Brain malformations - Hospital Universitari de Bellvitge

Malformations
Prof. Isidro Ferrer, Institut Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de
Bellvitge, Universitat de Barcelona, CIBERNED, Hospitalet de LLobregat; Spain
Major events of developing human brain
Neurulation: 20-30 gestational days (stages X-XII: 2-4 mm in length):
X:
First fusion of neural folds
XI: Anterior neuropore closes
XII: Posterior neuropore closes
Canalization: 30-50 gestational days (4-22 mm in length)
XIII-XX
XV: around day 35: Evagination of the cerebral hemispheres (9 mm in length)
Development of the corpus callosum with an anteroposterior gradient: days 60-100
Cerebellum
•hemispheric fusion begins on day 60
•appearance of the external granular layer
• day 120 vermis complete
•migration of last neuroblasts from the external to the internal granular layer: first post-natal year
Cerebral cortex
•migration of neuroblast to cerebral cortical plate starts by week 7 and finishes at about month 6
General principles of pathogenesis
Malformations of the nervous system result from different causes including genetic and environmental factors that
may act at different target stages of embryonic or fetal development
Genetic factors are usually the consequence of point mutations, and malformations are inherited as autosomal
dominant, autosomal recessive or X-linked. Similar malformations may have very different genetic defects
controlling separate metabolic pathways. In contrast, similar mutations may have different consequences in males
and females
Several brain malformations are a part of complex malformations affecting different organs and systems. Certain
chromosomal alterations (mainly trisomies 21, 13, 18, causative of Down syndrome, Patau’s syndrome and
Edwards syndrome, respectively) present with brain malformations of variable severity
Human brain malformations related with particular gene mutations have been reproduced in rodents although the
phenotype differs in many instances indicating species-specific particularities of genes involved in brain
development
Environmental factors are numerous and include X-irradiation, infectious agents (rubella, toxoplasmosis, mumps,
cytomegalovirus, herpes simplex, among others), drugs and chemicals (alcohol, retinoids, valproic acid), nutritional
deficits (vitamin deficiencies, e.g. folic acid), maternal metabolic diseases (diabetes), and vascular or circulatory
accidents (fetal hypoxia and focal ischemia)
Maternal hazards during pregnancy: traumatisms, hemorrhages, suicide attempts
Several animal models have reproduced human brain malformations following exposure to variegated injuries.
Effects largely depend on the extent and time of exposure to the noxious agent
Genetic factors may act as predisposing factors which modulate the effect of environmental factors
Neural tube closure defects
Craniorachischisis: exposure of the brain and spinal cord to the amniotic fluid
Exencephaly and anencephaly: defects of closure of the anterior neuropore
Myelomeningocele: defects of closure of the posterior neuropore
Encephalocele: protrusion of brain or meninges through a cranial defect
Duplication or splitting of the spinal cord; hydromyelia
Chiari malformations (Chiari types I-III)
Disorders of the forebrain induction
Holoprosencephaly: variable failure of hemispheric cleavage (alobar, semi-lobar and lobar)
Arhinencephaly: absence of the olfactory bulbs and tracts (usually in association with other pathologies)
Agenesis of the corpus callosum
Septo-optic dysplasia
Cavum septi pellucidi (anterior) and cavum vergae (posterior)
Anencephaly
Anencephaly results from massive cell death and abnormal development of structures related with the anterior neuropore
Anencephaly
Attached to the skull is an irregular mass of cystic vascular tissue containing cerebrospinal fluid. The anterior pituitary
is atrophic and the neurohypophysis is absent. Part of the medulla oblongata is found at the level of the usually
altered foramen magnum. Remnants of the brain stem and cerebellum may be found. Cervical spina bifida is often
encountered
α-fetoprotein (AFP), usually synthesized in the developing choroid plexus, leaks to the amniotic fluid and is
detectable in the maternal serum. AFP is part of the prenatal screening of neural tube defects
Occipital encephalocele
A large mass composed of meninges, fibrous
tissue and brain tissue protrudes into the
surface throughout an occipital cranial defect
Chiari malformations
Chiari malformations
Chiari type I: elongation of the cerebellar
tonsils and neighboring parts of the cerebellar
hemispheres protruding into the vertebral
canal
Chiari type II, Arnol-Chiari malformation:
herniation of the vermis together with
deformities of the tectal plate and medulla,
usually accompanied by myelomeningocele,
meningocele and other spinal anomalies
Chiari type III: Herniation of the cerebellum
through an occipito-cervical or high cervical
bony defect
Chiari malformation
Chiari type I malformation is characterized by
herniation of the tonsils, and it is usually accompanied
by early- or late-onset hydrocephalus, headache, neck
pain and apneic episodes, lower cranial nerve palsies,
and syringomyelia
Chiari type I and hydrocephaly
Herniation of the tonsils (arrow) accompanied by hydrocephalus
Arnol-Chiari (Chiari type II) malformation
The inferior vermis and part of the medulla
oblongata protrude into the foramen magnum
(thick arrow)
The tectal plate is abnormally flatenned and
covers the upper vermis (thin arrow): beak-like
deformity of the corpora quadrigemina
A large hydrocephalus further increases pressure
to the posterior fossa compartment
Other cerebral anomalies are common including
focal cortical dysplasia, cerebral ectopias in the
white matter, hypoplasia and agenesia of cranial,
pontine and olivary nuclei, malformed cerebellum,
and subependymal grey heterotopias
Spina bifida (not shown) is invariably present
Holoprosencephaly
Alobar holoprosencephaly: complete absence of a
midline fissure separating the two hemispheres
resulting in a single holosphere
Holoprosencephaly may be a part of different malformative
syndromes such as pseudo-trysomy 13, Smith-Lemli-Opitz
and Meckel syndromes, among others, but it is commonly
associated with chromosomal abnormalies, mainly trysomy
13, and with mutations in other genes such as SHH (Sonic
hedgehog) mapping within the minimal critical region of HPE3
in chromosome 7q36 (HPE3), and SIX3 (HPE2), TGIF
(HEP4), ZIC2 (HPE5) and PITCH (HPE7) on chromosomes
2p21, 18p11, 13q32 and 9q22.3, respectively. Other loci have
also been detected: HPE1 (21q22.3), HPE6 (2q37.1), HP8
(14q13); and HPE linked to mutations in TDGF1 and GLI2
Holoprosencephaly
Semilobar prosencephaly with partial formation of interhemispheric fissure in the occipital regions (arrow)
Anterior view: lack of interhemispheric fissure
Posterior view: rudimentarynterhemispheric
fissure (arrow)
Patau syndrome: trisomy 13
Most common brain abnormalities in trisomy 13 are the following: holoprosencephaly, Chiari malformation, spina bifida,
cerebellar malformations, and various defects affecting the eye and the optic nerves
*
Lobar prosencephaly with separation of the cerebral hemispheres but midline continuity of
the cerebral cortex (arrow) and variable diencephalosynapsis (asterisk)
Partial agenesis of the corpus callosum
Partial agenesis of the corpus callosum is characterized by absence of the posterior corpus callosum
and variable sparing of the rostrum and genum
Agenesis of the corpus callosum may occur as an isolated malformation or in association with other malformations. Over
100 syndromes have agenesis of the corpus callosum
Partial agenesis of the corpus callosum
Famial agenesis of the corpus callosum may occur
in several syndromes: Aicardi syndrome, autosomal
recessive agenesis of the corpus callosum with
seizures,
callosal
agenesis,
sensorimotor
neuropathy and dysmorphic features, callosal
agenesis, hypothermia and apnoeic spells, and
acrocallosal syndrome resulting from mutations in
the GLI3 gene, GLI family zinc finger 3, located in
chromosome 7p13
MASA syndrome (mental retardation, aphasia,
shuffling gait and adducted thumbs), spastic
paraparesis type I and X-linked agenesis of the
corpus callosum are due to mutations in L1CAM
(encoding the neural cell adhesion molecule L1)
located in Xq28. CRASH syndrome (corpus
callosum hypoplasia, retardation, adducted thumbs,
spastic paraplegia and hydrocephalus) is the
accepted name for this disease
Agenesis of the corpus callosum
Complete agenesis of the corpus callosum affects the anterior and posterior regions, and is often
associated with the presence of a grey matter tract known as bundle of Probst (arrow)
Septo-optic dysplasia
De Morsier syndrome: optic nerve hypoplasia and visual impairment, hypoglycemia, diabetes insipidus and low
levels of growth hormone. Occasional seizures and mental retardation may occur as well
Genetic studies have shown septo-optic dysplasia in association with mutations in HESX1 (3p21.2-p21.1) and
SOX3 (Xq27.1)
Cavum septum pellucidum
The cavum septum pellucidum is normal in the human fetus but it is obliterated towards term
Iniencephaly
Neural tube defect that combines extreme retroflexion (backward bending) of the head and variable defects of the brain and
spinal cord
Hypothalamic hamartoma
Hypothalamic hamartoma (arrow) is composed of mature neurons of variable size distributed at random; the
medial structure is reminiscent of diencephalosynapsis
Micro(en)cephaly
● Primary microcephaly:
-Primary autosomal recessive: linked to six different loci (MCPHs): MCPH1 (microcephalin, 8p2-pter);
MCPH2 (19q13.1-13.2); MCPH3 (CDK5RAP2, 9q33.3); MCPH4 (15q15-q21); MCPH5 (ASPM, 1q31);
MCPH6 (CENPJ, 13q12.2)
-Primary autosomal dominant
-X-linked microcephaly
● Microcephaly associated with chromosomal syndromes (Down, 21 trisomy; Edwards, 18 trisomy;
cri-du-chat, 5p; Wolf-Hirschhorn, 4p)
● Syndromes with congenital microcephaly (Amish microcephaly, 17q25; Nijmegen syndrome,
mutation in NBS-1 encoding nibrin; microcephalic osteodysplastic primordial dwarfisms; microcephalia,
microphthalmia, ectrodactily and proganatism syndrome; Smith-Lemli-Opitz; Rubinstein-Taybi
syndrome).
● Genetic disorders with post-natal progressive microcephaly (Rett syndrome; infantile neuronal
ceroid lipofuscinosis with granular deposits; Alpers syndrome)
● Secondary (non-genetic) microcephaly (i. Infections: congenital rubella; cytomegalovirus;
toxoplasmosis; AIDS; ii. Ionising radiation; iii. Fetal alcohol syndrome , FAS)
Primary familial microcephaly
Primary microcephaly associated with abnormal cortical gyri and impaired cortical organisation without
layering
Down syndrome
Microencephaly, reduced frontal lobe and dendritic spine dysgenesis (long and thin spines in the apical
dendrite of a cortical pyramidal neuron, Golgi method).
Down syndrome: spine dysgenesis
A
C
B
D
Spine dysgenesis is found in
the apical dendrite of cortical
neurons (A), soma of cortical
interneurons (B) and striatal
neurons (C), and soma of
Purkinje cells (D) at early
stages of development in
Down syndrome
Congenital toxoplasmosis
Microencephalia and cystic encephalomalacia accompanied by
inflammatory infiltrates in the meninge, and astrocytes in the
cerebral grey matter filled with Toxoplasma gondii
Microcephaly as a result of metabolic diseases during development
Infantile neuronal ceroid
lipofuscinosis:
Alpers syndrome: marked cerebral atrophy
and laminar destruction of the cortical ribbon
marked cerebral atrophy due
to massive neuronal loss and
remaining
neurons
with
autofluorescent pigment in the
basal ganglia
Fetal alcohol syndrome (FAS)
Massive neuroblast death occurs in FAS, resulting in
microcephalia and abnormal convolutional pattern
Reduced numbers of dendritic spines and dendritic spine
dysgenesis (long and thin spines), as revealed with the Golgi
method; cortical neurons, frontal cortex. A: control, B: FAS, 13: consecutive segments of the apical dendrite
A
B
C
D
Dendritic spine dysgenesis following exposure to chronic ethanol consumption during gestation in
rats. A, C: control rat; B, D: rats exposed to ethanol during pregnancy
Marginal zone
Cortical plate
Intermediate zone
Germinal zone
Rat: gestation day 16
Ventricular lumen
Migration of human cortical neurons
Week 5
Cerebral vesicles
Week 7
Primordium of the cortical gray matter
Week 8
Four layers in cerebral mantle
¾ Germinal
¾ Intermediate
¾ Cortical plate
¾ Marginal
Week 12-13 Future layers VI, V, IV
Month 6
Most neurons to the cerebral cortex already migrated
Radial glia and migrating neuron precursor (arrow). Neuroblasts use radial
glia to migrate from the periventricular germinal layer to the cortical plate. This
is the common way neuroblasts give rise to pyramidal neurons. Nonpyramidal neuron precursors migrate following a tangential pattern
Naturally-occurring cell death during the development of the nervous system
Cell death during normal development of the nervous
system is programmed, and usually has morphological
and biochemical features of apoptosis. Cytoplasmic cell
death and autophagocytosis are other common forms of
programmed cell death during normal development
A
Functions
•Elimination of populations which are no longer present in determinate orders through evolution
•Elimination of cells during cavitation, fusion, folding, and bending of the neural plate, neural tube, and
formation of the optic and otic vesicles
•Elimination of transient populations which are needed during precise times of development, but not
necessary in adulthood
•Elimination of damaged cells
•Elimination of cells as a result of competition for targets and growth factors, and as a result of the effect of
hormones
Naturally-occurring cell death during the development of the nervous system
Members of the Bcl2/Bax family, and
caspases are factors involved in naturallyoccurring cell death during normal
development (A-D active caspase 3
immunoreactivity)
Widespread cell death in the developing nervous system with morphological features of apoptosis (white arrows) involves
germinal cells, neuroblasts, glial precursors and neurons (C-E: Tunel method)
Over-production of dendrites and dendritic spines during
normal development
Over-production of dendrites and dendritic spines permits the modulation of
synaptic contacts during development. Redundant synapses are eliminated to
optimize neuronal connections
Newborn insectivorous bat Myotis myotis. Note expanded dendritic arbors of layer
II neurons in the molecular layer, a common feature of primitive cortical patterns in
Insectivora, Cetacea and Chiroptera which lack specific thalamic afferents
terminating at cortical midlevels and which reach the molecular layer instead
Neuronal ectopic masses in the rat following 200 cGy X-rays at embryonic day 14 (e14)
V
Cortical rosettes of germinal epithelium (long arrows) and thin cortical mantle are seen at day 16 (short arrow)
Inside-out gradient of neuroblast migration in the cortex above the neuronal ectopic masses is preserved
*
*
Subcortical ectopic masses are largely formed by groups of neurons with typical cortical morphology including
pyramidal neurons (A, B, D) and occasional bizarre cells (C). Axons expand within the ectopia (c1 and c2) and outside
of it (c). Afferents come from the neighboring cortex (thick arrow), suggesting connectivity between the cerebral cortex
and the subcortical ectopic masses
Four-layered cortex in the dorsal region in the rat following 200 cGy x-rays at e16
A
II-III
Layer 1: molecular layer; layer 2: external cellular layer in
continuity with normal layers V and VI in the lateral cortex; layer
3: white matter; and layer 4: inner cellular layer composed of
neurons committed to layers II and III in the normal cortex
B
1
A: H-E; B: calbindin immunohistochemistry recognizes cortical
interneurons and neurons in layers II and III of the rat cortex. C:
Parvalbumin immunoreactivity decorates basket cells and axoaxonic cells of the cerebral cortex
Neuroblast migration is interrupted here after migration of
neuroblasts to future layers II and III
2
3
II-III
4
V
VI
C
Segmentation of the cerebral cortex in the rat following 200 cGy X-rays at e15, e17 and e19
E18
B
E15
C
A
*
*
*
*
P30
A: Cell death in vulnerable proliferative units of the germinal neuroepithelium (embryonic day 15); B: Preserved neurogenesis
and migration in the remaining germinal zones forming cortical columns (embryonic day 18); C: Columnar architecture of the
cerebral cortex (arrows) in mature rats (postnatal day 30)
Cortical malformations induced during the late migration period
Wistar rats at postnatal days 1-7 were subjected to one of the following single and direct (uncovered meninges)
lesions: focal freezing, focal electrocoagulation, focal aspiration or focal brushing
Animals developed varied cortical lesions, including laminar necrosis of layer V, microgyria, status verrucous and
porencephaly
*
Laminar necrosis of the cerebral cortex (arrow)
Necrosis of the inner layers (asterisk)
H-E and parvalbumin immunohistochemistry
Left panel: Disrupted cerebral cortex with small gyri formation and altered organisation of cortical layers. Right
panel: Distribution of calcium-binding protein-immunoreactive cells in a similar cortical malformation produced
by focal freezing at postnatal day 3 in the rat
*
*
B
A
A. Status verrucosus (H-E)
B. Warts (arrow) (parvalbumin
immunohistochemistry)
C. Expanded apical dendrites of
neurons in cortical warts (Golgi
method, camera lucida drawing)
C
Disorders of cortical migration and cortical organization
Lissencephaly type I
Lissencephaly type II (cerebro-ocular dysplasia and muscular dystrophy)
Cortical dysplasia: microdysgenesis
focal cortical dysplasia
hemi-megalencephaly
Tuberous sclerosis
Polymicrogyria: four-layered, unlayered
Aicardi syndrome
Neuronal heterotopias in the cerebral white matter: diffuse neuronal heterotopia, nodular
heterotopia and laminar heterotopia
Leptomeningeal glioneuronal heterotopia
Nodular cortical dysplasia: brain warts and status verrucosus
Hippocampal malformations: dispersion and duplication of the granular layer of the dentate gyrus
Lissencephaly
● Lissencephaly type I: characterized by four cortical layers: molecular layer; upper cortical layer
composed of normal layers V and VI, sparse cellular layer, and deep cellular layer formed by neurons that
failed to migrate to normal layers IV-II; and reduced subcortical white matter.
Genetics: mutations in different genes
- LIS1 (17p13.3) deleted in Miller-Dieker syndrome
- XLIS = DCX (Xq22.3-q23) encoding doublecortin: lissencephaly in males and subcortical band heterotopia
in heterozygous females
- RELN (7q22) encoding reelin
-ARX (Xp22.13): lissencepahly in males
-VDLR
-TUBA1A encoding tubulin 1a
● Lissencephaly type II: characterized muscular dystrophy and cortical involvement; “cobblestone“
cortical surface, non-layered cortex in which upper neurons protrude in the molecular layer and leptomeniges
and inner neurons form coarse columns; cellular disorganization in the cerebellum.
-Walker-Warburg syndrome (WWS), mutations in POMPT1 (9q31-q33)
-Walker-Warburg syndrome (WWS), mutations in POMPT2 (14q24.3)
- Muscle-eye-brain disease (MEB), mutations in POMGnT1 (1p34-p33)
- Fukuyama congenital muscular dystrophy (FCMD), mutations in fukutin (9q31)
- Congenital muscular dystrophy type 1D
- Mutations in the fukutin-related protein (FKRP)
Lysencephaly type I (Miller-Dieker)
μ
wm
External surface of the cortex showing lissencephaly; sections of cerebral hemisphere stained for myelin show thick
cerebral cortex and reduced subcortical white matter; abnormal convoluted dentate nucleus of the cerebellum
Schematic representation of neurons and fibers in the lissencephalic cortex: a four-layered pattern is charecterized by:
layer 1, molecular layer; layer 2, upper cellular layer; layer 3, sparse-cellular layer; and layer 4: inner cellular layer
Lissencephaly I: Miller-Dieker.
Layer 2 is composed of cortical neurons of layers V and
VI in normal cortex. IP: inverted pyramidal neuron; P:
pyramidal neuron; MP: Martinotti cell. Rapid Golgi
method
Lissencephaly I: Miller-Dieker.
Large pyramidal neurons in layer 2
Cortical architectonics suggests impaired neuronal migration to the cerebral cortex once the first wave of
neurons migrating to the normal cortical layers V and VI has finalized
Lissencephaly type II: Walker-Warburg syndrome
Lissencephalic cortex. Abnormal organisation of the cortical
mantle with a columnar pattern
Muscle, eye and brain disease
A
C
B
Polymicrogyric cortex (A) is better visualized under
microscopy examination (B). Severe alteration of the
striated muscle (C)
Pachygyria
This term refers to lissencephalic cortex with altered cortical ribbon composed of small and altered convolutions
Periventricular (nodular) heterotopia (PH)
PH is often associated with other brain malformations and multi-organ syndromes. X-linked PH is due to
mutations in FLNA, filamin A gene (Xq28). Autosomal recessive PH has been linked to mutations in
ARFGEF2(20q13.13), brefeldin A-inhibited GEF2 protein, involved in vesicular transport from the Golgi complex
Periventricular nodular heterotopia (arrows). Nerve cells in heteropia are typical “cortical” neurons (Golgi
method)
Tuberous sclerosis
Autosomal dominant diseases caused by germline mutations of the TSC1 and TSC2 genes. Multiple focal
disorder in the CNS of nerve cell differentiation, migration, and neoplastic transformation: cortical tubers,
glioneuronal hamartomas, subependymal glial nodules and subependymal giant cell astrocytoma
TSC1 gene: 9q34, product: hamartin
TSC2 gene: 16p13.3, product: tuberin
*
Tuber (asterisk) and subependymal giant cell astrocytoma (arrow)
Other abnormalities: adenoma sebaceum, shagreen patch, hypomelanotic maculae, subungual fibroma, retinal hamartoma,
retinal giant cell astrocytoma, iris spot, angiomyolipoma of the kidney, cardiac rhabdomyoma, rectal polyps, liver hamartoma
Tuberous sclerosis
*
Coronal section of the brain showing periventricular nodule (long arrow) and two cortical tubers (short arrows).
Section of the brain stained with Klüver-Barrera showing ectopia in the white matter (arrow) just below a cortical
tuber (asterisk). Camera lucida drawing of a cortical tuber showing disorganized cerebral cortex and increased
cellularity due to augmented numbers of astrocytes
Tuberous sclerosis: a disorder of cell proliferation, cell migration and cell differentiation
A
B
A: cortical tuber with abnormal organization and dysplastic neurons;
B: subcortical white matter heterotopia composed of aberrant glial cells
Aberrant glial cells in the white matter heterotopias as seen with
the rapid Golgi method
Tuberous sclerosis
Abnormal distribution and orientation of neurons in the cortical tuber. Asterisk marks two confronted pyramidal
neurons. Rapid Golgi method
Tuberous sclerosis
A
B
C
D
E
F
G
H
I
Parvalbumin- (A-C), calbindin- (D-F) and GABAA R(G-I) immunoreactive abnormal neurons in cortical
tuber
Tuberous sclerosis
A
B
C
D
E
F
Hamartin (A, B), tuberin (C, D) and reelin (E, F) in large neurons at
midlevel of cortical tuber
Focal cortical dysplasia (type 2)
*
B
A
A: Dysplastic giant neurons in the cerebral cortex. B: Distribution of
parvalbumin-immunoreactive cells in the dysplastic area. Parvalbumin
is normally expressed in basket cells and axo-axonic neurons, and it
has been used as a good marker of these types of inhibitory
interneurons. Areas of the cerebral cortex lack parvalbuminimmunoreactive neurons whereas abnormal giant interneurons are
abundant in other areas of the dysplastic cortex. The abnormal
morphology and distribution of main inhibitory neurons probably
accounts for epilepsy as a major clinical manifestation of focal cortical
dysplasia
A
B
C
Abnormal basket cell (A) and axo-axonic interneuron (B), as revealed with parvalbumin immunohistochemistry, in focal
cortical dysplasia. Double-bouquet interneurons (C) in a consecutive section processed for calbindin immunohistochemistry.
Formation and development of the cerebral convolutions is the consequence of tangential forces, neuronal
plasticity and focal cell death
Polymicrogyria
Multiple small malformed convolutions oberving one of the
two following patterns:
Unlayered polymicrogyria with complete disorganization
of the cerebral cortex
Four-layered microgyria resulting from laminar necrosis
of layer V
Etiology: variable
Intrauterine ischemia (localization at the borders of
porencephalic clefts or in the territory of the middle
cerebral artery; intrauterine infections; maternal bleeding
As a part of syndromes and disorders: Aicardi syndrome,
mitochondrial diseases, peroxisomal diseases
(Zellweger’s syndrome and neonatal
adrenoleukodystrophy), maple syrup urine disease,
Pelizaeus-Merzbacher disease, and rare familial
polymicrogyria with autosomal recessive inheritance
linked to mutations in GPR56 (16q13), among others
Cat: prenatal day 56, first pos0tantal week; gyrus
and sulcus
Unlayered microgyria
Unlayered polymicrogyria at the borders of porencephalic clefts results from
radial necrosis of the cerebral cortex and reorganisation of remaining cells
Unlayered microgyria
Multiple small gyri with fused
molecular layers. Nissl
staining
Cortical neurons visualized
with the rapid Golgi method.
While the morphology of
cortical neurons is not
altered, their distribution and
organization is severely
impaired (A-E)
Unlayered microgyria in the borders of porencephaly
Focal microgyria at the borders of porencephalic clefts that communicate the ventricles with the subarachnoid space
Microgyri, with fused molecular layers and increased number of blood vessels (Nissl staining), are composed of
abnormally-oriented cortical neurons (Golgi method)
Camera lucida drawings of cortical neurons stained with the Golgi method in different areas of microgyric brain.
H: Horizontal cell; P: Pyramidal neuron; M: Martinotti cell; IP: Inverted pyramid; SP: Small pyramid; LS: Large
stellate neuron; SS: Small stellate neuron; DB: Double-bouquet cells; af: cortical afferent; ax:axon; RGC: Radial
glial cell
Aicardi syndrome
X-linked Aicardi syndrome (Xp22) is characterized by infantile spasms, chorioretinopathy,
mental retardation, and vertebral anomalies
Common neuropathological findings are polymicrogyric brain, agenesis of the corpus
callosum, subcortical white matter heterotopias, and colloid cyst
Aicardi syndrome
Unlayered microgyria is composed of abnormally-oriented cortical pyramidal and non-pyramidal neurons. Primary
altered migration of neuroblasts and post-migrational remodeling of the cerebral cortex have been proposed as
possible causes of the cortical malformation
Ongoing microgyria and secondary cortical dysplasia
Superficial necrotic lesions in
the developing cerebral cortex
Cortical haemorrhages
Ongoing microgyria
Multiple foci of altered neuronal organisation with characteristics
of focal necrosis and subsequent reorganisation of neurons
forming fused microgyri are characteristic findings. PC: Parietal
cortex; F: Frontal, and O: Occipital cortex. C: calcarine sulcus; S:
Silvius fissure
Congenital rubella
Cerebellar malformations
Dysplastic gangliocytoma of the cerebellum
Dandy-Walker malformation
Cerebellar heterotopias and other dysplasias
Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease)
Enlarged and coarse cerebellar folia, and reduced white matter are characteristic macroscopical lesions. The cerebellar
cortex is composed of large ganglionic cells and superficial bundles of fibers. Bizarre neurons are visualized with the
rapid Golgi method; these cells have morphological features reminiscent of giant granule cells, and delicate cell
processes (arrows). Some cell processes embrace neighbouring neurons (asterisk)
Many neurons and delicate neuronal processes are stained with anti-calbindin antibodies usually used as markers of
Purkinje cells
Camera lucida drawings of neurons (left) and cell processes (right) stained with the Golgi method in dysplastic gangliocytoma
of the cerebellum.. Some neurons are reminiscent of granule cells (A, E), whereas other types are categorized with difficulty as
Purkinje or granule cells (B, C). A detail of cellular processes forming a basket (asterisk) is shown in a photograph of a Golgistained section. Giant synapses filled with clear vesicles in contact with a post-synaptic density are very common, and their
presence suggests a complex intra-tumoral connectivity
Dandy-Walker malformation
Agenesis (absence) of the inferior vermis and formation of a large cavity in continuity with the fourth ventricle is
the characteristic lesion in Dandy-Walker malformation
Altered fluid dynamics leads to accompanying hydrocephalia
Dandy-Walker malformation (DWM) is usually sporadic but rare familial cases have been reported in combination
with other brain malformations: DWM with mental retradation and spastic paraplegia; DWM with myopia, facial
dysmorfism, macrocephaly and brachytelephalangy; DWM with craniofacial and cardiac anomalies; and DWM in
trisomies 9, 13 and 18
Cerebellar heterotopia
A
B
C
Large heterotopic masses are present in the cerebellar white matter (arrows). These are composed of large ganglionic cells
reminiscent of those encountered in the deep cerebellar nuclei
Staining with Golgi method further
supports the possible origin of
these heterotopias in the deep
cerebellar nuclei
Other heterotopias, mainly encountered in the vermis, are
composed of small neurons with morphological features of
granule cells. H.E
Heterotopic Purkinje cells
Ectopic Pukinje cells (A-E) can be
encountered below the granule cell
layer in variegated cerebellar
malformations.
p: Purkinje cell; g: granule cell layer
Cerebellar malformation: hemimegacerebellum and heterotopia. Trisomy 13
Hemi-megacerebellum is composed of large ectopic masses
of neurons reminiscent of granule cells
Congenital pontoneocerebellar hypoplasia
A
B
C
Microcephaly with preserved structure of the cerebral cortex and diencephalic nuclei (A); hypoplasia of the cerebellar
hemispheres with absent folia and relative preservation of the paleocerebellum (medial cerebellar structures; arrow)
(B); hypoplastic pontine nuclei and inferior olive, and absent arcuate nuclei; disorganization of the dentate nucleus
Reduction or absence of Purkinje cells and granule cells in the cerebellar hemispheres (C)
Primary atrophy of the granular cell layer of the cerebellum: granular layer aplasia
Lack of granule cells, altered position of Purkinje
cells and cactus-like structures (arrows) are typical
of this malformation
Marked atrophy of the cerebellum, particularly vermis, is accompanied
by mild microcephaly.
Primary atrophy of the granular cell layers of the cerebellum
Cactus-like structures, as seen with current histological methods, are dense arborisations of Purkinje
cell dendrites often located at the terminal branches of otherwise very simple dendritic arbors
Interneurons are seldom observed in the agranular cerebellar cortex
Encephaloclastic defects
Hydranencephaly
Porencephaly
Multicystic encephalomalacy
The term encephaloclastic defects refers to thedestruction of normally-developed structures due to external
factors during the course of embryonic or fetal development. These are, therefore, secondary malformations
A major problem is related with the appearance of accompanying developmental defects depending on the time
of the injury. For example, porencephalic clefts may be due to infarcts in the territory of the middle cerebral
artery that produce cystic necrosis of the affected territory. In addition, sub-acute ischemia and partial radial
necrosis of the cerebral mantle often occur at the borders of the porencephalic cleft, thus producing
polymicrogyria once remaining neuroblasts reorganize the damaged cortical surface. Infarcts occurring before
the end of the migration period usually impair the migration of neuroblasts to their definite sites in the cerebral
cortex thus producing periventricular neuronal heterotopias and groups of ectopic neurons in the subcortical
white matter.
Familial occurrence of encephaloclastic lesions has been explained in the context of twinning, particularly
monozygotic, monochorionic twins, and involving blood flow sequestering by one of the two twins
Maternal infection has been postulated in some cases
Fowler’s familial hydranencephalia is a rare condition of unknown origin manifested by widespread glomeruloid
vascular proliferation and periventricular calcification
Hydranencephaly
Hydranencephaly is a very dramatic encephaloclastic lesion resulting from massive necrosis of the cortical mantle.
Certain areas of the temporal lobes (arrows) and part of the basal ganglia are preserved, supporting the idea that
hydranencephaly occurs after migration of cortical neuroblasts. The cerebellum and brain stem are preserved
Schizencephaly is an old term that stresses a failure of growth and differentiation of nerve cells as a cause of what
is known today as encephaloclastic defects produced as a consequence of infarction of the anterior and middle
cerebral arteries. Yet mutations in EMX2 appear to be causative of rare familial schizencephaly
Hydranencephaly
Upper view showing lack of telencephalic mantle and exposed choroid plexuses.
Microscopic examination reveals barely preserved deep cerebral nuclei near the
choroid plexus
Porencephaly
Porencephalic clefts are often bilateral and asymmetric. The ventricles are separated from the subarachnoid space by a
fine, often perforated membrane. The rest of the cerebral hemisphere is usually well organized excepting the borders of
the porencephalic clefts in which unlayered polymicrogyric cortex represents the reorganization of subacute radial
necrosis
Porencephaly
Large porencephalic cleft of the right cerebral hemisphere preserves a small region of the temporal lobe and part of the
diencephalic nuclei. The contralaterl hemisphere shows polymicrogyria in the territory of the middle cerebral artery
Hemispheric sections stained with Woelke
Multicystic encephalomalacia
Necrosis and cystification of the cerebral hemispheres with moderate preservation of the basal ganglia and rare involvement of the
brain stem and cerebellum
Hydrocephalus
Causes
Sporadic cases:
aqueductal stenosis of unknown etiology; atresia, forking, and gliosis of the aqueduct; DandyWalker malformation; Chiari malformation; cysts of the posterior fossa; defects in the foramina of
the fourth ventricle; tumors; haemorrhages; ventriculitis of variable origin, including prenatal
infections (rubella, toxoplasmosis, cytomegalovirus, mumps, varicella and bacteria); nutritional
disorders during pregnancy; toxics; irradiation
X-linked hydrocephalus (Bickers and Adams):
MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs), spastic
paraparesis type I and X-linked agenesis of the corpus callosum are due to mutations in L1CAM
(encoding the neural cell adhesion molecule L1) located in Xq28. CRASH syndrome (corpus
callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia and hydrocephalus) is
the accepted name for this disease
Other locus has been reported in association with X-linked hydrocephalus (Xq27.3)
Autosomal recessive hydrocephalus:
Several familial cases with hydrocephalus and aqueductal stenosis have been reported
Hydrolethalus syndrome is linked to 11q23-25 and includes hydrocephalus, midline
abnormalities, facial anomalies, ocular anomalies, polyhydramnios, agenesis of the corpus
callosum, diencephalosynapsis, and hypoplasia of the cerebellum and brainstem
Hydrocephalia, aqueduct stenosis
Congenital stenosis of the aqueduct is often manifested as small, narrow lumens with duplicated or triplicated
small lumina (forking)
Hydrocephalia, ventriculitis
Ventriculitis and subsequent disruption of the
ependyma may involve the aqueduct of Silvius
thus reducing cerebro-spinal fluid flow and dealing
to the progresive dilatation of the third and lateral
ventricles: tricamenral hydrocephalia