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Embryology, Central Nervous System, Malformations
Introduction
The central nervous system (CNS) is composed of the brain and the spinal cord. They both develop from the embryonic ectoderm, alongside other structures such as the skin. Their development begins as early as the 3rd and 4th weeks of embryonic life, starting with the process of neurulation, which is the development of the neural tube. The neural tube closes spontaneously rostrally and caudally. In the fifth to sixth week, the first appearance of the brain marks the onset of prosencephalic development. The primitive brain is comprised of the prosencephalon, mesencephalon, and rhombencephalon. The prosencephalon divides further into telencephalon and diencephalon through a series of developmental stages, namely: formation, cleavage, and development of the midline.[1][2][3] Any developmental alteration in these leads to malformation of the developing brain.[4]
The topic describes the embryology of the central nervous system and the developmental malformations of the cerebral cortex and spinal cord. Developmental malformations of the brain and spinal cord lead to a range of diseases, from microcephaly to spinal bifida. The stages of development of the cerebral cortex encompass 3 main steps. Defects in 1 or a combination of these steps form the basis of the classification of abnormality of the cortical development as:
- The proliferation of neural cells: Excessive proliferation can lead to megalencephaly, whereas decreased proliferation can lead to microcephaly.
- Neuronal migration: Partial migration results in heterotopia and lissencephaly; excessive migration causes cobblestone malformation.
- Postmigrational cortical organization and connectivity: Irregular events in the post-migrational cortical organization cause focal cortical dysplasias and polymicrogyria.[1][5][6][7]
The defects of neural tube fusion consist of encephalocele, meningocele, myelomeningocele, and spina bifida occulta.[8] Specifically, alterations in the closure of the rostral neural tube result in conditions like anencephaly or encephalocele. Myelomeningocele occurs from the incomplete closure of the neural tube. Anencephaly typically occurs before the 24th day of life, while encephalocele and myelomeningocele occur about the 26th day of life.[1]
Pathophysiology
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Pathophysiology
Etiology/Pathophysiology
Several studies have implicated environmental factors in the malformation of the central nervous system during embryonic development. These include folate deficiency, illicit drug use, and prescribed medications that affect folate metabolism in the body.
Cellular/Biochemical/Molecular Mechanism
The PI3K-AKT3-TSC2-mTOR Pathway
Both genetic and molecular factors may disrupt the normal development of the cerebral cortex. Any alteration in the genes that regulate growth and metabolic pathways leads to malformation of cortical development. Generally, the mammalian target of the rapamycin (mTOR) pathway has been strongly recognized in these malformations. Inhibition of TSC or activation of PIK3CA or AKT3 hyperactivates the mTOR pathway, leading to dysregulated cell growth.[4][9]
The majority of neural tube defects are sporadic. Genetic factors remain strongly implicated in the pathogenesis of NTDs, and inheritance is typically multifactorial or polygenic. Maternal folate deficiency may contribute to the development of NTDs in genetically susceptible individuals. Studies have shown that mutations in the genes involved in mitochondrial folate metabolism increase the risk. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and its variant form (C677T genotype) (MTHFR C677T) are associated with the risk for NTDs.[10] Maternal folate level is a risk factor; however, only an inconsequential number of cases. In many cases, the maternal folate levels are within the normal range or are hardly clinically deficient. Folate facilitates the transportation of 1-carbon units from the mitochondria to the cytoplasm and plays a vital role in the biosynthesis and methylation of nucleotides.[11]
Clinical Significance
Developmental Malformation of the Cerebral Cortex
Holoprosencephaly
Holoprosencephaly is a malformation of the prosencephalon characterized by incomplete separation of both cerebral hemispheres. Chromosomal abnormalities such as Patau and Edward syndromes carry a higher risk for holoprosencephaly as well as gestation complicated with diabetes. Patau syndrome (trisomy 13) is the most commonly associated syndrome.[1][12] Holoprosencephaly is usually incompatible with life, and most children born with this malformation have very high mortality early in postnatal life. The subtypes of holoprosencephaly in order of increasing severity are middle interhemispheric, lobar, semi-lobar, and alobar variants. A brain CT scan or MRI can confirm the diagnosis and differentiate the subtypes of holoprosencephaly.[13] Genes like the Bone Morphogenetic Protein (BMP), Sonic hedgehog (Shh), Fibroblast Growth Factor (FGF) are all suspected to be associated with holoprosencephaly.[14]
Agenesis of Corpus Callosum (ACC)
ACC is a partial development or complete absence of the corpus callosum, which is the connecting structure between the 2 cerebral hemispheres.[15] A frameshift (loss of function) mutation of the DCC Netrin 1 receptor gene correlates with agenesis of the corpus callosum, and most of the cases had no neurological symptoms.[16] The clinical and radiological manifestations of this disease vary; MRI is a good imaging modality for diagnosis. Studies have shown a strong connection between individuals with ACC share many common features with autism, such as stereotypy. Antisocial behavior and lying are also commonly reported features of callosal dysgenesis.[17][18]
Septo-optic Dysplasia
This condition is an abnormality of the forebrain comprised of the triad of a defect in the midline forebrain structures - septum pellucidum n (with or without agenesis of the corpus callosum), hypoplasia of the optic nerve (cranial nerve II), and pituitary insufficiency. It most likely occurs in the 4th to 6th weeks of life. It is an uncommon condition with an incidence of 1 in 10,000 live births. It has links to mutations in HESX1, SOX2, SOX3, or OXT2.[19][20] These produce a constellation of neurological symptoms, including optic nerve abnormalities, nystagmus, and other clinical manifestations, such as pituitary insufficiency.
Megalencephaly
Megalencephaly is an increased head size above 2 standard deviations. Clinically, it is more applicable to define it as a brain size greater than 3 standard deviations above the mean to exclude familial megalencephaly. It results from congenital defects in neuronal migration, abnormal cell proliferation, or both. Megalencephaly is classified by etiology, genetic abnormalities, and metabolic and developmental abnormalities. Mutations in genes controlling major molecular pathways, such as the phosphatidylinositol 3-kinase (PI3K/AKT) pathway, have been implicated. On the other hand, megalencephaly requires differentiation from macrocephaly, which is an unusual increase in occipitofrontal circumference (OFC) at least 2 standard deviations caused by structural abnormalities of the cranium, brain, or cerebrospinal fluid (CSF) and related structures.[5][21][22][23]
Hemimegalencephaly
This is unilateral cerebral hemisphere enlargement involving part or the entire hemisphere. Commonly seen in association with hemimegaloencephaly, neurocutaneous syndromes like linear sebaceous syndrome, tuberous sclerosis, and neurofibromatosis. The common presentation of this disease includes psychomotor retardation, intractable seizures, cranial nerve palsies, and hemiparesis. The presence of seizures in the first year of life is indicative of a poor prognosis.[24][25] Several studies have identified mutations in genes that regulate major molecular pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT-mTOR pathway.[26]
Periventricular Heterotopia
This pathology is a genetic disorder resulting from a failure of neuronal migration, leading to abnormally located nodules around the ventricles. The most common clinical manifestation is an afebrile seizure. Research has shown that it occurs alongside other conditions such as EDS, Williams syndrome, and Cri du Chat. However, mutations in the filamin A (FLNA (Xq28) and ADP ribosylation factor guanine nucleotide exchange factor 2 (ARFGEF2 (20q13). X-linked FLNA is autosomal recessive, while ARFGEF2 is X-linked.[27][28][29]
Lissencephaly-Pachygyria
Lissencephaly-pachygyria is a spectrum of abnormal development of the cerebral gyri and sulci resulting from the abnormal migration of neurons. The term for a partial development is pachygyria, and the complete absence is agyria. Pachygyria typically has milder symptoms compared to lissencephaly. Type 1 is the classic lissencephaly, and type 2 is the cobblestone complex.[30][31] Cobblestone lissencephaly is associated with mutations in the TUBA1A and GPR56 genes. The cobblestone defect results from the combined effects of excessive migration of neural crest cells into the leptomeninges and abnormalities of the cerebral pia mater surface. The commonest gene mutations implicated in lissencephaly are LIS1 and DCX. Others include cell-structure proteins such as actin, dynein, kinesin, and tubulin genes; the genes CASP2 and RIPK1; and the domain-containing adaptor with death domain (CRADD).[32][33]
Polymicrogyria
As the name implies, it is simply an abnormally formed cerebral cortex with multiple small gyri. The severity of symptoms is strongly correlated with the extent of brain involvement, with the unilateral focal variant being the mildest form of the disease. It has little or no symptoms and is mostly controlled with antiepileptic medications. The most severe is the bilateral frontoparietal polymicrogyria with significant neurological manifestations. This severe form gets inherited in an autosomal recessive pattern, and the defect is on chromosome 16q12-21.[34] Polymicrogyria is commonly associated with Aicardi, Delleman, DiGeorge 22q11.2 (deletion), Sturge–Weber, and Warburg Micro syndromes.[35][36] Mutations in genes controlling major molecular pathways, such as the phosphatidylinositol 3-kinase (PI3K/AKT) pathway, have been implicated. Researchers have also noted that cobblestone lissencephaly is commonly associated with polymicrogyria. (25047116). Schizencephaly is generally classified as a subtype of polymicrogyria, a rare brain malformation characterized by a split in the brain parenchyma that extends to the ventricles.[23][33][37][38][33]
Focal Cortical Dysplasia
Focal cortical dysplasias (FCDs) are an umbrella name consisting of several subgroups of abnormal lamination of the cerebral cortex.[4] It has been demonstrated to be the most frequent cause of seizures, not amenable to medications. FCD is generally more prevalent in males than in females.[39] Type I FCD is an abnormal absence of cortical lamination. If it occurs in radial patterns, it is subclassified as Ia and Ib if tangential, Ic, on the other hand, is a combination of both patterns.[40][4] In contrast to type I, which is mild and more likely in adults, type II FCD is more clinically severe and is observed more in children.[41]
Strong evidence has been advanced to demonstrate that tuberous sclerosis 1 and 2 (TSC1 and TSC2) and the phosphatase and tensin homolog (PTEN) genes, which regulate mTOR, are also implicated in FCD type 2b, given its shared features with tuberous sclerosis.[5][39]
FCD type III is either type I or II co-occurring with other brain lesions.[41] If hippocampus sclerosis is present, it is further classified as IIIa, with tumors as IIIb, vascular malformations as IIIc, and extrinsic pathologic insults such as hypoxia, trauma, and encephalitis as IIId.[4][40]
Developmental Malformation of the Spinal Cord
Neural tube defects (NTDs) are malformations of the brain and spinal cord resulting from the failure of the neural tube closure in the third and fourth week of intrauterine development. They are the most prevalent congenital malformation of the CNS.[8] Even though routine prenatal folic acid supplementation has been effective in decreasing the disease prevalence, it remains 1 of the most common abnormalities of the newborn.[42] There are 2 major forms of NTDs: anencephaly and spina bifida.
Spina bifida is a common NTD in which the spinal cord is exposed or protrudes to the surface with the meninges into a sac-like structure through a defect in the vertebral wall. It includes myelomeningocele, meningocele, and myelocele.[43][44] When this closure defect involves herniation of cerebrospinal fluid alone, it is called a myelocele. A myelocele containing meninges is a meningomyelocele; when it contains both meninges and spinal cord, it is called a myelomeningocele. Commonly associated with spina bifida are hydrocephalus and Arnold-Chiari malformation type II (a combination of myelomeningocele and cerebellar tonsil herniation).[1][45]
Anencephaly is 1 of the common types of NTDs with a congenital absence of the brain or parts of the brain and cranium. It occurs as a result of the failure of the cranial portion of neural tube closure.[43][44]
Encephalocele is a rare NTD in which the brain protrudes through an abnormal opening of the cranium with or without the meninges, leaving a projection of a bag-like structure hanging on the head.[46] It is also frequently associated with other CNS abnormalities like hydrocephalus, especially with the posterior encephaloceles.[47] This condition may result from aqueductal stenosis or torsion and may also be a post-surgical complication of encephalocele repair.[48]
Investigation/Treatment
Most central nervous system (CNS) malformations are recognizable during routine laboratory screening and ultrasound scans. A second-trimester elevated alpha-fetoprotein (AFP) in a triple screen raises a very high suspicion for neural tube defects.[49] Further diagnostic workup is required if any abnormalities are detected.[13] Treatment of congenital malformations of the CNS requires a multidisciplinary approach and supportive management, including antiepileptics, gastrostomy tubes, and other surgical modalities.[13] The most widely practiced prevention for spina bifida is folic acid supplementation, with preconception use more beneficial than use in pregnancy. In spina bifida, the spinal cord is exposed to the amniotic fluid that contributes to further damage of the nervous tissues. Newly practiced in-utero surgical procedures to prevent the neurodegeneration of the exposed spinal cord have helped preserve the structures and improve outcomes.[50]
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