Pediatrics

Question 1

Germinal Matrix hemorrhage

Answer 1

Spontaneous hemorrhage in premature infants between 22-30 weeks gestation, usually weighing <1500g. The most common site is the germinal matrix at the median eminence (covering the basal ganglia). The most common site is the periventricular matrix zone located between the caudate nucleus and thalamus at the level of or slightly posterior to the foramina of Monro. The next common site is the occipital lobe. The least common site is the temporal horn of lateral ventricle.
Etiology: By the 18th to 20th week of gestation, the neocortical ventricular wall is lined by a prominent hypercellular well-vascularized zone known as the germinal matrix. This germinal zone is composed of undifferentiated, differentiating and migrating cells, radial glial fibers, polymorphous astrocytes, and thin-walled blood vessels. The germinal cells have very little structural support and the vessels are very fragile. A lot of angiogenesis and vessel remodeling is going on during this period and this may be the reason why this area is so susceptible to hemorrhage in younger premature infants. The control of blood pressure in the brain is not well developed in these infants. The hemorrhage is usually resulted of damage of the vessel wall. The mechanism may be damage of the endothelial cells by acidosis secondary to hypoxia. Birth injury seems to play a role as one-third of cases have difficult deliveries due to forceps rotations and breech presentation.

Question 2

Germinal matrix with subependymal hemorrhage only

Answer 2

Papile’s classification Grade I

Question 3

Germinal matrix hemorrhage with rupture into the ventricle

Answer 3

Papile’s classification Grade II

Question 4

Germinal matrix hemorrhage with intraventricular hemorrhage and ventricular dilation

Answer 4

Papile’s classification Grade III

Question 5

Germinal matrix hemorrhage with intraventricular hemorrhage with ventricular dilation and parenchymal extension

Answer 5

Papile’s classification Grade IV

Question 6

Chiari type I malformation

Answer 6

tonsil is herniated into the upper cervical cord. There is no obvious deformation of the pons and brainstem. The cerebellar vermis does not appear to be malformed.

Question 7

Chiari type II malformation

Answer 7

haracterized by displacement of the cerebellar vermis combined with deformities of the medulla and tectal plate with the later one leading to the tectum adopting the shape of a bird’s beak (so-called “beaking of the tectum”). It is often associated with syringomyelia, hydromyelia, spinal bifida, meningocele or meningomyelocele, and hydrocephalus. It can also associate with other malformations of the brain, cranium and meninges, cardiovascular, gastrointestinal and genitourinary systems. Chiari type II malformation is probably secondary to a neural tube defect. Chiar II malformations are typically associated neural tube defects such as meningomyelocele.

Question 8

Chiari III malformation

Answer 8

encephalocele formed by herniation of the structures of the posterior fossa, including the cerebellum, through an occipitocervical or high cervical bony defect. There may also be beaking of of the tectum, elongation and kinging of the brainstem and lumbar spina bifida.

Question 9

Dandy-Walker Syndrome

Answer 9

Syndromic malformation of the cerebellum and posterior fossa. The three essential features include:
-complete or partial agenesis of the vermis
-cystic dilatation of the fourth ventricle
-enlargement of the posterior fossa
Other common findings include:
-elevation of the tentorium cerebelli and lateral, transverse sinuses and torcula (torcular Herophilli)
-lack of patency of the foramina of Magendie and Luschka.
-Hydrocephalus
Other cerebral and visceral anomalies are present. It is the presence or absence of other cerebral and visceral abnormalities that determines the prognosis of individuals. About 68% of all cases have other developmental abnormalities of the CNS. Facial abnormalities may also be seen.

Question 10

Caudal regression syndrome

Answer 10

mermaid syndrome comprises a variable defect of lumbar vertebrae, sacrum, and coccyx. This is a severe developmental field defect of the posterior axis caudal blastema. The severest form is sirenomelia (mermaid syndrome). It is frequently associated with abnormalities of the anorectal and urogenital systems and lower limbs. The entire urinary tract can be absent. The pathogenesis is probably related to the failure of growth of the caudal eminence. The strongest association of caudal regression is with maternal diabetes, it has also been related to deletion of chromosome 7q, autosomal dominant and, probably, autosomal recessive transmission. Timing: it occurs in the primitive streak stage during week 3 of gestation before development of the allantois, and the allantoic vessels are usually absent. There is a single umbilical artery that arises directly from the aorta.

Question 11

Agenesis of corpus callosum

Answer 11

primary deficiency of axons of the corpus callosum cross the midline in the usual position are absent or deficient. Critical event(s) must have happened no later than 9th to 20th week of gestation, the peak time of development of corpus callosum. The corpus callosum develops in an anterior to posterior fashion, partial agenesis usually involves the posterior part while complete agenesis involves both anterior and posterior portions. If the anterior part of the corpus callosum is absent but the posterior part is present, a destructive mechanism should be seriously considered. Complete or partial agenesis of the corpus callosum rarely exists as an isolated entity. The cingulate gyrus overlying the residual portion of the corpus callosum has normal development. The more occipital portion of the cingulate gyrus, however, has vertical arrangement and is abnormal. Abnormal configuration of the cingulate gyrus is a constant association with agenesis of corpus callosum. In this particular case, Probst bundle, also called longitudinal corpora callosa. They are abnormal prominent bundle of fibers in median sagittal directions (longitudinal callosal fibers) in the lateral part of the roof of the lateral ventricles in cases of agenesis of corpus callosum. The volume of Probst bundle is significantly smaller than that of the corpus callosum.

Question 12

Colloid cyst

Answer 12

Most commonly found in the third ventricle

Question 13

Nodular heterotopia

Answer 13

Common, Heterotopic grey matter can be seen in anywhere within the brain but the ventricular surface is the most common site. There is a female predominance. It may consist of a single nodule of gray matter at the ventricular surface or a row of nodules at the ventricular wall creating an irregular ventricular surface. They are well demarcated from the underlying white matter. Bilateral ventricular nodular heterotopia is also associated with mutaion of filamin 1 gene on chromosome Xq28.

Question 14

Periventricular leukomalacia

Answer 14

PVL is often seen in premature babies and occurs most commonly in those that are born at or after 30 weeks of gestation. It is resulted from increased susceptibility of the white matter to hypoxic ischemic injury due to the inherent high metabolic rate of white matter during this stage of development. For premature babies that are born with more prematurity, such as those born with less than 28 weeks of gestation, germinal matrix hemorrhage is far more common than PVL. PVL occurs as a well demarcated, small, irregular lesion, sometime with cavity formation, in the white matter at a short distance from the ventricle. The affected brain tissue is often mineralized and gives the chalky appearance, but they can be very subtle and minute

Question 15

Alobar holoprosencephaly

Answer 15

On the frontal view, the two cerebral hemispheres appear to be fused in the midline although there is a falx like structure at the midline. In contrast, the cerebellum and the medulla seems to have split well into the right and left half. The cerebral hemispheres shows that the occipital portion is reduced to a thin translucent seam. The occipital portion of the parietal and occipital pallium is entirely converted into a thin membrane. The thalamus and the basal ganglia appear to have split into the left and right half. There is a single, dilated ventricle with no septum pellucidum.

Question 16

De Morsier Syndrome (Septo-optic dysplasia)

Answer 16

characterized by optic nerve hypoplasia, aplasia or defects of the septum pellucidum (an inconstant finding), and pituitary-hypothalamic dysfunction (hypopituitarism). Two of the three features must be present to fulfill the diagnostic criteria and only a minor portion of cases have all three features. The floor of third ventricle, a structure embryonically related to the development of the optic placodes, is abnormal in some cases. Olfactory aplasia is frequent. Other features include elevation of the tentorium cerebelli and lateral and transverse sinuses and torcula, lack of patency of the foramina of Magendie and Luschka, and hydrocephalus. Not all these features are present in every case. Although the septum pellucidum can be missing to suggest holoprosencephaly, the brain clearly splits normally into the left and right hemisphere.

Question 17

Leukodystrophy

Answer 17

white matter would lose its opaque white appearance and appears more translucent due to loss of myelin.

Question 18

32 week brain fetus

Answer 18

Fetus at 32 weeks of gestation has very little, if any, myelin in the cerebral hemisphere

Question 19

1 year old infant

Answer 19

brain is largely myelinated

Question 20

Thalamic gliosis

Answer 20

Bilateral thalami become white and rubbery with extension to the surrounding white matter. Bilateral thalamic gliosis is not a rare finding at autopsy. Thalamic neurons are vulnerable for hypoxic-ischemic insults in the premature and term newborn. They are also vulnerable to damage in utero when the mother sustains a cardiorespiratory or hypotensive event during pregnancy. Characterized by atrophy, firmness, and a chalky-white appearance. The rubbery firmness is due to gliosis.

Question 21

X-linked adrenal cortical leukodystrophy (X-ALD)

Answer 21

Disorder of peroxisomal fatty acid beta oxidation resulting in the build up of very long chain fatty acids (VLCFAs) within the body. This accumulation results in demyelination with macrophage infiltration and adrenal insufficiency. There is substantial loss of myelin in the cortical spinal tract but the myelination in the anterior spinal tract is relatively well preserved. This pattern is non-specific.
The adrenal glands are usually small and atrophic. Histologically, the zona glomerulosa is preserved but the cells in zona fasiculata and reticulata are enlarged, secondary to the accumulation of cytoplasmic birefringent striation. Lamellar cytoplasmic inclusions may be seen in the cells of the adrenal cortex.

Lipid lamellae: The lipid storage material stain poorly with traditional lipid stains. Under EM, the adrenal striations contain lamellae and lamellar lipid profiles. These lamellae are non-specific for X-ALD since they are also seen in other peroximal disorders including Zellweger syndrome, neonatal ALD, and infantile Refsum’s disease. These lipid droplets are seen in the cytoplasm of Schwann cells, testicular interstitial cells, liver, CNS macrophages, and oligodendrocytes.

Question 22

Globoid cell leukodystrophy (Krabbe disease)

Answer 22

A sphingolipidosis with an autosomal recessive inheritance pattern. It is caused by mutation of the GALC gene (14q31) which results in deficiency of the galactosylceramidase enzyme (lysosomal galactocerebroside b-galactosidase). Asymptomatic at birth, affected patients begin to develop symptoms within the first few months of life including irritability, stiffness, and delayed motor development. Accumulation of galactosylceramide in macrophages of the brain results in enlarged, multinucleated, globoid cells. White matter damage (leukodystrophy) occurs secondary to myelin degeneration and oligodendrocyte loss.Both peripheral and central nervous systems are involved. Infantile onset is most common but later or adult onset cases have also been described. Clinically features vary with the age of onset. The infantile form is associated with death at 1-2 years of age. Pathologically, the brain is markedly atrophic and shows extensive demyelination associated with large, multinucleated cells (globoid cells). The white matter but not grey matter is predominantly affected. Crystalline needle-like inclusions that correspond to the globoid material are seen under electron microscope. There is no globoid cells here to qualify even a suspicion of this diagnosis.

Question 23

Pelizaeus-Merzbacher disease

Answer 23

X-linked leukodystrophy caused by abnormalities of the proteolipid protein 1 (PLP1) gene (Xq22.2). Alteration of this gene results in hypomyelination and loss of oligodendrocytes with a characteristic sparing of the subcortical fibers. The peripheral nervous system is not affected.

Question 24

Alexander disease

Answer 24

leukodystrophy caused by a mutation of the GFAP gene (17q21). Microscopic changes include loss of myelin and marked formation of Rosenthal fibers, particularly in a perivascular and subpial distribution.

Question 25

Wilson disease (hepatolenticular degeneration)

Answer 25

(aka hepatolenticular degeneration) characterized by the accumulation of copper within the body. It is the result of mutation of the ATP7B gene which is involved in copper metabolism. With the accumulation of copper, patients develop cirrhosis, movement disorders, and psychiatric symptoms. Grossly, the brain may be discolored brown in the lenticular nucleus (putamen, globus pallidus).

Question 26

Status marmoratus

Answer 26

Status marmoratus literally refers to a firm chalky marble-appearing state. Status marmoratus is thought to occur if there is an hypoxic-ischemic insult occurring before the age of 6-9 months at the period of active myelination. It most frequently involves the caudate, putamen and thalamus in 80-90% of cases, and, less often the globus pallidus. Due to the perinatal hypoxic/ischemic insults, there is patchy destruction of the deep gray matter including the thalamus and basal ganglion. When myelin occurs, the landmark for normal myelination is lost. As a result, the final product is gliosis, mineralization of neurons, abnormal myelination pattern, and hypermyelination when myelination occurs.

Question 27

Hippocampal formation

Answer 27

The hippocampus is formed after the 16th week of gestation.

Question 28

Lamina dissecans

Answer 28

a transient hypocellular layer between the internal granular neurons and the Purkinje cells during development of the cerebellar cortex. It can be seen from about the 20th to 32th weeks of gestation.
During this period the fetal cerebellar folia has an extra layer of cells, the external granular layer. Neurons of the external granular layer will migrate inward, past the Purkinje cells, and form the internal granular layer. The lamina dissecans may represent the potential space where external granule cells can migrate in to form the internal granule cell layer. The lamina dissecans contains axonal terminals of mossy and climbing fibers as well as the processes of Purkinje and granule cells; it disappears by the 32nd week of gestation as the brain mature.
The lamina dissecans disappears in the midline first as these parts of the brain mature first and extends to the periphery of the cerebellar hemispheres. By comparing the pattern at the midline and the periphery, the approximate gestational age of the fetal brain can be estimated.

Question 29

External granular layer of the cerebellum

Answer 29

The external granular layer will persists until about 9 to 12 months after gestation. It is likely that some migration and differentiation of some granule cells continues through the first postnatal year. The external granular layer should not be mistaken as disseminated medulloblastoma or inflammatory cell infiltration.

Question 30

Cajal-Retzius neurons

Answer 30

aka horizontal cells of Cajal. Cajal-Retzius neurons can be seen in the developing cerebral cortex and immature hippocampus. In the human cortex, they are the first large neuron to appear in the cortex. seen in the mantle or marginal zone within the cortical plate. This is a heterogeneous population reeling-producing cells. Reelin is an extracellular matrix protein that is critical in acting as the stopping signal for radial neuronal migration.

Question 31

Pontine subicular necrosis

Answer 31

Hypoxic ischemic changes in premature infants are characterized by scattered eosinophilic cells with fragmented and condensed nuclei which are neurons undergoing apoptosis. These apoptotic cells can be seen in premature infants sustaining hypoxic/ischemic changes. The most common location is the subiculum and pons. Neuronal death in these locations when they occur simultaneously is called pontine subicular necrosis. However, this type of cell death is not limited to these locations and they can be seen in other areas such as the basal ganglia, colliculus, and thalamus. In contrast, neurons in the neocortex are usually not as affected.
The pattern of cell death in premature infants is different from adults. The pattern and cytologic features of neuronal death in adults and children at 3 years old are very similar. Neurons with hypoxic/ischemic injury will acquire cytoplasmic eosinophilia, loss of nuclear details, and contract contour that gives the cell a shape reminiscent to the flame of a candle (flame-shaped cells).

Question 32

Canavan disease

Answer 32

Demonstrates a very impressive signature gap between the molecular layer and internal granule layer.