Exam 1: Congenital Malformations, Hydrocephalus, Perinatal lesions (includes supplemental questions)

Question 1

A newborn infant is born close to full-term with an apparent CNS lesion. He is pictured below. What is the most likely diagnosis?

A. Anencephaly

B. Encephalocele

C. Arnold-Chiari, type 2

D. Dandy-Walker

E. Holoprosencephaly

F. Germinal matrix hemorrhage

Answer 1

B.

Encephalocele

• Note the presence of much of the skull, ears, and eyes. A mesodermal defect led to herniation (extrusion) of the brain through the defect. Thus, the posterior sac would contain brain with hemorrhage and would be covered with skin.
• Contrast this with anencephaly. The defect results from a failure of the neural tube to develop. The cerebral hemispheres (and sometimes the posterior fossa structures) do not form and there is no calverium.

Question 2

A 7 day-old is examined. Imaging is performed and is shown. What is the most likely diagnosis?

A. Anencephaly

B. Encephalocele

C. Arnold-Chiari, type 2

D. Dandy-Walker

E. Holoprosencephaly

F. Germinal matrix hemorrhage

Answer 2

D.

Dandy-Walker

• results from a failure of the cerebellar vermis (midline) to form. The 4th ventricle thus communicates (i.e. connects) directly with the subarachnoid space. A cyst developed that is filled with CSF. The posterior fossa becomes enlarged. Hydrocephalus is present. The above image shows the large posterior fossa cyst (at arrow in image on left).
• Contrast that to Arnold-Chiari Type II (Infantile) where the posterior fossa is too small. This is associated with herniation of the cerebellar vermis through the foramen magnum and elongation with kinking of the medulla. A meningomyelocele is present in 95% of the cases. Hydrocephalus is also present.

Question 3

—Agenesis of corpus callosum

Answer 3

No connection between cerebral hemispheres

• —Normal brain cerebral hemispheres are linked by the corpus callosum.
• —This can fail to form (completely or partially).
• —Can be clinically normal or with mental retardation

—• —Associated with other abnormalities

——• —Lipomas (benign fatty tumors) can be seen in the defect

• Note that in the image there is a total absence of the corpus callosum.

Question 4

—Anencephaly

Answer 4

Absence of (lack of) cerebral hemispheres

• Associated with folic acid deficiency, familial cases
• The neural tube is not closed at the anterior end. This significantly interferes with development of the brain.
• Note the absence of the skull and the mass of primitive neural tissues (area cerebrovasculosa) that replaces the normal brain.
• There is also a skull defect.

Question 5

—Arnold-Chiari, Type I

Answer 5

Herniation of cerebellar tonsils

Question 6

—Arnold-Chiari Type II

Answer 6

Herniation of cerebellar vermis, elongation/kinking of brainstem

*** —Symptomatic early in life (infantile) ***

—• Posterior fossa is too small and misshapen

—• Arnold-Chiari type II is characterized by downward displacement or herniation of the cerebellar vermis and brainstem through the foramen magnum (at the arrows).

—• The brainstem is often kinked.

——• Hydrocephalus develops.

——• A meningomyelocele is present in ~95% of cases.

——• Brainstem abnormalities

——• In the images note herniation of cerebellar vermis, elongation of medulla through foramen magnum, kinking of lower brainstem/upper spinal cord, hydrocephalus. In most cases, lumbar meningomyelocele is present.

Question 7

—Communicating Hydrocephalus

Answer 7

Enlarged ventricles after meningitis

—

—• Increase in ventricular size/CSF volume

• Communicating Hydrocephalus – CSF absorption disrupted (e.g. meningitis in subarachnoid space); no blockage within brain
• —Meningitis

Question 8

—Dandy-Walker

Answer 8

Enlarged posterior fossa, absent cerebellar vermis

—

• Agenesis of cerebellar vermis (roof of 4th ventricle)
• —4th ventricle connects directly with subarachnoid space creating a cyst

—•Posterior fossa is enlarged due to the cyst

—•Hydrocephalus

• —Can be associated with dysplasia of brainstem nuclei
• Dandy-Walker has enlarged posterior fossa, a 4th ventricular cyst secondary to agenesis of cerebellar vermis , and hydrocephalus. The 4th ventricle can directly communicate with the subarachnoid space. A cysts filled with CSF developed and enlarges the posterior fossa.
• Thus, in Dandy-Walker the posterior fossa is enlarged (due to the cyst formation). In Arnold-Chiari, the posterior fossa is too small (which leads to herniation of the cerebellar vermis and elongation/kinking of the brainstem).

Question 9

—Encephalocele

Answer 9

Herniation of brain through hole in skull

• In this case, the problem is not with closure of the neural tube per se. Rather, the skull fails to completely form. Hence, this is a mesodermal defect. This allows the otherwise normal brain to herniate (i.e. protrude) through the defect. This can be small and of limited consequence or large and incompatible with survival.

Question 10

—Holoprosencephaly

Answer 10

Single ventricle and cerebral hemisphere / absent olfactory bulbs

* common chromosomal abnormality of —Trisomy 13 & 18

—• A single cerebral hemisphere and ventricle (see left image)

• always with Arrhinencephaly: absence of the olfactory tract (and bulbs)

—• Other midline facial abnormality including cyclopia (fused eye); see right image.

Question 11

—Hydromyelia

Answer 11

Enlarged central canal of spinal cord

• Hydromyelia occurs when the central canal is enlarged.
• These cysts can interfere with tracts and other structures causes neurologic deficits.
• a photograph of hydromyelia. The central canal is enlarged. However, there is no extension beyond the central canal.

Question 12

—Hydrocephalus ex vacuo

Answer 12

Enlarged lateral ventricles due to caudate atrophy in Huntington Disease

—• Increase in ventricular size/CSF volume

• —Hydrocephalus Ex-vacuo – ventricular enlargement secondary to loss of brain substance (volume)

——• Degenerative disease (Alzheimer disease)

——• Hydrocephalus ex vacuo (Right) results from a loss of brain tissue (e.g. in the basal ganglia in Huntington disease). The ventricles expand secondarily. Compare to normal on the left. This can occur in other conditions with loss of brain substance (e.g. strokes, following brain surgeries/resections).

Thus, the enlargement of the ventricles is due to loss of brain tissue and not to an increase in CSF pressure.

Question 13

—Lissencephaly

Answer 13

No gyri

• In lissencephaly, there is an absence of gyri.
• If there are a few large gyri, this is termed pachygyria.
• The concept is that normal structure is needed for the brain to function normally. If there are too many (with other structural abnormalities) or there are too few gyri, the brain isn’t going to function normally. This can reflect genetic and other conditions.

Question 14

—Meningomyelocele

Answer 14

Spinal lesion with leg paralysis/increased AFP in amniotic fluid

• View of the back: CNS tissue is incorporated in the spinal defect in a meningomyelocele. The CNS tissue has herniated through the spinal defect. This is often associated with neural defects (e.g. bladder or lower extremity deficits).
• Note the lack of bone (arches) posteriorly. This section is from the lower spinal column (note the nerve roots). Although herniation or protrusion of the CNS tissue isn’t evident in this section, the designation of meningomyelocele would indicate involvement (i.e. herniation) of both meninges and CNS tissues in addition to the bony defect.

Question 15

——Micrencephaly (microcephaly)

Answer 15

Too small brain

* common chromosomal abnormality of —Trisomy 13

Question 16

—Neuronal Heterotopia

—

Answer 16

Neurons that failed to migrate / seizures

• Heterotopias result from a lack of neuronal migration. Heterotopias are often accompanied by gyral abnormalities.
• The nodules present on the ventricular surface include neurons that did not migrate to the cerebral cortex. These often act as seizure foci.
• Intellectual disability and other CNS congenital malformations are also common.

Question 17

Polymicrogyria

Answer 17

Too many gyri / 4-layered cortex

• In polymicrogyria, there is excessive gyration resulting in many (i.e. excessive) small gyri. The cytoarchitecture of the cortex is also altered; the normal 6-layered cortex becomes a 4-layered cortex).

Question 18

——Noncommunicating Hydrocephalus

—

Answer 18

Hydrocephalus due to stenosis (narrowing) of the cerebral aqueduct

—• Increase in ventricular size/CSF volume

• Noncommunicating Hydrocephalus - —Block of CSF pathway within brain by tumor, clot, stenosis (cerebral aqueduct), etc.

Question 19

——Syringomyelia

—

Answer 19

Cystic cavity in the spinal cord

• As the neural tube closes, the central canal of the spinal cord is also formed. This can occur abnormally. Syringomyelia occurs when there are additional cystic spaces within the spinal cord.
• Note that syringobulbia is the same process in the brainstem.
• There is a relationship of syringomyelia** with **Chiari malformation. (Adult Type I)
• a drawing of syringomyelia. Note the cystic space (the syrinx) within the spinal cord. If this is located centrally, pain and temperature would be preferentially affected.

Question 20

Germinal Matrix Hemorrhage

—

Answer 20

Occurs exclusively in premature infants

—• In premature* infants, germinal matrix hemorrhage can develop. The hemorrhage easily ruptures into the ventricles.

• Can extend to ventricles and subarachnoid space leading to hydrocephalus

*The germinal matrix disappears by birth. (Thus, this is a condition of premature infants, and is no longer present in full-term infants)

Question 21

Kernicterus

—

Answer 21

Sequela of Rh-incompatibility* / bilirubin damage because of incomplete BBB

——• In newborns, the blood-brain barrier is not complete. If bilirubin is elevated, it can leak through into the brain. Bilirubin is toxic to neurons.

——• The bilirubin-stained areas often appear yellow in color.

—• Adults with elevated serum bilirubin do not experience kernicterus due to an intact blood-brain barrier.

*Due to medical advances that prevents hemolysis through recognition of Rh mismatches and that can treat hyperbilirubinemia, kernicterus is now rare.

Question 22

Multicystic encephalopathy

—

Answer 22

Destruction of grey and white matter

• Anoxic-hypoxic; Without blood flow and/or oxygen delivery, the brain suffers ischemia or infarction of involved areas
• In extreme cases, there is necrosis of both the white and grey matter.

Question 23

Periventricular Leukocephalopathy

—

Answer 23

Adult with cerebral palsy with cystic lesions in deep cerebral white matter

• —Periventricular leukomalacia** – **Anoxic-hypoxic due to areas of necrosis without blood flow and/or oxygen delivery. The brain suffers ischemia or infarction of involved areas

• In PVL, infarct-like lesions develop in the white matter. These lesions can be seen in older children and adults with cerebral palsy.

Question 24

At Pediatric Autopsy conference, a stillborn infant is examined. The resident indicates anencephaly is present in this case. Which of the following is thought to have the most significant role in the pathogenesis of most cases?

A. Agenesis of corpus callosum

B. Folate deficiency

C. Herniation of the brain outside of the skull

D. Mechanical interference with closure

E. Trisomy 18

Answer 24

B.

Folate deficiency

(extra info from slide)

In many cases, the precise etiology is unclear. However, many studies have shown an association between folate deficiency and neural tube defects. Thus, a necessary prenatal step is to prescribe folate supplementation for the mother.

A few cases can be associated with mechanical interference with closure of the tube. For example, bands of amnion (placental membranes) can interfere with closure of the tube. Pathologic examination of such cases would show placental membranes intertwined with the CNS tissue.

Go back to the classifications per necessary steps/processes of development. Recognize that neural tube defects result from defects in the closure of the neural tube. Anencephaly would occur with failure of the anterior portion of the tube to close. Craniorachischisis totalis would be a failure of the entire neural tube to close.

The defect would lead to escape of fetal proteins (e.g. alpha fetoprotein) into the amniotic fluid. Some of this fetal protein can also leak into the maternal circulation. This can be used for prenatal screening.

See images in textbook, WebPath, or Robbins and Cotran Atlas of Pathology.

Question 25

A photograph from a **6 day old infant** is shown. **_Kenicterus_** is present. Which of the following **most likely contributed** to this condition? **A**. Bacterial meningitis **B**. Germinal matrix hemorrhage **C**. Infection from birth canal **D**. Incomplete blood-brain barrier **E**. Umbilical cord knot

Answer 25

**D**. **_Incomplete blood-brain barrier_** (extra info from slide) **Newborns** are **at risk** for **_kernicterus_** due to the **incomplete blood-brain barrier**. The **elevated bilirubin** can **leak into the brain** and **injure neurons**. Older infants and older individuals are not a risk due to the complete and intact blood-brain barrier.

Question 26

**Accumulation of** what **substance results** in the **indicated discoloration**? **A**. Conjugated bilirubin **B**. Copper **C**. Hemosiderin **D**. Rh antigen **E**. Unconjugated bilirubin

Answer 26

**E**. **_Unconjugated bilirubin_** (extra info from slide) See above. **Hemolytic anemia secondary** to the **Rh incompatibility** results in **_elevated unconjugated bilirubin_**. The **incomplete blood-brain barrier contributes** to this **susceptibility**. (Photograph from Robbins, 7th ed.)

Question 27

At braincutting, a specimen from a **3 year-old** girl is examined (**right**). Diagnosis in the **prenatal period** would most likely be **based on detection of** **which** of the following? **A**. Alpha fetoprotein **B**. Bilirubin **C**. Elevated WBC **D**. Folate **E**. Trisomy 21

Answer 27

**A**. **_Alpha fetoprotein_** (extra info from slide) **_Meningomyelocele_**, a **form of** **_spina bifida_**: The defect has allowed **herniation** of the **CNS tissues**. The **open spinal defect allows _alpha fetoprotein_** (**_AFP_**), a **liver protein** to **escape into** the **amniotic fluid** and **maternal blood**. This is **often used** in **prenatal diagnosis** of **neural tube defects**. The **microscopic picture shows skin** (adjacent to CNS tissue); there is **no bone** (i.e. spine) as expected.. Image can be found in and an earlier edition of Rubin’s Pathology (see LWW Health Library on ACOM’s electronic resources) . Compare **_meningomyelocele_** (sometimes termed **_myelomeningocele_**) with **_meningocele_**. In **_meningoceles_**, **CNS tissue _does not herniate_**. The defect only contains meninges. Thus, neurological deficits typically do not occur with meningocele. Meningomyeloceles often have lower limb deficits and neurogenic urinary bladders.

Question 28

A **16-year-old** with **cerebral palsy** presents for his annual comprehensive evaluation. The **cerebral palsy** was **secondary to** an **umbilical cord knot** and a **lack of blood flow/oxygen** to the brain. **_Periventricular leukoencephalopathy_** resulted. Examinations of his reflexes in affected regions would most likely show which of the following? **A**. Decreased reflexes **B**. Increased reflexes **C**. Normal reflexes **D**. No clear pattern

Answer 28

**B**. **_Increased reflexes_** (extra info from slide) **_Perinatal ischemia_** can result in **damage** (i.e. **perinatal lesion**) to the **previously normal** (i.e. **well-developing**) **brain**. **_Periventricular leukomalacia_** is the **most common perinatal lesion**. **Ischemia** results in _**infarction** in_ the **_periventricular white matter_** in the **cerebral hemispheres**. This _often results in **damage to motor tracts** and **upper motor neuron signs**_. **\* Spastic paralysis results**. **Reflexes are increased** (**_hyperreflexia_**). \* This effect on the reflexes **results from loss** of the **normal dampening** to the **reflex provided by** the **upper motor neurons**. _**Less dampening** leads to **increased reflexes**_. Other perinatal lesions includes germinal matrix hemorrhage (often with intraventricular extension) in premature infants.

Question 29

A brain is examined from a patient with a **history** of **_spastic right hemiplegia_**. **What type** of **_hydrocephalus_** is present? **A**. Communicating **B**. Ex Vacuo **C**. Noncommunicating

Answer 29

**B**. **_Ex Vacuo_** (extra info from slide) The **_infarcted area_** in the **thalamus/basal ganglia area** has **resulted in _secondary enlargement_** _of the **adjacent ventricle**_. This is **_due to the loss of tissue from the chronic infarct_**. It is larger than the ventricle on the opposite side. The space in the middle is due to separation of the leaflets of the septum pellucidum (cavum septum pellucidum) and is not significant. **_Communicating hydrocephalus_** occurs when the **_reabsorption of CSF_** _is_ **_**_blo_**cked_ within** the **subarachnoid space** by pus in meningitis or subarachnoid hemorrhage. There is no blockage of CSF pathways within the brain. **_Noncommunicating hydrocephalus_** occurs when **internal CSF _flow is blocked_**. This can be a **result of** a ventricular **tumor**, **stenosis** of the **cerebral aqueduct**, or another **lesion**.

Question 30

A **55 year-old** man develops **involuntary dance-like movements**. His **father** had **died of** the **same disease at 65**. Genetic analysis shows **42 and 9 CAG repeats**. **_Huntington disease_** is diagnosed. A **section of** his **caudate** is shown. What change is present? **A**. Cystic infarction **B**. Demyelination **C**. Gliosis **D**. Microglial nodules **E**. Neurofibrillary tangles

Answer 30

**C**. **_Gliosis_** (extra info from slide) In **_Huntington_**, the _**neurons** in the **caudate nuclei degenerate** due to the_ **_genetic abnormality_** (**increased CAG repeats**). The **caudate nuclei usually project into the lateral ventricles**. In **_Huntington Disease_**, that **atrophy causes** the **caudate nuclei** to be **very smooth** and **often concave**. This **results in** **_hydrocephalus ex vacuo_**. The ventricles enlarge to take the place of the loss tissue. The **bottom photograph** is taken from the **caudate**. **Neurons** have been **lost**; the **majority of the cells are astrocytes**. These **astrocytes proliferate** and **hypertrophy** with **injury** (including neuronal loss). **_This is gliosis_**. An **immunohistochemically stain** for **glial fibrillary acid protein** (**_GFAP_**) would **highlight the astrocytes**. The **_caudate_** is _**primarily** composed of **neurons**_ and **_not white matter_** (myelinated tissues). **_Gliosis_** can be **seen with chronic MS plaques/lesions**. However, this is **not a primary component of Huntington Disease**. **_Microglial nodules_** are **often seen** with **viral _CNS infections_**. **_Neurofibrillary tangles_** are seen with **_Alzheimer disease_**. These are best seen with **silver stains** or with **immunohistochemical stains** for **tau protein**.

Question 31

An archived slide from 1950 shows a section from the **spinal cord** in **_poliomyelitis_**. Several **dying neurons** are **pictured**. These neurons are **surrounded by** a **large number of cells** with **phagocytic properties**. What are these cells? **A**. Astrocytes **B**. Microglia **C**. Lymphocytes. **D**. Neutrophils **E**. Oligodendroglial cells

Answer 31

**B**. **_Microglia_** (extra info from slide) In **_polio_**, the **dying anterior motor neurons** are **surrounded by _phagocytic microglial_ cells**. This is **termed** **_neuronophagia_**. The **destruction** of the **anterior motor neurons** by the **viral infection** leads to **_lower motor neuron signs_** (e.g. **_atrophy_** of the **muscle**).

Question 32

A **40-year-old** man with **_HIV_** develops an **opportunistic viral infection** of his **brain** following **infection with** the **_JC virus_**. A section of his brain is shown. The **shown appearance** is most **likely due to** infection of which cell type? **A**. Astrocytes **B**. Ependymal cells **C**. Meningeal cells. **D**. Microglia **E**. Neurons **F**. Oligodendroglial cells

Answer 32

**F**. **_Oligodendroglial cells_** (extra info from slide) **Progressive _multifocal leukoencephalopathy_** (**PML**) results from **infection** of the **oligodendroglial cells** by the **JC virus**. This results in **foci of demyelination**. The photo on the left is stained with **Luxol Fast Blue**. This **section of _white matter_** should **normally stain all blue** (i.e. **myelinated**). The _**areas that are not blue** are **foci of demyelination**_. The photograph on the right showed the **oligodendroglial nuclei** with **viral inclusions**; the nuclei **appear enlarged** and **have empty-appearing areas**.