Congenital Brain Malformations

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Chapter 31

Congenital Brain Malformations

With advances in magnetic resonance imaging (MRI) and molecular biology and the availability of mutant mouse models of human cortical malformations, many malformations of brain development have been reclassified.1–3 Given the large number of congenital human brain malformations, the complexity of the molecular genetics, and the degree of anatomic variability, an in-depth discussion of some malformations is beyond the scope of this chapter. This chapter addresses malformations seen most often in clinical practice and those malformations that are less common but are distinctive and have a profound impact of early childhood development. The malformations presented here are grouped according to presumed dominant defect in embryologic or fetal development. Diffusion tensor imaging (DTI) is included in the diagnosis of malformations in which aberrant white matter tracts are a dominant feature.

A rudimentary description of relevant embryology is needed. Around 26 to 28 days after conception, the process of neurulation, in which the lateral edges of the neural plate elevate into neural folds, takes place.1 The folds then fuse medially to form the neural tube. At the cranial end of the neural tube, the primitive brain vesicles form and include the prosencephalon, mesencephalon, and rhombencephalon.1,2,4 The prosencephalon divides into the telencephalon, which gives rise to the cerebral hemispheres and the corpus striatum, and the diencephalon, which gives rise to the thalami and the hypothalamus. The cerebral peduncles and midbrain arise from the mesenchephalon. The rhombencephalon gives rise to the metencephalon, which forms the pons and cerebellum, and the myelencephalon, from which the medulla arises. Malformations of brain development may result from chromosomal aberrations, single gene mutations, teratogenic infections and agents, or ischemia.1,3 However, in 70% of malformations, the etiology is identifiable.

Defects of Neurulation


Complete failure of closure of the cranial end of the neuropore results in anencephaly, in which the forebrain, skull, and scalp are absent. Affected patients die soon after birth and postnatal imaging is not usually indicated. Less severe disorders of neural tube closure result in meningoceles and encephaloceles, which are protrusions of the meninges or brain, respectively, through a congenital defect of the skull and dura; the latter occurs in about 1 per 5000 live births.4 Encephaloceles tend to be midline. In the countries of the Western hemisphere, a predominance of posterior cephaloceles is seen, whereas in Asian children, encephaloceles tend to be anterior.1 Frontal encephaloceles include interorbital frontal, nasofrontal, nasoethmoidal, and naso-orbital lesions. Interorbital frontal encephaloceles protrude through a defect in frontal bone (Fig. 31-1). Nasofrontal encephaloceles involve the region of nasal bridge, the floor of the anterior cranial fossa, or both (Fig. 31-2). Nasofrontal encephaloceles are also referred to as nasal gliomas, although they are not neoplastic. These masses of neuroglial tissue are categorized as extranasal (60%), intranasal (30%), or mixed (10%).1,2,4 When telangiectasias occur on the skin overlaying an external nasal glioma, the lesion may be mistaken for a hemangioma. Often, hypertelorism is present with a broad nasal bridge. Intranasal glioma presents as an intranasal mass; biopsy should be avoided prior to imaging because of the risk of meningitis. With nasoethmoidal encephaloceles, frontal bone is intact. Neural tissue bulges into the ethmoid sinus through a defect in the floor of the anterior cranial fossa, and the nasal septum defines the posterior margin. A defect in the medial orbital wall results in a naso-orbital encephalocele, which protrudes into the orbit and produces unilateral exophthalmos. Other facial anomalies seen with anterior encephaloceles include a bifid nasal tip or complete midline splitting of the nose in an uncommon malformation known as frontonasal dysplasia (e-Fig. 31-3). Morning Glory syndrome includes midline facial defects, callosal agenesis, frontal encephaloceles, and characteristic eye anomalies.

Basal encephaloceles result from defects in the sphenoid bone (Fig. 31-4); the encephalocele herniates into the posterior nasopharynx anterior to the dorsum sella and may contain pituitary tissue, optic nerves, branches of the circle of Willis, or all (Fig. 31-5). Encephaloceles in the parietal bone range from large deforming “towering” lesions to small meningoceles (Fig. 31-6). Atretic encephaloceles or meningoceles present as small subcutaneous fibrofatty masses, which are often painful to palpation (Fig. 31-7). Occipital encephaloceles usually contain dysplastic cerebellar tissue alone or with the cerebral cortex (Fig. 31-8). Rarely, the brainstem may be within the encephalocele; this malformation is lethal.

Conditions and syndromes associated with encephaloceles include trisomy 13 and 18, amniotic band syndrome, Meckel-Gruber syndrome, dyssegmental dwarfism, Knobloch syndrome, Walker-Warburg (type II lissencephaly) syndrome, cryptophthalmos, and Voss syndrome. The prognosis depends on the severity of associated brain anomalies and the amount of dysplastic brain contained within the encephalocele.1,2,4

Imaging: High-resolution MRI is performed soon after birth to define contents of the encephalocele, the severity of the malformation, and the frequent associated anomalies. These include callosal agenesis, anomalies of cortical formation, and variable anomalies of the cerebellum, diencephalon, and brainstem. Although dysplastic nonfunctional neural tissue is usually resected during closure of the encephalocele, major dural venous sinuses are preserved. Therefore, magnetic resonance venography is essential for diagnosing large occipital and midline parietal encephaloceles that may contain dural venous sinuses. Basal encephaloceles containing optic chiasm or nerves or pituitary tissue cannot be closed without sacrificing these structures. Affected patients are at risk for meningitis and cerebrospinal fluid (CSF) leakage into the nasophayrnx. The typical intracranial manifestations of atretic parietal encephaloceles include posterior tenting of the tectal plate, a persistent falcine sinus with or without atresia of the straight sinus, and expansion of posterior interhemispheric CSF. Hydrocephalus is common after closure of large parietal and occipital encephaloceles.

Chiari II Malformations

Clinical Presentation: Chiari II malformations are the intracranial manifestations of posterior dysraphic defects such as myelomeningoceles. Neural tube defects have been reported with multiple chromosomal abnormalities, including trisomies 18, 13, and 9; triploidy; unbalanced translocations and deletions; and in Turner, DiGeorge, and velocardiofacial syndromes. The genes in the region of 22q11 have been implicated in the development of neural tube defects, although neural tube defects and the associated Chiari II malformation are probably caused by a combination of genetic polymorphisms and environmental factors, including dietary folate intake and maternal folate metabolism.5

The most commonly accepted unifying theory for the Chiari II malformation suggests that the failure of neural tube closure prevents the transient closure of the central canal, which is essential for the distension of the primitive ventricular system;6 this results in the premature fusion of the mesenchymal components that form the calvarium, whereas the hindbrain manifestations result from leakage of CSF through the neural tube defect. The Chiari II malformation is associated with a wide range of brain malformations;1,2,7,8 DTI shows disordered axonal migration, suggesting that the malformation is not explained by mechanical alterations caused by faulty CSF dynamics alone.8 The Chiari II malformation is characterized by mesodermal dysplasia, small and dysplastic lower cranial nerve ganglia, deficient tentorium cerebelli, hypoplastic and dysmorphic cerebellum, and thickened basal meninges.6 As in holoprosencephaly (HPE), these anomalies are attributable to a defective or deficient mesenchyme, which presumably deprives the skull base, hindbrain, and rhombencephalon of normal inductive effects.7 Clinical problems related specifically to the malformed hindbrain include apnea, aspiration, feeding difficulties, and recurrent respiratory infections.

Imaging: The calvarial manifestations of the Chiari II malformation include a bifid frontal bone and luckenschadel, or lacunar, skull. The latter is a manifestation of the mesodermal dysplasia of the membranous skull and is caused by nonossified fibrous bone in the inner and outer tables of the skull, resulting in the apparent cranial scalloping (Fig. 31-9); the affected cranium ossifies and appears normal by 6 months of age. Luckenschadel is not the result of increased intracranial pressure and is not synonymous with “the beaten copper skull.”

The intracranial stigmata of the Chiari II malformation are complex and variable; the hallmarks of the malformation are infratentorial. In the most severe forms, the foramen magnum is enlarged and the posterior cranial fossa is constricted, with effacement of CSF spaces; the cerebellum wraps around the ventral aspect of the brainstem (see Fig. 31-9), and the clivus and petrous ridges are concave. MRI shows caudal displacement of a dysplastic brainstem and a hypoplastic cerebellum into the upper cervical canal with “kinking” of the cervicomedullary brainstem (Fig. 31-10). The fourth ventricle is effaced and caudally displaced. The torcula and transverse sinuses are low lying, which presents a potential surgical hazard during decompressive suboccipital craniectomy, which may be performed for relief of symptomatic hindbrain compression. A “beaked” tectal plate is present, and a variably thickened massa intermedia may be so thick that the thalami appear virtually fused with partial atresia of the third ventricle.1,7 Common supratentorial abnormities include callosal dysgenesis, neuronal migration anomalies, and hydrocephalus. After ventricular shunt placement, the cerebral hemispheres drop away from the inner table of the skull, allowing interdigitations of the cortex across the midline under the hypoplastic falx and projection of the superior cerebellar vermis superiorly across a widened tentorial incisura. These findings are nonspecific manifestations seen after CSF diversion of severe congenital obstructive hydrocephalus. DTI of Chiari II malformations associated with more severe degrees of cerebellar hypoplasia shows absence of the dorsal transverse fibers at the level of the pons with preservation of the corticospinal tracts and mediolateral lemniscus fibers (Fig. 31-11). The cingulum may be anomalous, crossing the midline above the corpus callosum (Fig. 31-12). These alterations in axonal migration evident by DTI are difficult to appreciate with conventional MRI.

Chari III malformations are high cervical or low occipital encephaloceles.9 The term Chiari IV malformation describes severe cerebellar hypoplasia in association with a neural tube defect. A better description of affected patients would be Chiari II malformation with cerebellar hypoplasia or aplasia (e-Fig. 31-13). Defects of neurulation have also been reported to coexist in patients with HPE; the latter malformation is considered a disorder of differentiation of the dorsal neural plate.10,11 The coexistence of these malformations, traditionally considered disparate in embryologic timing and insult, may be explained, in part, by mutations in genes implicated in both developmental pathways.12,13

Disorders of Differentiation of Dorsal Neural Plate


Clinical Presentation: HPE is the most common anomaly affecting the ventral forebrain, resulting from a primary defect in patterning and induction of the basal forebrain expressed around the fifth to sixth week of gestation, and occurs in 1 in 250 embryos and 1 in 8300 to 16,000 live births.1,13,14 HPE is thought to be caused by a deficient or defective prechordal mesoderm, with failure of induction or abnormal fusion of normally paired and separate neo-cortex, caudates, and claustrum. The consequences of the inductive failure of the median and paramedian structures are most pronounced in the ventral forebrain and decline in severity from rostral to caudal and from medial to lateral. HPE is caused by a combination of genetic polymorphisms and environmental factors; the incidence of HPE is increased 200-fold in maternal diabetes mellitus. HPE is notable for its genetic heterogeneity. Mutations in single genes result in syndromic forms of HPE, triploidies of entire chromosomes (e.g., 13 and 18), deletions or duplications of regions of a chromosome, and copy number variants. At least 12 HPE loci that play some role in the midline of the developing nervous system have been identified, including Shh, Otx2, Emx, Pax, Nkx-2.2, and some POU domain genes.13 Although 24% to 45% of affected live-born individuals have chromosomal abnormalities, no known correlation exists between the type or severity of the holoprosencephalic defect and the specific mutation. In addition to controlling prosencephalic separation and differentiation, the inductive effects of the prechordal mesoderm also influence the corpus striatum, thalami, eyes, face, and cerebral vasculature.13 The spectrum of associated facial anomalies range from flattening of the nasal bridge, hypotelorism without metopic synostosis, a single central maxillary incisor, cleft lip or palate to facial clefting, and cyclopia with a central proboscis.15 More severe facial anomalies are seen with more severe variants of HPE, but mild facial anomalies may occur in the absence of brain anomalies. Clinical problems associated with HPE include developmental delay, seizures, hypothalamic and brainstem dysfunction with swallowing and respiratory problems, thermal instability, pituitary dysfunction, and erratic sleeping patterns.13,15

Imaging: The hallmark of HPE is incomplete separation of the forebrain, absence of the anterior interhemispheric falx, and fusion of central gray nuclei. The septum pellucidum is absent. Considerable topographic variation exists in HPE, which is most often characterized as alobar, semilobar, or lobar.13–19 The malformation represents a continuum, ranging from overt hypotelorism, with severe facial anomalies, to mild hypotelorism, with subtle fusion of basal forebrain and central gray nuclei. Hydrocephalus may be present.

Semilobar Holoprosencephaly

Relative preservation of the lateral and posterior cerebrum and the splenium exists in semilobar HPE. The posterior interhemispheric fissure and falx are present, whereas the hypoplastic frontal lobe is undivided. (Fig. 31-15).1,13,16 Lack of formation of the frontal lobes results in an anterior position of the Sylvian fissures, termed a “wide Sylvian angle” by Barkovich et al.17 The globus pallidi are absent or hypoplastic, and the caudate nuclei are fused, resulting in obliteration of or lack of formation of the septal region. The posterior limbs of the internal capsules are ventral to partially or totally fused thalami. The hippocampus is virtually always present, although usually incompletely or abnormally developed. A dorsal cyst may be present (e-Fig. 31-16).

Syntelencephaly (Middle Frontal Variant)

The middle frontal variant is an unusual variant of lobar HPE characterized by separation of the frontal and occipital poles, fusion of the middle portions of the cerebral hemispheres (Fig. 31-18), preservation of portions of the commissural fibers of the corpus callosum, and neuronal migration anomalies; thalamic fusion is variable.18,19

Septo-optic Dysplasia

Clinical Presentation: Septo-optic dysplasia (SOD) is considered along the continuum of disorders of ventral forebrain differentiation.20 Patients typically present in early childhood with nystagmus, optic nerve atrophy, short stature because of growth hormone deficiency, or panhypopituitarism without diabetes insipidus. Affected patients are at risk for Addisonion crisis from subclinical adrenal insufficiency, which may become clinically apparent only during illness or severe stress. Most cases of isolated SOD are sporadic.

Imaging: SOD is characterized by absence of the septum pellucidum and variable optic nerve hypoplasia (e-Fig. 31-19). The neurohypophysis is often ectopic or may be absent, in which case the pituitary stalk may be interrupted. However, agenesis of the septum pellucidum may be isolated with normal optic pathways and intact neuroendocrine function. Absence of the septal leaves results in downward displacement of the fornices into the third ventricle. SOD is associated with multiple malformations, such as schizencephaly, neuronal migration anomalies, and neural tube defects.

Callosal Agenesis or Dysgenesis

Complete or partial malformation of the corpus callosum has an incidence of 1 in 4000.21 Normal corpus callosal development requires a precise sequence of cellular proliferation and migration, axonal growth and guidance, and midline glial development and patterning. Disruptions in this sequence may result from gene mutations, genetic polymorphisms, intrauterine infections, ischemia, and toxins.21

The telencephalic commissures normally develop in a predictable sequence.1,21 The anterior commissure (AC) forms around 55 days after conception, arising from the primitive hippocampal formations and ultimately connecting the anterior temporal lobes. Approximately 3 weeks later, the initial interhemispheric migration of pioneering callosal axons occurs, aided by the “glial sling,” which consists of primitive subependymal glial cells. The “glial wedge” is composed of radial glial cells that guide callosal axons across the midline and then repel the axons away from the midline into the contralateral hemisphere.1,21 After crossing the midline, callosal axons grow into the contralateral hemisphere; their ultimate destination mirror-images their region of origin and is within the same cortical layer from which the axon arose.21,22 The crossing axons follow a rostrocaudal gradient with the callosal rostrum forming before the splenium; formation of the splenium is complete by around 85 days after conception. Many of the crossing axons undergo programmed cell death after reaching their final destination; this apoptosis commences during the second trimester, with pruning of axonal axons continuing after birth.1,22