Forebrain Developmental Disorders (eg, Holoprosencephaly)

The major forebrain developmental disorders.

Major forebrain malformations

Holoprosencephaly

• "Alobar": a poorly formed single-lobe, "lobar": mostly separated but partially connected, "semilobar" is somewhere in between.

Developmental disruptions

• Schizencephaly
• Porencephaly

Midline malformations

• Septo-optic dysplasia
• Callosal agenesis.

migrational defects

• Heterotopia
• Lissencephaly

normal brain development

The primary brain vesicles ("-cephalon") at 4 weeks development

From cranial to caudal:

• Prosencephalon
• Mesencephalon
• Rhombencephalon

And, caudally, show the neural tube, which later becomes the spinal cord.

The secondary brain vesicles at 5 weeks development

From cranial to caudal:

• Telencephalon
• Diencephalon
• Mesencephalon
• Metencephalon
• Myelencephalon

Again, caudally, include the neural tube.

The prosencephalon partitions into the telencephalon and diencephalon

The rhombencephalon partitions into the metencephalon and myelencephalon

The lateral view of the fetus at 6 months

• The telencephalon blossoms into the large cerebral hemispheres.
• The diencephalon is buried deep within the brain; it comprises the thalamic areas.
• We include the corpus callosum between them, which is often poorly formed in forebrain developmental disorders, as we'll see.
• The brainstem comprises from superior to inferior:
• The midbrain (from the mesencephalon)
• The pons (from the metencephalon)
• The medulla (from the myelencephalon).
• The cerebellum blossoms from the posterior pons; it is also a metencephalon derivative.

gyrification

• The formation of gyri, which are delineations in the contour of the brain; this is most considerable during the first couple years of life.

The forebrain malformations

holoprosencephaly

Alobar

This is the most severe

• There is a single-lobed, poorly developed brain.

Semilobar

• A single-lobed, vastly more developed brain with no interhemispheric fissure and poor occipital development.
• There is diencephalic (notably thalamic) fusion (a lack of separation),
• Agenesis (failure of development) of the septum pellucidum: the midline division of the frontal horn of the lateral ventricles.

Lobar holoprosencephaly

This syndrome includes

• Presence of an interhemispheric fissure (unlike in the semilobar variant)
• A widened 3rd ventricle and fusion of the frontal lobes.
• Separation of the diencephalon (specifically the thalami)
• Agenesis of the septum pellucidum, consistent with the frontal horn fusion.
• Hypoplasia (poor formation) of the corpus callosum, which accounts for the failure of complete division of the hemispheres: there is partial, but incomplete, separation of the frontal lobes.

Craniofacial abnormalities

• These disorders often include profound craniofacial abnormalities, including:
• A small head circumference (microcephaly)
• Cyclopia (a single eye)
• Severe forehead, nasal, and palatal abnormalities.

The developmental disruptions

Porcencephaly

• A large CSF filled cyst, which is lined with white matter.

Schizencephaly

• A cleft in the brain that is lined with heterotopic (aberrant) gray matter.

midline malformations

Septo-optic dysplasia

A syndrome of midline dysplasia. In septo-optic dysplasia, there is:

• Corpus callosum hypoplasia
• Septum pellucidum agenesis (failure to develop), a characteristic radiographic finding.
• Optic nerve hypoplasia, which manifests with vision impairment (and the related but more rare finding of nystagmus) – this is best seen as the thin optic nerves that track from the chiasm to the orbits.
• Pituitary hypoplasia, which manifests with endocrinopathies:
  -Short stature
  -Hypoglycemia
  -Impairment in sexual development, including cryptorchidism (an absence of testes from the scrotum).

• Additional symptoms of septo-optic dysplasia include:
  -Seizures
  -Developmental delay
  -Motor deficits (hypotonia).

Callosal agenesis

• Absence of the corpus callosum (agenesis of the corpus callosum).
• In callosal dygenesis the the corpus callosum is no longer plump or smooth but rather ragged and thinned.
• Callosal agenesis can occur from congenital syndromes or acquired disorders, such as nutritional deficiencies.
• A classic cause of callosal agenesis is Aicardi Syndrome, which is an X-linked disorder that manifests with infantile spasms and chorioretinal lacunes.

Cortical migration disorders

Normal Migration

• The midline CSF space is surrounded by the ventricular zone (the ependymal layer) from which we see that neurons migrate outward to the intermediate zone (the neuronal layer).
• Heterotopia occurs if this migration is impaired.

Periventricular nodular heterotopia

• When the heterotopia lies close to subependymal germinal matrix.

Band (aka laminar) heterotopia

• Heterotopic bands of neurons that arrest in their migration between the cortex and the lateral ventricles.

This ectopic (out-of-place) gray matter is a key cause of seizures – as we can imagine, they are a nidus for aberrant electrical discharges.

Lissencephaly

• A failure of formation of delineated gyri, hence its name: "smooth brain".

Type 1 Lissencephaly

• Agyria: Smooth

Type 2 Lissencephaly

• Pachygyria: Cobblestone (abnormally large gyri that taken together form a cobblestone appearance).
• Lissencephaly may be isolated or a part of a more generalized syndrome, notably:
  -Miller-Dieker syndrome causes lissencephaly and band heterotopias along with microcalcifications and numerous other abnormalities.
  -Walker-Warburg syndrome manifests with type 2 lissencephaly and posterior fossa abnormalities (Dandy Walker malformation).

Polymicrogyria

• Small, numerous, underdeveloped gyri.
  -In Zellweger cerebrohepatorenal syndrome, which is a perioxisomal biogenesis disorder, there is a combination of both pachygyria and polymicrogyria.