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Annals of Neurology Nov 2017We aimed to (1) assess the concordance between various polymicrogyria (PMG) types and the associated epileptogenic zone (EZ), as defined by stereoelectroencephalography...
OBJECTIVE
We aimed to (1) assess the concordance between various polymicrogyria (PMG) types and the associated epileptogenic zone (EZ), as defined by stereoelectroencephalography (SEEG), and (2) determine the postsurgical seizure outcome in PMG-related drug-resistant epilepsy.
METHODS
We retrospectively analyzed 58 cases: 49 had SEEG and 39 corticectomy or hemispherotomy.
RESULTS
Mean age at SEEG or surgery was 28.3 years (range, 2-50). PMG was bilateral in 9 (16%) patients and unilateral in 49, including 17 (29%) unilobar, 12 (21%) multilobar, 15 (26%) perisylvian, and only 5 (9%) hemispheric. Twenty-eight (48%) patients additionally had schizencephaly, heterotopia, or focal cortical dysplasia. The SEEG-determined EZ was fully concordant with the PMG in only 8 (16%) cases, partially concordant in 74%, and discordant in 10%. The EZ included remote cortical areas in 21 (43%) cases and was primarily localized in those in 5 (10%), all related to the mesial temporal structures. All but 1 PMG patient with corticectomy or hemispherotomy had a unilateral PMG. At last follow-up (mean, 4.6 years; range, 1-16), 28 (72%) patients remained seizure free. Shorter epilepsy duration to surgery was an independent predictor of seizure freedom.
INTERPRETATION
PMG-related drug-resistant epilepsy warrants a comprehensive presurgical evaluation, including SEEG investigations in most cases, given that the EZ may only partially overlap with the PMG or include solely remote cortical areas. Seizure freedom is feasible in a large proportion of patients. PMG extent should not deter from exploring the possibility of epilepsy surgery. Our data support the early consideration of epilepsy surgery in this patient group. Ann Neurol 2017;82:781-794.
Topics: Adolescent; Adult; Brain; Child; Child, Preschool; Drug Resistant Epilepsy; Electroencephalography; Female; Humans; Male; Middle Aged; Polymicrogyria; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 29059488
DOI: 10.1002/ana.25081 -
Pediatric Clinics of North America Jun 2015Malformations of cortical development (MCDs) are a common cause of neurodevelopmental delay and epilepsy and are caused by disruptions in the normal development of the... (Review)
Review
Malformations of cortical development (MCDs) are a common cause of neurodevelopmental delay and epilepsy and are caused by disruptions in the normal development of the cerebral cortex. Several causative genes have been identified in patients with MCD. There is increasing evidence of role of de novo mutations, including those occurring post fertilization, in MCD. These somatic mutations may not be detectable by traditional methods of genetic testing performed on blood DNA. Identification of the genetic cause can help in guiding families in future pregnancies. Research has highlighted how elucidation of key molecular pathways can also allow for targeted therapeutic interventions.
Topics: Child; Diagnostic Imaging; Genetic Variation; Genomics; Humans; Malformations of Cortical Development; Mutation
PubMed: 26022163
DOI: 10.1016/j.pcl.2015.03.002 -
American Journal of Medical Genetics.... Aug 201722q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and...
22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes.
Topics: Abnormalities, Multiple; Brain; Cerebellum; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 22; Developmental Disabilities; DiGeorge Syndrome; Female; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Malformations of Cortical Development; Nervous System Malformations
PubMed: 28577347
DOI: 10.1002/ajmg.a.38304 -
Biological & Pharmaceutical Bulletin 2018Folds of the cerebral cortex (gyri and sulci) are among the most important properties of the mammalian brain. Uncovering the physiological roles, developmental... (Review)
Review
Folds of the cerebral cortex (gyri and sulci) are among the most important properties of the mammalian brain. Uncovering the physiological roles, developmental mechanisms and evolution of the cortical folds would greatly facilitate our understanding of the human brain and its diseases. Although the anatomical features of the cortical folds have been intensively investigated, our knowledge about their molecular bases is still limited. To overcome this limitation, we recently established rapid and efficient genetic manipulation techniques for the brain of gyrencephalic mammal ferrets (Mustela putorius furo). Using these techniques, we successfully uncovered the molecular mechanisms of cortical folding. In this article, I will summarize our recent research on the molecular mechanisms of development and diseases of cortical folding.
Topics: Animals; Brain; Callithrix; Disease Models, Animal; Electroporation; Ferrets; Polymicrogyria
PubMed: 30175769
DOI: 10.1248/bpb.b18-00142 -
NeuroImage May 2021The mammalian brain cortex is highly folded, with several developmental disorders affecting folding. On the extremes, lissencephaly, a lack of folds in humans, and...
The mammalian brain cortex is highly folded, with several developmental disorders affecting folding. On the extremes, lissencephaly, a lack of folds in humans, and polymicrogyria, an overly folded brain, can lead to severe mental retardation, short life expectancy, epileptic seizures, and tetraplegia. Not only a specific degree of folding, but also stereotyped patterns, are required for normal brain function. A quantitative model on how and why these folds appear during the development of the brain is the first step in understanding the cause of these conditions. In recent years, there have been various attempts to understand and model the mechanisms of brain folding. Previous works have shown that mechanical instabilities play a crucial role in the formation of brain folds, and that the geometry of the fetal brain is one of the main factors in dictating its folding characteristics. However, modeling higher-order folding, one of the main characteristics of the highly gyrencephalic brain, has not been fully tackled. The simulations presented in this work are used to study the effects of thickness inhomogeneity in the gyrogenesis of the mammalian brain in silico. Finite-element simulations of rectangular slabs are performed. These slabs are divided into two distinct regions, where the outer region mimicks the gray matter, and the inner region the underlying white matter. Differential growth is introduced by growing the top region tangentially, while keeping the underlying region untouched. The brain tissue is modeled as a neo-Hookean hyperelastic material. Simulations are performed with both homogeneous and inhomogeneous cortical thicknesses. Our results show that the homogeneous cortex folds into a single wavelength, as is common for bilayered materials, while the inhomogeneous cortex folds into more complex conformations. In the early stages of development of the inhomogeneous cortex, structures reminiscent of the deep sulci in the brain are obtained. As the cortex continues to develop, secondary undulations, which are shallower and more variable than the structures obtained in earlier gyrification stage emerge, reproducing well-known characteristics of higher-order folding in the mammalian, and particularly the human, brain.
Topics: Brain Cortical Thickness; Cerebral Cortex; Computer Simulation; Humans; Models, Anatomic
PubMed: 33548459
DOI: 10.1016/j.neuroimage.2021.117779 -
Cureus Dec 2018Septo-optic dysplasia plus is a rare congenital syndrome characterized by the classic triad of optic nerve hypoplasia, hypothalamic-hypophyseal dysfunction, and midline...
Septo-optic dysplasia plus is a rare congenital syndrome characterized by the classic triad of optic nerve hypoplasia, hypothalamic-hypophyseal dysfunction, and midline abnormalities, with associated malformations of cortical development. Clinical manifestations include optic nerve disease, epilepsy, intellectual delay, and endocrine dysfunction. We present the case of an 18-year-old man with a history of seizures, growth hormone deficiency, and optic nerve disease that was diagnosed with septo-optic dysplasia plus syndrome with characteristic imaging findings.
PubMed: 30800538
DOI: 10.7759/cureus.3727 -
Radiology Jun 2012To determine the diagnostic accuracy of fetal magnetic resonance (MR) imaging for malformations of cortical development by using postnatal MR imaging as reference...
PURPOSE
To determine the diagnostic accuracy of fetal magnetic resonance (MR) imaging for malformations of cortical development by using postnatal MR imaging as reference standard.
MATERIALS AND METHODS
Eighty-one patients who had undergone fetal and postnatal MR imaging of the brain were identified in this institutional review board-approved, HIPAA-compliant study. Images were retrospectively reviewed in consensus by two pediatric neuroradiologists who were blinded to clinical information. Sensitivity and specificity were calculated according to retrospective review of the images and clinical reports for fetal MR images. The Fisher exact test was used to compare results for fetuses imaged before and after 24 gestational weeks and for image review versus clinical reports for fetal MR images.
RESULTS
Median gestational age at fetal MR imaging was 25.0 weeks (range, 19.71-38.14 weeks). Postnatal MR imaging depicted 13 cases of polymicrogyria, three cases of schizencephaly, and 15 cases of periventricular nodular heterotopia. Sensitivity and specificity of fetal MR imaging were 85% and 100%, respectively, for polymicrogyria; 100% each for schizencephaly; and 73% and 92%, respectively, for heterotopia. When heterotopia was seen in two planes, specificity was 100% and sensitivity was 67%. Sensitivity for heterotopia decreased to 44% for fetuses younger than 24 weeks. According to reports for fetal MR images, prospective sensitivity and specificity, respectively, were 85% and 99% for polymicrogyria, 100% and 99% for schizencephaly, and 40% and 91% for heterotopia.
CONCLUSION
Fetal MR imaging had the highest sensitivity for polymicrogyria and schizencephaly. Specificity was 100% for all cortical malformations when the abnormality was seen in two planes. Sensitivity for heterotopia was lower for fetuses younger than 24 weeks. Knowledge of the gestational age is important, especially for counseling patients about heterotopia.
Topics: Adult; Diagnosis, Differential; Female; Gestational Age; Humans; Magnetic Resonance Imaging; Malformations of Cortical Development; Neuroimaging; Pregnancy; Retrospective Studies; Sensitivity and Specificity
PubMed: 22495681
DOI: 10.1148/radiol.12102492 -
American Journal of Medical Genetics.... Sep 2021In this review, we explore evidence that hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects, but also patterns... (Review)
Review
In this review, we explore evidence that hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects, but also patterns of anomalies that suggest that hypoxia can exert a more classic teratogenic effect, using the brain as one example. We review neuropathology in the context of intrauterine hypoxia, particularly as it relates to carbon monoxide poisoning, in utero strokes, and homozygous alpha-thalassemia. In general, the associated brain injuries resemble those seen with other causes of hypoxic-ischemic injury. Fetal strokes during development usually lead to loss of brain tissue in areas that do not follow a typical embryologic pattern, and therefore are considered disruptions. However, there is also evidence that fetal brain ischemia can cause more classically recognized patterns of abnormal embryonic neuronal migration and organization such as polymicrogyria, cortical dysplasia, or dysgenesis, including select types of focal cortical dysplasia. This study summarizes available literature and evidence to raise clinicians' awareness regarding the association between hypoxia and congenital anomalies, including brain malformations.
Topics: Abnormalities, Multiple; Congenital Abnormalities; Humans; Hypoxia; Teratogenesis; Teratogens
PubMed: 33938618
DOI: 10.1002/ajmg.a.62235 -
Proceedings of the National Academy of... Jan 2023Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly...
Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in , which encodes a multi-pass transmembrane protein of unknown function. null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.
Topics: Animals; Female; Humans; Mice; Pregnancy; Central Nervous System; Cilia; Ferrets; Hedgehog Proteins; Mice, Knockout; Signal Transduction
PubMed: 36669111
DOI: 10.1073/pnas.2209964120 -
Molecular Genetics & Genomic Medicine Jan 2018Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with... (Review)
Review
BACKGROUND
Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects.
METHODS
We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS.
RESULTS
We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS.
CONCLUSION
Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.
Topics: Abnormalities, Multiple; Brain; Child, Preschool; Chromosome Disorders; Chromosomes, Human, Pair 12; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Karyotyping; Male; Malformations of Cortical Development; Megalencephaly; Mosaicism; Tetrasomy
PubMed: 29222831
DOI: 10.1002/mgg3.351