Malformations of cortical development Desikan, Rahul S.; Barkovich, A. James
Annals of neurology,
December 2016, Volume:
80, Issue:
6
Journal Article
Peer reviewed
Open access
Malformations of cortical development (MCDs) compose a diverse range of disorders that are common causes of neurodevelopmental delay and epilepsy. With improved imaging and genetic methodologies, the ...underlying molecular and pathobiological characteristics of several MCDs have been recently elucidated. In this review, we discuss genetic and molecular alterations that disrupt normal cortical development, with emphasis on recent discoveries, and provide detailed radiological features of the most common and important MCDs. Ann Neurol 2016;80:797–810
Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders ...contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.
The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of ...the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.
Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied ...resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.
► Two cases showing trisomy 1q in brain tissue were associated with hemimegalencephaly ► A third hemimegalencephaly case had a somatic mosaic-activating mutation in AKT3 ► AKT3 is the most prevalent of the three AKT paralogues during human neurogenesis ► Phosphorylated AKT is expressed in apical progenitors of the developing cortex
Poduri et al. identify trisomy on chromosome 1q, which encompasses AKT3, and a separate activating AKT3 somatic mutation in patients with the developmental brain disorder hemimegalencephaly. Results suggest that somatic mutations limited to the brain may contribute to neurodevelopmental disorders.
Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending ...on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.
Summary Historically, the midbrain and hindbrain have been considered of secondary importance to the cerebrum, which has typically been acknowledged as the most important part of the brain. In the ...past, radiologists and pathologists did not regularly examine these structures—also known as the brainstem and cerebellum—because they are small and difficult to remove without damage. With recent developments in neuroimaging, neuropathology, and neurogenetics, many developmental disorders of the midbrain and hindbrain have emerged as causes of neurodevelopmental dysfunction. These research advances may change the way in which we treat these patients in the future and will enhance the clinical acumen of the practising neurologist and thereby improve the diagnosis and treatment of these patients.
Focal cortical dysplasias (FCD) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has ...been included in the diagnosis of FCD. An ILAE task force proposes an international consensus classification system to better characterize specific clinicopathological FCD entities.
Thirty-two Task Force members have reevaluated available data on electroclinical presentation, imaging, neuropathological examination of surgical specimens as well as postsurgical outcome.
The ILAE Task Force proposes a three-tiered classification system. FCD Type I refers to isolated lesions, which present either as radial (FCD Type Ia) or tangential (FCD Type Ib) dyslamination of the neocortex, microscopically identified in one or multiple lobes. FCD Type II is an isolated lesion characterized by cortical dyslamination and dysmorphic neurons without (Type IIa) or with balloon cells (Type IIb). Hence, the major change since a prior classification represents the introduction of FCD Type III, which occurs in combination with hippocampal sclerosis (FCD Type IIIa), or with epilepsy-associated tumors (FCD Type IIIb). FCD Type IIIc is found adjacent to vascular malformations, whereas FCD Type IIId can be diagnosed in association with epileptogenic lesions acquired in early life (i.e., traumatic injury, ischemic injury or encephalitis).
This three-tiered classification system will be an important basis to evaluate imaging, electroclinical features, and postsurgical seizure control as well as to explore underlying molecular pathomechanisms in FCD.
ACR guidance document on MR safe practices: 2013 Kanal, Emanuel; Barkovich, A. James; Bell, Charlotte ...
Journal of magnetic resonance imaging,
March 2013, Volume:
37, Issue:
3
Journal Article
Pediatric neuroimaging is challenging due the rapid structural, metabolic, and functional changes that occur in the developing brain. A specially trained team is needed to produce high quality ...diagnostic images in children, due to their small physical size and immaturity. Patient motion, cooperation and medical condition dictate the methods and equipment used. A customized approach tailored to each child's age and functional status with the appropriate combination of dedicated staff, imaging hardware, and software is key; these range from low-tech techniques, such as feed and swaddle, to specialized small bore MRI scanners, MRI compatible incubators and neonatal head coils. New pre-and post-processing techniques can also compensate for the motion artifacts and low signal that often degrade neonatal scans.
•Rapid brain growth and development make pediatric neuroimaging challenging.•Imaging infants using feed and swaddle can minimize motion without sedation.•Custom hardware, software, and well-trained staff produce high quality images.•Automated and quantitative techniques are revolutionizing pediatric neuroimaging.
To assess the trajectory of perioperative brain growth in relationship to cardiac diagnosis and acquired brain injuries.
This was a cohort study of term neonates with hypoplastic left heart syndrome ...(HLHS) and d-transposition of the great arteries (d-TGA). Subjects underwent magnetic resonance imaging of the brain pre- and postoperatively to determine the severity of brain injury and total and regional brain volumes by the use of automated morphometry. Comparisons were made by cardiac lesion and injury status.
A total of 79 subjects were included (49, d-TGA; 30, HLHS). Subjects with HLHS had more postoperative brain injury (55.6% vs 30.4%, P = .03) and more severe brain injury (moderate-to-severe white matter WM injury, P = .01). Total and regional perioperative brain growth was not different by brain injury status (either pre- or postoperative). However, subjects with moderate-to-severe WM injury had a slower rate of brain growth in WM and gray matter compared with those with no injury. Subjects with HLHS had a slower rate of growth globally and in WM and deep gray matter as compared with d-TGA (total brain volume: 12 cm3/wk vs 7 cm3; WM: 2.1 cm3/wk vs 0.6 cm3; deep gray matter: 1.5 cm3/wk vs 0.7 cm3; P < .001), after we adjusted for gestational age at scan and the presence of brain injury. This difference remained after excluding subjects with moderate-to-severe WM injury.
Neonates with HLHS have a slower rate of global and regional brain growth compared with d-TGA, likely related to inherent physiologic differences postoperatively. These findings demonstrate the complex interplay between cardiac lesion, brain injury, and brain growth.
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