Selected References

Cotes C et al: Congenital basis of posterior fossa anomalies. Neuroradiol J. 28(3):238-53, 2015

Chiari Malformations

Chiari 1

Abu-Arafeh I et al: Headache, Chiari malformation type 1 and treatment options. Arch Dis Child. 102(3):210-211, 2017

Alperin N et al: Magnetic resonance imaging-based measures predictive of short-term surgical outcome in patients with Chiari malformation type I: a pilot study. J Neurosurg Spine. 26(1):28-38, 2017

Wang J et al: Acquired Chiari malformation and syringomyelia secondary to space-occupying lesions: a systematic review. World Neurosurg. 98:800-808.e2, 2017

Poretti A et al: Chiari type 1 deformity in children: pathogenetic, clinical, neuroimaging, and management aspects. Neuropediatrics. 47(5):293-307, 2016

Chiari Variants

Moore HE et al: Magnetic resonance imaging features of complex Chiari malformation variant of Chiari 1 malformation. Pediatr Radiol. 44(11):1403-11, 2014

Hindbrain Malformations

Cystic Posterior Fossa Anomalies and the Dandy-Walker Continuum

Abdel Razek AA et al: Magnetic resonance imaging of malformations of midbrain-hindbrain. J Comput Assist Tomogr. 40(1):14-25, 2016

Boltshauser E et al: Cerebellar cysts in children: a pattern recognition approach. Cerebellum. 14(3):308-16, 2015

Nelson MD Jr et al: A different approach to cysts of the posterior fossa. Pediatr Radiol. 34(9):720-32, 2004

Miscellaneous Malformations

Poretti A et al: Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause. J Med Genet. ePub, 2017

Abdel Razek AA et al: Magnetic resonance imaging of malformations of midbrain-hindbrain. J Comput Assist Tomogr. 40(1):14-25, 2016

Poretti A et al: Cerebellar and brainstem malformations. Neuroimaging Clin N Am. 26(3):341-57, 2016

Poretti A et al: Preand postnatal neuroimaging of congenital cerebellar abnormalities. Cerebellum. 15(1):5-9, 2016

Poretti A et al: Prenatal cerebellar disruptions: neuroimaging spectrum of findings in correlation with likely mechanisms and etiologies of injury. Neuroimaging Clin N Am. 26(3):359-72, 2016

Poretti A et al: The pediatric cerebellum. Neuroimaging Clin N Am. 26(3):xiii-xiv, 2016

Poretti A et al: Fetal diagnosis of rhombencephalosynapsis. Neuropediatrics. 46(6):357-8, 2015

Poretti A et al: Cerebellar hypoplasia: differential diagnosis and diagnostic approach. Am J Med Genet C Semin Med Genet. 166(2):211-26, 2014

Corpus callosum dysgenesis and malformations of cortical development (MCDs) are two of the most important congenital brain anomalies. Anomalies of the cerebral commissures are the most common of all congenital brain malformations, and corpus callosum dysgenesis is the single most common malformation that accompanies other developmental brain anomalies.

Although they affect very different parts of the forebrain, commissural and cortical malformations share a very important feature: they arise when migrating precursor cells fail to reach their target destinations.

We begin this chapter with a brief consideration of normal development and anatomy of the cerebral commissures, then focus on callosal dysgenesis as the most important anomaly that affects these white matter tracts.

We devote the second half of the chapter to MCDs, which are intrinsically epileptogenic and may be responsible for 25-40% of all medically refractory childhood epilepsies. Prior to the development of high-resolution MR techniques, many complex partial epilepsies were considered cryptogenic. Their imaging detection, localization, and characterization have become increasingly important in patient management.

Normal Development and

Anatomy of the Cerebral

Commissures

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(37-1) Graphic shows anterior commissure and corpus callosum segments: rostrum , genu , body , isthmus , and splenium .

(37-2) Sagittal graphic shows white matter tracts of corona radiata converging to form corpus callosum.

crossing and normal development of white-matter projections throughout the human CNS.

The AC is the first forebrain commissure to develop (eighth fetal week). The hippocampal commissure (HC) forms posteriorly around week 11 and is followed by axons that eventually become the posterior body and splenium of the CC.

The CC forms in two separate segments. Between 13 and 14 fetal weeks, anterior axons cross a guiding structure called the glial sling, while others follow the HC posteriorly. The genu, rostrum, and body appear in rapid succession; the splenium does not form until 18-19 weeks. Fiber bundles in the anterior and posterior callosum eventually unite to form a single continuous structure, the definitive corpus callosum.

At birth, the CC is very thin and relatively flat in gross appearance. It continues to grow for several postnatal months. As myelination proceeds, the genu and splenium thicken noticeably. Both the length and thickness of the CC also increase. By 10 months of age, the overall appearance resembles that of a normal adult.

Normal Gross and Imaging Anatomy

Corpus Callosum

The CC is the largest and most important of the forebrain commissures. It is composed of five parts. From front to back, these are the rostrum, genu, body, isthmus, and splenium. The rostrum is the smallest segment and connects the orbital surfaces of the frontal lobes. A prominent anterior "knee"—the genu—connects the lateral and medial frontal lobes (37-1). White matter fibers curve anterolaterally from the genu into the frontal lobes as the forceps minor.

The longest CC segment is the body (also called the truncus or trunk). Its fibers pass laterally and intersect with projection fibers of the corona radiata. The body connects broad regions of each hemispheric cortex together and forms a red X on axial DTI scans (37-3).

The isthmus is a shorter, slightly narrower area that lies between the posterior body and splenium. The isthmus connects the preand postcentral gyri and auditory cortex with their counterparts in the contralateral hemisphere. The splenium is the expanded, rounded termination of the CC. Most of its fibers curve posterolaterally into the occipital lobes (37-2) as the forceps major.

Sagittal T1 and T2 scans demonstrate the rostrum as a thin WM tract that curves posteroinferiorly from the genu. The dorsal CC surface is typically not straight but has a slightly "wavy" appearance with a distinct posterior narrowing—the isthmus—just before the CC widens again into the splenium

(37-4).

Coronal scans show the CC curving from side to side across the midline. Anteriorly, the genu is seen as a continuous band of WM connecting the frontal lobes. More posteriorly, the CC lies above the fornices. Bands of WM fibers fan outward from the splenium into the forceps major.

Anterior Commissure

(37-3) DTI shows normal red X-shaped corpus callosum formed by the genu with forceps minor, body , splenium with forceps major.

The AC is a transversely oriented bundle of compact, heavily myelinated fibers that crosses the midline anterior to the fornix. It is much smaller than the CC but is a crucial anatomic landmark for stereotactic neurosurgery.

The AC lies in the anterior wall of the third ventricle (37-5). From the midline, it curves laterally in the basal forebrain and splits into two fascicles.

The smaller more anterior bundle courses toward the orbitofrontal cortex and olfactory tract. The much larger posterior bundle splays out into the temporal lobe. The AC connects the anterior parts of the temporal lobes (37-6) and lies anterosuperior to the temporal horn of the lateral ventricle.

On sagittal T1 scans, the AC is seen as a hyperintense ovoid structure lying midway up the anterior wall of the third ventricle. On axial T2 scans, the AC can be identified as a compact well-defined hypointense band of tissue lying just in front of the third ventricle. As it courses laterally, both sides of the AC curve slightly anteriorly to resemble an archer's bow on axial MR scans.

Hippocampal Commissure

The HC is the smallest of the three major commissures. It is a transversely oriented fiber bundle that crosses the midline in the posterior pineal lamina.

In contrast to the CC and AC, the HC is less easily distinguished on MR scans. In the midline sagittal plane, its myelinated fibers blend imperceptibly with those of the inferomedial WM in the CC splenium. On coronal scans through the lateral ventricle atria, the HC can be seen lying below the CC, where its fibers blend in with those of the fornices.

Commissural Anomalies

Any one of or combination of the three forebrain commissures can be affected by developmental failures. Recognizing the surprisingly broad spectrum of commissural malformations and delineating any associated abnormalities is essential for accurate and complete diagnosis.

We now discuss corpus callosum malformations together with some representative syndromes and associated lesions.

Callosal Dysgenesis Spectrum

Terminology

The corpus callosum (CC) can be completely absent (agenesis) (37-7) (37-8) or partially formed (hypogenesis). Complete CC agenesis is almost always accompanied by the absence of the hippocampal commissure (HC). The anterior commissure (AC), which forms 3 weeks earlier than the CC, is usually present and normal. If the CC is hypogenetic, the posterior segments and the inferior genu and rostrum are usually absent.

Pathology

In complete CC agenesis, all five segments are missing. The cingulate gyrus is absent on sagittal sections, whereas the hemispheres demonstrate a radiating "spoke-wheel" gyral pattern extending perpendicularly to the roof of the third ventricle (37-9).

On coronal sections, the "high-riding" third ventricle looks as if it opens directly into the interhemispheric fissure. It is actually covered by a thin membranous roof that bulges into the interhemispheric fissure, displacing the fornices laterally. The lateral ventricles have upturned, pointed corners

(37-8).

A prominent longitudinal WM tract called the Probst bundle is situated just inside the apex of each ventricle (37-7). These bundles consist of the misdirected commissural fibers, which should have crossed the midline but instead course from front to back, indenting the medial walls of the lateral ventricles.

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(37-4) Sagittal T2WI shows anterior commissure (AC) , rostrum , genu , body , isthmus, and splenium of CC.

(37-5) Axial T2WI shows the compact, hypointense, bow-shaped AC passing in front of the third ventricle .

(37-6) Coronal T2WI shows the AC , third ventricle , and body of the corpus callosum .

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(37-7) Agenesis of CC (ACC) shows "Viking helmet," "high-riding" 3rd ventricle , pointed lateral ventricles , and Probst bundles .

(37-8) Coronal autopsy of coronal agenesis shows thin third ventricle roof , Probst bundles . (Courtesy J. Townsend, MD.)

(37-9) ACC in Aicardi syndrome shows "radiating" gyri converging on "high-riding" third ventricle. (Courtesy R. Hewlett, MD.)

The septi pellucidi often appear absent but actually have widely separated leaves that course laterally—not vertically—from the fornices to the Probst bundles.

Axial sections show that the lateral ventricles are parallel and nonconverging. The occipital horns are often disproportionately dilated, a condition termed colpocephaly.

The gross pathology of CC hypogenesis varies according to which segments are missing. The splenium is usually small or absent.

Clinical Issues

Epidemiology and Demographics. CC dysgenesis is the most common CNS malformation and is found in 3-5% of individuals with neurodevelopmental disorders. It has a prevalence of at least 1:4,000 live births. Nonsyndromic CC dysgenesis is found in patients of all ages.

Presentation. Minor CC dysgenesis/hypogenesis is often discovered incidentally on imaging studies or at autopsy. Major commissural malformations are associated with seizures, developmental delay, and symptoms secondary to disruptions of the hypothalamic-pituitary axis.

CALLOSAL DYSGENESIS: PATHOETIOLOGY AND CLINICAL ISSUES

Terminology

•Complete absence of corpus callosum (CC) = agenesis

○Hippocampal commissure (HC) absent

○Anterior commissure (AC) often present

○All 3 absent = tricommissural agenesis

•Hypogenetic, dysgenetic CC

○Rostrum, splenium often absent in partial agenesis

○Partial posterior agenesis = HC, splenium, ± posterior body

Etiology and Pathology

•Embryonic guiding mechanisms fail

○Axons may fail to form

○Molecular guidance fails

○Glial sling and/or HC fail to develop normally

○Failure to guide axons across midline

•Multiple genes implicated

Clinical Issues

•Most common CNS malformation

•Found in 3-5% of neurodevelopmental disorders

Imaging

CT Findings. Axial NECT scans show parallel, nonconverging, widely separated lateral ventricles. Disproportionate enlargement of the occipital horns is common.

MR Findings. Sagittal T1 and T2 scans best demonstrate complete CC absence or partial dysgenesis.

Complete Corpus Callosum Agenesis. With complete agenesis, the third ventricle appears continuous with the interhemispheric fissure and is surrounded dorsally by fingers of radiating gyri that "point" toward the third ventricle (37-10).

A midline interhemispheric cyst may be present above the third ventricle. Such cysts can be ventricular outpouchings or separate structures that do not communicate with the ventricular system.

An azygous anterior cerebral artery (ACA) can be seen "wandering" upward in the interhemispheric fissure. Look for associated malformations of the eyes, hindbrain, and hypothalamic-pituitary axis.

Axial scans demonstrate the parallel lateral ventricles especially well. The prominent myelinated tracts of the Probst bundles can appear quite prominent (37-14).

Coronal scans show a "Viking helmet" or "moose head" appearance caused by the curved, upwardly pointed lateral ventricles and "high-riding" third ventricle that expands into the interhemispheric fissure. The Probst bundles are seen as densely myelinated tracts lying just inside the lateral ventricle bodies. The hippocampi appear abnormally rounded and vertically oriented. Moderately enlarged temporal horns are common. Look for malformations such as heterotopic gray matter (37-13).

DTI is especially helpful in depicting CC agenesis. The normal red (right-to- left encoded) color of the corpus callosum is absent. Instead, prominent front-to-back (green) tracts of the Probst bundles are seen (37-15).

Corpus Callosum Hypogenesis. In partial agenesis, the rostrum and splenium are usually absent (37-11), and the remaining genu and body often have a "blocky," thickened appearance (37-12). The hippocampal commissure is typically absent, but the AC is generally preserved and often appears quite normal or even larger than usual.

Angiography. In complete CC agenesis, CTA, DSA, and MRA demonstrate an azygous ACA that courses directly upward within the interhemispheric fissure (37-16B).

Differential Diagnosis

The major differential diagnosis of CC dysgenesis is destruction caused by trauma, surgery (callosotomy), or ischemia. Occasionally, if the hippocampal commissure forms but the CC is absent, the HC may mimic a remnant portion of the CC on sagittal images. Coronal views show that the HC connects the fornices, not the hemispheres.

CALLOSAL DYSGENESIS: IMAGING AND DDx

Sagittal

•Partial or complete CC agenesis

•Third ventricle appears "open" to interhemispheric fissure

•Cingulate gyrus absent → gyri "radiate" outward from third ventricle

Axial

•Lateral ventricles parallel, nonconverging, widely separated

•Probst bundles = WM along medial margins of lateral ventricles

Coronal

•"Viking helmet" or "moose head" appearance

•"High-riding" third ventricle

•Pointed, upcurving lateral ventricles

•Probst bundles

Differential Diagnosis

•Corpus callosum present but damaged

○Trauma

○Surgery (callosotomy)

○Ischemia (rare)

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(37-10) "Spoke-wheel" gyri converge on third ventricle . Anterior commissure is normal . Hippocampal commissure is absent. This is ACC.

(37-11) Genu , remnant of body are present. Rostrum , splenium are absent. This is CC hypogenesis.

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(37-13) Coronal T2WI shows "Viking helmet" of ACC with curving, upturned lateral ventricles , Probst bundles , and heterotopic GM .

(37-14) Axial scan shows parallel, "nonconverging" lateral ventricles and Probst bundles .

(37-15) Axial DTI shows absence of normal red X- shaped corpus callosum. Probst bundles are green, indicating anterior-to-posterior course.

Associated Anomalies and Syndromes

The corpus callosum (CC) forms at the same time the cerebral hemispheres and cerebellum are undergoing rapid changes. Neuronal migration also peaks during the same period. Although CC dysgenesis can occur as an isolated phenomenon, it is not surprising that—of all the malformations—CC anomalies are the single most common malformation associated with other CNS anomalies and syndromes.

Malformations Associated With Callosal Dysgenesis

Chiari 2 malformation, Dandy-Walker spectrum, frontonasal dysplasia, median cleft face syndromes, syndromic craniosynostoses, hypothalamicpituitary anomalies, cerebellar hypoplasia/dysplasia, and malformations of cortical development all have an increased prevalence of CC anomalies. CC agenesis and regional increases in cortical thickness are the most common brain morphologic defects in fetal alcohol syndrome.

Genetic Conditions With Callosal Involvement

Anomalies of the cerebral commissures have been described in nearly 200 different syndromes! A few of the more striking examples are included here.

Aicardi Syndrome. Aicardi syndrome is an X-linked neurodevelopmental disorder associated with severe cognitive and motor impairment. It occurs almost exclusively in female patients and is defined by the diagnostic triad of CC dysgenesis, chorioretinal lacunae, and infantile spasms. Other common associated abnormalities are polymicrogyria, periventricular and subcortical heterotopic gray matter, and choroid plexus papillomas.

Callosal agenesis or hypogenesis—often with interhemispheric cysts—is the most common anatomic abnormality in Aicardi syndrome (37-16). DTI in patients with Aicardi syndrome shows gross deficits in white matter organization, with absence of multiple major corticocortical association WM tracts such as the left arcuate fasciculus.

Apert Syndrome. Apert syndrome is also called acrocephalosyndactylia type 1. Apert syndrome is characterized by craniostenosis, mid-face hypoplasia, and symmetric syndactylia of the hands and feet. Associated CNS malformations are frequent; the most common are CC or septi pellucidi hypoplasias.

CRASH Syndrome. CRASH syndrome—also known as X-linked hydrocephalus and hereditary stenosis of the aqueduct of Sylvius—is a rare inherited disorder characterized by corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus. CRASH is caused by mutation in the gene (L1CAM) that regulates the L1 cell adhesion molecule, which plays an essential role in normal development of the CNS.

L1CAM mutations cause neurological alterations, including severe intellectual disabilities summarized as L1 syndrome.

22q11.2 Deletion Syndrome. The 22q11.2 deletion syndrome (22qDS) is also known as DiGeorge syndrome. Atypical facial morphometry, obsessivecompulsive disorder, autistic spectrum disorder, and other psychological disturbances are common in patients with 22qDS. Many patients have an abnormally large, misshapen CC.

Williams Syndrome. Williams syndrome (WS) is caused by a microdeletion of genes on locus 7q11.23, which is crucial for neuronal migration and maturation. Overall brain size is reduced, and some degree of CC dysgenesis is typical. The CC in WS is smaller or shorter than normal with a less concave shape.

Fragile X Syndrome. Fragile X syndrome is an X-linked disorder caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome and the most common inherited cause of mental retardation in boys. The CC is generally thinned but present.

Morning Glory Syndrome. Morning glory syndrome is a rare optic disc anomaly named for its characteristic appearance on funduscopic examination. A wide funnel-shaped excavation of the optic disc (37-17) with whitish central gliosis is surrounded by retinal vessels that emerge from the disc periphery. CNS findings include retinal coloboma (37-18), scleral staphyloma, optic nerve cyst, and midline disorders such as CC dysgenesis, basal encephalocele, and frontonasal dysplasia.

MALFORMATIONS AND SYNDROMES ASSOCIATED WITH CALLOSAL DYSGENESIS

Malformations

•Chiari 2

•Dandy-Walker

•Frontonasal dysplasia, clefts

•Cerebellar hypoplasia/dysplasia

•Hypothalamic-pituitary axis malformations

•Malformations of cortical development

•Malformations

Inherited Syndromes (> 200)

•Aicardi syndrome

•Apert syndrome

•CRASH syndrome

•22q11.2 deletion syndrome (DiGeorge)

•Morning glory syndrome

Thick Corpus Callosum

An congenitally thick corpus callosum ("mega" corpus callosum) is an extremely rare condition. Only a few genetic disorders are associated with mega corpus callosum (37-19). Reported syndromes include neurofibromatosis type 1 (NF1), FG syndrome, and Cohen syndrome. A constellation of findings designated megalencephaly-polymicrogyria-mega- corpus callosum syndrome is recognized as an Online Mendelian Inheritance in Man disorder (OMIM 603387).

Malformations of Cortical

Development Overview

Three Stages of Malformations

The umbrella term malformations of cortical development (MCD) is used to denote a heterogeneous group of focal or diffuse lesions that develop during cortical ontogenesis.

The three major stages of cortical development are proliferation, neuronal migration, and postmigrational development. These stages have some overlap; proliferation continues after neuronal migration starts, and postmigrational development (e.g., process of cortical organization) begins before neuronal migration ends. In addition, cells resulting from abnormal proliferation often neither migrate nor organize properly.

Barkovich et al. suggest classifying MCDs according to which of the three development stages is primarily affected. Group I consists of abnormalities

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(37-16A) Sagittal T2WI in Aicardi shows ACC with absent cingulate gyrus, "high-riding" third ventricle , radiating gyri , azygous ACA .

(37-16B) Axial T2WI shows interhemispheric cyst, azygous ACA , parallel lateral ventricles, heterotopic GM , and pachygyria .

(37-16C) Coronal T2WI has "moose head," highriding 3rd ventricle , pointed lateral ventricles, Probst bundles , and heterotopic GM .

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(37-17) Funduscopic photograph shows morning glory syndrome with enlarged, cup-shaped optic disc . (From Diagnostic Ophthalmology.)

(37-18) CECT shows coloboma with dehiscence of posterior globe through large optic disc . (From Diagnostic Ophthalmology.)

(37-19) Sagittal T1WI shows thickened corpus callosum in FG syndrome, an X-linked disorder with hypotonia and intellectual disabilities.

of neuronal and glial proliferation or apoptosis (resulting in either too many or too few cells). Three subcategories reflect malformations due to (A) reduced proliferation or accelerated apoptosis (congenital microcephalies),

(B)increased proliferation or decreased apoptosis (megalencephalies), and

(C)abnormal proliferation (focal and diffuse dysgenesis and dysplasia).

Group II represents abnormalities of neuronal migration and has been divided into four subgroups: (A) abnormalities in the neuroependyma during initiation of migration cause periventricular nodular heterotopia; (B) lissencephalies are caused by generalized abnormalities of transmantle migration; (C) localized abnormalities of transmantle migration result in subcortical heterotopia; and (D) terminal migration anomalies and defects in the pial limiting membranes result in cobblestone malformations.

MALFORMATIONS OF CORTICAL DEVELOPMENT

I. Malformations Secondary to Glial/Neuronal Proliferation or Apoptosis

•A. Microcephaly

•B. Megalencephaly

○Polymicrogyria and megalencephaly

•C. Cortical dysgeneses with abnormal cell proliferation

○Cortical tubers

○Focal cortical dysplasia (FCD IIb, Taylor type)

○Hemimegalencephaly

II. Malformations Secondary to Abnormalities of Neuronal Migration

•A. Heterotopia

○Periventricular nodular heterotopia

•B. Lissencephaly spectrum

○Agyria

○Pachygyria

○Subcortical band heterotopia

•C. Subcortical heterotopia and sublobar dysplasia

○Large focal collections of neurons in deep WM

•D. Cobblestone malformations

○Congenital muscular dystrophies

III.Abnormalities of Postmigrational Development

•A. Polymicrogyria

•B. Schizencephaly

•C. Focal cortical dysplasia (types I and III)

•D. Postmigrational microcephaly

Abnormalities of postmigrational development comprise group III. These result from injury to the cortex during later stages and are associated with prenatal and perinatal insults.

Malformations With Abnormal

Cell Numbers/Types

Microcephalies

Microcephaly (MCPH), which literally means "small head," can be primary (genetic) or secondary (nongenetic).

Primary MCPH is a congenital malformation caused by a defect in brain development. Secondary MCPH is an acquired disorder resulting from an insult that affects fetal, neonatal, or infantile brain growth. Ischemia, infection, maternal diabetes, and trauma are the most common causes. A

few examples of MCPH microcephaly induced by intrauterine infection are illustrated in Chapter 12. In this section, we focus on primary (congenital) microcephaly.

Terminology and Classification

Microcephaly is defined as a head circumference more than three standard deviations below the mean for age and sex. In primary MCPH, there is no evidence of other causes of small brain such as craniostenosis, perinatal infection, or trauma.

Barkovich et al. classify primary MCPH on the basis of morphologic characteristics such as gyral patterns, cortical thickness, the presence of heterotopias or other malformations, and normal versus delayed myelination. The gyral pattern can be normal, "simplified," microgyric, or pachygyric.

Three types of primary microcephaly are recognized. Microcephaly with simplified gyral pattern (MSG) is the most common and the mildest form (37-20). Simplified gyri and abnormally shallow sulci are the hallmarks of MSG. The cortex is normal or thinned, not thickened. The gyri are also reduced in number and demonstrate a "simplified" pattern. Various MSG subtypes are described with normal or delayed myelination, heterotopias, and arachnoid cysts.

Microlissencephaly is characterized by severe microcephaly and abnormal sulcation. The brain is extremely small, and the sulcation pattern appears greatly simplified or almost completely smooth (37-22). The cortex is thickened, usually measuring more than 3 mm. In microcephaly with extensive polymicrogyria, the brain is small, and polymicrogyria is the predominant gyral pattern (37-21).

Etiology and Pathology

Glioneuronal proliferation and apoptosis both play key roles in determining brain size, so abnormalities in either can result in microcephaly. Familial primary microcephaly is an autosomal-recessive disorder with a single clinical phenotype and genetic heterogeneity.

Several chromosomal syndromes are characterized by mental retardation and microcephaly. These include trisomy 21 (Down), trisomy 18 (Edward), cri- du-chat ("cat cry," 5p syndrome), Cornelia de Lange, and Rubinstein-Taybi syndromes.

Clinical Issues

Epidemiology and Demographics. The incidence of primary MCPH ranges from 1:10,000-30,000. Most cases of primary (genetic) microcephaly are detected in utero or shortly after birth.

Presentation and Natural History. Mental retardation, developmental delay, and seizures are the most common clinical symptoms. Prognosis is variable.

Imaging

General Features. The craniofacial ratio is decreased (usually ≤ 1.5:1). The forehead is often slanted, and the calvarial sutures may appear overriding.

CT Findings. Bone CT shows a small cranial vault, often with closely apposed and overlapping sutures. In older children, the skull is thickened, and the sinuses appear overpneumatized.

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(37-20) Autopsy shows microcephaly, simplified gyral pattern. The gyri appear less convoluted than normal. (Courtesy R. Hewlett, MD.)

(37-21) Microcephaly also shows polymicrogyria, abnormal veins in sylvian fissure , large vein of Trolard . (Courtesy R. Hewlett, MD.)

(37-22) Microcephaly with LIS looks like that of a 24-week fetus with smooth surface, shallow sylvian fissure. (Courtesy R. Hewlett, MD.)

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The cortical surface can be normal, simplified, microlissencephalic, or polymicrogyric. The ventricles may appear normal or moderately enlarged.

MR Findings. Sagittal T1WI demonstrates slanted frontal bones and a marked decrease in cranial-to-facial proportions (37-23). The brain can appear small but relatively normal, small with simplified gyral pattern, or microlissencephalic.

In microcephaly with simplified gyral pattern, the gyri are fewer in number and appear simplified. The sulci are shallow (25-50% of normal depth). Delayed myelin milestones may be present. Associated anomalies such as callosal dysgenesis and cephaloceles are common.

T2* (GRE, SWI) sequences are helpful to delineate secondary insults with hemorrhagic residua.

Differential Diagnosis

The major diagnostic dilemma is differentiating primary from secondary microcephaly. Calcifications, cysts, gliosis, and encephalomalacia are more common in microcephaly secondary to TORCH, Zika virus infection, trauma, or ischemic encephalopathy.

Focal Cortical Dysplasias

The distinctive histological features of focal cortical dysplasia (FCD) were first characterized by Taylor et al. (1971). It is now recognized that FCD is a common cause of medically refractory epilepsy in both children and adults. Surgical resection is an increasingly important treatment option, so recognition and accurate delineation of FCD on imaging studies are key to successful patient management.

(37-24) Resected surgical specimen from a patient with intractable epilepsy shows a classic "funnel-shaped" area of thickened cortex, blurred gray-white interface . Contrast with adjacent normal sulcus and gyrus . (Courtesy R. Hewlett, MD.)

Terminology and Classification

FCDs—sometimes called Taylor cortical dysplasia—are localized regions of nonneoplastic malformed gray matter.

The International League Against Epilepsy (ILAE) has established a three-tiered classification of FCD based on clinical, imaging, and neuropathologic findings (e.g., lamination disturbances or cytoarchitectural/cellular dysplasia).

FCD type I is an isolated malformation with abnormal cortical layering that demonstrates either vertical (radial) persistence of developmental microcolumns (FCD type Ia) or loss of the horizontal hexalaminar structure (FCD type Ib) in one or multiple lobes. FCD type Ic is characterized by both patterns of abnormal cortical layering.

FCD type II is an isolated lesion characterized by altered cortical layering and dysmorphic neurons either without (type IIa) or with balloon (type IIb) cells. Type II is the most common type of FCD.

The third type of FCD, FCD type III is a postmigrational disorder associated with principal pathologies such as ischemia, infection, trauma, etc. In such cases, cytoarchitectural abnormalities occur together with hippocampal sclerosis (FCD type IIIa), epilepsy-associated tumors (FCD type IIIb), vascular malformations (FCD type IIIc), or—in the case of FCD type IIId—other epileptogenic lesions acquired in early life.

Etiology

The molecular pathology and genetics of FCD are intensely investigated but incompletely understood. Decreased

(37-25) T2WI (L), FLAIR (R) show pathologically proven FCDIIb. Note funnel-shaped malformation with indistinct gray-white matter interface and curvilinear hyperintense foci extending toward the lateral ventricle.

expression of BMP-4 and increased expression of double cortin-like protein that is critically involved in neuronal division and radial migration have been found in both FCDIIb and cortical tubers.

The most convincing data implicate mammalian target of rapamycin (mTOR) cascade abnormalities as the cause of FCD. FCD type IIb specimens typically have sequence alterations in the TSC1 (hamartin) gene and resemble the cortical tubers in tuberous sclerosis complex (TSC).

Extensive cortical malformations can be caused by prenatal infections (e.g., TORCH). HPV-16 infection and oncoprotein expression have also been found in a large series of resected FCDIIb specimens.

Pathology

Gross Pathology. Surgical specimens often appear grossly normal. A funnel-shaped configuration of mildly thickened, slightly firm cortex with poor demarcation from the underlying white matter is characteristic (37-24).

Microscopic Features. The histopathologic hallmarks of FCD are disorganized cytoarchitecture and neurons with abnormal shape, size, and orientation.

FCD type II has pronounced cytoarchitectural disturbances. Dysmorphic neurons with increased diameter of their cell bodies and nuclei are found in both types IIa and IIb. Cortical thickness is increased, and the gray-white matter interface is blurred in both subtypes.

Prominent balloon cells together with lack of myelin and oligodendrocytes are typical of type IIb. These balloon cells are

(37-26) Images show subtle findings of FCD . Signal intensity is similar to GM on both T2/FLAIR. T1 C+ shows enhancement of "primitive" cortical veins over the focal dysplasia. (Courtesy P. Hildenbrand, MD.)

histologically identical to giant cells in the tubers from TSC patients.

Clinical Issues

Epidemiology and Demographics. As a group, FCDs are the single most common cause of severe early-onset drugresistant epilepsy in children and young adults. FCD type II is found in 15-20% of patients undergoing epilepsy surgery. There is no sex predilection.

Presentation and Natural History. FCD-associated seizures usually begin in the first decade but can present in adolescence or even adulthood. Patients with FCD type Ia are typically young with early seizure onset and severe psychomotor retardation.

Treatment Options. Medically resistant chronic epilepsy secondary to FCD may be treated by surgical resection. Outcome varies with FCD subtype; excellent seizure control is reported in 70-100% of patients with FCD type IIb.

Imaging

General Features. Imaging findings of FCD are often subtle. Most foci are smaller than 2 cm in diameter and can be difficult to detect, especially on standard imaging studies. Larger lesions can mimic neoplasm or focal demyelination.

CT Findings. CT scans are usually normal unless the lesion is unusually large. A few patients with calcified FCD type IIb lesions have been reported (37-27).

MR Findings. MR findings in FCD depend on lesion size and type. For example, FCD type Ia causes only mild hemispheric hypoplasia without other visible lesions.

(37-27) Images in a different patient show very subtle findings of FCD , including a tiny focus of calcification on NECT. This is biopsy-proven FCD. (Courtesy P. Hildenbrand, MD.)

FCD type IIb shows a localized area of increased cortical thickness and a funnel-shaped area of blurred gray-white interface at the bottom of a sulcus, the "transmantle MR" sign (37-25). Signal intensity varies with age. In neonates and infants, FCD type IIb appears hyperintense on T1WI and mildly hypointense on T2WI. In older patients, FCD appears as a wedge-shaped area of T2/FLAIR hyperintensity extending from the bottom of a sulcus into the subcortical and deep WM

(37-26).

A subcortical linear or curvilinear focus of T2/FLAIR hyperintensity sometimes extends toward the superolateral margin of the lateral ventricle (37-25).

FCD type IIb does not enhance on T1 C+. It shows increased diffusivity and decreased FA on DWI. MRS shows decreased NAA:Cr and elevated myoinositol. Perfusion MR shows normal or reduced rCBV.

The recently defined FCD type III is primarily encountered in patients with hippocampal sclerosis (FCD IIIa). Anterior temporal lobe volume loss with abnormal WM hyperintensity on T2/FLAIR with otherwise normal-appearing cortex is characteristic.

Voxel-based morphometry, statistical parametrical mapping, and texture analysis are advanced techniques that may increase detection of epileptogenic lesions in patients with negative standard MR scans.

Functional Imaging. Ictal SPECT, PET, and magnetoencephalography (MEG) can be beneficial tools in patients with normal MRs who are suspected of harboring FCD. Fused images have been used to guide intraoperative lesionectomy. Functional imaging has also been used in

(37-28A) Hemimegalencephaly shows enlarged right hemisphere with "overgrown" WM. Note pointed frontal horn and enlarged occipital horn .

conjunction with subdural and depth electrodes to localize the ictal zone.

FOCAL CORTICAL DYSPLASIA

ILAE Classification

•FCD I: Cortical dyslamination

•FCD II: Cortical dyslamination with dysmorphic neurons

○FCD IIA = without balloon cells

○FCD IIb = with balloon cells (most common)

•FCD III: Cortical lamination abnormalities + additional pathology in adjoining area

Pathology and Clinical Issues

•Mass-like with thickened cortex, indistinct GM-WM junction

•Most common cause of refractory epilepsy

Imaging

•Focal/wedge-shaped mass, blurred GM-WM interface

•Subcortical T2/FLAIR hyperintensity

Differential Diagnosis

The major differential diagnosis of FCD (especially type IIb) includes neoplasm, tuberous sclerosis, and demyelinating disease. The most common cortically based neoplasms associated with longstanding epilepsy include dysembryoplastic neuroepithelial tumor (DNET), ganglioglioma, oligodendroglioma, and low-grade diffusely infiltrating astrocytoma (WHO grade II). It may be difficult (if not impossible) to distinguish between FCD and neoplasm on the basis of imaging findings alone.

(37-28B) More cephalad image shows large hemisphere/ventricle with subependymal heterotopic GM , polymicrogyria , and "overgrown" WM with abnormal myelination . (Courtesy B. Horten, MD.)

The cortical lesions in tuberous sclerosis complex can look very similar to FCD type IIb. Both can calcify; both are funnelor flame-shaped and involve the cortex and subcortical WM. TSC usually demonstrates other imaging stigmata such as subependymal nodules.

A solitary demyelinating lesion can mimic FCD. The myelin and oligodendrocyte loss in FCD results in similar signal intensity changes, i.e., T2/FLAIR hyperintensity. "Tumefactive" demyelination often has an incomplete enhancing rim, whereas FCD does not enhance. Serial MRs may be helpful in distinguishing FCD from demyelinating disease.

Hemimegalencephaly

Terminology

Hemimegalencephaly (HMEG)—also called unilateral megalencephaly—is a rare malformation characterized by enlargement and cytoarchitectural abnormalities of all or part of one cerebral hemisphere.

Etiology

The precise etiology of HMEG is unknown. Some investigators believe HMEG and FCD represent a single disease spectrum with phenotypic variability. In this view, HMEG represents a hemispheric FCD with aberrant PI3K/AKT/mTOR signaling playing the key role in developing malformations of cortical development ("TORopathies").

HMEG can occur as an isolated malformation, but approximately 30% of cases are syndromic. Associations with Proteus, Klippel-Weber-Trenaunay, and epidermal nevus

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syndromes, neurofibromatosis type 1, and hypomelanosis of Ito have been reported.

Pathology

Gross Pathology. The affected hemisphere appears enlarged and grossly dysplastic. Abnormal gyral pattern, cortical dysgenesis, enlarged lateral ventricle, and white matter hypertrophy are common. Areas of dysplastic hamartomatous overgrowth are present, and the gray-white matter junction is often indistinct (37-28).

Microscopic Features. Severe cortical dyslamination, hypertrophic and dysmorphic neurons, and parenchymal and leptomeningeal glioneuronal heterotopias are typical histologic features of HMEG. Balloon cells are identified in half of all cases.

The white matter is often grossly abnormal and poorly myelinated. Gray matter heterotopias and clusters of

(37-29A) NECT in a 4y girl with hemimegalencephaly, intractable seizures shows enlarged right hemisphere, hemicranium with enlarged WM in the corona radiata . Compare this to the normal-appearing WM of the left hemisphere . (37-29B) T2WI in the same patient shows enlarged hemisphere, hyperintense WM , enlarged deformed lateral ventricle, thickened dysplastic cortex . Again compare to the normal left side.

(37-29C) T2WI through the corona radiata in the same patient shows hypertrophied heterogeneously hyperintense WM and pachygyria . (37-29D) Coronal T2WI in the same patient shows the hyperplastic, hyperintense WM , deformed pointed lateral ventricle , and polymicrogyria .

hypertrophic astrocytes are frequent findings. Gliosis, WM vacuolation, and cystic changes are common.

Clinical Issues

Epidemiology and Demographics. HMEG is rare, representing less than 5% of MCDs diagnosed on imaging studies.

Presentation, Natural History, and Treatment Options.

HMEG usually presents in infancy and is characterized by macrocrania, developmental delay, and seizures. Extracranial hemihypertrophy of part or all of the ipsilateral body may be present.

Prognosis is poor because seizures are usually intractable and developmental delay is severe. HMEG-associated seizures are usually resistant to anticonvulsants. Anatomic or functional hemispherectomy has had variable success, as abnormalities in

the contralateral "normal" hemisphere are common and so should be carefully searched for as part of surgical planning.

Imaging

General Features. HMEG is characterized by an enlarged, dysplastic-appearing hemisphere with abnormal gyration, thickened cortex, and white matter abnormalities. The lateral ventricle usually appears enlarged and deformed. In rare cases, the dysplastic changes involve only part of one hemisphere ("focal," "localized," or "lobar" hemimegalencephaly).

CT Findings. NECT shows an enlarged hemisphere and hemicranium. The posterior falx often appears displaced across the midline (37-29). Abnormal white matter myelination may increase in attenuation, making the contralateral "normal" WM appear unusually hypodense. Dystrophic calcifications are common.

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CECT may disclose abnormal, "uncondensed," primitiveappearing superficial veins over regions of severely dysplastic cortex.

HEMIMEGALENCEPHALY

Pathology

•Enlarged hemisphere

•Thick cortex + focal subcortical masses of dysplastic GM

•WM abnormally myelinated

Imaging

•Large, dysplastic-appearing hemisphere

•Ipsilateral ventricle large, malformed

•Falx inserts off midline

•Focal mass(es) of heterotopic GM can mimic neoplasm

•DDx = FCD, TSC, neoplasm (gangliocytoma)

(37-30A) NECT scan in a

35w premature infant shows enlarged right hemisphere, lateral ventricle . The right hemispheric WM appears less hypodense than the left. (37-30B) More cephalad scan in the same patient shows the enlarged right hemisphere, lateral ventricle , and offmidline insertion of the falx . Initial diagnosis was left MCA stroke.

(37-30C) T2WI in the same patient shows expanded right hemispheric WM that appears "dirty" (i.e., less hyperintense than the unmyelinated left WM). Note the markedly enlarged fornices . (37-30D) More cephalad T2WI shows that corona radiata WM is less hyperintense than normal , and there is extensive cortical thickening with polymicrogyria . Note the prominent, primitiveappearing veins .

(37-31) Axial graphic shows extensive bilateral subependymal heterotopia lining the lateral ventricles. The gray matter cortical ribbon is thin, and the sulci are shallow.

(37-32) Autopsy specimen shows nodules of subependymal heterotopic gray matter . Ventricles are enlarged, and the overlying cortex is thin. (Courtesy J. Ardyn, MD.)

MR Findings. The cortex often appears thickened and "lumpybumpy" on T1 scans. Myelination is disordered and accelerated with shortened T1. Neuronal heterotopias are common. The ipsilateral ventricle is usually enlarged and deformed. In severe cases, almost no normal hemispheric architecture can be discerned.

T2 scans show areas of pachyand polymicrogyria with indistinct borders between gray and white matter (37-30). White matter signal intensity on T2/FLAIR is often heterogeneous with cysts and gliosis-like hyperintensity (3729).

Differential Diagnosis

The major differential diagnosis of HMEG is a focal malformation of cortical development. Although the entire hemisphere is usually involved in HMEG, cases of "focal" or "lobar" megalencephaly are difficult to distinguish. They show identical histologic features. The presence of associated extracerebral abnormalities (e.g., limb hemihypertrophy) may be a helpful differentiating feature.

Tuberous sclerosis complex with widespread cortical dysplasia does not enlarge the hemisphere and exhibits other imaging stigmata, such as subependymal nodules, cortical/subcortical tubers, and radial glial bands.

Cases of severe HMEG with almost no identifiable normal anatomic landmarks can be mistaken for neoplasm, typically gangliocytoma. Other than dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), tumors consisting only of neoplastic neurons (often with dysplastic features) are exceptionally rare. The newly described multinodular and vacuolating neuronal tumor of the cerebrum has a distinct

imaging appearance, i.e., a focal cluster of T2/FLAIR hyperintense "bubbles" on the undersurface of the cortex, and does not have the dysmorphic appearance of HMEG.

In all of the differential diagnostic considerations listed above, color FA maps are helpful in delineating the GM-WM junction and demonstrating the WM hypertrophy or hypermyelination so characteristic of HMEG.

Abnormalities of Neuronal

Migration

Abnormalities of neuronal migration are divided into four main subgroups as discussed above. We begin with the heterotopias and then turn to lissencephaly spectrum disorders. The section concludes with a brief discussion of subcortical heterotopias, sublobar dysplasias, and cobblestone complex.

Heterotopias

Arrest of normal neuronal migration along the radial glial cells can result in grossly visible masses of "heterotopic" gray matter. These collections come in many shapes and sizes and can be found virtually anywhere between the ventricles and the pia. They can be solitary or multifocal and exist either as an isolated phenomenon or in association with other malformations.

Periventricular Nodular Heterotopia

Periventricular nodular heterotopia (PVNH) is the most common form of cortical malformation in adults. Here one or

more subependymal nodules of gray matter (GM) line the lateral walls of the ventricles (37-31) (37-32). PVNH can be unilateral focal, unilateral diffuse, bilateral focal, and bilateral diffuse. Nodules of PVNH follow GM in density/signal intensity and do not enhance following contrast administration (3733).

PVNH commonly occurs with other abnormalities. The most common is ventriculomegaly followed by agenesis of the corpus callosum and cortical dysplasia. FLNA mutations, when present in the X-linked dominant form, cause bilateral ectopic GM nodules, which are perinatal lethal in male patients.

Less commonly, PVNH lines most or even all of the lateral ventricular walls. Collections of round or ovoid nodules indent the lateral walls of the ventricles, giving them a distinctive "lumpy-bumpy" appearance. They follow GM on all sequences, do not enhance, and—unlike the subependymal nodules of tuberous sclerosis—do not calcify. The overlying cortex often

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appears thinned, but sulcation and gyration are typically normal.

The major differential diagnosis of PVNH is the subependymal nodules of tuberous sclerosis.

Subcortical Heterotopias

Subcortical heterotopias are malformations in which large, focal, mass-like collections of neurons are found in the deep cerebral white matter anywhere from the ependyma to the cortex (37-34). The involved portion of the affected hemisphere is abnormally small, and the overlying cortex appears thin and sometimes dysplastic (37-35).

In other forms of heterotopia, focal masses of ectopic GM occur in linear or swirling curved columns of neurons that extend through normal-appearing white matter from the ependyma to the pia. The overlying cortex is thin, and the underlying ventricle often appears distorted (37-36). The

(37-33A) Axial T2WI in a patient with corpus callosum agenesis shows multiple nodules of subependymal heterotopic gray matter . Cortex shows perisylvian areas of pachyand polymicrogyria. (37-33B) More cephalad image in the same patient shows additional foci of subependymal heterotopic GM and cortical dysplasia .

(37-33C) Coronal T2WI in the same patient nicely demonstrates the subependymal heterotopias and pachyand polymicrogyria. (37-33D) T2WI through the atria of the lateral ventricles shows the subependymal heterotopias . The heterotopias followed gray matter signal intensity on all sequences.

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(37-34) Graphic depicts subcortical heterotopia. The large, focal, mass-like collection of gray matter , thin overlying cortex are typical.

(37-35) Autopsy shows dysplastic lateral ventricle, mass-like GM heterotopias under thin, polymicrogyric cortex . (AFIP Archives.)

(37-36) T1 (L), T2 (R) show mass of heterotopic GM , thin overlying cortex , deformed underlying ventricle mimicking neoplasm.

masses follow GM on all sequences, do not demonstrate edema, and do not enhance.

Occasionally ribbon-like bands of heterotopic GM (subcortical band heterotopia) form partway between the lateral ventricles and cortex (3737). Although these have been described with megalencephaly and polymicrogyria, most are probably part of the "double cortex" form of lissencephaly (see below).

The major differential diagnosis of subcortical heterotopia is neoplasm, most specifically gangliocytoma. Because the histologic features of GM heterotopia are so similar to those of gangliocytoma, recognizing that the imaging findings are characteristic of a PVNH is essential to avoid misdiagnosis.

Lissencephaly Spectrum

Malformations due to widespread abnormal transmantle migration include agyria, pachygyria, and band heterotopia. All are part of the lissencephaly spectrum.

Terminology

The term lissencephaly (LIS) literally means "smooth brain." The spectrum of LISs ranges from severe (agyria) to milder forms, including abnormally broad folds (pachygyria) or a heterotopic layer of gray matter embedded in the white matter below the cortex (subcortical band heterotopia).

In classic LIS (cLIS), the brain surface lacks normal sulcation and gyration. cLIS is also called type 1 lissencephaly or four-layer lissencephaly to differentiate it from cobblestone cortical malformation. Agyria is defined as a thick cortex with absence of surface gyri ("complete" lissencephaly).

True agyria with complete loss of all gyri is relatively uncommon. Most cases of cLIS show parietooccipital agyria with some areas of broad, flat gyri ("pachygyria") and shallow sulci along the inferior frontal and temporal lobes ("incomplete" LIS).

Some rare forms of LIS are associated with a disproportionately small cerebellum and are referred to as lissencephaly with cerebellar hypoplasia.

Variant LIS (vLIS) consists of thick cortex and reduced sulcation without a cell-sparse zone. Examples include X-linked LIS with callosal agenesis and ambiguous genitalia and LIS with RELN signaling pathway mutations.

Subcortical band heterotopia is also called "double cortex" syndrome and is the mildest form of cLIS (37-37).

Etiology

Genetics. Between 5 and 22 gestational weeks, primitive neurons (neuroblasts) are generated from mitotic neural stem cells in the ventricular zone (VZ), a region close to the lateral ventricles. Guided by radial glial fibers, postmitotic neuroblasts migrate outward from the VZ to populate the cortical plate.

cLIS is caused by mutation in three genes that regulate the outward migration of neuroblasts: PAFAH1B1 (often called it alias LIS1), DCX (double cortex gene) and TUBA1A. The majority of patients with cLIS have LIS1 defects. Another 10-15% have DCX mutations, whereas TUBA1A accounts for 1-4% of cLIS cases.

LIS1 is deleted in all patients with Miller-Dieker syndrome. DCX mutations can cause cLIS (typically in male patients) but are also common in female patients with subcortical band heterotopia (SBH). Almost all cases of familial

SBH are due to DCX mutations. TUBA1A-related LIS typically demonstrates a posterior to anterior gradient of severity and can also be associated with cerebellar hypoplasia, dysmorphic basal ganglia, callosal dysgenesis, and congenital microcephaly.

Pathology

Gross Pathology. In cLIS, the external surface of the brain shows a marked lack of gyri and sulci. In the most severe forms, the cerebral hemispheres are smooth with poor operculization and underdeveloped sylvian fissures. Coronal sections demonstrate a markedly thickened cerebral cortex with broad gyri and reduced volume of the underlying white matter (37-38).

Microscopic Features. In cLIS, the normal six-layer cortex is replaced by a thick four-layer cortex. From the outermost to the innermost, these layers are (1) a thin subpial molecular layer, (2) a thin outer cortex composed of disorganized large

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pyramidal neurons, (3) a "cell-sparse" zone that consists mostly of axons (myelinated after the age of 2 years), and (4) a broad inner band of disorganized neurons. The white matter is severely reduced in volume and often contains foci of heterotopic neurons.

Clinical Issues

Epidemiology and Demographics. LIS occurs in 1-4:100,000 live births. Patients with band heterotopia are almost always female.

Presentation. Patients with cLIS typically exhibit moderate to severe developmental delay, impaired neuromotor functions, variable mental retardation, and seizures. Microcephaly and mildly dysmorphic facies are frequent. Patients with band heterotopia typically present with developmental delay and a milder seizure disorder.

(37-37) Axial graphic shows classic lissencephaly in the left hemisphere with thick subcortical gray matter band , thin cortex, and "cell-sparse" zone . The right hemisphere demonstrates milder lissencephaly with band heterotopia ("double cortex" syndrome) and thin outer cortex . (3738A) Lissencephaly shows shallow sylvian fissure , near-complete lack of sulcation. A few shallow surface indentations are present.

(37-38B) Coronal section shows "hourglass" configuration with shallow sylvian fissures, absent sulci, and thick incompletely layered cortex . (37-38C) Posterior coronal section shows occipital horn dilatation ("colpocephaly") and alternating bands of GMand WM . (Courtesy R. Hewlett, MD.)

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(37-39A) NECT shows smooth brain with shallow sylvian fissures , thick cortex , and reduced WM . The ventricles are moderately enlarged.

(37-39B) T1WI shows flat gyri, thin outer, thick inner layers of GM separated by a hypointense "cell-sparse" layer . WM volume is reduced.

(37-39C) Coronal T2WI shows thin cortex , hyperintense "cell-sparse" layer , thickened inner band of GM and primitive veins .

Patients with cLIS and severe facial deformities are diagnosed with MillerDieker syndrome (MDS). Frontal bossing, hypertelorism, upturned nose, small jaw, and prominent upper lip with thin vermilion border are characteristic features of MDS.

Imaging

General Features. Imaging in patients with complete cLIS (agyria) shows a smooth, featureless brain surface with shallow sylvian fissures and large ventricles. The cortex is thickened, and the WM is diminished in volume. The normal finger-like interdigitations between the cortical GM and subcortical WM are absent. In some cases, the cerebellum appears hypoplastic.

CT Findings. Axial NECT scans in cLIS show an "hourglass" or "figure-eight" appearance caused by the flat brain surface and shallow, wide sylvian fissures. A thick band of relatively well-delineated dense cortex surrounds a thinner, smooth band of white matter (37-39A).

CECT scans show prominent "primitive-appearing" veins running in the shallow sylvian fissures and coursing over the thickened cortices.

MR Findings

Classic Lissencephaly. In cLIS, T1 scans show a smooth cortical surface, a thick band of deep GM that is sharply demarcated from the underlying WM, and large ventricles. T2 sequences are best to distinguish the separate cortical layers. A thin outer cellular layer that is isointense with GM covers a hyperintense "cell-sparse" layer. The WM layer is smooth and reduced in volume. A deeper, thick layer of arrested migrating neurons is common and may mimic band heterotopia (37-39B) (37-39C).

Callosal anomalies are common in cLIS. The predominant abnormality is callosal hypogenesis. The corpus callosum has a thin flat body with a more vertically oriented splenium. DTI shows marked "pruning," rarefaction, and disorganization of subcortical association fibers (U-fibers). FA and axial diffusivity are decreased, and radial diffusivity is increased. The main WM tracts also appear aberrant and heterotopic.

Variant Lissencephaly. In vLIS, sulcation is reduced, and the cortex appears thick (although not as thick as in cLIS). There is no "cell-sparse" layer.

Band Heterotopia or "Double Cortex" Syndrome. In band heterotopia, a band of smooth GM is separated from a relatively thicker, more gyriform cortex by a layer of normal-appearing white matter.

MR scans show a more normal gyral pattern with relatively thicker cortex. The distinguishing feature of band heterotopia is its "double cortex," a homogeneous layer of gray matter separated from the ventricles and cerebral cortex by layers of normal-appearing WM (37-40).

Differential Diagnosis

Extremely premature brain is smooth at 24-26 gestational weeks and normally has a "lissencephalic" appearance (see Chapter 35). Although in utero MR can identify fetal lissencephaly between 20 and 24 weeks, false positives are common in the second trimester. Full sulcation and gyration do not develop completely until approximately 40 weeks.

In microcephaly with simplified gyral pattern, the head circumference is at least three standard deviations below normal. Too few gyri, abnormally shallow sulci, and a normal or thin (not thick) cortex are present.

cLIS should also be distinguished from the so-called cobblestone lissencephalies (type 2 lissencephaly or LIS2). Here the brain surface appears

"pebbly" instead of smooth. LIS2 is typically associated with congenital muscular dystrophies (see below).

Pachygyria histologically resembles cLIS but is more localized, often multifocal, and usually asymmetric. In contrast to cLIS, the gray-white matter junction along the thickened cortex is indistinct.

Cytomegalovirus-associated LIS may demonstrate periventricular calcifications as well as germinal zone and anterior temporal cysts.

LISSENCEPHALY SPECTRUM

Classic Lissencephaly (cLIS)

•Pathology: thick, 4-layer cortex

○Thin subpial layer

○Thin outer cortex

○"Cell-sparse" zone

○Broad inner band of disorganized neurons

•Clinical issues

○cLIS + severe facial anomalies = Miller-Dieker

•Imaging

○Smooth, "hourglass" brain

○Flat surface, shallow "open" sylvian fissures

Band Heterotopia ("Double Cortex")

•Clinical issues

○Almost always in female patients

•Imaging: looks like "double cortex"

○Thin, gyriform cortex

○Normal-appearing WM under cortex

○Smooth inner band of GM

○Normal-appearing periventricular WM

Differential Diagnosis

•Extremely premature brain

○cLIS looks like 20to 24-week fetal brain

•Microcephaly with simplified gyral pattern

○Brain size ≥ 3 standard deviations below normal

•Cobblestone lissencephalies (type 2 LIS)

○Associated with congenital muscular dystrophies

○"Pebbly" (cobblestone) surface, not smooth

•Pachygyria

○More localized, often multifocal

○GM-WM interface indistinct

•Congenital CMV

○Often microcephalic

○Smooth brain, periventricular Ca++

Cobblestone Lissencephaly

Cobblestone lissencephaly is also known as type 2 lissencephaly and is genetically, embryologically, pathologically, and radiologically distinct from type 1 ("classic") lissencephaly.

Terminology

Cobblestone lissencephaly is also called cobblestone cortical malformation (CCM) and is characterized by an uneven, nodular, "pebbly" brain surface that resembles a cobblestone street. Almost all cases of cobblestone lissencephaly are associated with ocular anomalies and occur as a part of a congenital muscular dystrophy (CMD) syndrome.

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(37-40A) Sagittal T1WI shows band heterotopia with thin outer cortex, myelinated WM, band of GM , periventricular WM ("double cortex").

(37-40B) Coronal SPGR in the same patient nicely demonstrates bilateral homogeneous-appearing bands of subcortical heterotopic gray matter .

(37-40C) Axial T2WI in the same patient shows that the subcortical bands follow GM signal intensity. The overlying cortex is thin.

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Three major CMD phenotypes are associated with CCM:

Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), and Fukuyama congenital muscular dystrophy (FCMD).

Etiology

Cobblestone cortex results from abnormalities caused by defects in the limiting pial basement membrane. Overmigration of neuroblasts through these breaches results in an extracortical layer of aberrant gray matter nodules—the "cobblestones"—on the brain surfaces.

CCM is genetically heterogeneous but is mostly due to autosomal-recessive defects in α-dystroglycan-O-glycosylation and is therefore termed a dystroglycanopathy.

Pathology

Gross Pathology. Grossly, the brain is usually small. Broadened gyri and loss of sulci give the brain its lissencephalic appearance. The affected areas exhibit a "lumpy-bumpy" appearance (37-41). In WWS, the entire brain is often involved, whereas patients with MEB and FCMD show variable amounts of affected cortex, usually the posterolateral parietal and occipital lobes.

The cerebral WM volume is reduced, and the cortex appears irregularly thickened. The GM-WM junction can have an irregular and nodular appearance.

The brainstem is almost always small. The cerebellum is often small, and its folia are frequently fused and disorganized. From 15-20% of patients with WWS also have a Dandy-Walker malformation.

Microscopic Features. The histopathology of type 2 lissencephaly shares many features with polymicrogyria. The cortex is unlayered and highly disorganized. Unlike type 1 ("classic") lissencephaly, no recognizable laminations are identified. There are numerous areas in which a breach in the pial-glial limitans has occurred, possibly providing a migratory route for aberrant neurons.

Histopathology of skeletal muscle shows classic features of CMD, i.e., degenerating and regenerating muscle fibers with marked fibrosis.

Clinical Issues

Epidemiology and Demographics. All the CMDs are rare. WWS is the most severe form and is found worldwide. MEB is intermediate in severity and is found primarily in Finland. FCMD—the mildest form—occurs almost exclusively in Japan and in patients of Japanese descent.

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Presentation and Natural History. The hallmark of all type 2 lissencephalies is the combination of CMD with CNS involvement. Most patients present during the first year of life, but the relative degree of weakness varies.

WWS is characterized by the triad of CMD, brain anomalies (primarily cobblestone cortex), and ocular abnormalities. Infants with WWS have profound hypotonia ("floppy baby"), ocular abnormalities (such as colobomas and persistent hypoplastic primary vitreous), severe developmental delay, and seizures. Most affected individuals do not survive beyond 1 or 2 years.

MEB patients are hypotonic and have impaired vision, seizures, and mental retardation. The eye findings are usually present at birth, and motor retardation often presents earlier than symptoms caused by brain involvement.

(37-42A) Sagittal T2WI shows a patient with cobblestone lissencephaly associated with muscle- eye-brain disease. Note enlarged, fused collicular plate , small pons with "kinked" appearance to the midbrain, and the thin upwardly arched corpus callosum. (37-42B) Axial T2WI in the same patient shows frontalpredominant cobblestone lissencephaly .

(37-42C) More cephalad scan in the same patient nicely demonstrates the distinctive cobblestone appearance of the thickened frontal gyri . (37-42D) Coronal T2WI in the same patient shows delayed myelination , cobblestone cortex , and cerebellar cysts .

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Infants with FCMD present with hypotonia, developmental delay, and seizures. The eye abnormalities are less severe than those of WWS or MEB.

Imaging

Walker-Warburg Syndrome. WWS has a distinctive appearance on MR. Part or all of the cortex is grossly thickened with nodules of disorganized neurons on the surface (accounting for the cobblestone appearance) and linear bundles of GM that project into the underlying WM. Hydrocephalus is common. The brainstem is usually hypoplastic and appears "kinked", the tectum is enlarged, and the cerebellum appears small and dysmorphic with abnormal foliation.

Multiple tiny cerebellar cysts are typical of WWS. They are best demonstrated on thin-section, high-resolution T2WI and suppress completely with FLAIR.

(37-43) Coronal oblique graphic shows the thickened "pebbly" gyri of polymicrogyria involving the frontal and temporal opercula. Note abnormal sulcation and the irregular corticalwhite matter interface in the affected regions. (37-44) Autopsy shows pachyand polymicrogyria. Note several foci of tiny nodules ("gyri piled on top of gyri") , giving brain surface irregular "pebbly" appearance. (R. Hewlett, MD.)

(37-45A) Axial T2WI in a

2w infant with seizures shows multiple foci of polymicrogyria . The left hemisphere is much more severely affected than the right. (37-45B) Coronal T2WI in the same patient also shows the polymicrogyria . The appearance of multiple tiny nodules of gray matter piled on top of gyri is characteristic.

Muscle-Eye-Brain Disease. Retinal detachment with microphthalmia is typical with MEB. Cortical dysplasia, polymicrogyria, and hypoplasia of the inferior vermis are typical (37-42) although the cortical dysplasia may not be apparent on MR until several postnatal months.

Fukuyama Congenital Muscular Dystrophy. Patients with FCMD have temporooccipital cobblestone cortex. The brainstem is small, and the collicular plate appears enlarged and fused. The cerebellum is grossly dysmorphic with disorganized folia and subcortical T2/FLAIR hyperintense cysts.

Differential Diagnosis

The major differential diagnosis of type 2 lissencephaly with CMD includes type 1 ("classic") lissencephaly and polymicrogyria. CMD is not a feature of type 1 lissencephaly. In polymicrogyria, the absence of eye anomalies and muscle weakness are helpful distinguishing features.