developmental neuropathology of cortical dysplasia

1. DEVELOPMENTAL
NEUROPATHOLOGY OF CORTICAL
DYSPLASIA
Amanda Rivera-Begeman D.O.
Perinatal and Pediatric Pathologist
Dell Children’s Medical Center
Department of Pathology
Austin, TX

2. Goals of this lecture
•Brain development
•Neuronal migration, cortical development
•Cortical dysplasia and clinical correlates

3. 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

4. Neurulation: weeks 3-4 of embryonic
development

5. Cerebral vesicle formation, AKA
‘regionalization’ (4-7 weeks) gestation
Unknown author of diagram, retrieved from internet

6. Corticogenesis: neural cell migration leads to
Cortical plate formation (8-16 wks)
Telencephalic
wall
Illustration by Lydia V. Kibiuk, Baltimore, MD

7. Neural development
Induced by exogenous cues
from the microenvironment
*
Unknown author of diagram, retrieved from internet

8. 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.

9. 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)

10. neocortex
Molecular layer
External granular layer
External pyramidal layer
Internal granular layer
Internal pyramidal layer
Multiform layer

11. 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

12. Malformations of cortical
development
ranging from defective gyral
formation to focal cortical dysplasia

13. 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

14. 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

15. 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

16. 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

17. Malformations of cortical development:
Extent of involvement
• Diffuse
• Focal
• Gross
• Microscopic

18. 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

20. Pachygyria
Agyria or
lissencephaly

21. 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

22. Miller-Dieker syndrome
Lateral view
Superior view

23. Miller-Dieker syndrome
Reversal of the gray-white matter ratio
Large ventricles
Subependymal heterotopic nodules
Normal

24. Miller-Dieker Syndrome:
abnormal neuroblast migration
inner
outer
Jeffrey A. Golden & Brian N. Harding. (2004). Developmental Neuropathology. The International Society of Neuropathology

25. 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.

30. 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

31. Kabat J and Krol P. Focal cortical dysplasia – review. Pol J Radio, 2012;77(2):35-43.

32. 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.

33. 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.

34. 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.

35. 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.

36. 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

37. 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

38. 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?

39. 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.