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Approach to Brain Malformations

A General Imaging Approach to BrainMalformationsWhenever an infant or child is referred for imaging because ofeither seizures or delayed development, the possibility of abrain malformation should be carefully investigated. If thechild appears dysmorphic in any way (low-set ears, abnormalfacies, hypotelorism), the likelihood of an underlying brainmalformation is even higher, but a normal appearance is noguarantee of a normal brain. In all such cases, imaging shouldbe geared toward showing a structural abnormality. Theimaging sequences should maximize contrast between graymatter and white matter, have high spatial resolution, and beacquired as volumetric data whenever possible so that imagescan be reformatted in any plane or as a surface rendering. Thehigh resolution and ability to reformat will aid in the diagnosisof subtle abnormalities. High-resolution T1-weightedvolumetric images are essential for this purpose. High-resolution 2D coronal T2 images remain a workhorse forevaluation of midline structures, hippocampi, and opticnerves. High-resolution 3D FLAIR images may be particularlyhelpful in evaluating for focal cortical dysplasia. The use ofdiffusion tensor imaging (DTI) to acquire color fractionalanisotropy (FA) maps and perform tractography is useful tobetter understand the connectivity of the malformed brain,particularly in the brainstem, and may become clinically usefulin the near future.

After acquisition of appropriate images, image analysis musttake place in an orderly manner. The midline structures(including cerebral commissures, septum pellucidum, noseand rhinencephalon, pituitary gland, optic chiasm, andhypothalamus), the cerebral cortex (cortical thickness, gyralpattern, and cortical gray matter-white matter junction), thecerebral white matter (myelination, presence of nodules orclefts), the basal ganglia, the ventricular system (all ventriclescompletely present and of normal size and shape), theinterhemispheric fissure, and the midbrain hindbrainstructures (brainstem and cerebellum) should all bescrutinized in every patient.

Evaluate the midline structures first, as many diseaseprocesses of children take place in the midline, includinganomalies of the cerebral commissures (corpus callosum,anterior commissure, and hippocampal commissure), midlinetumors (suprasellar, pineal, brainstem, and 4th ventricle),anomalies of the cerebellar vermis, and anomalies of thecraniocervical junction. Anomalies of the cerebralcommissures are the most common brain malformations;more than 130 syndromes involving them have beendescribed. Many of these malformations are associated withanomalies of the hypothalamus, so always look at thehypothalamus and pituitary gland to ensure that the posteriorpituitary lobe is in the sella turcica and not in the medianeminence of the hypothalamus. The midline leptomeningesare important in commissural development, so be sure to lookfor other anomalies associated with abnormal midlineleptomeninges, such as interhemispheric lipomas andinterhemispheric cysts, when the commissures are absent ordysmorphic. Remember that large CSF spaces in the posteriorfossa may be a sign of associated anomalies of thecerebellum. The reason for this has only recently beendiscovered. Several cerebellar growth factors derive from theoverlying leptomeninges. Therefore, abnormalities of thecerebellar leptomeninges may result in anomalies of thecerebellum itself, as well as abnormalities of the surrounding

CSF spaces. This is the basis for development of the Dandy-Walker malformation; it requires abnormal development ofthe cerebellum itself and of the overlying leptomeninges.Looking at the midline image also gives an idea of the relativehead size through assessment of the craniofacial ratio. In thenormal neonate, the ratio of the cranial vault to the face onmidline images is 5:1 or 6:1. By 2 years, it should be 2.5:1, andby 10 years, it should be about 1.5:1.

After looking at the midline, evaluate the brain from outsideto inside. Start with the cerebral cortex. Is the thicknessnormal (2-3 mm)? If it is too thick, think of pachygyria orpolymicrogyria. Is the cortical white matter junction smooth orirregular? If it is irregular, think of polymicrogyria orcobblestone cortex. Polymicrogyria is seen in many underlyingdisorders, including congenital cytomegalovirus and geneticsyndromes, among others. Cobblestone cortex may beassociated with congenital muscular dystrophies, such asmuscle-eye-brain disease. Pachygyria that is more severe inthe parietal and occipital lobes suggests a mutation of LIS1 orTUBA1A (TUBA1A is also associated with microcephaly),whereas pachygyria that is worst in the frontal lobes suggestsa mutation of DCX. Similarly, there are many differentpolymicrogyria syndromes that depend upon the location ofthe polymicrogyria. Bilateral frontal polymicrogyria is adifferent entity than bilateral perisylvian polymicrogyria orbilateral parasagittal parietooccipital polymicrogyria; it isimportant to be specific in reporting the location of theabnormality. If the cortex is abnormally thin and associatedwith diminished underlying white matter, one should think ofa prenatal injury (infectious or ischemic), particularly if thethinning is focal or multifocal.

After the cortex, look at the cerebral white matter. Make suremyelination is appropriate for age (there are many sources ofnormal myelination charts, including journal articles andtextbooks). Then, look for areas of abnormal myelinationwithin the deep white matter. Diffuse layers ofhypomyelination or amyelination associated with overlyingpolymicrogyria should raise suspicion for congenitalcytomegalovirus infection. Generalized ipsilateral ↑T1 & ↓T2signal in the white matter of a neonate with overlying corticalmalformation should prompt one to think ofhemimegalencephaly, which is often accompanied byipsilateral hemisphere & ventricular enlargement. Focalcortical dysplasias (FCDs) are often most conspicuous at birthwith ↑T1 & ↓T2 in the subcortical white matter. Aftermyelination, FCDs are typically most conspicuous on FLAIR,where one may see a curvilinear cone-shaped abnormalitycoursing from the cortex to the superolateral margin of alateral ventricle (known as the transmantle sign). Narrowingthe window on FLAIR images increases conspicuity of FCD.Also, look for nodules of heterotopic gray matter in theperiventricular or deep white matter. Transmantle graymatter heterotopia typically extends from the cortex all theway to the lateral ventricular wall, whereas periventricularnodular heterotopia is more localized to the immediatesubependymal/periventricular region. Heterotopia might bedifficult to differentiate from unmyelinated or injured whitematter on T1-weighted images, so be sure to look at T2-weighted images or FLAIR images to ensure that the lesion isisointense to gray matter on all sequences.

The basal ganglia are sometimes abnormal in neuronal-migration disorders, as they are formed from neuronsgenerated in the medial and lateral ganglionic eminences, the

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Approach to Brain Malformations

Brain Anomaly Imaging Checklist

Anomaly FindingsAnomalies of Cerebral Cortex

Agyria/pachygyria Thick cortex, smooth inner margin, few shallow sulci

Polymicrogyria Nodular cortex & gray matter-white matter junction

Cobblestone cortex Thick cortex, irregular inner margin, abnormal myelin

Focal cortical dysplasia Thick cortex, blurred gray-white junction, ± deep sulcus

White Matter Abnormalities With Cortical Malformation

Hemimegalencephaly ↑ T1, ↓T2 in neonatal white matter; dysplastic neurons

Cobblestone cortex Delayed myelination, patchy hypomyelination

Congenital cytomegalovirus Deep layers of hypomyelination/gliosis

Focal cortical dysplasia "Tail" of signal abnormality extending toward ventricle

Malformations Associated With Absent Septum Pellucidum

Septo-optic dysplasia ON hypoplasia, pituitary anomaly, ± PMG/schizencephaly

Holoprosencephaly Varying degrees of incomplete hemispheric separation

Malformations with severe prolonged hydrocephalus Absent septum typically thought to be destructive

ON = optic nerve; PMG = polymicrogyria.

same germinal zones that produce GABAergic neurons thatmigrate to the cerebral cortex. In particular, the basal gangliatend to be dysmorphic in appearance in patients withsubcortical heterotopia. In addition, the hippocampi are oftenabnormal in cortical-development malformations. In patientswith lissencephaly, in particular, the hippocampi areincompletely folded. Sometimes the only structuralabnormalities in children with developmental delay arehippocampal; always ensure that they are fully folded and nottoo round. In the case of longstanding seizures, carefullyinspect the hippocampi for asymmetric atrophy and increasedsignal to suggest hippocampal sclerosis.

Always look at the entire interhemispheric fissure (IHF); if thecerebral hemispheres are continuous across the midline,holoprosencephaly should be diagnosed. In severeholoprosencephalies, the IHF is completely absent, whereas inmilder forms of holoprosencephaly, certain areas of the IHFwill be absent (anterior IHF in semilobar holoprosencephaly,central IHF in syntelencephaly). Look at the septumpellucidum; absence of the septum is seen in corpus callosumdysgenesis/agenesis and septo-optic dysplasia. When septo-optic dysplasia is identified, look carefully for pituitaryabnormalities, most commonly an ectopic posterior pituitary.Additionally, whenever septo-optic dysplasia is suspected, acareful search for associated schizencephaly or polymicrogyriais warranted. If present, a diagnosis of septo-optic dysplasiaplus is established. While checking the septum, look at thelateral ventricles to ensure they are normal in size and shape.Abnormally enlarged trigones and temporal horns are oftenassociated with callosal anomalies and pachygyria. Enlargedfrontal horns are often seen in bilateral frontal polymicrogyria.

Remember to look carefully at the posterior fossa; anomaliesof the brainstem and cerebellum are commonly overlooked.Make sure that the 4th ventricle and cerebellar vermis arenormally sized. In newborns, the vermis should extend fromthe inferior colliculi to the obex, whereas infants and olderchildren should have a vermis that extends from theintercollicular sulcus to the obex. Also, make sure you seenormal vermian fissures. If the fissuration of the vermis looks

abnormal, refer to an axial or coronal image to make sure thevermis is present; if the cerebellar hemispheres arecontinuous without a vermis between them, make a diagnosisof rhombencephalosynapsis. Whenever aqueductal stenosis isencountered, look carefully for rhombencephalosynapsis. Ifthe 4th ventricle has an abnormal rectangular shape (with ahorizontal superior margin) with a narrow isthmus and smallvermis, consider a molar tooth malformation. To confirm thisdiagnosis, look on axial images for the molar tooth sign of thelower midbrain, consisting of large, horizontal superiorcerebellar peduncles extending posteriorly toward thecerebellum, and a longitudinal cleft in the superior vermis.Make sure that the brainstem components are of normal size;in a child, the height of the pons should be double that of themidbrain on the midline sagittal image. Looking at the size ofthe pons compared to that of the cerebellar vermis canprovide an important clue. Because much of the anterior ponsis composed of the decussation of the middle cerebellarpeduncles, development hypoplasia of the cerebellum isnearly always associated with hypoplasia of the ventral pons. Ifthe pons is normal in the setting of a small cerebellum, it ismost likely that the cerebellum lost volume near the end ofgestation or after birth. Remember that in a small posteriorfossa, intracranial hypotension, or intracranial hypertensioncan result in descent of the cerebellum below the foramenmagnum. Look for causes of a small posterior fossa (clivalanomaly, anomaly of the craniovertebral junction), intracranialhypertension (space-occupying mass, hydrocephalus), orevidence of intracranial hypotension (large dural venoussinuses, large pituitary gland, "slumping" brainstem) beforemaking a diagnosis of Chiari 1 malformation. Finally,remember to look at the size of the CSF spaces in theposterior fossa, enlargement of which may be a sign ofabnormal leptomeningeal development.

Selected References1. Desikan RS et al: Malformations of cortical development. Ann Neurol.

80(6):797-810, 20162. Shekdar K: Posterior fossa malformations. Semin Ultrasound CT MR.

32(3):228-41, 2011

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Approach to Brain Malformations

(Left) Sagittal T1WI MR in a 7year old with multipleanomalies shows a short, thin,& dysmorphic corpus callosum.Note the poorly formedsplenium & rostrum ofthe corpus callosum. Isolateddysgenesis of the corpuscallosum is uncommon, so lookcarefully for associatedanomalies. (Right) SagittalT1WI MR shows a largepericallosal lipoma andsevere associated callosaldysgenesis . Note theenveloping of vessels bythe fatty mass, a commonfinding in large tubulonodularlipomas.

Callosal DysgenesisCallosal Dysgenesis With Pericallosal

Lipoma

(Left) Coronal T2WI MR in a 1year old with seizures showsmarked thickening of multiplegyri and decreased sulcation symmetrically within bothfrontal lobes, consistent withpachygyria. Ventricles may beenlarged secondary to smallbrain volume. (Right) AxialT2WI MR in a 4 year old withcongenital CMV shows corticalthickening with irregularcortical surface & an irregularGM-WM junction with shallowsulci, consistent withpolymicrogyria . Note thewhite matter abnormalities, findings often seen incongenital CMV.

PachygyriaPolymicrogyria in Congenital

Cytomegalovirus

(Left) Coronal FLAIR images ina 3 year old with focal corticaldysplasia (FCD) type 2B with varying contrastwindowing. Note how the FCDis much more conspicuous inthe image on the right withgreater windowing contrast.Windowing is an importantmeans to increasing detectionof subtle FCD lesions. (Right)Axial T2WI MR in a 4 year oldwith callosal agenesis &extensive bilateralperiventricular nodular graymatter heterotopia .Malformations of corticaldevelopment are common incallosal abnormalities.

Focal Cortical Dysplasia Subependymal Gray Matter Heterotopia

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(Left) Coronal T2WI MR in a 5year old with septo-opticdysplasia shows absence ofseptum pellucidum & a verysmall left optic nerve . Rightoptic nerve looks grosslynormal in size. Asymmetricoptic nerve hypoplasia is verycommon in this diagnosis.(Right) Axial T1WI MR showsbilateral schizencephaly linedby dysplastic gray matter. Theright side is open lip & theleft is closed lip . Again notethe bifrontal polymicrogyria & absence of the septumpellucidum st in this patientwith septo-optic dysplasia plussyndrome.

Septo-Optic DysplasiaBilateral Schizencephaly in Septo-Optic

Dysplasia

(Left) Axial T2WI MR in a 2year old with semilobarholoprosencephaly showsabsence of the septumpellucidum , fused thalami, & extension of gray matter across the posteriormidline. Also note the nearabsence of the frontal horns &the azygos anterior cerebralartery . (Right) Axial T2WIMR in a 3 year old withaqueductal stenosis &rhombencephalosynapsisshows absence of thecerebellar vermis withextension of cerebellar whitematter tracts acrossmidline.

Semilobar Holoprosencephaly Rhombencephalosynapsis

(Left) Axial T2WI MR in a 13year old with oral digital facialsyndrome shows thickenedsuperior cerebellar peduncles & typical anterior clefting of the midbrain, consistentwith a molar tooth sign. Themolar tooth sign is associatedwith a number of variousconditions. (Right) SagittalT2WI in an infant with classicDandy-Walker malformationshows marked cysticenlargement of theposterior fossa in continuitywith the 4th ventricle,hypogenetic cerebellar vermis, & elevation of the torculaHerophili .

Joubert Syndrome & Related Disorders Dandy-Walker Malformation