Malformations of Cortical Development.pptx

Cortical developmental malformation

1. Malformations of Cortical Development Malformations of cortical development (MCDs) are structural anomalies that disrupt the normal process of cortical development. Present with intractable epilepsy, developmental delay, neurologic deficits, and cognitive impairment . Diagnosis should start with neuroimaging , followed by clinical phenotyping and genetic analysis, which assist in further subclassification .

2. Schematic for normal brain embryogenesis (   A  ) Neurulation . After gastrulation and induction of the neural plate, the neural plate fuses at the dorsal midline by 4 weeks post-fertilization to create a neural tube that defines the neural axis from brain to spinal cord. (   B  ) Hemispheric separation . By 4 weeks to 6 weeks post-fertilization , 2 discrete vesicles form defining the right and left cerebral hemisphere. (  C  ) Neuronal precursor proliferation . From weeks 6 to 16, neuronal precursors proliferate in the ventricular and sub-ventricular zones to produce the neurons, which will eventually invest the gray matter .

3. (  D  ) Callosum formation . Between weeks 11 to 20, neurons cross the midline through the rudimentary corpus callosum increasing its posterior extent. (  E  ) Neuronal migration/organization. During weeks 8 to 24, neuronal precursors migrate radially outward to populate the cortex and eventually organize into 6 distinct cortical layers. (  F  –  H  ) Gyral maturation . Axial T2-weighted imaging of the. Although the brain at 20 weeks and even 28 weeks lacks the gyral complexity (and also the size that is not well appreciated) of the brain at term, the basic morphology of the brain has already been determined at mid-gestation by the events schematically depicted above. 20 wks post-conception 28 wks Term

4. MRI PROTOCOL It includes isotropic (0.9-mm) T1-weighted and fluid-attenuated inversion recovery (FLAIR) MR imaging as well as high-resolution T2-weighted MR imaging in the axial and coronal planes. Magnetization prepared T1WI at  isotropic resolution beautifully depicts gray-white matter interfaces with any regional abnormality easily compared with multiple cortical ribbons seen elsewhere in the same slice. The  volumetric FLAIR MR imaging accentuates subtle signal abnormalities (cortical as well as white matter) that can indicate a cortical dysplasia; some institutions supplement this sequence with magnetization transfer imaging.   Finally, diffusion-weighted MR imaging can complement other imaging sequences in characterizing suspected gray matter heterotopias because heterotopias should follow gray matter sequences on all sequences, including diffusion-weighted sequences.

5. 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 MC of all congenital brain malformations, and corpus callosum dysgenesis is the single most common malformation that accompanies other developmental brain anomalies.

6. Callosal Dysgenesis Spectrum

7. Malformations of Cortical Development

8. The latest and the most popular classification came up in 2012  and is based on the pivotal stages of embryologic development of cortex causing MCD due to disruption . According to this classification, MCDs are of 4 major groups :

9. GROUP IV -malformation of cortical development, not otherwise classified . • A: Secondary to inborn errors of metabolism • B: Other unclassified malformations

10. Group I.A Microcephaly with normal to simplified cortical pattern  microcephaly with lissencephaly microcephaly with extensive  polymicrogyria Group I.B Megalencephaly / macrocephaly Group I.C The cortical dysgenesis with abnormal cell proliferation group contains a number of both neoplastic and non- neoplastic conditions.  Non- neoplastic cortical hamartomas of tuberous sclerosis cortical dysplasia with balloon cells  hemimegalencephaly type II focal cortical dysplasia Neoplastic gangliogliomas gangliocytomas dysembryoplastic neuroepithelial tumours (DNET) Group I: abnormal cell proliferation or apoptosis 

11. Microcephaly with Simplified Gyral Pattern/ Microlissencephaly Microcephaly -means a small head size. Defined as having a HC - >3 SD below the mean for age and sex. Primary microcephaly (congenital ) presents as a small head with a simple gyral pattern. This form is associated with impaired neurogenesis , resulting in a reduction in the number of neurons.    Secondary microcephaly develops as a result of disruption in the post- neurogenesis phase and occurs due to insults such as infection, ischemia, or trauma. 

12. MRI features common to all types of microcephaly - decrease in the craniofacial ratio (≤1.5:1) (ratio of the area of the intracranial structures to the area of the face in the midsagittal plane) with a slanted forehead . In microcephaly with a simplified gyral pattern , there is a reduction in the number of gyri with shallow sulci (<50% of normal depth), but the cortical thickness remains normal . It can be associated with delayed myelination and with other anomalies like heterotopia , polymicrogyria , and callosal dysgenesis .  Whenever lissencephaly is associated with microcephaly , there is increased cortical thickness (> 3 mm) in addition to a decrease in gyration and sulcation and is termed  microlissencephaly  .    Secondary microcephaly presents with features of the causative etiology and may show features like cysts, calcification, and gliosis .

13. Microcephaly with simplified gyral pattern in 3-month-old male. Sagittal (  A  ) and axial T2WI (  B  ) showing decreased craniofacial ratio (<1.5:1) with normal thickness of the cortex and decreased number of gyri and sulci . (   C  ) Multiple areas of gyral T1 hyperintensities in subcortical location in bilateral frontal lobes (  D  )showing blooming on fast field echo images suggestive of calcifications.

14. Hemimegalencephaly It occurs when there is hamartomatous enlargement of 1 cerebral hemisphere or a part of it. Caused by either an increase in cell proliferation or a decrease in apoptosis. Can be associated with various neuro-cutaneous syndromes like Proteus syndrome, NF type 1, Klippel-Trenaunay syndrome, and tuberous sclerosis.   On MRI, there can be overgrowth of an entire cerebral hemisphere or only part of it. It may be associated with normal or dysplastic cortex and may show enlargement and deformity of the ipsilateral lateral ventricle . Occasionally, the ipsilateral cerebellar hemisphere and brainstem may show enlargement as well.

15.   Hemimegalencephaly . Images showing enlarged left cerebral hemisphere with mildly reduced white matter and thickened cortex.

16. Focal Cortical Dysplasia It constitutes a variety of brain malformations wherein there is dyslamination of the cortex with or without the presence of abnormal cell types. Patients MC present with intractable and refractory seizures.  The International League Against Epilepsy in 2011 categorized FCD into 3 pathologic subtypes : Type 1 FCDs are characterized by ( Ia ) alterations in columnar/radial migration of neurons or ( Ib ) laminar/tangential composition of neocortex or ( Ic ) they can have features of both. These lesions are radiologically subtle or occult. For FCD type Ia , a relatively specific finding is asymmetric lack of subcortical myelination . 

17. Type II FCDs Have dyslamination of the cortex and dysmorphic neurons . Subdivided pathologically into – ( IIa ) Those without balloon cells ( IIb )Those with balloon cells.   Type II FCDs are easily recognized on MRI.  Common imaging findings include thickening of the cortex, blurring of G-W matter junction, abnormal gyral and sulcal patterns, signal abnormalities of cortical or subcortical area, and a funnel-shaped T2/FLAIR subcortical hyperintensity , which is radially oriented and points toward the ipsilateral lateral ventricle ( transmantle sign)  . The transmantle sign is characteristic of FCD type IIb .  Another sign that is seen is cortical swelling in the acute phase, followed by volume loss in the chronic phase.

18. FCD type I in a 3 Y/boy with focal right upper extremity motor seizures (  A  ,  B  ). An axial T1WI (  A  ) demonstrates thickening and indistinctness of the left frontal operculum and insular cortical ribbon . The same area demonstrates cortical T2W hyperintensity . FCD type IIb in a 6Y/girl with epileptic encephalopathy (  C  ,  D  ). Coronal FLAIR (  C  ) and coronal T1W (  D  ) images demonstrate a left frontal transmantle sign with cortical/ subcortical signal increase that tapers to a point in the periventricular white matter. This is a specific sign for type IIb FCD.

19. FCD type II in a 9-year-old child with complaints of medically refractory epilepsy. Altered signal intensity lesion in right parietal lobe involving the cortex and subcortical white matter with blurring of gray-white matter interface. The lesion is isointense on T1W, hyperintense on T2W & FLAIR and does not show any enhancement on postcontrast T1W sequence.

20. Type III FCDs Include FCD 1 along with another lesion within the same lobe of brain . Accordingly, it can be classified as: IIIa ) When there is hippocampal sclerosis , IIIb ) When there is a tumor , IIIc ) when there is a vascular malformation , or IIId ) when there are lesions from early life . 

21. The important D/D for FCD include cortical-based, low-grade tumors associated with epilepsy such as ganglioglioma / glioma . Points in favor of FCD include a frontal location, predominantly located in gray matter with little or no edema/ gliosis and no contrast enhancement.

22. Group II: Malformations Due to Abnormal Neuronal Migration Group II.A subependymal heterotopia marginal glioneuronal heterotopia Group II.B  lissencephaly type I:  subcortical band heterotopia spectrum ( band heterotopia ): under migration lissencephaly type II ( cobblestone complex ): over migration Group II.C subcortical heterotopia  (not including band heterotopia )

23. Heterotopias It refer to the presence of normal neurons at abnormal locations ranging from the subependymal region up to the cerebral cortex as a result of arrest of migration of neuroblasts .  MC present with refractory seizures, mainly of the complex partial seizure type, along with developmental delay. On the basis of the location and morphology, heterotopias can be of various types.

24. Periventricular Nodular Heterotopia Heterotopia in the ventricular wall proximity. MC site - region of the occipital horn and trigone of lateral ventricle. A/K/A subependymal nodular heterotopia .   Usually bilateral (predilection for the right side as postulated by later migration of right-sided neuroblasts ) On MRI, round or ovoid nodules are seen in subependymal locations that are isointense to gray matter on all sequences with no contrast enhancement . May be situated within the ventricular wall or protrude into the ventricle lumen, or they may even lie in the periventricular white matter . Important D/D are the subependymal nodules seen in tuberous sclerosis , however, those nodules do not show isointense signal to cortex and may show calcification or enhancement .

25. Periventricular nodule along the frontal horn of right lateral ventricle, which follows gray matter signal intensity on axial T1WI ( A ), T2WI ( B ), and FLAIR ( C ) sequences without any enhancement on T1C+ ( D ).

26. Subcortical Heterotopia It includes neurons dispersed in the hemispheric white matter.   The lesions are located in the subcortical or deep periventricular white matter and show connection to either the overlying cortex or ventricular wall. Nodular subcortical heterotopia - nodules that extend from the ependymal lining into the white matter without any contiguity with the cortex. It shows a heterotopic nodule, which is isointense to gray matter on T1- and T2WI extending from periventricular white matter up to a variable degree to the cortex with a thin overlying cortex and separated by a band of white matter . Curvilinear subcortical heterotopia denotes heterogenous curvilinear masses of gray matter that extend from the cerebral cortex into the white matter and appear similar to the cerebral convolutions. The mixed type shows convolutions in the superficial part with the nodule in the periventricular region.

27. Subcortical and periventricular nodular heterotopia in a patient with CC dysgenesis . Multiple nodules are isointense to gray matter in the periventricular and subcortical white matter of B/L frontal lobes on T2WI. Associated CC dysgenesis evidenced by widely parallel-oriented lateral ventricles with a large interhemispheric cyst along with “spoke wheel” gyri .

28. Lissencephaly It is characterized by cortical thickening accompanied with gyral abnormality, which can range from agyria to pachygyria . Clinically, there can be 2 forms, complete and incomplete. In the complete form , patients may have seizures and developmental delay, whereas in the incomplete form , patients can present with hypotonia , complex seizures, microcephaly , or facial dysmorphism .

29. MRI features- Agyria in the complete form, while the incomplete form commonly shows agyria in the parietooccipital region with pachygyria in the frontotemporal region ; however, any gradient may occur. There is thickening of the cortex with thinning of the subcortical white matter . A circumferential band showing high T2 signal is seen predominantly in the parietooccipital region pertaining to the cell sparse zone. The cerebral hemispheres achieve a “ figure-of-8” or “hourglass” configuration along with shallow Sylvian fissures .

30. A 4-year-old male with classic lissencephaly . Smooth cortical surface with inward cortical thickness in bilateral cerebral hemispheres with shallow and open bilateral Sylvian fissures (  A−D  ). T1 hypointense and T2 hyperintense linear cell sparse zone is seen with overlying thin cortex and thick inner band of gray matter and reduced volume of underlying periventricular white matter. FLAIR image shows prominence of temporal horn of lateral ventricles compared with the frontal horn. Coronal T2WI shows few broad and flat gyri in bilateral temporal lobes s/o pachygyria .

31. Subcortical Band Heterotopia It is now classified under the lissencephaly spectrum.  It is the mildest form of classical lissencephaly that is identified almost exclusively in females as a result X-linked inheritance.   It is characterized by a smooth band of poorly organized neurons with arrested migration in deep or subcortical white matter lying below the cortex. On imaging, the heterotopic abnormal gray matter band is separated from both the cortex and ventricular wall by a layer of white matter ; hence it was previously referred to as a “ double cortex ”. On the basis of its location, the subcortical band may be global, anterior, or posterior biased.

32. Subcortical band heterotopia A thin band of gray matter, which is isointense to gray matter on T1W, T2W, and coronal T1 IR sequences in bilateral frontal subcortical location separated from overlying cortex by white matter on both sides.

33. A 6-year-old girl child with subcortical band heterotopia A gray matter band, which is isointense to gray matter on axial spoiled gradient-recalled (  A  ), coronal SPGR (  B  ), and T2WI (  C  ) in B/L cerebral hemispheres diffusely in a subcortical location separated from overlying cortex by white matter on both sides.

34. Cobblestone Malformation In this type, instead of the smooth brain surface, there is pebbly appearance of the cortex , which gives this name  cobblestone malformation. It usually occurs as a part of congenital muscular dystrophies and includes the spectrum of Walker-Warburg syndrome (most severe form), muscle-eye-brain disease (intermediate), and Fukuyama congenital muscular dystrophy (mildest form ). On MRI- U ndersulcation of the brain surface with a thickened cortex and indistinct and blurred gray-white matter junction along with multiple vertical striations is seen.    There are associated varying degrees of cerebellar dysmorphism , brainstem hypoplasia , and ocular abnormalities .

35. Group III: abnormal post migrational development Group III.A polymicrogyria  and  schizencephaly bilateral polymicrogyria syndromes schizencephaly polymicrogyria or schizencephaly as part of multiple congenital anomaly/intellectual disability syndromes​ Group III.B cortical dysgenesis secondary to inborn errors of metabolism mitochondrial and pyruvate metabolic disorders peroxisomal disorders Group III.C type I and type III focal cortical dysplasia Group III.D post- migrational   microcephaly  (also in group I)

36. Polymicrogyria PMG appears as tiny to small convolutions that are separated by shallow sulci . PMG can have multiple etiologic factors, such as prenatal infection, ischemia, exposure to toxins, or chromosomal anomaly . MC location- perisylvian region.   In 2003 Takanshi and Barkovich discovered 2 patterns of PMG: Pattern 1 shows a fine undulating cortex with normal cortical thickness , which is more commonly seen in infants and in the anterior frontal region, Pattern II shows a bumpy cortical appearance with a thick cortex , seen mainly in the frontal, parietal, and perisylvian regions

37. B/L perisylvian PMG shows primitive Sylvian fissures, draining veins, and dysplastic operculum.    B/L frontoparietal PMG is common in India and presents as PMG in bilateral frontoparietal regions with decreasing severity as it goes from anterior to posterior.  The most important D/D of polymicrogyria is cobblestone malformation with the main distinction being association of muscular dystrophies with the latter.

38. Case of asymmetric ventriculomegaly , interhemispheric cyst and dysgenesis of the corpus callosum spectrum with polymicrogyria , subcortical , and periventricular nodular heterotopia in a 1-month-old male. Axial T2W and coronal T2W showing polymicrogyria in the right perisylvian region with few nodules isointense to gray matter in right frontal periventricular and subcortical white matter. Another case showing polymicrogyria along bilateral Sylvian fissures on axial T1W(   C  ) and along right Sylvian fissure on T2WI (   D  ).

39. Schizencephal y It is a CSF cleft lined by dysplastic gray matter and is seen between the subarachnoid spaces and ventricular system . It results from injury that occurs during the period of cortical organization. It is associated with absent septum pellucidum , septo -optic dysplasia, and polymicrogyria . On MRI, the anomaly can be of 2 types, open-lip and closed-lip. Closed-lip schizencephaly - The gray matter−lined lips are closely apposed with each other. Open-lip schizencephaly - CSF-filled cleft is lined by gray matter.

40. Open-lip schizencephaly in a 2-year-old child. A wide CSF cleft lined by gray matter extending from left lateral ventricle to the subarachnoid space and associated absent septum pellucidum on axial T1WI (   A  ), FLAIR(   B  ), T2W ( C   ), and coronal T2W (  D  ) images.

41. An important differential diagnosis for open-lip schizencephaly is a porencephalic cyst , which is secondary to trauma or ischemic insult. However, unlike schizencephaly , porencephalic cysts are lined by white matter .

42. Disorder Embryologic Stage Cause Clinical Findings Genes Involved Microcephaly Proliferation (2nd to 4th month intrauterine) Decreased proliferation Small head size, seizures MCPH1, CENPJ, CDK5RAP2, WDR62, NDE1, NDE1, ASPM, CDK5RAP2, TUBA1A, TUBB2B, TUBB3, TUBG1, LIS1, DCX, DYNC1H, KIF5C, and NDE1 Hemimegal-encephaly Proliferation (2nd to 4th month intrauterine) Increased proliferation Developmental delay PI3K-AKT-mTOR pathway Focal cortical dysplasia Proliferation (2nd to 4th month intrauterine) Abnormal proliferation Intractable and refractory seizures PI3K-AKT-mTOR pathway Lissen-cephaly Migration (3rd to 5th month intrauterine) Undermigration Seizures, developmental delay, hypotonia, facial dysmorphism LIS1, RELN, DCX genes

43. Subcortical band heterotopia Migration (3rd to 5th month intrauterine) Undermigration Seizures and developmental delay X linked inheritance DCX gene Cobblestone malformation Migration (3rd to 5th month intrauterine) Overmigration Associated with muscular dystrophies LAMB1, LAMB2, GPR56 genes Periventricular nodular heterotopia Migration (3rd to 5th month intrauterine) Ectopic migration Developmental delay and seizures FLN-1 and ARFGEF-2 genes Subcortical heterotopia Migration (3rd to 5th month intrauterine) Ectopic migration Developmental delay and seizures FLN-A gene Polymicrogyria Postmigration development (22 weeks intrauterine to 2 years of age) Disorganization Epilepsy and cognitive delay mTOR ,  tubulin genes Schizencephaly Postmigration development (22 weeks intrauterine to 2 years of age) Disorganization Developmental delay and seizures EMX2 gene

44. Holoprosencephalies , Related Disorders

45. Anencephaly Anencephaly (literally meaning "no brain") occurs when the cephalic end of the neural tube fails to close, resulting in absence of the forebrain, skull, and scalp. The remaining brain—usually only the brainstem —is not covered by bone or skin. Two rare lethal malformations— aprosencephaly and atelencephaly (AP/AT)—are intermediate in the continuum between anencephaly and holoprosencephaly . AP/AT is now considered the most severe end of the holoprosencephaly spectrum . These three extreme malformations are usually diagnosed at fetal MR, sonography , or postmortem examination.

46. HOLOPROSENCEPHALY Rare congenital malformation resulting from incomplete sepaartion of the two hemispheres. Holo – single ventricle Pros- prosencephalon Encephaly - brain

47. Embryology

48. Types Classic- alobar , semilobar and lobar (based primarily on the presence or absence of midline fissure separating the hemispheres) Variants- Syntelencephaly – a/k/a middle interhemispheric variant of HPE Septopreoptic HPE. Minimal HPE. Microform HPE.

49. ALOBAR HPE Most severe. No midline fissure , no identifiable lobes. Fused basal ganglia. Agyric /disordered gyri /shallow sulci . Single crescentric monoventricle - opening dorsally into large CSF filled dorsal cyst.

50. SEMILOBAR HPE Intermediate form. Primitive ventricle horns, third ventricle. Fused basal ganglia & hypothalami , thalami often separated. Rudimentary falx , posterior interhemispheric fissure. Posterior CC forms while anterior aspects are absent.

51. LOBAR HPE Best differentiated. IHF and falx are clearly developed with shallow and dysplastic appearing anterior aspects. Third and lateral ventricles are well formed. CSP is always absent. Rudimentary frontal horns are typical and only the most inferior portions of frontal lobes are fused.

52. SYNTELENCEPHALY CC genu , splenium absent, middle present. (only brain malformation with this morphology) Mid section of falx and interhemispheric fissure absent. Posterior frontal gray-white matter fused across the midline.

53. Solitary median maxillary central incisor syndrome Single midline incisor. Often coexists with nasal anomalies. Brain anomalies of fornix, CC and septum pellucidi common.

54. CONGENITAL NASAL PYRIFORM APERTURE STENOSIS. Choanal atresia , midnasal stenosis , pyriform aperture stenosis . Often coexists with SMMCI. HPA axis dysfunction common.

55. Related midline disorders Septo -optic dysplasia. SOD plus- associated with other anomalies ( schizencephaly / callosal agenesis ) Arrhinenecphaly .

56. Septo -optic dysplasia Aka de- morsier syndrome. Absence of septum pellucidi . squared off frontal horns, pointed inferiorly on coronal T2W. Hypoplastic optic nerves,chiasm . Look for – malformation of cortical development. Thin stalk , small gland , ectopic posterior pituitary.

57. Arrhinencephaly Absent olfactory bulbs and tracts. Often seen with other midline facial abnormalities (cleft lip/palate) Kallman syndrome. CHARGE syndrome- in 25% with olfactory agenesis.

58. MIMICS Hydranencephaly - consequence of severe brain destruction in utero . Water bag brain Small nubbins of remnant brain with a normal falx cerebri and posterior fossa . Hemihydranencephaly .

59. D/D severe obstructive hydrocephalus. Alobar holoprosencephaly . Severe bilateral open lip schizencephaly .