Perinatal Disorders & CNS Malformations

Why is the distinction hard?

1. Brain development is long: it continues after birth (myelination; late-migrating cerebellar granule cells).
2. Timing changes the look: the same insult produces different morphology at different ages (selective vulnerability).
3. Repair changes over time: macrophage responses appear well before astrocytes can react.
   • Early disruption → dead tissue is resorbed without glial repair → a smooth-walled hole/pore with no gliosis.
   • Late disruption → glial scar forms → looks more destructive.
4. Limited repertoire: the brain can only react in a few ways, so one anomaly (e.g., polymicrogyria) can come from many causes, genetic or environmental.

How common, and how severe?

• Birth prevalence: 5–10 per 1,000 births; CNS malformations are present in ≈15% of infants who die of birth-defect-related causes.
• Spectrum of severity:
  • Gross defects that threaten life directly → anencephaly, myelomeningocele, encephalocele.
  • Subtle defects whose main consequences are epilepsy and intellectual disability → lissencephaly, polymicrogyria, cortical dysplasia, tuberous sclerosis.
  • Functional deficits → learning and behavior problems.

• The neural tube is the precursor of the entire CNS. It forms when the neural folds fuse in the midline (primary neurulation).
• Closure starts ≈day 22 after ovulation (closure site 1, cervical region), then at a second site, and zips both cranially and caudally.
• Anterior neuropore closes ≈day 26; posterior neuropore ≈day 28.
• Secondary neurulation (after primary closure): the lowest sacral cord and other non-epidermal tissues form from multipotent stem cells in the tail bud.
• Neural tube defect (NTD) = dysraphic disorder: failure of the neural folds to close (primary or secondary neurulation), so the tube and its bony/skin coverings stay open or malformed.

• Disorders of forebrain induction = hemispheric anomalies from failed separation of the forebrain vesicles (prosencephalon → two hemispheres) and failed commissure development (corpus callosum).
• Main example: holoprosencephaly (a disorder of forebrain induction/patterning; ventral midline signaling = Sonic hedgehog).
• Forebrain separation happens in weeks 5–6, right after neural tube closure. The face forms at the same time from the same midline signals → face and forebrain fail together.

• Learn the malformation list by group, with a one-line definition for each: NTDs → Chiari → forebrain induction → neuronal migration → cerebellum/brainstem/cord → hydrocephalus.

• Mechanism: anterior neuropore fails to close → the cranial vault never forms over it → exposed neural tissue sits in neurotoxic amniotic fluid and degenerates.
• Gross:
  • Absent/hypoplastic cranial vault and overlying tissue; brain replaced by a ragged, vascular mass = area cerebrovasculosa (disorganized vessels + neuroglial tissue).
  • Flat skull base, abnormal sphenoid, shallow orbits with protruding eyes, shallow sella turcica.
  • Absent hypothalamus and neurohypophysis.
  • Somatic associations: adrenal hypoplasia (no ACTH drive), large thymus, pulmonary hypoplasia.
• Epidemiology: the most common congenital brain malformation in human fetuses; F > M; sporadic or familial; ≈10× more common in Wales and Ireland (≈1–6 per 1,000) than in the US (0.5–2 per 1,000); ↑ maternal serum AFP.
• Outcome: incompatible with prolonged life after birth.

• Definition: the most severe spinal NTD, because both meninges and cord herniate (meningocele = meninges only).
• Location: lumbosacral most common, usually solitary, ≈equal sex ratio. Lesions above T12 → female predominance and more malformations elsewhere.
• Gross: fluctuant CSF-filled mass covered by skin or a thin membrane; dilated central canal; the posterior cord is open and blends with skin; nerve roots end blindly in the skin; at the defect the cord is a flat, highly vascular plate = area medullovasculosa (epithelializes after birth).
• Micro: islands of disorganized neural tissue (neurons, glia) packed with dilated, thin-walled vessels, next to squamous epithelium.
• Associations: Chiari II in >95%, plus hydrocephalus.

• Mechanism: failure of the forebrain (prosencephalon) to cleave into two hemispheres; ventral midline patterning signal (SHH) is weak or absent.
• A spectrum: alobar (worst) → semilobar → lobar (mildest). All forms lack a corpus callosum.

• Neurons are born near the ventricles and migrate outward along radial glia to build a 6-layer cortex (inside-out: deep layers first). Migration depends on microtubule machinery (LIS1/dynein, doublecortin) and stop signals (reelin).
• Neuronal migration disorders: gyri are too few, too many, too big or too small, and neurons are not where they belong.
• Vocabulary: lissencephaly = "smooth brain" (term borrowed from lower animals); agyria = no gyri; pachygyria = few, broad gyri. A spectrum from totally smooth to focal smooth areas to large, simplified gyri.
• Lissencephaly type I (classic):
  • Gross: smooth surface, open operculum (Sylvian fissure not covered), malformed gyri in a radial pattern.
  • Coronal: markedly thick cortex, thin white matter.
  • Micro: 4-layer cortex: molecular layer → thin outer neuronal layer → thin cell-sparse (white matter) layer → thick deep neuronal layer of neurons that never finished migrating.

• Many small, malformed convolutions: "gyri on gyri", a cobblestone / Morocco-leather surface. Underneath, the cortex is thin and abnormally layered (often 4-layered or unlayered), with fused molecular layers between microgyri.
• Patterns: diffuse; symmetric in arterial territories; at the margins of pores (schizencephaly/porencephaly); focal anywhere; perisylvian/opercular; symmetric parietal and insular.
• The "arterial territory" and "pore margin" patterns hint at a disruptive (ischemic or infectious) cause during mid-gestation.

• Malformations of cortical development result from abnormal proliferation, migration and differentiation of neurons and glia.
• FCD = a focal patch of cortex with loss of normal lamination + large neurons in abnormal locations.
  • Dysmorphic neurons: enlarged, abnormally rotated or inverted, tortuous dendrites, clumped Nissl substance; inclusions can stain with Luxol fast blue (blue aggregates) and may even be GFAP-positive (a glial marker inside a neuron).
  • Balloon cells: large cells with glassy eosinophilic cytoplasm and an eccentric (peripheral) nucleus; some show membranous CD34 (stem-cell marker) staining → they are immature, mixed neuron/glia cells.
• Normal cortex vs FCD: FCD shows absence of lamination + large nerve cells in an abnormal location.
• Histologically, FCD IIb ≈ cortical tuber ≈ hemimegalencephaly.

• Anencephaly: diagnosed in utero; ↑ AFP; polyhydramnios; often ↓ fetal movement; absent vault and protruding eyes at birth.
• Myelomeningocele: diagnosed in utero; deficits depend on lesion level (motor and sensory loss below it); loss of sacral innervation → bladder and bowel incontinence; lower-limb deformities (club feet).
• Encephalocele: mass at the back of the skull, often ulcerated/infected; contains loose connective tissue, disorganized glia ± cortex and choroid plexus.
• Occult spina bifida: asymptomatic or later tethered cord (back pain, leg weakness, bladder trouble during growth spurts).

• Chiari III: rare; hindbrain (cerebellum ± brainstem) herniates through a low occipital/high cervical encephalocele.

CSF path: lateral ventricles → foramina of Monro → 3rd ventricle → cerebral aqueduct → 4th ventricle → foramina of Luschka (lateral) and Magendie (median) → subarachnoid space → arachnoid granulations → dural venous sinus.

• In infants (open sutures) hydrocephalus → enlarging head circumference, bulging fontanelle, splayed sutures, "sunset eyes" (upward-gaze palsy from pressure on the dorsal midbrain).

• Prenatal diagnosis: NTDs and holoprosencephaly. Cortical malformations → early-childhood epilepsy, not seen in utero.
• Myelomeningocele → Chiari II (>95%) + hydrocephalus; the level of the lesion predicts function (see LO 5).

• Miller-Dieker = LIS1 + adjacent genes → microcephaly, bitemporal hollowing, small jaw, profound mental/motor retardation, feeding problems; early hypotonia → later hypertonia and seizures.
• Holoprosencephaly chromosomes: half have a normal karyotype; trisomy 13 is the most frequent abnormality.
  • Genes: SHH (7q36), SIX3 (2p21), ZIC2 (13q32).
  • Deletions: del(18p), del(7q36), del(2p21), del(13q32), del(21q22.3); duplication dup(3p24-pter).

• Animal clue: lambs of ewes grazing on Veratrum californicum develop cyclopia → the plant alkaloid cyclopamine blocks SHH signaling (Smoothened).

• Cause is mostly unknown; familial in some cases, without a clear inheritance pattern.
• Primary prevention: folic acid to mothers in the periconceptional period (introduced 1990; also grain fortification). It reduces but does not eliminate NTD risk.
• Inositol may be a useful adjunct.
• Mouse models: Splotch mice → anencephaly that is folate-preventable; curly tail mice → folate-resistant NTDs that are prevented by myo-inositol.

• Perinatal period = 20 gestational weeks → 28 postnatal days: a critical window of brain growth.
• Most injury comes from hypoxia and/or ischemia, especially intrapartum during prolonged or difficult labor.
• Clinical "asphyxia" = hypoxemia + poor perfusion → CO₂ retention and acidosis.
• Unlike malformations, the cause is usually clear and the brain was built normally.

• Preterm (<32–34 wk): the germinal matrix is still present and fragile → hemorrhage; immature oligodendrocytes in periventricular white matter → PVL.
• Third trimester / term: mature cortex and white matter → global ischemia causes multicystic encephalopathy (and watershed or basal ganglia patterns).

• Germinal matrix = part of the subventricular zone along the lateral ventricles (over the head of the caudate, caudothalamic groove) that produces immature neurons and glia; persists until ≈34 weeks.
• The commonest site of origin of periventricular and intraventricular hemorrhage in preterm infants (= subependymal hemorrhage).

Why it bleeds

• Highly cellular zone with anastomosing capillaries and no supporting stroma; very vascular.
• Sits at the border zone of striate and thalamic arteries.
• Drains into thin-walled venules (dilate progressively from 23 weeks; only thicken after 34 weeks).
• Hypoxic stress → loss of autoregulation → over-perfusion → rupture of fragile vessels; blood-pressure swings (ventilation, resuscitation) push flow straight into them.
• Poor hemostasis with excess fibrinolytic activity in the matrix.

Risk factors

• Gestational age at birth = the most important determinant: ≈10% at 30 wk, ≈40% at 26 wk, >50% at 24 wk.
• Most bleeds occur in the first 3–24 hours after birth; most often in infants ventilated for immature lungs; hypoxia/ischemia; blood-pressure fluctuation.
• Late bleeds (>24 h): respiratory distress syndrome, vigorous resuscitation, hypoxemia, seizures, BP fluctuation.

Grades (extent of the bleed)

• Grade 1: confined to the germinal matrix (subependymal).
• Grade 2: intraventricular, ventricle not distended.
• Grade 3: intraventricular + ventricular distension / hydrocephalus.
• Grade 4: rupture into surrounding white matter (parenchymal).

• Definition: infarcts of the periventricular white matter in premature infants (≈24–32 weeks).
• Mechanism:
  • Watershed: the periventricular white matter sits at the end-zone between long penetrating (ventriculopetal) arteries → most vulnerable when perfusion drops.
  • Preterm infants have poor cerebral autoregulation → hypotension = ischemia.
  • Pre-oligodendrocytes are exquisitely sensitive to glutamate excitotoxicity, free radicals and inflammatory cytokines (chorioamnionitis, sepsis).
• Gross: chalky white-yellow plaques next to the lateral ventricles (often near the angles of the ventricles); later cysts (cystic PVL), white matter loss, thin corpus callosum and ventriculomegaly.
• Micro: coagulative necrosis, axonal swellings (spheroids), mineralization (calcium), lipid-laden macrophages, then reactive gliosis.

• Also called multicystic encephalomalacia / leukoencephalopathy.
• When: later in gestation (3rd trimester), at or after birth; history of ↓ fetal movement or a co-twin dying in utero.
• Mechanism: severe, global hypoxia-ischemia (trauma, placental failure, cardiac arrest, co-twin death) → liquefactive necrosis of cortex and white matter → macrophages clear debris → cysts.
• Gross: "global hemispheric necrosis": small, light brain (e.g., 218 g vs normal 516 g at 2 months; 240 g vs 392 g at 16 days); multiple cysts in white matter and cortex; enlarged ventricles from tissue loss = hydrocephalus ex vacuo; a "spider's web" of fine gliovascular bands crossing the cavities.
• Micro: loss of parenchyma, cavities, gliosis, calcium deposits, vascular dilatation.

• Mostly no. They are acquired injuries driven by prematurity, hypoxia-ischemia, blood-pressure instability and infection/inflammation. There is no single "PVL gene". Unlike malformations, the etiology is clear (perinatal hypoxia-ischemia).
• Genes enter indirectly:
  • Fetal genetic disease that causes asphyxia: congenital heart disease (e.g., tetralogy of Fallot, which can be part of 22q11.2 deletion), neuromuscular or metabolic disease, CNS malformations.
  • Vessel-wall genes: COL4A1/COL4A2 (type IV collagen of basement membranes) variants → fragile small vessels → fetal/neonatal intraventricular hemorrhage and porencephaly; can recur in families.
  • Thrombophilia (e.g., factor V Leiden, prothrombin G20210A) → placental thrombosis/infarcts and perinatal arterial stroke.
  • Maternal conditions with genetic components (diabetes, hypertension, autoimmune disease) → placental dysfunction.
• Molecular mechanism (shared by all three): energy failure → glutamate excitotoxicity (NMDA/AMPA receptors) → Ca²⁺ overload → free radicals, cytokines (IL-1, IL-6, TNF-α from infection) → cell death (necrosis and apoptosis). Pre-oligodendrocytes lack antioxidant defenses → PVL.

• Survivors of perinatal injury (any lesion): intellectual disability, seizures, and cerebral palsy with ataxia, spasticity and choreoathetosis.

• Multicystic encephalopathy: no specific treatment; death within weeks, months or years. Survivors: microcephaly, spastic quadriplegia, intractable epilepsy, severe ID, cortical blindness, feeding failure (G-tube), aspiration.
• Perinatal injury overall → death, or ID, seizures and cerebral palsy with spasticity, ataxia and choreoathetosis (basal ganglia/thalamic injury after acute profound term asphyxia).