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Nervous System Disorders

= HPE = spectrum of congenital structural forebrain + midface anomalies characterized by failure of prosencephalon to divide (= cleavage disorder) → varying degrees of frontal lobe “fusion” (= noncleavage of cerebral hemispheres)

Etiology: multifactorial with environmental factors (maternal diabetes, ethyl alcohol, cigarette smoking, retinoic acid); chromosomal and genetic abnormalities; teratogen exposure; syndromic associations

Classic holoprosencephaly is a primary defect of ventral induction and patterning → total / partial failure of separation of prosencephalon into 2 separate hemispheres.

Pathogenesis:

arrested lateral ventricular growth in 6-week embryo → lack of cleavage / diverticulation of forebrain (= prosencephalon), laterally (cerebral hemispheres), transversely (telencephalon, diencephalon), horizontally (optic + olfactory structures) → cortical brain tissue develops to cover monoventricle and fuses in midline → posterior part of the monoventricle becomes enlarged and saclike

Associated with: agenesis of corpus callosum, septo-optic dysplasia, absence of cavum septi pellucidi

Sequence of disorders in prosencephalic ventral induction:

aprosencephaly → atelencephaly → alobar HPE → semilobar HPE → syntelencephaly → lobar HPE

Prevalence: 1÷10,000 in live and stillbirths; M÷F = 1÷1

Classification (DeMyer):

  1. alobar = no hemispheric development
  2. semilobar = some hemispheric development
  3. lobar = frontal and temporal lobation + small monoventricle

Associated with:

polyhydramnios (60%), genital defects (24%), postaxial polydactyly (8%), vertebral defects (5%), limb reduction defects (4%), transposition of great arteries (4%), renal and cardiac anomalies; chromosomal anomalies (predominantly trisomy 13 + 18 in 24–45%)

Associated borderline syndromes←diencephalic malformation:

  1. Anophthalmia
  2. Microphthalmia
  3. Aplasia of pituitary gland
  4. Olfactogenital dysplasia
  5. Septooptic dysplasia

Prognosis: not uniformly lethal depending on severity of brain and facial malformations, presence of chromosomal abnormalities, involvement of other organs, and presence of multiple anomaly syndrome

DDx:

  1. Severe hydrocephalus (roughly symmetrically thinned cortex)
  2. Dandy-Walker cyst (normal supratentorial ventricular system)
  3. Hydranencephaly (frontal + parietal cortex most severely affected)
  4. Agenesis of corpus callosum with midline cyst (lateral ventricles widely separated with pointed superolateral margin)

Alobar Holoprosencephaly!!navigator!!

= extreme form in which the prosencephalon does not divide

  • minimal motor activity, little sensory response (ineffective brain function); seizures
  • severe facial anomalies (“the face predicts the brain”):
    1. Normal face in 17%
    2. Cyclopia (= midline single orbit); may have proboscis (= fleshy supraorbital prominence)
      + absent nose [pro, Greek = forward; boscos, Greek = feed;proboskis, latinized = forward feeder, eg, elephant trunk]
      Embryology: developmental interruption of single midline eye field into L + R eyes under signaling influence of prechordal plate
    3. Ethmocephaly = 2 hypoteloric orbits + proboscis between eyes and absence of nasal structures
    4. Cebocephaly = 2 hypoteloric orbits + single nostril with small flattened nose + absent nasal septum
      [kebos, Greek = monkey; kephale, Greek = head]
    5. Median cleft lip + cleft palate + hypotelorism
      • absent philtrum
    6. Others: micrognathia, trigonocephaly (early closure of metopic suture), microphthalmia, microcephaly

In alobar holoprosencephaly prosencephalic cleavage fails → single midline forebrain with primitive monoventricle often associated with a large dorsal cyst.

  • crescent-shaped holoventricle = single large ventricle without occipital or temporal horns:
    • “horseshoe” / “boomerang” configuration of brain
      = peripheral rim of cerebral cortex displaced rostrally (coronal plane)
      1. ball configuration (most common) = complete covering of monoventricle without dorsal cyst
      2. cup configuration = more cortex visible posteriorly
      3. pancake configuration = cortex covers monoventricle to edge of dorsal cyst

    • cerebral mantle pachygyric
  • absence of: anterior commissure, cavum septi pellucidi, falxcerebri, interhemispheric fissure, corpus callosum, fornix, optic tracts, olfactory bulb (= arrhinencephaly), internal cerebral veins, superior + inferior straight sagittal sinus, vein of Galen, tentorium, sylvian fissure, opercular cortex
  • normal / fused / absent optic nerves
  • fused thalami:
    • protrusion of anteriorly placed fused hypothalamic and thalamic nuclei + basal ganglia into monoventricle resulting in absence of 3rd ventricle
  • large dorsal cyst (in 92%) occupying most of calvarium widely communicating with single ventricle
    Cause: fused thalami obstruct CSF flow → posterior ballooning of 3rd ventricle through suprapineal recess (= point of least resistance)
  • pancakelike cerebrum in posterior cranium
  • ± single / azygos anterior cerebral artery:
    • ± absence of middle + anterior cerebral arteries replaced by network of vessels arising from ICA + basilar vessels
  • midbrain, brainstem, cerebellum structurally normal
  • midline clefts in maxilla + palate

Prognosis: death within 1st year of life / stillborn

DDx: severe hydrocephalus, hydranencephaly (normal thalamic cleavage, partially visualized falx cerebri)

Semilobar Holoprosencephaly!!navigator!!

= intermediate form with incomplete cleavage of prosencephalon (more midline differentiation + beginning of sagittal separation) with >50%fusion of frontal lobes

  • absent / mild facial anomalies: midline cleft lip + palate
  • hypotelorism
  • mental retardation
  • single ventricular chamber with partially formed occipital horns + rudimentary temporal horns
  • peripheral rim of brain tissue is several cm thick
  • partially fused thalami anteriorly situated + abnormally rotated resulting in small 3rd ventricle:
  • dorsal cyst (in 28%) → macrocephaly (if cyst large)
  • absence of septum pellucidum + corpus callosum + olfactory bulb:
  • part of corpus callosum may be present between posteriorly separated hemispheres
  • rudimentary falx cerebri + interhemispheric fissure form posteriorly + caudally with partial separation of occipital lobes
  • incomplete hippocampal formation

Prognosis: infants survive frequently into adulthood

Lobar Holoprosencephaly!!navigator!!

= mildest form with formation of 3rd ventricle + some frontal horn + splenium and posterior body of corpus callosum

  • May be part of septooptic dysplasia!
  • usually not associated with facial anomalies except for hypotelorism, mild to severe mental retardation
  • spasticity, athetoid movements
  • interhemispheric fissure present along nearly entire midline
  • separation into 2 cerebral hemispheres + 2 lateral ventricles
  • closely apposed bodies of mildly dilated lateral ventricles
  • distinct occipital + frontal horns
  • colpocephaly
  • dorsal cyst (in 9%)
  • rudimentary unseparated frontal horns of angular squared shape + flat roof (on coronal images) ← dysplastic frontal lobes
  • dysplastic anterior falx + interhemispheric fissure
  • absence of septum pellucidum + sylvian fissures
  • corpus callosum usually normal / incomplete
  • hippocampal formation nearly normal
  • basal ganglia + thalami completely / almost completely separated
  • pachygyria (= abnormally wide + plump gyri), lissencephaly (= smooth gyri)

Prognosis: survival into adulthood

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