1. Neuropathology and Epilepsy Neuronal migration defects Hippocampal sclerosis April 18, 2015

2. Overview Neuronal migration defects – Pachygyria/Lissencephaly – Polymicrogyria – Neuronal heterotopia – Cortical dysplasia Hippocampal sclerosis

3. Neuronal migration defects Diverse causes and risk factors – Inherited/sporadic – Environmental risk factors EtOH Retinoic acid Heavy metals Irradiation – Viral infections – Ischemia

4. Vocabulary Match the defect to the definition PachygyriaSmall disorganized convolutions PolymicrogyriaDisorganization of neurons with cytologic abnormalities Neuronal heterotopiaCleft that extends from pial surface to ventricle lined with cortex Cortical dysplasiaMisplaced collections of normal appearing neurons SchizencephalyWidened gyri

5. Trivia Question During normal development, when do gyri and sulci begin to appear in the fetal brain? a. 10-12 weeks b. 18-20 weeks c. 25-28 weeks d. 32-34 weeks

6. Clinical Case 7 month old boy is brought to the epileptologist for intractable seizures. On examination, he has a short small chin, thin upper lip, and low set ears. He has spastic quadriparesis and requires a feeding tube because of recurrent aspirations. MRI brain shows essentially smooth frontal, parietal, occipital lobes with a thick cortex and without sulci or gyri. What is the most likely diagnosis? a. Miller-Dieker syndrome b. Lissencephaly type II c. Subcortical band heterotopia d. Cobblestone lissencephaly e. Polymicrogyria

7. Miller Dieker Syndrome Microcephaly and characteristic facies: bitemporal hollowing, short nose with broad nasal bridge and upturned nares, thin upper lip, small chin, low-set posteriorly rotated ears Neonatal period with hypotonia which progresses to spastic quadriparesis Seizures that are difficult to control Global developmental delay with life expectancy ~1year Microdeletions chromosome 17 (LIS1 gene) Associated with LISSENCEPHALY TYPE 1 Can have isolated lissencephaly without the syndrome…

8. Lissencephaly Type I Impaired formation of gyri resulting in reduced number of enlarged gyri (pachygyria) Most severe form: agyria or “smooth brain” Imaging: smooth, cerebral cortex thickened with variable preservation of white matter Pathology: Thick cortex with 4 layers instead of 6

9. Lissencephaly Other types – Lissencephaly X linked mutations in DCX gene on X chromosome (males) usually lethal – Lissencephaly Type II “cobblestone” lissencephaly – irregular and less smooth in appearance associated with other disorders such as Walker- Walburg syndrome, Fukuyama muscular dystrophy, muscle-eye-brain disease of Santavuori

10. Pathology: Lissencephaly/Pachygyria H&E

11. Clinical Case A five month old baby is being evaluated for seizures. He has multiple dysmorphic features and severe hypotonia, and MRI of the brain shows pachygyria. Skeletal radiographs show calcific stippling of the patella. Very long-chain fatty acid levels are elevated in plasma. Which of the following is incorrect regarding this condition? a.This is a peroxismal disorder b.Liver cirrhosis occurs in these patients c.Kidney cysts can be seen in these patients d.White matter is not involved e.Polymicrogyria may be seen in these patients

12. Zellweger Syndrome “Cerebrohepatorenal Syndrome” Peroxisomal disorder with white matter changes and abnormalities in neuronal migration Dysmorphic features Chonodroplasia puncata (stippling of patella) Eye issues, hypotonia, cirrhosis, PCKD Caused by mutations in PEX genes Short life expectancy Associated with pachygyria and/or polymicrogyria

13. Polymicrogyria Disorganized confluence of small gyri that appear to be partially fused May be unilateral or bilateral Perisylvian is MOST common Thought to occur later in development at 17-26 weeks Can occur with schizencephaly Often as feature of various syndromes Associated with seizures and intellectual disability

14. Pathology: Polymicrogyria H&E NeuN

15. Heterotopias Which of the following is incorrect regarding periventricular nodular heterotopia? a.It is a disorder of neuronal migration b.It is more common in females c.It is most commonly X-linked d.Seizures are a common clinical manifestation e.Heterotopias are clusters of defective neurons in an area of otherwise normal cortex

16. Heterotopia Abnormally located normal neurons Theory: neurons never began migration and stayed in subventricular area where the cortical neurons originate Diverse – Sporadic vs inherited – Independent vs part of syndrome – Asymptomatic vs associated with seizures and developmental delays Periventricular nodular heterotopias (also called subependymal) – Least severe, most common Majority of cases result from mutations in FLNa gene on X chromosome – Males do not survive embyronic period – Women develop seizures and/or intellectual disability

17. Periventricular nodular heterotopia

18. Heterotopia: Pathology Subependymal heterotopia – H&E H&E – NeuN NeuN

19. Cortical Dysplasia Local expansion of the cortical gyri with blurring of the border between the cerebral cortex and underlying white matter Disorganization of neurons with cytologic abnormalities Binucleated cells, reactive glial cells, balloon cells Areas may be surgically resected in cases of medically intractable epilepsy

20. Cortical dysplasia: Pathology H&E GFAP NeuN

21. Clinical Case 21 year old man comes to the clinic because he has been having spells in which he suddenly stops what he was previously doing and stares for about a minute, sometimes picking at his nose and his shirt. He cannot recall what happens during the spell itself. He says, however, that he knows when a spell is going to happen because he experiences a warm sensation in his epigastric region, followed by a sensation of fear and rapid recollection of episodes of past life experiences along with palpitations. He may have post-ictal confusion. His EEG shows focal spikes. Which of the following best describes the type of seizure this patient has? a.Temporal lobe seizures (focal seizure with secondary generalization and alteration of awareness) a.Frontal lobe seizures b.Absence seizures c.Occipital lobe seizures d.Parietal lobe seizures

22. Hippocampal Sclerosis AKA Mesial temporal sclerosis Gliosis and neuronal loss in the hippocampus in association with long standing seizure disorder Imaging: atrophy of hippocampus with dilation of temporal horn of lateral ventricle, usually unilateral

23. Hippocampal sclerosis Unclear whether sclerosis is the cause or the consequence of seizures Possible link between prolonged infantile febrile convulsions and later development of temporal lobe epilepsy/ hippocampal sclerosis Cases of successful treatment of medically intractable epilepsy with surgical resection points to sclerosis as cause of epilepsy

24. Hippocampal sclerosis: Pathology Developmental – H&E H&E – GFAP GFAP – NeuN NeuN Epilepsy – H&E H&E

25. Summary Neuronal migration defects and hippocampal sclerosis are pathological changes associated with epilepsy Pachygyria/lissencephaly and polymicrogyria describe size of gyrus and are associated with various syndromes Neuronal heterotopia are normal neurons in the wrong places Cortical dysplasia are abnormal neurons in setting of disorganized cortical architecture Hippocampal sclerosis may the cause or consequence of epilepsy

26. References 1. Neuropathology (Prayson). Chapter 4: Congenital Malformations, Perinatal Diseases, and Phacomatoses by Folkerth and Lidov. 2. Comprehensive Board Review in Neurology by Borsody 3. Comprehensive Review in Clinical Neurology (multiple choice question book) by Chen-Ching et al