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 cafe-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.
Diagnosis
History
- A comprehensive family history assessing for members with known syndromes, intellectual disabilities, severe developmental delays, autism, epilepsy, unexplained deaths, frequent miscarriages, or parental consanguinity.
- Close attention should be paid to the pregnancy, inquiring about possible prenatal exposures (ethanol, medications, etc.), infections, or trauma/bleeding.
- Most children with CNS malformations will have developmental delays, thus a detailed developmental history should be obtained.
- Repetitive movements, alterations in consciousness, or other paroxysmal episodes should be asked about as seizures/epilepsy is common in this population.
Physical Exam
- At initial presentation, a full physical exam should be performed, paying close attention to head circumference, dysmorphic features, organomegaly, skin findings, and detailed neurologic examination.
- In anencephaly, there is little-to-no overlying skull present. Encephaloceles may be visible as soft, skin-covered protrusions through the skull. In Meckel syndrome, encephalocele is associated with microcephaly, microphthalmia, cleft lip/palate, polydactyly, polycystic kidneys, and ambiguous genitalia.
- Holoprosencephaly may be accompanied by facial anomalies such as absent or malformed nose, single or hyperteloric eyes, in addition to other organ system anomalies such as congenital heart disease, GI, GU, or skeletal defects.
- Skin findings such as hypomelanosis of Ito and linear sebaceous nevus raise concern for hemimegalencephaly.
- Neurofibromatosis type I has characteristic physical findings including macrocephaly, multiple cafe-au-lait macules, Lisch nodules, axillary/inguinal freckling, and palpable peripheral neurofibromas.
- "Ash-leaf " hypopigmented lesions, facial angiofibromas, and shagreen patches are seen in TSC.
- Miller-Dieker syndrome, associated with lissencephaly, has characteristic facial dysmorphisms including prominent forehead; short upturned nose; thin, protuberant upper lip; and small jaw. Spastic quadriparesis is often noted.
Diagnostic Tests & Interpretation
- Many of the malformations can be appreciated on prenatal ultrasound, leading to in utero diagnosis. Many tertiary centers are now able to perform fetal MRI, allowing for a more accurate image of the fetal brain.
- If not diagnosed prenatally, brain MRI should be performed on any patient where there is suspicion for a developmental malformation.
- CT is of little use, as it has low resolution and exposes the child to radiation.
- Once a malformation has been diagnosed via imaging, laboratory investigation should be pursued for known associated genetic etiologies.
- As mentioned prior, many malformations are associated with monogenic variations. Specific genes are available for testing in certain circumstances (e.g., TSC1 and 2,DCX, and LIS1).
- In the presence of other congenital anomalies, cerebral malformations may be associated with chromosomal changes, thus karyotyping is important in such cases.
- When malformations are known to be associated with metabolic disorders, blood, urine, and CSF should be analyzed.
- When seizures are suspected, video EEG is valuable in assessing for epileptiform activity.
Differential Diagnosis
- Focal cortical dysplasia may be difficult to distinguish from low-grade glioma on MRI.
- Vascular anomalies and remote infarcts can be mistaken for congenital malformations.
Treatment
Most cortical malformations are irreversible. Treatment centers around management of comorbid conditions such as epilepsy, spastic quadriparesis, language delay, and other sequelae.
Medication
- Any child with a malformation and epilepsy should be maintained on appropriate antiepileptic medication in conjunction with an experienced neurologist.
- Spasticity may be treated with antispasmodic agents such as baclofen or diazepam.
- In certain cases, such as TSC, novel agents (mTor inhibitors) are being investigated to halt progression of the disease.
Surgery/Other Procedures
- Cortical malformations often result in medically refractory epilepsy. Some patients may benefit from surgical treatment to cure or palliate their epilepsy. This process is done very systematically via an experienced epilepsy surgery center.
- More restricted malformations which lead to medically refractory epilepsy may be amendable to resection and result in seizure freedom or reduction.
- More extensive lesions, such as hemimegalencephaly, may be treated with functional hemispherectomy.
Ongoing Care
- Long-term prognosis varies depending on underlying malformation. The more extensive/severe the malformation, the more neurologic impairment is present.
- Significantly affected children require multidisciplinary care from a host of pediatric specialists including regular neurology visits.
- Families of children with known genetic etiologies should undergo formal genetic counseling to assess risk for other family members.
Additional Reading
- Barkovich AJ, Guerrini R, Kuzniecky RI, et al. A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012;135(5):1348 " 1369. [View Abstract]
- Hehr U, Schuierer G. Genetic assessment of cortical malformations. Neuropediatrics. 2011;42(2):43 " 50. [View Abstract]
- Sisodiya SM. Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol. 2004;3(1):29 " 38. [View Abstract]
Codes
ICD09
- 742.2 Congenital reduction deformities of brain
- 742.4 Other specified congenital anomalies of brain
- 742.0 Encephalocele
- 740.0 Anencephalus
- 742.8 Other specified congenital anomalies of nervous system
- 758.1 Patau 's syndrome
- 758.2 Edwards ' syndrome
ICD10
- Q04.3 Other reduction deformities of brain
- Q04.2 Holoprosencephaly
- Q01.9 Encephalocele, unspecified
- Q00.0 Anencephaly
- Q91.3 Trisomy 18, unspecified
- Q91.7 Trisomy 13, unspecified
- Q04.8 Other specified congenital malformations of brain
- Q07.8 Other specified congenital malformations of nervous system
SNOMED
- 253153000 Cortical dysplasia (disorder)
- 30915001 Holoprosencephaly sequence (disorder)
- 55999004 encephalocele (disorder)
- 89369001 anencephalus (disorder)
- 10572007 13q partial trisomy syndrome (disorder)
- 66985009 18q partial trisomy syndrome (disorder)