foramen of Magendie fails to develop, the normally transient Blake pouch endures as an extension of the inferior aspect of the fourth ventricle. Persistent Blake pouch appears as a cystic collection of cerebrospinal fluid inferior and posterior to the cerebellum and can be associated with hydrocephalus. In some cases, the fourth ventricle and posterior fossa may also enlarge, and the brainstem may be compressed. Because the cerebellar vermis is normal in development and position, persistent Blake's pouch is a separate entity from the DandyWalker spectrum. The cerebellum is also typically normal. The pouch is lined by ependyma and choroid plexus is along the superior wall. Persistent Blake pouch is usually an isolated finding.49,51,54 Figure 23 A 30-day-old male infant with Dandy-Walker malformation. (A) Axial T2 image shows a large posterior fossa cyst (#) directly communicating with the fourth ventricle (n). (B) Sagittal T1 image showing the cyst (#) lifting the hypoplastic cerebellar vermis (nn) and torcula (þ).

Mega Cisterna Magna and Arachnoid Cyst The cisterna magna is the extracerebral cerebrospinal fluid space caudal to the cerebellum and posterior to the medulla.

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The differential diagnosis of mega cisterna magna includes posterior fossa arachnoid cyst. Arachnoid cysts are cerebrospinal fluid collections that may or may not communicate with the subarachnoid space. They result from separation of the inner and outer leaflets of the arachnoid lining. Cysts may vary in size over time from a ball valve mechanism, fluid secretion into the cyst, or osmosis. Unlike mega cisterna magna, arachnoid cysts may distort the adjacent brain parenchyma or cause hydrocephalus. Other diagnoses to consider when evaluating arachnoid cysts are persistent Blake pouch and epidermoid cyst. A normal fourth ventricle helps differentiate an arachnoid cyst from a persistent Blake pouch. If the lesion in question demonstrates restricted diffusion on diffusion-weighted MRI, the lesion is an epidermoid cyst. Cisternography is currently the only definitive way to diagnose arachnoid cysts, which demonstrate delayed or absent enhancement. Arachnoid cysts are typically incidental findings and asymptomatic. Symptomatic arachnoid cysts may be treated surgically.49,51

Joubert Syndrome The diagnostic criteria for Joubert syndrome include the following: – – – –

Figure 24 A 4-day-old female infant with Dandy-Walker variant. (A) Axial T2 image shows a small cerebellar vermis (nn) and prominent extracerebral cerebrospinal fluid space in the dorsal and caudal posterior fossa. (B) Sagittal T1 image of the same patient again demonstrates a prominent posterior fossa cerebrospinal fluid space communicating with the fourth ventricle (#), which is partially covered by a hypoplastic cerebellar vermis (nn), consistent with Dandy-Walker variant.

The superior aspect of the fourth ventricle communicates with the cisterna magna via the foramen of Magendie; the inferior aspect communicates via the perimedullary subarachnoid spaces. Mega cisterna magna occurs when the cisterna magna is enlarged, but there is no abnormality of the cerebellar vermis or hydrocephalus. However, debate exists concerning the normal size limits of the cisterna magna. Because there is no obstruction of cerebrospinal fluid flow, hydrocephalus is absent and patients are asymptomatic. Therefore, mega cisterna magna is an incidental finding on imaging, and surgical shunting is not indicated. If hydrocephalus is present without other explanation, the diagnosis favors persistent Blake pouch rather than mega cisterna magna.49,51

Hypoplasia of the cerebellar vermis Hypotonia Developmental delay Abnormal breathing or abnormal eye movements

Joubert syndrome consists of a constellation of posterior fossa malformations caused by an autosomal recessive mutation.49,55 On imaging, the cerebellar vermis is absent or hypoplastic. Therefore, the fourth ventricle communicates with the cisterna magna via a midline cleft, which results in a batwing or umbrella appearance of the fourth ventricle on axial and coronal images. The superior cerebellar peduncles are thickened, elongated, and oriented nearly perpendicularly to the brainstem. There is deepening of the interpeduncular fossa. The cerebellar cortex is thin with loss of Purkinje cells and heterotopia of Purkinje-like neurons. The cortical medullary nuclei and tracts are dysplastic with absence of the normal superior cerebellar peduncular, central pontine, and corticospinal tract decussations, which can be confirmed on tractography (Fig. 25). Without the contours of the pyramids and olives, the medulla appears small. The cerebellar hemispheres are dysplastic and separated with fragmentation of the dentate nuclei. Although the fourth ventricle is moderately enlarged, hydrocephalus is not typically present. When combined, these findings result in the classic “molar tooth sign” present in 85% of patients with Joubert syndrome on axial images. It should be noted that the “molar tooth sign” may be present in other entities, including Arima syndrome, Senior-Loken syndrome, and COACH syndrome, which collectively constitute a group of pathologies called cerebellar-ocular-renal syndromes.49,55-57 Clinically, patients present with varying degrees of hypotonia, ataxia, respiratory abnormalities, psychomotor retardation, and oculomotor apraxia or nystagmus. The

Congenital brain malformations in the neonatal and early infancy period

117 nuclei and superior cerebellar peduncles. Developmental disruption is thought to occur at 28-41 days of gestation, although the pathogenesis is debated. Unlike Joubert syndrome where a large midline cleft between the fourth ventricle and cisterna magna forms, the cerebellar folia and fissures transverse continuously across midline. If the cerebellar hemispheres are asymmetric, the folia and fissures may cross at an angle. The anterior cerebellar vermis is absent and the posterior vermis is hypoplastic or absent. The fused dentate nuclei appear in a horseshoe configuration. There is a variable amount of fusion of other posterior fossa structures, including the middle cerebellar peduncles, superior and inferior colliculi, and cerebellar tonsils. The fourth ventricle may vary in size but typically has a keyhole configuration and points posteriorly. The posterior fossa is small (Fig. 26).49,58 Rhombencephalosynapsis is often seen in conjunction with supratentorial and midline abnormalities. There may be fusion

Figure 25 A 31-day-old female infant with Joubert syndrome. (A) Axial T2 image showing a molar tooth configuration of the brainstem. (B) Eigenvector color maps demonstrate the absence of the cerebellar peduncle decussation (arrow). Normally, efferent fiber bundles extend from the deep cerebellar nuclei, course along the dorsal pons and dorsolateral wall of the fourth ventricle, cross at the level of the inferior colliculus, and terminate in the red nuclei or thalamus. (Color version of figure is available online.)

severity of posterior fossa abnormality seen on imaging does not predict the amount of neuropsychological dysfunction. In general, prognosis is poor. Most patients die of prolonged apnea and sudden infant death syndrome by 3 years of age. Surviving patients have severe global developmental delay.49,55 A number of disorders inclusive of Joubert syndrome and other findings exist and are classified as subtypes of Joubert syndrome and related disorders.49,55

Rhombencephalosynapsis Rhombencephalosynapsis is characterized by complete or partial fusion of the cerebellar hemispheres, hypogenesis or agenesis of the cerebellar vermis, and fusion of the dentate

Figure 26 A 16-month-old male infant with rhombencephalosynapsis. (A) Axial T2 image shows fused cerebellar hemispheres with folia and fissures traversing midline (arrow). The cerebellar vermis is absent, and the posterior fossa is small. (B) Coronal T2 image of the same patient again demonstrates findings of rhombencephalosynapsis.

118 of the thalami, cerebral peduncles, and fornices. The temporal lobes, particularly the hippocampi, may be hypoplastic. The septum pellucidum, corpus callosum, and anterior commissure may be absent or hypoplastic. Abnormalities of the ventricular system include aqueductal stenosis with hydrocephalus, holoprosencephaly, and absence of the ventricles. Extracranial anomalies include midline face malformations, musculoskeletal abnormalities of the spine, phalanges, and radii, and rarely cardiovascular, genitourinary, and respiratory system defects.49,58 Isolated rhombencephalosynapsis may be an incidental finding on imaging or because of mild ataxia. Most patients with rhombencephalosynapsis exhibit symptoms related to other brain malformations associated with rhombencephalosynapsis. The prognosis of these patients is poor. Few survive infancy or childhood to become adults. Most patients present with ataxia or gait abnormalities with variable developmental delay. Symptoms from supratentorial anomalies are also common, including seizures and psychiatric abnormalities. MRI is important to help differentiate rhombencephalosynapsis from other disorders, such as the Dandy-Walker continuum, Joubert syndrome, tectocerebellar dysplasia, and cerebellar dysplasia of lissencephaly. Management includes treating hydrocephalus, seizures, and derangements of the hypothalamic-pituitary axis. Rhombencephalosynapsis is usually sporadic, but it also demonstrates an autosomal recessive pattern of inheritance.49,58,59

Conclusion Congenital brain malformations are a prevalent and diverse group of disorders that can cause significant morbidity and mortality. The complexity of congenital brain malformations stems from the intricate embryogenesis of the central nervous system. Therefore, having an understanding of brain development helps to recognize specific constellations of structural abnormalities on imaging, which contributes to establishing accurate diagnoses and directing management. In addition, as imaging modalities evolve, new concepts about the pathogenesis, presentation, and treatment emerge. Acquiring greater insights to the imaging findings can significantly affect the outcome of patients with congenital brain malformations.

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