Neuronal Migration Disorders

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A review of neuronal migration disorders

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Neuronal Migration Disorders:

Neuronal Migration Disorders Dr. Pratheep. Joseph. Kottam DM Neuro, Assistant Professor in Neurology, MOSC Medical College, Kolenchery, Kerala, India .

Normal stages of CNS development:

Normal stages of CNS development Neurulation or formation of neural tube Neuronogenesis - Mitotic proliferation of neuroblasts Apoptosis - Programmed death of excess neuroblasts Neuroblasts migration Axon & dendrite growth Electrical polarity of cell membrane Synaptogenesis Neurotransmitter biosynthesis Myelination of axons

Proliferation and Migration:

Proliferation and Migration Germinal matrix adjacent to the lumen of neural tube (future ventricles) contains stem cells of the neurons and two types of glial cells. Neuronal precursor cells migrate along specialized cells called radial glial cells, to one of the six layers of cerebral cortex. Once at adult site – establish synaptic connections with neighbouring neurons & send axons to targets Generally migrate centrifugally towards brain surface

Proliferation and Migration…:

Proliferation and Migration … In cerebellum – external granular cells first spread over surface & then grow into folia Migration occur in successive waves – at specific timings The new cells first reach pial surface & then form deep layers In hippocampus – opposite – earliest migrated neurons are most superficial

Timing of Neuroblast migration:

Timing of Neuroblast migration Cerebrum – neuroblasts – begin by 6 weeks – last till 34 th weeks Cerebrum – glioblast – migrate till early post natal period Brainstem – migration of neuroblast complete by 2 months Cerebellum – continue till 1 year

Molecules which control migration:

Molecules which control migration Molecules of Cytoskeleton Initiators – Filamin-A, ADP ribosylation factor GEF2 Mediators of progression – Doublecortin, LIS1 Signalling molecules – Reelin Molecules modulating glycosylation – stop signals POMT1 – Walker Warburg POMGnT1 – Muscle Eye Brain disease Fukutin – Fukayama dystrophy

Mechanisms of migration :

Mechanisms of migration Guided by radially oriented Glial fibers Glial cells with cell body in sub ventricular zone & feet extending radially till pial surface Astrotactin – secreted by neuroblasts – facilitate migration Adhesion molecules - facilitate migration L1 adhesion molecule is defective in X linked hydrocephalus with polymicrogyria & pachygyria Lissencephaly – Miller Dieker syndrome – improper LIS1 expression Normal centrifugal shifting band of gliosis – 28 weeks to 6 years – periventricular zone to sub cortical shifting of frontal lobe astrocytes

Mechanisms of migration…:

Mechanisms of migration… Tangential migration along axons Far smaller number Occur in brainstem, olfactory bulb, cerebrum Perpendicular to glial fibres Originate from foetal ganglionic eminence which later become BG These cells are unique in calretinin synthesis Sub pial region – another site where glial guided migration do not occur

Formation of sulci & gyri :

Formation of sulci & gyri Migrating neuroblasts necessitate more surface area without increasing volume Proliferation of Glia Growth of dendrites & axons

Neuronal Migration Disorders:

Neuronal Migration Disorders True migration disorders Neurons fail to reach their intended destination. 1. Lissencephaly (agyria, pachygyria and sub-cortical band heterotopia). 2. Cobble stone complex malformation. 3. Heterotopias. Malformations of cortical organization. Microscopic abnormality in cortical arrangement. 1. Polymicrogyria. 2. Schizencephaly. 3. Focal cortical dysplasia.

Lissencephaly:

Lissencephaly Lissencephaly - Greek: “ Smooth Brain” Diffuse brain malformation. Migrated & reached cortex – lacks correct lamination LIS1 gene or Reelin gene defect Non genetic causes like infections also can cause it Cytoarchitecture – 2 forms 4 layer cortex instead of normal 6 layers Disorganized neurons – no recognizable layers

Lissencephaly…:

Lissencephaly… Smooth cerebral surface. Cerebellum & brainstem also abnormal Thalamus & BG –normal Enlarged / dysplastic ventricles .

Pathological descriptions in Lissencephaly :

Pathological descriptions in Lissencephaly Agyria : Absence of gyri Pachygyria: Reduced number of broadened flat gyrus with less folding. Both may be seen in the same brain. Sub cortical Heterotopia: - Sub-cortical, symmetric and circumferential bands of gray matter, separated from the cortex by a thin band of white matter - “double cortex”.

Lissencephaly…:

Lissencephaly… Lissencephaly and band heterotopia are distinguished by both pattern and severity of the malformation. Pattern or gradient may be . Anterior more severe than posterior A>P. . Posterior more severe than anterior P>A. . Less often seen; anterior similar to posterior A=P. Patterns and grades are important to distinguish different syndromes and gene association.

Lissencephaly 1 :

Lissencephaly 1 Most common. Pachygyria or Polymicrogyria can coexist Microcephaly with typical facies – micrognathia, high forehead, thin upper lip Developmental delay, MR, seizures, spasticity Death before 1 year LIS1 mutation

Classic Lissencephaly -Type I…:

Classic Lissencephaly -Type I… Thick cortex (10-20mm). Four cortical layers. - Marginal layer. - Superficial cellular layer -corresponds to cortical plate - Cell sparse zone. - Deep cellular layer composed of heterotopic neurons. Lissencephaly and band heterotopia comprise a single malformation syndrome. Gene – LIS1 , A > P.

Lissencephaly:

Lissencephaly

:

Lissencephaly

Lissencephaly with band heterotopia:

Lissencephaly with band heterotopia

Lissencephaly with sub cortical band heterotopia. :

Lissencephaly with sub cortical band heterotopia. Clinical features Normal at birth. Seizures uncommon on 1 st day of life. Seizures at 3-6 months, later infantile spasm and Lennox- gastaut syndrome. Profound MR . Early hypotonia, later spastic quadriplegia and opisthotonus .

Cobble Stone Lissencephaly (Type2):

Cobble Stone Lissencephaly (Type2) Brain malformations includes Cobble stone cortex. Abnormal White matter. Enlarged ventricles / Hydrocephalus Small brainstem. Small dysplastic cerebellum.

Cobble stone cortex:

Cobble stone cortex Cortex is severely disorganized with no recognizable layer with disruption by abnormal vascular channels and fibroglial bands. White matter is poorly myelinated with large number of heterotopic neurons.

Cobble stone complex:

Cobble stone complex

Clinical features…:

Clinical features… Profound mental retardation. Severe hypotonia. Mild distal Spasticity. Typically poor vision.

Cobble stone malformation syndrome:

Cobble stone malformation syndrome Fukuyama’s congenital muscular dystrophy least severe. Muscle – eye – brain disease - Intermediate severity. Walker – Warburg Syndrome - most severe. All are genetic with Autosomal recessive inheritance.

Fukuyama’s Congenital Muscular Dystrophy:

Fukuyama’s Congenital Muscular Dystrophy Mild cobble stone complex. Moderate to severe MR. Severe CMD joint contractures. Elevated CPK. Gene – FCMD gene .

Muscle – eye - brain Disease :

Muscle – eye - brain Disease Moderate cobblestone dysplasia. Severe MR/Epilepsy. Complex eye abnormalities. * Retinal, choroidal hypoplasia . * Optic nerve pallor, High grade myopia. * Glaucoma, Cataracts . * Iris hypoplasia / colobomas . CMD with contractures. Gene : POMGn T1, POM T1, LARGE .

Walker – Warburg Syndrome:

Walker – Warburg Syndrome Severe cobblestone. Severe brainstem, cerebellar malformation / Hydrocephalus. Absent septum pellucidum, agenesis of corpus callosum. Occipital cephalocele . CMD. Eye abnormalities. Severe MR with epilepsy. Gene : POM T1, FKRP, FCMD .

Other Lissencephaly Syndromes :

Other Lissencephaly Syndromes Miller- Dieker Syndrome – MDS. Isolated Lissencephaly Sequence – ILS. Sub cortical Band Heterotopia – SBH. Several types of heterotopia with cerebellar hypoplasia. X linked Lissencephaly with abnormal genitalia - XLAG. Baraitser - winter syndrome.

Miller – Dieker Syndrome:

Miller – Dieker Syndrome Multiple congenital anomaly. Classic Lissencephaly without gradient . Typical Facial appearance . * Prominent forehead. * Bitemporal hollowing. * Short nose. * Upturned nares . * Protuberant upper lip. * Small jaw. Gene involved LIS1 .

Isolated Lissencephaly Sequence:

Isolated Lissencephaly Sequence Normal facial appearance . Classic lissencephaly – No gradient / A>P. Most patients are female. Represents carrier phenotype found in female relatives of male with DCX – related Lissencephaly. Genes affected DCX, LIS1 .

Isolated sub cortical band heterotopias :

Isolated sub cortical band heterotopias Most patients are female . Mild to moderate MR. Intractable seizures. Pyramidal signs, Dysarthria . Gene – LIS1 , DCX

Subcortical band heterotopia-Double cortex:

Subcortical band heterotopia-Double cortex Sub-cortical, symmetric, circumferential bands of gray matter, separated from cortex by thin band of white matter. “Double cortex” appearance.

Subcortical band heterotopia - Double cortex:

Subcortical band heterotopia - Double cortex

Heterotopia with cerebellar hypoplasia:

Heterotopia with cerebellar hypoplasia 4Yr old, delayed developmental mile stones, intractable seizures, cerebellar ataxia.

Baraitser – Winter Syndrome:

Baraitser – Winter Syndrome Facial Dysmorphisms * Trigonocephaly, * Shallow orbit, * Coloboma iris / retina. Lissencephaly with an A>P gradient . Gene affected DCX (Double cortin gene ).

X Linked Lissencephaly with abnormal genitalia - XLAG:

X Linked Lissencephaly with abnormal genitalia - XLAG Male . Severe postnatal microcephaly / profound MR. Intractable epilepsy onset on the first day of life . Hypotonia / poor feeding / chronic diarrhea. Hypothalamic dysfunction – poor temperature regulation. Ambiguous / hypoplastic genitalia . Gene affected : Mutation of ARX gene . Lissencephaly with P>A gradient .

Heterotopias :

Heterotopias Group of neurons is an inappropriate location – either below or above the cerebral cortex.

Subcortical curvilinear heterotopia:

Subcortical curvilinear heterotopia

Sub cortical nodular heterotopia:

Sub cortical nodular heterotopia Large mass of heterotopia tissue expanding a portion of one cerebral hemisphere . Generally unilateral . Associated with ACC, Vermis hypoplasia .

Peri-ventricular (sub ependymal) nodular heterotopia :

Peri -ventricular (sub ependymal ) nodular heterotopia X linked – Filamin A defect Most common / May be asymptomatic. Adjacent to the lateral ventricle - Never started migrating Partial intractable seizures / 80-90% have epilepsy. Intelligence is normal in female/ MR in males. Few present with chronic headache. Gene affected – FLAMIN-A (FLNA) . Temporal lobe surgery for Peri ventricular heterotopia with hippocampus sclerosis – NOT successful.

Periventricular nodular heterotopia:

Periventricular nodular heterotopia

Sub-ependymal nodular heterotopia:

Sub- ependymal nodular heterotopia

Periventricular laminar heterotopia:

Periventricular laminar heterotopia

Periventricular laminar heterotopia:

Periventricular laminar heterotopia X linked – Doublecortin gene mutation Started migrating, stopped in sub cortical region Severe childhood seizures MR ± Rare, lacks features of nodularity.

PowerPoint Presentation:

Trans-mantle heterotopia Column of gray matter without nodular feature extends from ventricular wall to cortical surface.

Malformation of cortical organization:

Malformation of cortical organization Most neurons reach cortex but do not form normal cortical layers or intra cortical connection. Abnormal gyral pattern with increased cortical thickness 5-10mm (Normal 3-4 mm). It includes, Polymicrogyria and Schizencephaly. Focal cortical dysplasia with normal cells and microdysgenesis.

Polymicrogyria and Schizencephaly:

Polymicrogyria and Schizencephaly Polymicrogyria : Abnormal cortical lamination, excessive cortical in folding resulting in many small gyri separated by shallow sulci, associated with heterotopia. Schizencephaly: Consists of a deep cleft lined by cortex extending from pial surface to ventricular wall and Polymicrogyria involving cortex of the cleft and surrounding brain surface. Polymicrogyria and Schizencephaly must be considered together.

Layered polymicrogyria:

Layered polymicrogyria Marginal layer. Superficial cellular layer Thin cell sparse zone. Deep cellular zone. Unlayered polymicrogyria Layers are not distinct. Small tightly packed polymicrogyria mimic pachygyria .

MRI in Polymicrogyria:

MRI in Polymicrogyria Loss of normal gyral pattern, irregular or pebbled brain surface. Increased number of small 2-5 mm wide gyri separated by very shallow sulci. Irregular border between the cortex and underlying thin white matter.

Polymicrogyria:

Polymicrogyria

Polymicrogyria:

Polymicrogyria

Polymicrogyria:

Polymicrogyria

Pathogenesis:

Pathogenesis Genetic. Intrauterine viral infections. Impaired vascular supply.

Clinical features:

Clinical features Depends on head size, localization and extend of malformation. When imaging is in doubt, clinical picture helps to differentiate between Lissencephaly & polymicrogyria. * Lissencephaly – Diffuse hypotonia with no spasticity or minimal spasticity. * Polymicrogyria – Severe spasticity .

Common Clinical Problems:

Common Clinical Problems Developmental delay / MR. Seizures / spasticity. Unfavorable prognostic factors : * Congenital Microcephaly. * Involvement of extensive areas . * Spastic quadriparesis. Perisylvian area involvement results in psendobulbar palsy, oromotor and speech apraxia.

Polymicrogyria and Schizencephaly Syndrome:

Polymicrogyria and Schizencephaly Syndrome Bilateral frontal polymicrogyria. Bilateral fronto – parietal polymicrogyria. Perisylvian polymicrogyria ( congenital perisylvian syndrome). Mesial parieto – occipital polymicrogyria. Occipital polymicrogyria.

MRI in Schizencephaly:

MRI in Schizencephaly Reveals polymicrogyria. Deep clefts either open-lipped ( separated by CSF) or closed lipped where borders are apposed appearing as a column of gray matter.

Schizencephaly - Closed lipped:

Schizencephaly - Closed lipped

Schizencephaly – Open lipped:

Schizencephaly – Open lipped

Schizencephaly:

Schizencephaly Cleft brain is a common brain malformation. Unilateral - mild impairment, Bilateral lesion - severe MR. Present with MR / seizures / spasticity. Closed lipped Schizencephaly - Hemiparesis/Motor delay Open lipped schizencephaly - Seizures / Hydrocephalus. Gene involved : EMX2, GPR56.

Schizencephaly Syndrome:

Schizencephaly Syndrome Usually occurs with no other malformation except polymicrogyria . Schizencephaly may occur with septo- optic dysplasia (absent septum pellucidum, optic nerve hypoplasia). Schizencephaly with ACC .

Focal Cortical dysplasia with normal cell types:

Focal Cortical dysplasia with normal cell types Pure architectural Dysplasia * Abnormal cortical lamination. * Ectopic neurons in white matter. Present with – Epilepsy / learning disability. MRI : Lobar / gyral hypoplasia, atrophy of underlying white matter blurring of gray- white border. Increased T2 & decreased T1 signal intensity.

Focal cortical dysplasia with abnormal cell types (balloon cells):

Focal cortical dysplasia with abnormal cell types (balloon cells) Cytoarchitectural dysplasia It is clear only with histopathology, not with MRI

Microdysgenesis:

Microdysgenesis Microscopic malformation that consists of Neurons in the marginal layer Mild changes in laminar architecture Excess neurons in white matter. Seen in autism / schizophrenia.

Focal Cortical dysplasia:

Focal Cortical dysplasia

Focal Cortical dysplasia:

Focal Cortical dysplasia è è

Learning Points :

Learning Points 1. Lissencephaly cause major developmental problem and may shorten life. 2. Type II Lissencephaly associated with eyes or muscle disorders. 3. Some of less severe migrational and organizational abnormalities may be clinically silent but, associated with learning difficulties or seizures or motor disability.

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4. Many of them are discovered in MRI, some are microscopic and is relevant in the assessment of refractory seizure. 5. Combined malformations may be found in infants with severe developmental / neurological problem. 6. Patients with ACC may have no neurological problem. It is important to be guarded about the prognosis when such abnormalities are found early in lie.

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