Published on March 27, 2014
DEVELOPMENTAL NEUROPATHOLOGY OF CORTICAL DYSPLASIA Amanda Rivera-Begeman D.O. Perinatal and Pediatric Pathologist Dell Children’s Medical Center Department of Pathology Austin, TX
Goals of this lecture •Brain development •Neuronal migration, cortical development •Cortical dysplasia and clinical correlates
Brain development - Overview Neurulation (3-4 weeks) Cerebral vesicle formation (4-7 weeks) Corticogenesis (8-16 weeks) Maturation (16 weeks on) Illustration by Lydia V. Kibiuk, Baltimore, MD
Neurulation: weeks 3-4 of embryonic development
Cerebral vesicle formation, AKA ‘regionalization’ (4-7 weeks) gestation Unknown author of diagram, retrieved from internet
Corticogenesis: neural cell migration leads to Cortical plate formation (8-16 wks) Telencephalic wall Illustration by Lydia V. Kibiuk, Baltimore, MD
Neural development Induced by exogenous cues from the microenvironment * Unknown author of diagram, retrieved from internet
Neuronal migration Inner surface Outer surface Telencephalic wall Bear, M., Connors, B., & Paradiso, M. (2007). Neuroscience: Exploring the Brain (Third Edition). Baltimore: Lippincott Williams & Wilkins. Purves, D., Augustine, G., & Fitzpatrick, D. (2004). Neuroscience (Third Edition). Sunderland, MA: Sinauer Associates.
External layer/marginal zone Cortical plate Subcortical plate/external Intermediate zone Intermediate zone/subventricular layer Ventricular layer/germinal matrix Cortical Plate Formation (from 7-16 weeks)
neocortex Molecular layer External granular layer External pyramidal layer Internal granular layer Internal pyramidal layer Multiform layer
Gyral development • Convolutions occur because the cortical surface expands as cell migration and stem cell production continue but proliferation rate of VZ cells decrease. • However, the convolutions (gyri) are not randomly created. • The intermediate zone (subcortical white matter) becomes crisscrossed by a large number of axonal fascicles forming connections that contribute to the shape of the convolution. • It has been hypothesized that the tension created by these fascicles is responsible for the stereotyped shape and orientation of the gyri Toro, R., and Burnod, Y. (2005). A morphogenetic model for the development of cortical convolutions. Cereb. Cortex 15, 1900–1913. Poduri A et. Al. somatic mutation, genomic variation, and Neurological disease. Science 5 July 2013: Vol 341 no. 6141
Malformations of cortical development ranging from defective gyral formation to focal cortical dysplasia
CNS Malformations • Congenital deviations in form and structure. – Primary malformations due to genetic or chromosomal anomalies – Secondary malformations depend on exogenous causes • Developing nervous system is subjected to damage during the whole gestation and early postnatal life. – Hypoxia, trauma, toxins and infectious agents • The earlier the insult in brain development, the more severe the brain malformation
CNS Malformations often manifest clinically as neurodevelopmental disorders • The cerebral cortex plays key role in memory, attention, perceptual awareness, thought, language, and consciousness. • Some common disorders that are neurodevelopmental in origin or have neurodevelopmental consequences when they occur in infancy and childhood: – Autism and autism spectrum disorders – Fetal alcohol spectrum disorder – Motor disorders – Traumatic brain injury (including congenital injuries that cause cerebral palsy) – Communication, speech and language disorders – Genetic disorders, such as fragile-X syndrome – Down syndrome – Attention deficit hyperactivity disorder
Specific malformations of cortical development • Abnormal proliferation or apoptosis of glial and neuronal cells (may be localized or diffuse) – Decreased neuronal number, eg. microencephaly – Increased proliferation, eg. megencephaly – Abnormal proliferation, eg. Tuberous sclerosis/ cortical tubers, neoplastic • Abnormal neuroblast migration – Lissencephaly – Heterotopia
Specific malformations of cortical development • Abnormal late neuroblast migration and cortical organization – Polymicrogyria and schizencephaly – Cortical dysplasia with balloon cells – Microdysgenesis • Other malformations with frequently associated cortical maldevelopment – Holoprosencephaly – failure of differentiation of the prosencephalon
Malformations of cortical development: Extent of involvement • Diffuse • Focal • Gross • Microscopic
Gross cortical dysplasia • Agyria/lissencephaly: ‘smooth brain’ or total absence of convolutions • Pachygyria: intermediate form with rare and broad gyri • Both may coexist in the same brain and may overlie an abnormal cortical plate
Pachygyria Agyria or lissencephaly
Miller-Dieker syndrome - Rare, 1 per 100,000 live births. - Microdeletion 17p13.3 Craniofascial abnormalities: microcephaly with high narrow forehead, low-set ears and small mandible. Neurologic impairment: decreased activity, abnormal tone, profound mental retardation, seizures
Miller-Dieker syndrome Lateral view Superior view
Miller-Dieker syndrome Reversal of the gray-white matter ratio Large ventricles Subependymal heterotopic nodules Normal
Miller-Dieker Syndrome: abnormal neuroblast migration inner outer Jeffrey A. Golden & Brian N. Harding. (2004). Developmental Neuropathology. The International Society of Neuropathology
Case study • 8-year-old female with a history of intractable epilepsy, normal gross brain development • She initially presented in status epilepticus at an outside institution, requiring several weeks of intubation in the ICU. • MRI: abnormal thickening and blurring of the gray- white junction in the inferior posterior frontal lobe and anterior mesial frontal lobe, concerning for focal cortical dysplasias. • Transferred to DCMC, had grid electrodes placed, and eventually had surgery for resection of these areas.
Case study: Focal cortical dysplasia with dysmorphic cells and balloon cells • Patient did well, but several weeks later, her seizures returned and were similar as before. • Imaging revealed residual cortical dysplasia between the two resected foci. • Therefore, the patient was brought back to surgery for a second resection. • Histopathologic examination confirmed residual cortical dysplasia
Kabat J and Krol P. Focal cortical dysplasia – review. Pol J Radio, 2012;77(2):35-43.
Histopathology of FCD type 1a Abnormal radial lamination and abundant microcolumns Blumcke et al. The clinico-pathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc task force of ILAE Diagnostic methods commission. Epilepsia. 2011 January; 52(1):158-174.
Histopathology of FCD type 1b Abnormal tangential layer composition Blumcke et al. The clinico-pathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc task force of ILAE Diagnostic methods commission. Epilepsia. 2011 January; 52(1):158-174.
Histopathology of FCD type 2a Disorganized cortical layers and dysmorphic neurons Neu N Abnormal NF Prominent Nissl bodies Blumcke et al. The clinico-pathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc task force of ILAE Diagnostic methods commission. Epilepsia. 2011 January; 52(1):158-174.
Histopathology of FCD type 2b Disorganized cortical layers, dysmorphic neurons and balloon cells GFAP synaptophysin •Blumcke et al. The clinico-pathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc task force of ILAE Diagnostic methods commission. •Epilepsia. 2011 January; 52(1):158-174.
Why do cortical dysplasias cause epilepsy? • Abnormal neurons, eg. Balloon cells – Generate bursting behavior or intrinsic hyperexcitability • Altered synaptic connectivity – More excitatory cortical afferents – Decreased numbers of inhibitory neurons
Treatment for epilepsies due to malformations of cortical development • Medical – High rate of medical intractability, supported by high rates of dysplasia found in epilepsy surgery specimens. – Hospital based study on 2200 adult outpatients with epilepsy found that only 24% of those with cerebral dysgenesis attained seizure freedom (Semah et al., 1998). – Treatment is best guided by choosing appropriate medication for seizure type and epilepsy syndrome • Surgical – best results with Taylor type focal cortical dysplasia • Ketogenic diet – high fat, low carbohydrates has documented efficacy in intractable childhood epilepsy
Is cortical dysplasia a cause for autism? • Recent research published in the New England Journal of Medicine supports this idea – ‘Patches of Disorganization in the Neocortex of Children with Autism’ N Engl J Med 370;13. March 27, 2014 issue, pgs 1209-1219. • Researchers found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. • Their data support a probable dysregulation of layer formation and layer- specific neuronal differentiation at prenatal develomental stages. • Questions that arise: – Are these maldeveloped brains the cause for autism or the first “hit” in putting the brain at a higher risk to further damage from secondary causes (eg. Hypoxia, trauma, toxins, infectious agents) that can occur any time during pre and post natal brain maturation? – Can similar types of epilepsy treatment (medical, surgical, dietary) be done for focal cortical dysplasia and it’s complications in autism?
References • Blumcke et al. The clinico-pathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc task force of ILAE Diagnostic methods commission. Epilepsia. 2011 January; 52(1):158-174. • Ellison & Love: Neuropathology: A reference text of CNS pathology. 2004. • Kabat, J and Krol, P. Focal cortical dysplasia – review. Pol J Radiol. 2012;77(2):35-43. • Hamiwka, L and Wirrel, E. Epilepsy in patients with cerebral malformations. Handbook of Clinical Neurology, Vol. 87 (3rd series). Malformations of the Nervous System. Editors: Sarnat, H.B. and Curatolo, p. 2008. Chapter 21. Pages 390-407. • Sadler, T.W. Langman’s Essential Medical Embryology. Lippincott Williams & Wilkins. 2005. Neurulation and establishment of body form (chapter 3, pgs 15-19). Central Nervous System (chapter 9, pgs 103-116). • Gilbert-Barness, Kapur, Oligny & Siebert. Potter’s Pathology of the Fetus, Infant, and Child. Elsvier. 2007. Chapter on Central Nervous System neuropathology. • Stoner R et al. Patches of Disorganization in the Neocortex of Children with Autism. N Engl J Med 370;13 March 27, 2014, pgs. 1209-1219.
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