1. Congenital Brain Malformations: How Mishaps in Embryological Development Result in Various Imaging Findings
Obara P., Kikano R., Poon C.

2. Objectives Overview of fetal brain development
Correlate failure in normal development to eventual brain malformation
Discuss brain malformations and their imaging findings

3. CNS Development Rudimentary brain and spinal cord formation
Dorsal induction
Ventral induction
Cortex formation
Neuronal proliferation
Neuronal migration
Cortical organization
Myelination

4. Dorsal Induction Failure
neuroectoderm
During normal dorsal induction, notochord induces surface ectoderm to differentiate into the neural tube, which separates to form spinal cord and brain (A, B, C).
Dorsal induction disorders primarily affect the spinal cord:
Premature separation of neural tube from ectoderm allows mesenchymal cells to enter neural tube, resulting in lipomeningocele and intradural lipoma (D).
Lack of neural tube separation from cutaneous ectoderm results in open spinal dysraphisms, most commonly myelomeningocele (E). The fused neural tube and ectoderm form the neural placode, which is exposed to the surface and becomes herniated under CSF pressure.
Cranial malformations resulting from dorsal induction can result in:
Calvarial dysraphisms
Encephalocele – the brain herniates outside the calvarium through focal defect
Exencephaly – extreme version of encephalocele where whole brain is outside the cranium due to a large defect
Anencephaly – herniated brain is destroyed by necrosis
cutaneous ectoderm A
notochord
neural crest B D
neural placode C E

5. Chiari Malformations Chiari II
Characterized by small posterior fossa due to myelomeningocele
Escape of CSF through spinal defect (myelomeningocele) fails to maintain adequate 4th ventricle distension and leads to ectoderm and mesoderm closure around a poorly distended neuroectoderm. This mechanism results in a hypoplastic posterior fossa.
Chiari III
Same mechanism as Chiari II but spinal dysraphism occurs at high cervical or low occipital level, and usually have encephalocele containing cerebellum
Chiari IV
Controversial but may represent severe cerebellar hypoplasia associated with Chiari II
Chiari I
Separate entity from other Chiari malformations that is not associated with spinal defect

6. Chiari II Fetal ultrasound: Myelomeningocele detected by 10 weeks
Lemon shaped skull – bifrontal inward convexity of skull
Banana sign – compressed cerebellum in small posterior fossa looks like banana
Lemon shaped skull
Banana shaped cerebellum and effaced cisterna magna

7. Chiari II Imaging FindingsE F C D
Small posterior fossa leads to:
Low lying tonsils (A)
“Towering cerebellum”: upward herniation through incisura
Cerebellum wrapped around medulla (B)
Beaked tectum (C)
Cervicomedullary kink
Elongated pons (D)
Elongated 4th ventricle
Callosal agenesis/dysgenesis (E)
Large massa intermedia (F)
Falx hypoplasia leads to interdigitating cerebral gyri (G) A G B

8. Chiari I
Not related in mechanism to other Chiari malformations because etiology not related to spinal dysraphism
Inferior displacement of cerebellar tonsils more than 5-6 mm below foramen magnum, with associated obliteration of surrounding CSF space
Normal cerebellar tonsils can extend through foramen magnum, but only < 5 mm in adults (in kids < 4 yo can normally extend up to 6 mm)
In mild cases (<5-6 mm), need to see “pointed” tonsil appearance to make Chiari I diagnosis
4th ventricle usually normal but may be slightly deformed
Altered CSF flow dynamics at cervicomedullary junction lead to syrinx formation in 20-25%, most commonly in cervical cord
Inferior displacement of “pointed” or “peg shaped” tonsils with obliteration of surrounding CSF space

9. Ventral Induction Forebrain (A) cephalic flexure
Cranial portion of neural tube forms flexures and three dilations (vesicles)
Vesicles then undergo cleavage to produce:
Paired structures: cerebral hemispheres, optic nerves, thalami and basal ganglia
Midline structures: optic chiasm, septum pellucidum, corpus callosum, hypotholamus and pituitary stalk, facial structures and orbits, falx cerebri
Midline structures of hindbrain also form during this time:
fourth ventricle, cerebellar vermis
Ventral induction disorders correspond to failure in either 1) vesicle cleavage, 2) midline development, or 3) normal hindbrain formation
Failure of vesicle cleavage results in holoprosencephalies
Failure in midline structure formation results in corpus callosum agenesis or septo-optic dysplasia
Failure of posterior fossa formation results in Dandy-Walker Malformation or vermis hypoplasia
Forebrain (A)
cephalic flexure
Cephalad to caudad direction of cleavage B
Midbrain (B) A
cervical flexure C
Hindbrain (C)
pontine flexure

10. Holoprosencephaly
Failure of hemisphere separation during vesicle cleavage leads to partial or complete contiguity of brain tissue across midline (required for diagnosis)
Normal cleavage occurs from posterior to anterior (caudal to rostral) so get spectrum of disorders depending on how far anteriorly cleavage proceeds:
Alobar – most severe. Complete failure of hemisphere and ventricle separation.
Semilobar – intermediate. Some hemisphere separation in posterior to anterior direction but anterior cerebrum fused.
Lobar – least severe but not well defined what exactly differentiates from semilobar. Near complete cleavage with some residual frontal lobe fusion.
Classification into categories may be difficult since abnormalities are a continuum:
Recent study by Barkovich et al. has suggested the use of amount of brain tissue located anterior to Sylvian fissure and angulation of Sylvian fissure to assess severity: less brain tissue anterior to fissure and greater fissure angle imply higher severity.
Shared imaging findings of holoprosencephalies:
Absence of septum pellucidum
Abnormal falx cerebri
Completely absent in alobar
Hypoplastic anteriorly in lobar
Etiology: unknown and likely multifactorial
May be related to defective cranial mesenchyme , which fails of induce proper differentiation of midline structures (including face and brain)

11. Alobar Holoprosencephaly
Monoventricle surrounded by thin “pancake” of cortex anteriorly
Fused thalamus
No interhemispheric fissure, falx, corpus callosum or septum pellucidum
Always associated with facial anomalies such as central incisor
Potential mimickers
Hydranencephaly
Little or no cortex due to ACA/MCA infarct (vs cortical mantle in holo)
Cleavage of thalami
Presence of central falx
Present septum pellucidum
Severe hydrocephalus
Thin, compressed cortex BUT falx present
Compressed but cleaved thalami
Ventricular differentiation
Holoprosencephaly (monoventricle with pancake of cortex fused across midline)
Hydranencephaly (note absence of cortical mantle, cleaved thalami and presence of falx)
Severe hydrocephalus (note presence of falx and thin but separated cortex)

12. Semilobar Holoprosencephaly
Intermediate form
Falx absent anteriorly
Rudimentary lateral ventricle occipital horns but no separation of frontal horns
Variable fusion of thalami

13. Lobar Holoprosencephaly
Least severe form but unclear separation from semilobar
Incomplete cortex separation anteriorly (A)
Anterior interhemispheric fissure and falx hypoplastic (B)
Lateral ventricles are normal posteriorly but frontal horns are rudimentary
3rd ventricle fully developed
Thalami usually separated
Septum pellucidum absent
Posterior portions of corpus callosum may be formed
Differentiate from partial agenesis of corpus callosum which will have anterior portion formed B

14. Septo-Optic Dysplasia (De Morsier syndrome)
Failure to form septum pellucidum which is associated with large, squared appearing lateral ventricles that point down
Associated abnormalities:
Bilateral optic nerve hypoplasia in 70%
Pituitary abnormalities in 45%
Thin corpus callosum
Midline lipoma or arachnoid cyst
Schizencephaly in 50%
Patients with schizencephaly will usually have part of septum spared and a normal visual apparatus
Note abnormal lateral ventricle morphology, with squaring superiorly and pointed appearance inferiorly

15. Agenesis of Corpus Callosum
Failure of axon guidance across the midline during ventral induction results in:
absent corpus callosum (A)
absent cingulate gyrus (A)
elevated 3rd ventricle that extends to outward radiating gyri (A)
non-crossing white matter bundles (Probst bundles) located on medial aspect of lateral ventricles(B)
Lateral ventricles have pointed frontal horns, are parallel and widely separated (B)
Occipital horns may be dilated (colpocephaly) (B)
Since CC formation occurs front to back, partial agenesis results in absence of posterior portion (C)
This is the opposite of lobar holoprosencephaly, where anterior portion is absent (D) B D

16. Ventral Induction Failure Posterior Fossa
Sagittal depictions of hindbrain
During normal development (A,B,C) the roof of the hindbrain forms a diamond shape, divided into two triangles.
Cephalic triangle, aka. anterior membranous area (AMA) is invaded by neural cells to become vermis and cerebellum.
Caudal triangle, a.k.a. posterior membranous area (PMA) initially expands to form Blake’s pouch (B), but eventually eventually disappears to form Foramen of Magendie (C).
Dandy-Walker malformations represent spectrum disorders that result in cystic posterior expansion. The pathogenesis of these disorders likely originates with abnormal formation of the vermis. Lack of a normal vermis leads herniation of anterior membranous area, resulting in posterior fossa cyst (D, E).
AMA
PMA A
Blake’s pouch D B E C

17. Classic Dandy-Walker Classic DW is defined by three findings:
Large posterior fossa
Cyst in posterior fossa that communicates with dilated 4th ventricle
Hypoplastic vermis, which is often superiorly rotated by cyst
Other findings include hypoplastic cerebellar hemispheres and lambdoid-torcula inversion
Lamdoid torcula inversion refers to the abnormal position of the torcula (the posterior confluence of venous sinuses) above the lambda (the midline confluence of the lambdoid and sagital skull sutures).
During normal development the dura and venous sinuses migrate inferiorly to end up in a position below the lambda (A). The pressure exerted by the posterior fossa cyst in DW prevents this downward migration, resulting in the torcula located superiorly to the lambda (B).
Absent vermis and communication of cyst with 4th ventricle
lambda A
torcula
lambda B
Lambdoid-torcular inversion

18. Dandy Walker Variant
As in classic DW, the vermis is hypoplastic. However, the posterior fossa is not as small as in classic DW.
An abnormal “keyhole” dorsal opening of 4th ventricle into cisterna magna is a characteristic finding.
A posterior fossa cyst may absent or small in size. Lack of associated pressure from the cyst allows normal inferior torcula migration, so no lambdoid-torcula inverion is observed.
Keyhole opening of 4th ventricle into cisterna magna

19. Mega Cisterna Magna B A
Least severe of the DW spectrum, MCM (shown in A and C) is an asymptomatic enlargment of the cisterna magna. Unlike, classic DW and DW variant, the posterior fossa size and vermis are normal. Patients are asymptomatic.
A posterior fossa arachnoid cyst may mimic a MCM. However, a MCM is crossed by the falx cerebelli and small veins (arrow in A); this is not seen in arachnoid cyst (B). There is also no mass effect on the cerebellum or 4th ventricle in MCM (C), which can be seen in arachnoid cyst (D). C D

20. Potential DW MimickersDifferential:
Joubert syndrome (aka. Congenital vermian hypoplasia)
Absent or split vermis allows cerebellar hemispheres to come together.
Unlike DW, posterior fossa is normal in size
There may be a narrow cleft that connects the 4th ventricle to the cisterna magna, sometimes giving 4th ventricle an“umbrella” appearance.
Brainstem may have molar tooth appearance due to maldeveloped superior cerebellar peduncles
Trapped 4th ventricle
Obstruction of cerebral aquaduct and foramina of Magendie and Lushka leads to cystic expansion of 4th ventricle
Unlike DW, vermis is normal and there is no abnormal connection between 4th ventricle and cisterna magna
Molar tooth brainstem and absent vermis in Joubert syndrome
Trapped 4th ventricle

21. Cortex Malformations
Cortex malformations can be classification into three main groups based on stage in which disorder occurs:
Neuronal proliferation
Neuronal migration
Cortical organization
Insults:
Genetic mutations
Toxins: ethanol, cocaine, radiation, anticonvulsant drugs, mercury
Infections: CMV, toxoplasmosis, rubella

22. Cell Proliferation
Neuronal proliferation takes places in perivernticular germinal matrix
Disorders of proliferation can be thought of as either abnormally decreased or increased:
Decreased
Microcephalies
Increased
Normal neurons
Megalencephalies
Abnormal neurons
Non-neoplastic: focal cortical dysplasia, hamartomas in TS
Neoplastic: DNET, gangloglioma, gangliocytoma

23. Proliferation - decreased
Microcephaly
Head circumference less than 3 standard deviations below normal
May cause mental retardation although some children have normal intelligence
Abnormal imaging findings are better predictor of intelligence than actual head size
Simplified gyral pattern but normal cortical thickness – mild form (and usually isolated)
Microlissencephaly - very small brain and thickened cortex (>3mm) – severe form
Broad range of conditions/causes included in definition

24. Proliferation – increased (abnormal cells)
Focal Cortical Dysplasia ( Transmantle Dysplasia or Taylor FCD)
Focal cortical malformations which include:
Focal cortex thickening (may be subtle)
Widened, deep sulci
Enlarged CSF space overlying cortical dimple
Increased T2 signal in underlying white matter that tapers towards ventricle
Abnormal neurons with excess amount of cytoplasm fail to migrate properly and are found in band extending from ventricular surface to cortex
Patients prone to seizures
Frontal lobe preference
If see similar abnormalities in temporal lobe consider neoplasm instead (ganglioglioma, DNET, gangliocytoma)
Focal cortical thickening. Pathology revealed cluster of large neurons consistent with focal cortical dysplasia.

25. Proliferation – increased (normal cells)
Hemimegalencephaly
Hamartomatous overgrowth of cerebral hemisphere due to too many neurons and not enough apoptosis
Thickened cortex and enlarged white matter on affected side.
Lateral ventricle on the affected side will also be enlarged, which can be a feature used to differentiate from an infiltrative lesion
Other features include:
Disorganized sylci/gyri
Poor gray-white differentiation
Increased white matter T2 signal
Abnormal proliferation can affect one or both hemispheres
Can be isolated or associated with other syndromes:
Epidermal nevus syndrome
Klippel-Trenauney
Soto syndrome
NF 1
Left hemimegalencephaly. Affected side has enlarged ventricle, thickened white matter, and increased white matter T2 signal. Thickened cortex difficult to appreciate on this image.

26. Migration Disorders
Neural cells normally migrate from periventricular region to cortical surface along radial glial cells
First neurons migrate to deep cortical layers and last migrate to superficial surface
Neuronal migration disorders can be broken down into three categories:
Ectopic migration – subependymal and subcortical heterotopia
Undermigration – lissencephaly, band heterotopia, pachygyria
Overmigration – cobblestone lissencephaly

27. Ectopic Migration - Heterotopias
Subependymal Heterotopia
Round to ovoid nodules isointense to gray matter project into lateral ventricles
Trigone and occipital horns most commonly affected
Mild ventricular dilation may be seen
Right sided preference (due to later migration)
Callosal and caudate surfaces always spared
Overlying cortex may be thinned
Main differential is subependymal hamartoma in tuberous sclerosis; unlike heterotopia, hamartomas will not exactly follow gray matter signal
Sucortical Heterotopia – less common (not shown)
Heterotopic cells are contiguous with overlying cortex
May be mass like with swirling internal convolutions resembling cortex

28. Undermigration Spectrum
Pachygyria (incomplete lissencephaly)
Decreased number of broad, smooth gyri
May look like polymicrogyria
Thick cortex (like polymicrogyria)
Shallow but symmetric sulci (not symmetric in polymicrogyria)
Lissencephaly (Agyria)
Severe form of migration arrest causing complete loss of sulcal/gyral patter ( smooth brain)
Cortex is thick due to layers of cells arrested along the way
Sylvian fissures poorly developed due to lack of operculization (covering of insula), causing hour-glass shape
Band (Laminar) Heterotopia
Rare and typically found in females
“Double cortex” – second, smooth layer of gray matter deeper to surface gray matter

29. Overmigration Cobblestone lissencephaly (type 2)
Excessive migration of last neurons into subarachnoid space and meninges causes nodular surface irregularities (cobblestone appearance)
Associated with ocular anomalies and congenital muscular dystrophy
Walker-Warburg Sydnrome
Most severe form
Vermis and cerebellar hypoplasia
Fukayama muscular dystrophy
Mildest form
Cerebellar cysts
Muscle-eye-brain (MEB) disorder
Intermediate form

30. Failure of Cortical Organization
Organization of cortical layers occurs by formation of intracortical and extracortical neuronal connections (starts weeks), and eventually results in mature gyral pattern
Two main disorders of organization are:
Polymicrogyria
Schizencephaly

31. Polymicrogyria Etiology:
After neurons have reached cortical surface, abnormal laminar necrosis in a layer of neurons causes increased infolding of cortex
Imaging features include:
Multiple small involutions create microgyri and shallow sulci
Thickened cortex, but less thick than pachygyria
Sulci are not symmetric (unlike pachygyria)
Bumpier appearance than pachygyria
Serrated appearance of gray-white junction due to interdigitation of white matter into gyri
Subcortical layer of increased T2 signal representing laminar necrosis (not always seen)
CMV is frequent cause and important to recognize because does not carry genetic implications
Associated with anomolous venous drainage (these do not represent “vascular malformations”)
Region of Sylvian fissure affected most commonly
May be associated with abnormal or simplified Sylvian fissure morphology bilaterally, in which case is called Perisylvian Syndrome

32. Schizencephaly A Etiology:
Likely due to germinal matrix infarction, which causes fusion of pial and ependymal surfaces, inhibiting normal migration and organization
Cleft extending from ventricle to pial surface, which is lined by dysplastic gray matter (usually polymicrogyria)
Types (depending on separation of cleft surfaces):
I: Closed lip
No separation of cleft surfaces, which may be occasionally difficult to idenfity. Look for a dimple at the ventricle-cleft interface. Nodular heterotopias at ventricle aspect of cleft may also be seen.
II: Open lip
Wide separation of cleft surfaces (A) associated with greater symptoms
High association with septo-optic dysplasia (about 50%) and polymicrogyria
May have truncated anterior corpus callosum (B)
DDx:
Porencephaly – cleft is lined by white matter. Results from MCA infract during later fetal development. B

33. Schizencephaly Porencephaly
Ischemic insult causes “hole in brain” that may appear as cleft similar to schizencephaly but will not be lined by gray matter
Defect also may not extend all the way to subarachnoid space
Open lip schizencephaly imitating holoprosencephaly
Note that frontal lobes are separated by fissure and falx, ruling out holoprosencephaly

34. Summary
When dealing with congenital brain malformation, consider steps of normal development to put abnormality in context

35. References
Raybaud, Levrier, Brunel, Girard, Farnarier. MR imaging of the fetal brain malformations. Children’s Nervous System :
Kollias, Ball, Prenger. Cystic Malformations of the posterior fossa: differential diagnosis clarified through embryologic analysis. Radiographics 1993; 13:
Razek, Kandell, Elsorogy, Elmongy, Basett. Disorders of cortical formation: MR imaging features. AJNR 2009; 30: 4-11.
Barkovich, Simon, Clegg, Kinsman, Hahn. Analysis of the Cerebral Cortex in Holoprosencephaly with Attention to the Sylvian Fissures. AJNR 2002; 23:
Patel, Barovich. Analysis and Classification of Cerebellar Malformations. AJNR 2002; 23;
Utsunomiya, Yamashita, Takano, Ueda, Fujii. Midline cystic malforations of the brain: imaging diagnosis and classification based on embyologic analysis. Radiat Med 2006; 24:
Neuroradiology: the requisities. Yousem, Grossman rd edition.