Malformations of Cortical Development

Basics

Description

  • Cortical malformations are important in clinical neurology, as they are associated with developmental disorders, motor impairments, and epilepsy.
  • Defining the underlying malformation has prognostic value for patient’s family, as well as possible genetic counseling implications.
  • Classification schemes now emphasize the stage of embryogenesis which is disrupted.
  • Disorders of neurulation
    • First key step to development of the CNS is neural tube closure around days 21–26 of gestation. Disruptions to rostral closure may lead to encephalocele or anencephaly.
      • Encephalocele: herniation of the intracranial contents through a midline skull defect; may occur frontal (orbit, nose, or forehead), basal, or occipital
      • Anencephaly: congenital absence of both cerebral hemispheres with preserved forebrain and upper brainstem
  • Prosencephalic development
    • The prosencephalon is the precursor to the cerebral hemispheres and deep nuclei. Initial development begins at 4 weeks followed by cleavage occurring in weeks 5–6 and midline development from weeks 7–20.
      • Holoprosencephaly: 3 subtypes: (1) Alobar consists of a single spheroid cerebral structure with a common ventricle, fused thalami and basal ganglion, absent corpus callosum, and hypoplastic or single optic nerve. (2) Semilobar consists of anterior fusion with posterior cleavage and less fusion of deep structures. (3) Lobar is least severe, consisting of near total separation of the hemispheres with fusion in the most rostral and ventral aspects.
      • Agenesis of the corpus callosum (ACC): Corpus callosum fails to develop, ranging from complete to only mild thinning.
      • Septo-optic dysplasia: optic nerve hypoplasia, hypothalamic and pituitary hypoplasia plus midline and forebrain abnormalities (ACC, absent septum pellucidum)
  • Neuronal proliferation
    • Neuronal progenitor cells proliferation peaks during the 1st and 2nd month of human gestation leading to rapid cell growth and differentiation into neurons, astrocytes, oligodendrocytes, etc.
      • Hemimegalencephaly: unilateral enlargement of one cerebral hemisphere, with possible abnormal cortical development in the abnormal hemisphere
      • Megalencephaly: brain measuring >2 SD or >98% for age
      • Microcephaly: defined as occipitofrontal head circumference >2 SD below the mean for patient’s age
      • Tuberous sclerosis complex (TSC): Multiorgan disease with CNS involvement including cortical tubers (discrete areas of dysplastic cortex, paler and firmer in appearance than normal cortex), subependymal nodules, and subependymal giant cell tumors (SEGA).
      • Neurofibromatosis type I: characterized by café-au-lait spots, Lisch nodules in the eye, and benign and malignant tumors in CNS and PNS
  • Migration/organization
    • Neurons migrate from the subependymal zone to cortex between 3 and 5 months of human gestation with gyration and organization peaking by 26–28 weeks.
      • Lissencephaly type I: characterized by thickened cerebral cortex with a smooth surface lacking gyral formation. The underlying cytoarchitecture is abnormal, containing less than the normal six layers.
      • Pachygyria: abnormally formed cortex which contains a few coarse gyri
      • Subcortical band heterotopia: also referred to as “double cortex”; consists of a circumferential symmetric band of cortex located in the white matter just below typical cortex
      • Lissencephaly type II: also known as “cobblestone cortex.” Characterized by lissencephaly with protrusions of neurons over the brain surface into the subarachnoid space. On gross inspection, the surface of the brain has a cobblestone appearance.
      • Schizencephaly: consists of a deep cleft extending from cortical surface to the ventricle. The cleft may be lined with polymicrogyria cortex. The cleft may be bilateral or unilateral, with the Sylvian fissure being a common location. Subdivided into open and closed lip, with the former having a wide separation of the cleft wall and the latter having the cleft walls touching.
      • Polymicrogyria: defined as a malformation consisting of multiple small placations of the cortical surface in a festoon-like or glandular formation resulting in cortex with numerous small gyri. It may be subdivided depending on location.
      • Focal cortical dysplasia: consists of areas of cortex with abnormal lamination with ± balloon cells
      • Heterotopias: defined as collections of neurons in the periventricular or subcortical white matter

Epidemiology

  • Incidence of malformations varied depending on specific malformation but overall is quite rare.
  • The majority of malformations are associated with an increased incidence of epilepsy, ranging from 50–90%.
  • Some malformations, such as anencephaly, have been associated with low socioeconomic status.

Pathophysiology

  • Any disruption to the development of the CNS during the prenatal stage may lead to a malformation.
  • These disruptions include genetic mutations, metabolic derangements, infections, and toxic/environmental exposures.
  • With infectious and toxic etiologies, the timing of the incident is key in determining the resultant malformation.

Etiology

  • Genetic
    • Holoprosencephaly: trisomy 13 and 18; monogenic mutations including 2p21 (SIX3), 7q36 (SHH), 18q11 (TGIF), and 21q22
    • Microcephaly vera: 1q31 (ASPM), 8p23 (MCPH1), 9q33.2 (CDKL5RAP2), 13q12 (CENPJ), 19q13.12 (WDR62)
    • TSC: TSC1 9q34.13 (Hamartin), TSC2 16p13 (Tuberin)
    • Neurofibromatosis type I: 17q11 AD mutation of neurofibromin gene
    • Hemimegalencephaly: 1q43 (AKT3)
    • Lissencephaly: Miller-Diecker syndrome (lissencephaly, microcephaly, facial dysmorphism, syndactyly) LIS1 gene 17p13.3
    • Lissencephaly with cerebellar hypoplasia: Reelin 7q22
    • X-linked lissencephaly with abnormal genitalia: ARX Xp22.13
    • X-linked lissencephaly and subcortical band heterotopia: DCX Xq22.3-q23
    • Cobblestone cortex: may be seen in Walker-Warburg syndrome, Fukuyama congenital muscular dystrophy (FCMD), or muscle-eye-brain (MEB) disease
      • Walker-Warburg syndrome and MEB: (POMT1) 9q34.13, (POMGnT1) 1p33-34, (FKRP) 19q13.3, (LARGE) 22q12-q13.1
      • FCMD: (FKTN) 9q31.2
    • Schizencephaly w/ microcephaly: 19q13.12 (WDR62)
    • Polymicrogyria (PMG): known association with 22q11 deletions
    • Bilateral frontoparietal PMG: 16q13 (GPR56)
    • Occipital PMG: 9q34.12 (LAMC3)
    • Periventricular heterotopia: Xq28 protein filamin A (FLNA), autosomal recessive 20q11 (ARFGE2)
  • Some malformations associated with neurocutaneous syndromes
    • Hemimegalencephaly seen in hypomelanosis of Ito, linear sebaceous nevus syndrome, or Klippel-Trenaunay-Weber syndrome
    • Megalencephaly: Sturge-Weber syndrome, neurofibromatosis, tuberous sclerosis
  • Vascular (ischemia or hemorrhage)
    • Microcephaly: may be attributed to chronic placental insufficiency
    • Schizencephaly: often caused by MCA territory prenatal infarcts
    • Polymicrogyria: prenatal hypoxic ischemic injury
  • Toxins/exposures
    • Antiepileptic medications (valproic acid [VPA], phenytoin [PHT]): dysraphic states
    • Ethanol, radiation, mercury, retinoids: holoprosencephaly
    • Hyperthermia: encephalocele, anencephaly
    • Maternal diabetes
  • Infectious
    • Schizencephaly, microcephaly, anencephaly, polymicrogyria have been associated with various prenatal infections including CMV, toxoplasmosis, rubella, herpes
  • Metabolic syndromes
    • Common to see macrocephaly in metabolic disorders, as there may abnormal metabolite accumulation (Canavan, glutaric aciduria, etc.)
    • PMG has been observed in Zellweger syndrome, Refsum disease, and Menkes disease.

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